Section VII: Psychiatric Disorders

OBJECTIVES

PREVALENCE & BURDEN

Schizophrenia, the most common primary psychotic disorder, has a lifetime prevalence of approximately 1% worldwide, is equally common in males and females, and affects individuals from all racial and ethnic groups. The typical age of onset is in late adolescence to early adulthood, with females having an illness onset of approximately 5 to 10 years later. Prepubescent onset is rare, but those who present with early-onset schizophrenia have a more severe illness course. Late-onset schizophrenia after the age of 45 years is more common in females. The prevalence of schizophrenia is higher in densely populated areas and in developed nations. Life expectancy in patients is 10 to 20 years lower relative to the general population, which is attributed to increased rates of suicide (6% completed suicide rate), accidents, smoking, and poor physical health. Direct and indirect costs in the United States are estimated at about $100 billion annually, with productivity losses being the largest component of the overall societal cost.

MAJOR THOUGHT DISORDERS

Schizophrenia

Schizophrenia is a complex, heterogeneous syndrome believed to be multifactorial, with genetic and environmental components. Patients vary widely in their symptomatology, course of illness, and treatment response, to the point that the diagnosis may identify individuals who share few or no symptoms in common. The validity of traditional clinical subtypes (eg, paranoid schizophrenia, catatonic schizophrenia) as nosologic entities has been questioned, and their prognostic value is limited. Dimensional models of psychosis suggest that symptoms and disease course are better explained in terms of continuous distributions. The psychopathology can be described along the following symptom domains: (1) positive symptoms, which include delusions, hallucinations, and disorganization of thought and speech; (2) negative symptoms, which include apathy, alogia, poor attention, flat affect, and anhedonia; and (3) cognitive deficits, which include working memory and episodic memory deficits, impairment in executive function, and decreased attention span. Negative symptoms can be divided into primary and secondary negative symptoms. Primary symptoms are regarded as part of the illness, whereas secondary negative symptoms have other causes, such as preoccupation with hallucinations or delusions, suspicious withdrawal, depression, medication side effects, or social isolation. Approximately 25% to 30% of patients suffer from persistent primary negative symptoms, also known as the deficit syndrome (see later discussion). Patients with significant negative symptoms may have poor awareness of their symptoms. Cognitive deficits are present in approximately 75% to 85% of all patients; the extent is variable, but patients typically score about a standard deviation lower on standardized assessments than would be expected for the general population. Memory is the cognitive domain showing the most pronounced deficits, with working memory and episodic memory appearing to be primarily affected. Cognitive dysfunction often predates emergence of positive symptoms and also is reported in high-risk individuals and unaffected family members of patients with schizophrenia, suggesting significant genetic contribution. The extent of these deficits is most predictive of long-term outcome and social functioning. Positive symptoms have a tendency to relapse and remit, but negative and cognitive symptoms tend to be chronic, even when patients receive antipsychotic treatment.

The diagnosis of schizophrenia is made clinically; no diagnostic tests or biomarkers are available. The patient must have 2 of the following 5 symptoms: (1) delusions, (2) hallucinations, (3) disorganized speech, (4) disorganized or catatonic behaviors, and (5) negative symptoms. To make a diagnosis, symptoms must have been present for 6 months (including prodromal and residual phase) with at least 1 month of active symptoms. A detailed personal and family history, physical examination, laboratory testing, and neuroimaging can help differentiate primary psychotic disorders from psychosis due to general medical conditions, delirium, and substance-induced psychosis.

The Deficit Syndrome

The deficit syndrome is a subtype of schizophrenia characterized by primary and enduring negative symptoms. These are present during and between episodes of positive symptom exacerbation and can be observed regardless of the patient’s medication status. The deficit syndrome is associated with worse premorbid adjustment, more global impairment, lower quality of life, and poorer long-term outcome. Symptoms are evident at initial presentation and progress in severity in the first 5 years following the onset of the illness, with high temporal stability thereafter. Prevalence is estimated at 6% to 15% in first-episode patients and 25% to 30% in chronic schizophrenia. It is still unknown which neurodevelopmental or neurodegenerative processes manifest as negative symptoms in schizophrenia. Conventional antipsychotics, with the exception of clozapine, and psychosocial therapies have no clear effects on reducing primary negative symptoms.

Schizophreniform Disorder

Schizophreniform disorder is a type of psychosis that presents the same as schizophrenia, but the patient does not yet meet the time criterion for schizophrenia (ie, symptoms have been present for <6 months but >1 month). Treatment is the same as that for schizophrenia.

Brief Psychotic Disorder

This disorder is characterized by a sudden onset of 1 or more psychotic symptoms that last at least 1 day but <1 month. Negative symptoms are not part of the diagnostic criteria. The typical illness onset is 30 to 50 years of age, and the average brief psychotic episode lasts approximately 2 weeks. Brief psychotic disorders often occur in context of significant stressors. A higher incidence is also found among immigrants to developed countries and within 4 weeks postpartum. Short-term hospitalization and antipsychotic treatment may be required; cognitive-behavioral therapy can be used to help patients learn to cope with stress. Most people only have 1 episode, after which they return to their premorbid level of functioning; however, some will eventually develop a chronic psychotic condition.

Catatonia

Historically, catatonia has been conceptualized as a subtype of schizophrenia, but it frequently occurs in patients with a primary mood disorder and in association with neurologic diseases and other general medical conditions. Epidemiologic studies suggest that catatonia is associated with schizophrenia in approximately 20% of cases, with mood disorders in 45% of cases, and with somatic causes including epilepsy, systemic lupus erythematosus, intermittent porphyria, dementia, and encephalopathies in approximately 25% of cases.

Catatonia should be considered in any patient exhibiting marked deterioration in psychomotor function and overall responsiveness. Catatonia is defined as ≥3 of the following symptoms: (1) catalepsy; (2) waxy flexibility; (3) stupor; (4) agitation, not influenced by external stimuli; (5) mutism; (6) negativism; (7) posturing; (8) mannerisms; (9) stereotypies; (10) grimacing; (11) echolalia; and (12) echopraxia. The Bush-Francis catatonia rating scale is one of the most commonly used instruments to aid in the diagnosis. The prognosis of catatonia is good, especially with early and aggressive treatment, but longer duration of an episode is linked to a less favorable prognosis. Several recognized subtypes of catatonia are based on the predominant signs and symptoms. Retarded catatonia, the most common subtype is characterized by mutism, posturing, rigidity, and repetitive actions. Excited catatonia is marked by excessive and purposeless movements, agitation, restlessness, and talkativeness. Malignant catatonia is associated with hyperthermia and autonomic instability (diaphoresis, tachycardia, blood pressure instability, and varying degrees of cyanosis); the severe levels of metabolic decompensation can be lethal and warrant emergent treatment. Putative neurobiological mechanisms underlying catatonia include glutamatergic and γ-aminobutyric acid (GABA)-ergic neurotransmitter system abnormalities.

Schizoaffective Disorder

Schizoaffective disorder has features of both schizophrenia and a mood disorder. It is defined by intervals of significant mood disturbances and the presence of psychotic symptoms for >2 weeks in the absence of mania or depression. The mood episode must be present for the majority of the illness. Subtypes are defined as bipolar type (if manic episodes are part of the presentation) and depressive type (if only major depressive episodes occur). Schizoaffective disorder appears to occupy an intermediate position between schizophrenia and bipolar disorder in terms of symptomatology, neuroimaging findings, response to treatment, and prognosis.

Delusional Disorder

This disorder typically develops in middle to late adult life and is characterized by persistent delusional beliefs with minimal impairment of daily functioning and absence of negative or cognitive symptoms. Hallucinations are usually not present. Delusions cannot be due to effects of prescription or illicit drugs or a general medical condition. Delusional disorder cannot be diagnosed in patients with a prior diagnosis of schizophrenia. Six types of delusional disorder are described: (1) erotomanic, the belief that someone is in love with the patient, often someone who is famous; (2) grandiose, the belief that the patient is superior or unique; (3) persecutory, the belief that someone is wanting to harm the patient; (4) jealous, the belief that the partner is cheating on the patient; (5) somatic, the belief that someone has a medical condition; and (6) mixed, having features of >1 subtype of delusion. Personal beliefs should be evaluated with great respect to cultural and religious differences to avoid a false diagnosis of delusional disorder when the belief is widely accepted in the patient’s culture.

Substance-Induced Psychosis

Intoxication or withdrawal from a number of substances is associated with acute onset of psychotic symptoms. Cocaine, amphetamines, phencyclidine, ketamine, cannabis, and alcohol have long been recognized to precipitate psychotic symptoms. More recently developed designer drugs including cathinones (bath salts) and synthetic cannabinoids have toxicity syndromes that often manifest with psychosis, agitation, and tachycardia. The main diagnostic feature is prominent delusions or hallucinations that are determined to be caused by effects of a psychoactive substance. If patients are aware that hallucinations are not real or psychotic symptoms occur only during delirium, a diagnosis of substance-induced psychosis cannot be made. Substance-induced psychoses manifest shortly after drug consumption and resolve quickly after cessation, often without the need for treatment. However, with continuing use, stimulants, cannabis, newer designer drugs, and alcohol seem to cause prolonged psychosis. Supportive therapy and drug counseling may be helpful after psychotic symptoms have resolved to prevent recurrence. If psychotic symptoms persist, antipsychotic medications should be considered.

Although illicit drug use is the most common cause of substance-induced psychosis, a number of prescription medications can also cause these symptoms. These include amphetamines, angiotensin-converting enzyme inhibitors, antihistamines, anticholinergics, β-blockers, cephalosporins, fluoroquinolone antibiotics, procaine derivatives, nonsteroidal anti-inflammatory drugs, salicylates, and dopamine receptor agonists, among others. Corticosteroid-induced psychosis often includes agitation, anxiety, insomnia, irritability, and restlessness. Symptoms often develop after a few days of corticosteroid treatment, but they can also occur late in the treatment. The risk for steroid-induced psychosis increases with greater corticosteroid doses, with an incidence of approximately 2%. Management includes tapering of corticosteroids or decreasing to the lowest possible dose. If a taper is not possible or symptoms are severe, low-dose antipsychotic medications can be prescribed. A history of psychiatric disorders or previous corticosteroid-induced psychosis is not predictive of future episodes, but steroids need to be used with caution in patients with psychotic disorders.

Psychosis Due to General Medical Conditions

Medical conditions associated with psychosis include autoimmune, endocrine, neurologic, and nutritional disorders. Endocrine conditions include thyroid and parathyroid dysfunction. Neurologic conditions include temporal lobe epilepsy, Parkinson disease, and Lewy body disease. A subacute onset of psychosis that is not primary should raise suspicion for an oncologic cause, such as a hormone-secreting tumor, space-occupying brain lesion, or paraneoplastic syndrome. Genetic or heritable diseases, such as Huntington disease, should also be considered. The temporal relationship and course of psychotic symptoms, as well as the patient’s age, background, and general medical conditions, may provide diagnostic clues. A physical and neurologic exam with laboratory testing and neuroimaging may be necessary.

There has been a substantial increase in interest in autoimmune encephalitis that is characterized by brain inflammation and circulating autoantibodies, often in context of a paraneoplastic process. N-Methyl-D-aspartate (NMDA) receptors, α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors, and GABA receptors seem to be the main targets. Psychiatric symptoms generally occur early in the illness but may appear at any time during the course of the disease. Bizarre behaviors, confabulations, agitation, hallucinations and delusions, and confusion and disorientation are common. Neurologic symptoms may or may not be present. Magnetic resonance imaging can aid in the diagnosis. Nonspecific abnormalities on fluid-attenuated inversion recovery sequences are commonly found in the medial temporal lobes, basal ganglia, cerebellum, and cerebral cortex (Figure 38–1). Antipsychotics, benzodiazepines, and mood stabilizers have very limited effectiveness in the treatment of these symptoms. Steroid treatment, removal of antibodies by plasma exchange, or intravenous immunoglobulin therapy generally results in clinical improvement.

NATURAL HISTORY

Clinical staging is a useful tool in medicine. It assumes that pathologic indices are progressing in subsequent stages, that patients in individual stages present with similar pathologic changes, and that treatment should be most effective in earlier stages. Several stages are defined to characterize the clinical course of schizophrenia: the prodromal phase, the active phase (first psychotic episode followed by chronic phase), and the residual phase (Figure 38–2).

The term prodrome is derived from the Greek word prodromos, meaning the forerunner of an event. The prodromal phase typically predates the first psychotic break and is characterized by gradually increasing social withdrawal, poor motivation, restricted affective range, and cognitive deficits. Symptoms can also include brief self-limited intermittent psychotic symptoms (BLIPS; presence of psychotic symptoms of up to 7 days followed by remission with no hospitalization or treatment) and attenuated psychotic symptoms (APS; symptoms are present in attenuated form and duration and warrant clinical attention). It is important to note that only approximately 15% to 30% of patients with prodromal symptoms later develop a psychotic illness; therefore, a “watch and wait” approach with frequent clinical contact and regular assessment rather than antipsychotic medication is recommended in this population.

Active-phase symptoms emerge following the prodrome, often in context of significant life stress or substance use. There is considerable evidence that longer duration of untreated psychosis (ie, the time between symptom onset and first treatment) is related to poorer long-term outcomes. The average duration of untreated psychosis in the United States is estimated to be approximately 18 months. Clinicians are often concerned that an initial first episode schizophrenia diagnosis, if incorrect, may impede clinical care and lead to stigmatization, despite the high diagnostic stability of schizophrenia spectrum disorders. This may have profound effects, not only on pharmacotherapy and specific forms of psychotherapy used, but also on the prognosis provided to newly diagnosed patients and their families as to what lies ahead. Approximately one-third of patients with a first psychotic episode will have a favorable illness course, recovering with minimal or no long-term impairment. The remainder of patients have either an intermediate or poor outcome.

The residual phase is characterized by a stable course of persisting negative and/or cognitive symptoms, with only few positive symptoms. Frank psychotic behaviors may subside, but the patient may continue to hold strange beliefs. The residual phase is established after positive symptom severity is minimal for at least 1 year, in the absence of a neurodegenerative disease. It is recommended that antipsychotic medication be continued.

PATHOPHYSIOLOGY

Genetic & Environmental Factors

Epidemiologic studies suggest a greater concordance of schizophrenia in monozygotic than in dizygotic twins, supporting a genetic basis.

The heritable component is estimated to be approximately 70% to 80%. Genome-wide association studies have identified >100 distinct genetic loci containing fairly common alleles with small effects, suggesting that a range of single-nucleotide polymorphisms contribute to the risk. Eleven copy number variants that confer a relatively high risk have also been identified. Thus, genetic risk of schizophrenia is generally due either to the presence of a very rare, large-effect copy number variant or to the coincident inheritance of many alleles with small effect size. The genetic risk is also highly pleiotropic and does not map onto the existing disease definitions. For example, many risk alleles are shared between schizophrenia and bipolar disorder. Some of the risk variants identified encode glutamate receptors, voltage-dependent calcium channels, and the dopamine D₂ receptor. Others regulate neuronal plasticity, maturation, modulation, and regeneration. It is important to note that most genetic markers are considered to be associated with schizophrenia but do not serve as biomarkers per se.

The dominant paradigm for understanding the environmental contributions to schizophrenia has been the neurodevelopmental hypothesis, which posits risk factors that affect early neurodevelopment during pregnancy, including maternal stress, nutritional deficiencies, maternal infections, and birth complications. Other environmental risk factors include socioeconomic factors, childhood adversity, immigration, and being raised in cities. The use of cannabis is estimated to carry up to a 40% greater risk for development of psychosis, with a dose–effect relationship between cannabis use and schizophrenia risk. It is also thought that cannabis use in adolescence results in an earlier onset of psychosis than in those without a history of cannabis use.

Neurotransmitter Abnormalities

Dopamine has been a focus in investigating schizophrenia pathophysiology, based on the observations that drugs that cause psychosis increase dopaminergic neurotransmission and that antipsychotic medications act as dopamine receptor blockers. Research on mechanisms underlying schizophrenia indicates the following: (1) striatal dopamine synthesis and release capacity are increased; (2) dopamine release capacity in prefrontal cortical and other extrastriatal regions may be decreased; and (3) postsynaptic dopamine receptors and transporters are not consistently altered in the striatum or extrastriatal regions of the brain. However, dopaminergic alterations do not explain the full range of clinical symptoms, specifically negative symptoms and cognitive deficits.

The dissociative anesthetics phencyclidine (PCP) and ketamine act as noncompetitive NMDA receptor blockers. They have psychotomimetic effects in healthy humans that mimic symptoms of schizophrenia including some of the cognitive deficits. Ketamine also exacerbates psychotic symptoms in patients with schizophrenia. Alterations in NMDA receptors on parvalbumin-positive interneurons are thought to lead to disinhibition of excitatory pyramidal cells and result in a shift of the excitation/inhibition balance (Figure 38–3). This could interfere with brain synchronicity and cause some of the symptom complexes observed in the illness. Evidence of GABAergic abnormalities comes predominantly from postmortem studies that find decreased interneuron numbers (predominantly fast-spiking interneurons) and decreased activity of glutamate decarboxylase, the enzyme that synthesizes GABA. Although glutamatergic and GABAergic alterations may be more proximal to the root causes of schizophrenia, this does not contradict the dopamine hypothesis. On the contrary, circuit-based models that integrate findings suggest that glutamate-related disinhibition in the hippocampus may result in malfunction of the feedback loop to the ventral tegmental area and result in a hyperdopaminergic state.

Structural & Functional Brain Abnormalities

Neuroimaging and postmortem studies have attempted to identify altered structure or function of particular brain regions and, more recently, brain circuits. The first evidence of structural brain abnormalities in schizophrenia was published in 1976, reporting enlarged ventricle size in patients compared to controls. The finding that is perhaps most replicated in volumetric studies in schizophrenia is hippocampal volume loss. In addition, reductions in cortical gray matter volume appear widespread, particularly in the medial temporal, superior temporal, and prefrontal areas, and may in part be associated with exposure to antipsychotic medications. Interestingly, this volume loss does not appear to reflect a gross loss of cell bodies, but rather decreased neuropil (ie, reduced dendritic complexity and synaptic density).

Contemporary models postulate that schizophrenia is caused by faulty interactions between brain regions that lead to symptoms across domains, rather than abnormalities in isolated brain areas. White matter tracts that structurally connect spatially disparate brain regions have decreased integrity, which is thought to be related to dysmyelination and oligodendrocyte pathology. Abnormal interactions between networks of brain regions during cognitive tasks and at rest in patients with schizophrenia also support the dysconnectivity hypothesis.

MANAGEMENT & OUTCOMES

A Brief History of Antipsychotic Medications

Antipsychotic medications are the cornerstone of acute and maintenance treatment of schizophrenia and are effective in treating hallucinations, delusions, and thought disorders, regardless of etiology. The discovery of antipsychotic medications was serendipitous. More than half a century ago, the observation was made, quite accidentally, that the antihistamine chlorpromazine also relieves psychotic symptoms. Between 1954 and 1975, approximately 15 first-generation, or “typical,” antipsychotic medications were introduced in the US market. All typical antipsychotics were found to have comparable efficacy but had significant neurologic side effects, such as neuroleptic malignant syndrome. In the late 1950s, a group of tricyclic compounds was synthesized based on the antidepressant imipramine. One of these compounds, clozapine, showed antipsychotic properties without causing disabling extrapyramidal side effects in trials in animals and humans. In 1975, soon after clozapine had slowly gained acceptance as a promising antipsychotic, a study reported severe blood dyscrasias in 18 patients with 9 fatalities, and clozapine was pulled off the market. In 1988, a seminal 6-week double-blind study comparing clozapine and chlorpromazine showed definitive superiority of clozapine for positive and negative symptoms. Because of the lack of extrapyramidal symptoms, the drug was considered “atypical.” Based on these findings, clozapine was reintroduced and continues to be the drug of choice for treatment-refractory schizophrenia. In the 1990s, several other atypical (second-generation) antipsychotics were developed. They are considered as effective as the typical antipsychotics with lower propensity to develop extrapyramidal side effects, but with higher metabolic liability.

Mechanism of Action of First- & Second-Generation Antipsychotic Agents

All antipsychotic medications act as full or partial dopamine D₂ receptor antagonists in nigrostriatal, mesocortical, and tuberoinfundibular pathways (Figure 38–4). Oral antipsychotics undergo extensive first-pass metabolism by the liver and are subject to extensive metabolism via the cytochrome P450 system, with 1 exception, paliperidone, which is predominantly excreted unchanged via the kidneys. Smoking may significantly affect drug levels through induction of the cytochrome system. Patients who are stabilized on antipsychotics in a nonsmoking environment such as a hospital may experience a decrease in serum levels upon resuming smoking, which may necessitate a dose increase.

Positron emission tomography studies have established that about 65% to 70% occupancy of the dopamine D₂ receptor is required to achieve therapeutic benefits. Exceptions are quetiapine and clozapine, which require substantially lower receptor occupancy to have therapeutic efficacy. Receptor occupancy of approximately 80% or higher leads to gross motor side effects.

Adverse Effects

Because of the widespread localization of dopamine binding throughout the central nervous system, dopaminergic antagonists can cause a variety of side effects, particularly extrapyramidal side effects. The immediate cause of acute and subacute extrapyramidal symptoms is considered to be the blockade of dopaminergic inhibition of striatal cholinergic neurons, leading to increased cholinergic activity in the basal ganglia. Several antipsychotic-induced extrapyramidal syndromes are known. Acute dystonic reactions, such as torticollis, oculogyric crisis, or laryngospasm, are observed within a few hours of administration of a single dose of antipsychotic medications, especially after parenteral administration, and typically resolve within 24 to 48 hours. These can be painful and distressing and can erode patient trust and medication adherence. Risk factors include male gender, younger age, black race, previous dystonic reactions, family history of dystonia, cocaine use, hypercalcemia, hyperthyroidism, and dehydration. The risk of acute dystonic reactions is greater with high-potency, first-generation antipsychotics but can be mitigated by using prophylactic anticholinergics. Drug-induced parkinsonism is a subacute syndrome that mimics Parkinson disease; bilateral rigidity of the neck, trunk, and extremities, which can be “cogwheel,” is a core finding. The risk of drug-induced parkinsonism is greater with older age, female gender, brain structural abnormalities, and preexisting extrapyramidal disease. Close monitoring for parkinsonian symptoms and antipsychotic dose adjustments are recommended in these cases, and evidence for use of anticholinergic drugs is limited. Akathisia is characterized by inner tension, restlessness, anxiety, an urge to move, and drawing sensations to the legs and has been associated with violence and suicide. Risk factors include older age, female gender, negative symptoms, iron deficiency, and concomitant parkinsonism. Benzodiazepines can be useful due to their anxiolytic and sedative properties, and β-blockers have been shown to be effective in some studies.

Neuroleptic malignant syndrome is a rare but potentially lethal form of extrapyramidal side effects. Classic signs are hyperthermia, tremor, altered consciousness, and “lead pipe” rigidity. In its severe form, patients develop elevated serum creatine kinase, myoglobinuria, leukocytosis, and hypoxia. Neuroleptic malignant syndrome may develop within hours but usually evolves over days, and many cases occur within 1 to 2 weeks of drug initiation. If not recognized, it can be fatal due to renal failure, cardiorespiratory arrest, disseminated intravascular coagulation, pulmonary emboli, or aspiration pneumonia. Risk factors include dehydration, agitation, catatonia, high doses of high-potency antipsychotics given parenterally at a rapid rate, use of multiple antipsychotics, and coincident treatment with lithium, selective serotonin reuptake inhibitors (SSRIs), or serotonin-norepinephrine reuptake inhibitors.

Tardive dyskinesia is a movement disorder that most commonly presents as choreiform movements often affecting orofacial and lingual musculature. It has an insidious onset after prolonged antipsychotic treatment and is often masked by ongoing treatment. Tardive dyskinesia is usually mild but often irreversible, and it can become socially stigmatizing and compromise eating, speaking, breathing, or ambulation. The cumulative incidence of tardive dyskinesia is estimated at 2% to 5% annually. The incidence of tardive dyskinesia with second-generation antipsychotics is 6- to 12-fold lower compared to haloperidol. Clozapine generally does not cause tardive dyskinesia. Risk factors include longer duration of antipsychotic treatment, higher cumulative drug doses, greater negative symptoms, substance abuse, and diabetes.

Atypical or second-generation antipsychotics potently block 5-hydroxytryptamine (5-HT) 2A serotonin receptors in addition to dopamine D₂ receptors, which is suggested to be the basis for lower overall risk of extrapyramidal side effects with second-generation antipsychotics. Common side effects associated with second-generation antipsychotics include weight gain and metabolic syndrome, hypotension, hyperprolactinemia, anticholinergic symptoms, extrapyramidal symptoms, and sexual dysfunction. Rare side effects include neuroleptic malignant syndrome, seizures, and agranulocytosis. There is increased risk of mortality from all causes, especially in older adults with dementia-related psychosis, for which the US Food and Drug Administration has issued a black box warning that should be weighed before prescribing these drugs in elderly patients. Metabolic monitoring is recommended for all patients chronically treated with second-generation antipsychotic medications. This include a baseline assessment of personal/family history of metabolic risk factors, quarterly assessments of the body mass index and waist circumference, and blood pressure, fasting glucose, and fasting lipids 12 weeks after antipsychotic initiation and annually thereafter.

The Clinical Antipsychotic Trials for Intervention Effectiveness (CATIE), a multicenter, double-blind, randomized controlled trial, compared the relative effectiveness of second-generation antipsychotic medications to the first-generation antipsychotic perphenazine. Surprisingly, efficacy measures did not differ between any of the antipsychotic medications included in the trial. Approximately three-quarters of patients discontinued the antipsychotic before the end of the 18-month trial; olanzapine had the lowest discontinuation rates but had the highest side effect burden overall. The Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS) from the United Kingdom similarly reported no advantage of second-generation antipsychotics in terms of quality of life or symptom burden over 1 year.

General Management Strategies

Acutely psychotic patients often require hospitalization for their safety. Oral second-generation antipsychotic agents are considered first-line treatment. For patients who are acutely agitated or likely to harm themselves or others, short-acting injectable antipsychotics, alone or in combination with benzodiazepines, are available. Electroconvulsive therapy (ECT) can be used as a last resort in acutely agitated patients or those with catatonia (see later discussion of ECT).

Most patients with chronic schizophrenia achieve a full response to a medication within 2 to 6 weeks. The goal of maintenance treatment is to prevent relapse and optimize functioning. The same medication dosage that resulted in control of acute symptoms is appropriate to use for maintenance treatment. In some cases, to minimize side effects or maximize clinical response, dosing can be further adjusted in clinically stable patients. In patients with multiepisode schizophrenia, treatment with antipsychotic medications will be indefinite. There is little evidence to support augmentation of nonclozapine atypical antipsychotic medications in non–treatment-resistant patients. Rather, a strategy of serial trials of antipsychotic monotherapy is preferred (Figure 38–5). When switching antipsychotic medications, cross-tapering of medications is advised, unless the patient has acute, severe adverse effects.

The United Kingdom National Institute for Health and Care excellence guidelines recommend that cognitive-behavioral therapy and family intervention should be offered to all patients with schizophrenia.

Management in First-Episode Schizophrenia

Evidence-based treatment guidelines in first-episode psychosis support the value of early intervention following a first episode of psychosis including low doses of antipsychotic medications, cognitive behavioral-psychotherapy, family education and support, and educational and vocational rehabilitation. Recovery-oriented first-episode clinics offer specialized services over a 2- to 5-year period after psychosis onset, with the goal to improve long-term clinical and functional outcomes. Initial results from the Recovery After an Initial Schizophrenia Episode (RAISE) research initiative indicates that mental health providers across multiple disciplines can implement the principles of coordinated specialty care for first-episode psychosis patients, which emphasizes shared decision making, addressing unique recovery goals of individuals, and engaging family members. Doses for most antipsychotics required for first-psychosis treatment are lower than those needed for multiepisode patients. The proper duration for trying a particular antipsychotic before switching due to lack of efficacy is considered 8 weeks at minimum, but approximately 25% of first-episode patients respond to longer treatments of up to 16 weeks. The recommended initial antipsychotic treatment should be risperidone, aripiprazole, quetiapine, or ziprasidone. If positive symptoms persist, a switch to another first-line medication is recommended. If risperidone was not the initial medication, it should be considered as the second. In addition, nonadherence as reason for lack of clinical response needs to be considered. If this is suspected, switching to a long-acting injectable formulation of risperidone is recommended as second trial. Clozapine can be considered for first-episode patients with persistent positive symptoms after trials of 2 antipsychotics, unless contraindicated or refused by the patient.

Management in Patients with Nonadherence to Oral Medications

Patients cite poor medication efficacy, difficult to tolerate side effects, personal beliefs that medication is unnecessary, stigma of taking antipsychotic agents, and cost as the most common reason for nonadherence with antipsychotic medications. For a significant subset of patients, nonadherence leads to relapse and hospitalization. Long-acting injectable antipsychotics were developed with the primary aim of addressing both hidden and overt nonadherence and are administered every 2 to 12 weeks. They offer several advantages, including more consistent bioavailability and reduced peak/trough plasma levels, transparency of adherence, and the possibility of early interventions if patients fail to take their medication. However, meta-analyses find no robust evidence of better tolerability or efficacy of long-acting injectables, with the possible exception of aripiprazole (this is likely at least in part explained by a selection bias, as those who would almost certainly benefit from a treatment are typically not recruited in clinical trials where they might not receive that medicine). It is recommended that the choice of formulation should be based on a shared decision-making process, taking into consideration patients’ preference and pragmatic considerations on treatment adherence and potential risks of incorrect drug administration.

Management in Treatment-Resistant Schizophrenia

Patients with treatment-resistant schizophrenia are defined as patients who have experienced treatment failure with 2 different antipsychotic medications at adequate dose and duration (at least 6 weeks in duration at therapeutic doses in multiepisode schizophrenia). Clozapine is the only currently available antipsychotic medication with superior efficacy; it is estimated that approximately 30% to 50% of patients who fail to respond to other agents will respond to clozapine. Clozapine has a complex pharmacologic profile. It binds loosely and transiently to dopamine D₂ receptors. It has a high affinity for serotonergic, adrenergic, muscarinergic, and histaminic receptors. Receptor occupancy is approximately 40%, which is significantly lower than is needed for therapeutic effects of other antipsychotics. It is extensively metabolized by the cytochrome P450 system, and the elimination half-life averages about 14 hours. Clozapine is different from other antipsychotics in several ways, including its (1) absence of tardive dyskinesia; (2) lack of serum prolactin elevations; (3) ability to treat positive symptoms without exacerbating motor symptoms in patients with Parkinson disease who become psychotic due to exogenous dopaminergic agents; (4) ability to improve primary and secondary negative symptoms; (5) ability to improve some domains of cognition in schizophrenia; and (6) indication for persistent suicidality or self-injurious behavior. Pretreatment assessments include evaluation of the patient’s cardiovascular health, complete blood count, electrocardiogram, abnormal involuntary movement scale, and pregnancy test in women of childbearing age. A slow titration with divided doses is recommended to minimize side effects such as orthostatic hypotension. The target dose of clozapine ranges between 200 and 900 mg/d (in divided doses) for most patients. Therapeutic plasma range is 250 to 350 ng/mL. Once an effective maintenance does is reached, most of the daily dose may be given at bedtime, which will aid in patients getting sleep while avoiding daytime sedation. If clozapine treatment is interrupted for >2 days, clozapine titration must be restarted at low doses, but titration can be done more quickly if tolerated by the patient.

Clozapine is associated with a number of severe adverse effects. Agranulocytosis occurs in approximately 0.8% of treated patients, and leukopenia occurs in 3%. These most commonly occur within the first 6 weeks of treatment. All patients, prescribers, and dispensing pharmacies have to be registered in the Clozapine Risk Evaluation and Mitigation Strategy (REMS) program, which provides guidelines for monitoring of leukopenia and agranulocytosis. It also documents routine neutrophil monitoring (weekly during the first 6 months, every other week during the second 6 months, and monthly thereafter for the duration of treatment). Myocarditis, likely an immunoglobulin E–mediated acute hypersensitivity reaction, can present with malaise, chest pain, shortness of breath, and elevated peripheral eosinophil counts, sedimentation rates, or troponin levels. Incidence is estimated to be between 0.001% and 0.2%. Clozapine needs to be discontinued promptly, and patients should not be rechallenged after myocarditis has resolved. The seizure risk associated with clozapine increases substantially in doses >600 mg/d; myoclonus can precede full-blown tonic-clonic seizures and can be valuable in determining when antiepileptic drugs are indicated. Gastrointestinal hypomotility is another potentially life-threatening side effect that can manifest in paralytic ileus, bowel obstruction, or acute megacolon. If patients do not respond to treatment with adequate doses of clozapine monotherapy for 6 months, the regimen may be augmented with another antipsychotic medication or a trial of ECT.

Management of Catatonia

A broad range of medical complications can occur in patients with catatonia. Some patients require a high level of nursing care, intravenous fluids and/or tube feeds, and anticoagulation therapies in order to reduce the risk of morbidity and mortality caused by immobility and poor nutrition. Antipsychotic agents should be discontinued because they may aggravate the catatonic state and can increase the risk of developing neuroleptic malignant syndrome. Benzodiazepines are the mainstay of treatment for catatonia, regardless of the underlying condition, and can also be helpful as a diagnostic probe. A positive lorazepam challenge validates the diagnosis of catatonia. After the patient is examined for signs of catatonia, 1 to 2 mg of lorazepam is administered intravenously. After 5 minutes, the patient is reexamined. If there is no change, a second dose of lorazepam is given, and the patient is assessed again 5 minutes later. The challenge is considered positive if marked improvement of symptoms is observed. However, a negative lorazepam challenge does not rule out a diagnosis of catatonia. With an adequate dose, response is usually seen within 3 to 7 days, but occasionally, response can be more incremental. A commonly suggested starting dose is 1 to 2 mg of lorazepam every 4 to 12 hours, with dose adjustments based on the patient’s clinical response. Doses of 8 to 24 mg of lorazepam per day are common and tolerated without ensuing sedation. There is no consensus as to how long benzodiazepines are to be continued, but they are generally gradually tapered after the illness has remitted. If symptoms do reemerge during a taper, it is suggested that benzodiazepines be continued to be used for an extended period of time. Bilateral ECT should be started in patients who do not respond to benzodiazepines or in severe cases with life-threatening conditions such as malignant catatonia. Benzodiazepines need to be discontinued before initiation of ECT. Response rates with ECT are estimated at approximately 85%. The number of treatments needed to improve symptoms is variable. Often a rapid response is seen after only a few sessions. However, en block daily treatments for 3 to 5 days may be necessary for malignant catatonia. Maintenance ECT can be considered for sustained symptom remission. A few case reports suggest that zolpidem, a positive allosteric modulator of GABA_A receptors, may be a treatment alternative in patients who have failed treatment with benzodiazepines and ECT. Treatment in children and adolescents should follow the same principles as in adults.

Management Strategies in Schizoaffective Disorder

Patients often receive a combination of antipsychotic medications and mood stabilizers or antidepressants. Antipsychotic treatment recommendations mirror those in schizophrenia, and management of mood symptoms is equivalent to that in bipolar disorder or major depressive disorder.

Management Strategies in Delusional Disorder

A major challenge in the management of delusional disorder is the lack of insight in many patients, which results in high rates of noncompliance with treatment recommendations. Antipsychotic medications typically do not work well. A small number of case reports suggest that pimozide may have superior efficacy in the somatic subtype of delusional disorder, but data from controlled trials are lacking. Pimozide acts as an antagonist of the dopamine D₂, D₃, and D₄ receptors as well as the 5-HT₇ receptor. It is contraindicated in patients with acquired, congenital, or a family history of QT interval prolongation and is not advised in patients with a personal or family history of arrhythmias. It is also contraindicated in patients receiving SSRIs and those who receive CYP3A4, CYP1A2, and CYP2D6 inhibitors. Given these considerations, pimozide should be considered as a last resort. Psychotherapy can include cognitive-behavioral therapy or supportive therapy, with the goal to reduce the strength of conviction of the belief and improve social inclusion. Insight-oriented therapy is rarely indicated. ECT is not indicated in delusional disorder.

Management of Neuroleptic Malignant Syndrome

Initial management consists of early diagnosis and removal of the causative agent along with other potential contributing psychotropic agents (eg, lithium, anticholinergic medications, serotonergic agents). Supportive medical care includes maintenance of cardiorespiratory stability and an euvolemic state, use of cooling blankets for fevers, and use of benzodiazepines to control agitation if necessary. In addition, use of dopamine agonists and dantrolene has been reported to reduce mortality rates in retrospective studies, but a small prospective study suggests a more prolonged course and higher incidence of sequelae in those receiving dantrolene or bromocriptine compared to those receiving supportive care alone. ECT may decrease mortality rates and hasten recovery, but cardiovascular complications have been reported. ECT is generally only recommended for patients not responding to other treatments. Patients restarted on antipsychotic medications may or may not have a recurrent episode of neuroleptic malignant syndrome. To minimize the risk of recurrence, it is recommended to wait at least 2 weeks before resuming therapy, use lower potency agents, start low doses and slowly titrate, avoid concomitant lithium treatment, and prevent dehydration.

Management of Tardive Dyskinesia

Tardive dyskinesia usually appears after prolonged use of antipsychotic drugs. Prevention and early detection and treatment of potentially reversible cases of tardive dyskinesia are paramount, because symptoms are often irreversible despite cessation of the offending drug. Long-term use of antipsychotics in nonpsychotic illnesses should be discouraged, and patients with psychotic disorders should be maintained at the lowest effective antipsychotic dose. Withdrawal of antipsychotics may initially lead to worsening of tardive dyskinesia, but approximately 30% to 50% of patients will eventually have symptom reduction. However, a complete and permanent reversibility may be uncommon. Because of the risk of psychotic relapse, cessation of antipsychotic medication is generally not recommended. As a first step, a decision should be made about whether continuation of concomitant anticholinergic drugs is necessary, because these can probably worsen tardive dyskinesia. For patients who develop tardive dyskinesia on a first-generation antipsychotic, a switch to a second-generation antipsychotic can be considered, and the CATIE trial has shown reductions in severity of tardive symptoms when switching. Clozapine has been recommended for suppressing tardive movement disorders, especially the tardive dystonia variant. Vitamin E and its antioxidant properties have been thought to reverse possible toxic effects of free radicals produced during chronic antipsychotic treatment, but results from clinical trials were conflicting. A meta-analysis of 6 small, placebo-controlled trials suggests vitamin E does not improve tardive dyskinesia. Gingko biloba was found to be effective in a small randomized controlled trial, in which a 12-week treatment significantly reduced involuntary movements. Recently, the US Food and Drug administration has approved two dopamine depleting medications, valbenazine and deutetrabenazine, as treatments for tardive dyskinesia. Deep brain stimulation of the globus pallidus has been shown to improve symptoms in a small number of patients with severe tardive dyskinesia resistant to pharmacologic treatments.

Management of Antipsychotic-Induced Hyperprolactinemia

Prolactin level measurements prior to initiating antipsychotic medications and routine monitoring during antipsychotic therapy are not universally recommended. The strongest predictors of hyperprolactinemia are the type and dose of the antipsychotic prescribed, with increased levels observed at higher doses. Haloperidol and risperidone are among the most common antipsychotics that elevate prolactin level, whereas clozapine and aripiprazole rarely elevate prolactin. If a temporal relationship between prolactin level elevation and initiation of antipsychotic treatment cannot clearly be established, laboratory testing, including assessment of liver, renal, and thyroid function, as well as magnetic resonance imaging of the pituitary gland (especially if patient reports headaches and visual field defects), should be considered. Discontinuation of antipsychotic drugs is not recommended in asymptomatic patients or in female patients with only mild galactorrhea. However, known risks such as osteoporosis and elevated risk of pituitary adenomas may present a justifiable reason to reevaluate established antipsychotic therapy despite a lack of symptoms. If patients are significantly symptomatic, a switch to olanzapine, quetiapine, ziprasidone, or clozapine can be considered. Alternatively, aripiprazole as an adjunct medication, particularly in those who are psychiatrically stable, has been shown to result in normalization of prolactin levels in approximately 79% of patients. This may be because of its dual agonism/antagonism properties on the dopamine D₂ receptor, which may mitigate effects of other antipsychotic medications on the pituitary gland. Because the addition of a dopamine receptor agonist such as amantadine or bromocriptine may cause a psychotic relapse, this is typically not recommended in patients with primary psychotic disorders.

OBJECTIVES

PREVALENCE & BURDEN

Mood disorders are a major and common public health problem, with a 12-month prevalence of 9.5%. They consist of major depressive disorder and bipolar disorders. Both are serious medical illnesses with mood, cognitive, and physical symptoms. Major depression is relatively common, with a 12-month prevalence of 7% in the United States. It is more common in females, occurring 1.5 to 3 times more often than in males. The rate of major depression varies with age: 5.7% among youth aged 12 to 17 years, 20% among adults aged 20 and 30 years, and approximately 10% among adults aged 40 to 59 years. Adults age 60 years and older have a significantly lower rate of depression (5.4%).

In bipolar disorder, the individual experiences manic or hypomanic episodes alternating with depressive episodes, with periods of normal mood between episodes. The 12-month prevalence in the United States is between 0.6% and 0.8%. In contrast to major depression, bipolar disorder affects women and men at almost the same rate. The mean age at onset for bipolar disorder is approximately 25 years, and men have an earlier age of onset than women.

Mood disorders are associated with increased healthcare utilization, decreased qualify of life, and impairment in social and occupational functioning that significantly affects patients’ lives. Studies have shown that major depression is a leading cause of disability. The economic burden of depression, including both direct and indirect costs, was estimated to be $210.5 billion in 2010 in the United States. Although bipolar illness is less common, on a per-case basis, it is the most expensive behavioral healthcare diagnosis because it costs more than twice as much as depression per affected individual due to medical care expenses and lost productivity.

ETIOLOGY

The cause of mood disorders remains unknown, but a combination of genetics, epigenetics, and environment is believed to contribute. Emerging evidence has shown the presence of neurochemical, structural, and functional brain abnormalities in patients with major depression and bipolar disorders.

Genetics

Both major depression and bipolar disorder clearly have inheritable risk factors. Increased risk for mood disorders in the first-degree relatives of patients with either major depression or bipolar disorder is well documented. For example, children of a parent with a mood disorder have a roughly 25% chance of developing a mood disorder themselves, and when both parents are affected, the risk is greater than 50%. First-degree relatives of patients with bipolar disorder have an estimated 12% lifetime prevalence of bipolar disorder, which is about 10 times higher than the general population. Despite this strong evidence for a role of genetics, few individual genes for mood disorders have been identified, and at present, genetic testing for risk of mood disorders is not available.

Epigenetics

Epigenetic changes are modifications of chromatin, such as methylation of DNA or post-translational modifications of histone proteins, that can have long-lasting effects on gene expression. Work on epigenetic effects in mood disorders is just beginning, but initial findings seem quite promising. Alterations in DNA methylation of the glucocorticoid receptor gene are associated with stress vulnerability, altered histone modification is associated with use of antidepressants, and altered methylation status of DNA in the brains of patients with bipolar disorders has emerged as a potential factor in the pathogenesis of mood disorders. In addition, small noncoding RNA molecules known as microRNAs also appear to play a role in psychiatric disorders, including major depression and bipolar disorders. Together, these epigenetic changes emphasize the complex genetic and genomic factors that contribute to mood disorders.

Environment

Environmental factors also appear to contribute to mood disorders. Factors such as childhood maltreatment (ie, early life stress) may predispose to later development of mood disorders. Mood disorders may also be caused or exacerbated by ongoing psychosocial stress. Although there are few hard data on gene–environment interactions, understanding these effects is likely to be critical to a full understanding of the etiology of mood disorders.

Chemical Abnormalities

Research in humans and animal models has revealed that there are abnormalities in multiple neurotransmitters and neuroendocrine systems in major depression and bipolar disorders (Figure 39–1). Common chemical pathways for bipolar disorders or major depression are believed to include the following: (1) deficiencies in serotonin, norepinephrine, dopamine, γ-aminobutyric acid, or the serotonin transporters; (2) regulators of intracellular signaling pathways, including phosphodiesterase 11A and brain-derived neurotrohic factor (BDNF); (3) components of the hypothalamic-pituitary-adrenal axis, including the glucocorticoid receptors; and (4) inflammatory factors.

Among these chemical pathways, the function of serotonin transmission and serotonin signaling has been well studied. Serotonergic abnormalities are believed to be central to depressive symptoms. The primary origins of serotonergic innervation of the brain are neurons located in the midline raphe nuclei in the brainstem. Serotonergic dysfunction is the basis for the most commonly used treatment of depressive disorders, selective serotonin reuptake inhibitors (SSRIs), which work by blocking serotonin transporters (SERTs) and increasing synaptic serotonin.

There are also structural changes in the brain in mood disorders. Reduced numbers of neurons are found in the anterior cingulate, hippocampus, and prefrontal cortex in bipolar disorders or major depression. Stress is a well-known risk factor or precipitator of depressive symptoms; stress can reduce both neuron number in the dentate gyrus as well as neural process length. Changes in neurotrophic factors have been proposed as an underlying mechanism (Figure 39–2). These changes in neuron structure and function may also, at least in part, be related to changes in serotonin because both effects can be prevented or reversed by SSRIs. In addition, serotonin has an effect on neurogenesis from neural stem cells in the brain. Studies of postmortem human brain samples show greater neurogenesis in the dentate gyrus in patients with major depression treated with SSRIs compared with patients with untreated major depression (see Figure 39–2).

Immune dysregulation in mood disorders has attracted growing attention, and a large number of studies have reported increased levels of inflammatory molecules, such as tumor necrosis factor-α, interleukin-6, and C-reactive protein, in the serum or postmortem brain samples of patients with major depression. Concentrations of proinflammatory cytokines are also reportedly elevated during mania or hypomania. Although most studies have focused on cytokines, additional support for the role of inflammation in mood disorders is derived from gene expression studies of peripheral blood mononuclear cells that have demonstrated the existence of increased messenger RNA expression for proinflammatory factors. However, most of these studies are observational; interventional studies will be required to establish a definite cause–effect relationship between inflammation and mood disorders.

Structural & Functional Changes in Brain

The recent widespread use of the structural and functional magnetic resonance imaging (MRI) has provided new information on the brain networks involved in mood disorders and how changes in these networks may affect mood regulation and cognition. The areas of the prefrontal cortex, anterior cingulate cortex, and amygdala are specifically implicated to be associated with mood symptoms. Reduced activity in the ventral and orbitofrontal cortices appears to be related to remission, whereas amygdala activity is persistently increased during remission. Taken together, all of these findings indicate that causes of mood disorders are multifactorial and heterogeneous.

CLINICAL FEATURES OF MOOD DISORDERS

The core feature of any mood disorder is a distinct period of abnormally and persistently altered mood, during which patients suffer from impaired function at work, at school, or in the community. Although many patients with mood disorders have only 1 episode during their lives, most have multiple episodes, alternating with periods of remission or normal moods. However, some individuals may never experience remission. Therefore, another feature of any mood disorder is a tendency toward cycles of episodes, from response or remission to recurrence, which follows a longitudinal course. Besides altered mood, patients with mood disorders can also experience behavioral, cognitive, and psychomotor changes. Both depressive disorders and bipolar disorders have several subtypes, and each of them has very specific presentations, causes, and durations (Figure 39–3).

DEPRESSIVE DISORDERS

Major Depressive Disorder

Depression as a term in popular use is mostly considered to be synonymous with low mood or feeling down or blue. Major depressive disorder as a mental disorder, however, is characterized by a variety of psychological, behavioral, cognitive, and psychomotor symptoms. Major depression is also referred to as unipolar depression, which is differentiated from bipolar disorders. Different depressive symptoms are classified within diagnostic systems, such as the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V). According to the DSM-V, a person must experience 5 or more symptoms from the list below for a continuous period of at least 2 weeks to be diagnosed with an episode of major depressive disorder. Most symptoms must be present every day or nearly every day and must cause significant distress or problems in daily life function.

• Feelings of sadness, hopelessness, and depressed mood

• Loss of interest or pleasure in activities that used to be enjoyable (anhedonia)

• Change in weight or appetite (either increase or decrease)

• Change in activity: psychomotor agitation (being more active than usual) or psychomotor retardation (being less active than usual)

• Insomnia (difficulty sleeping) or sleeping too much

• Feeling tired or not having any energy

• Feelings of guilt or worthlessness

• Difficulties concentrating and paying attention

• Thoughts of death or suicide

Psychological Symptoms

Major depressive disorder is characterized by a pervasive and persistent depressed mood that is accompanied by low self-esteem or sense of inadequacy for at least 2 weeks. When describing their depressed mood, patients express it as “sad,” “low,” “down,” or “blue” feelings. It may also be expressed as a feeling of emptiness or the need to cry. In addition, some patients may feel anxious, irritable, or even hostile, which is often seen in children or adolescents. Another psychological core symptom is anhedonia, the loss of interest or pleasure in normally enjoyable things, people, and activities. Patients state that they are not interested in things or activities they normally enjoy, such as food, sports, or sex, or that they just do not care anymore. They seem to have a flat or blunt affect and feel apathetic and unenthusiastic. Their anhedonia can be accompanied by fatigue or loss of energy, for which they feel guilty and worthless. Depressed patients also have intense pessimism and hopelessness. They feel that their future has been destroyed and they will never feel “normal” or well again, triggering their anxious feelings. Fears of being alone and lack of support from others are common as well. A triad of worthlessness, hopelessness, and helplessness often leads to suicidal thoughts and suicidal behavior.

Suicide

Suicide is the act of intentionally causing one’s own death. Since 2010, suicide has been the 10th leading cause of death in the general population in the United States. Approximately two-thirds of people who commit suicide suffered from depression. Depressed patients tend to feel extremely hopeless and pessimistic when their attempts to solve problems fail again, especially when they lack social support or feel their existence is a burden on family and friends. They frequently become angry, self-punishing, and self-critical. They often describe themselves as “miserable” and have distorted thoughts such as, “I will be better off dead” or “I deserve to die.” Some depressed patients have constant suicidal thoughts but do not have the intent or wish to die (passive suicidal thoughts). In contrast, other patients with suicidal thoughts have an intense wish to die and then act on their thoughts and commit suicide. Another subset of depressed patients can present with deliberate nonsuicidal self-injurious behavior but without the wish to die (eg, multiple superficial cuttings). Many patients who engage in nonsuicidal self-injury state that they feel a sense of “relief” or even “euphoria” when they injure themselves.

Behavioral Symptoms

Depressed patients can have behavioral changes in sleep pattern, energy level, appetite, and libido. These symptoms are also referred as “vegetative” symptoms because they affect essential survival skills. Sleep disturbance can be divided into insomnia, hypersomnia, or daytime sleepiness. Insomnia is the most common complaint and includes difficulty falling asleep (sleep-onset insomnia), difficulty staying asleep (sleep-maintenance insomnia), and early morning awakening. Depressed patients may have 1 type of insomnia or a combination of the 3 types of insomnia. Up to 20% of depressed patients report hypersomnia, especially patients with atypical features. Patients usually state they have no appetite to eat or do not feel hungry, leading to a significant weight loss during the depressive episode. Insomnia and poor appetite are the classic symptoms of depression. In contrast, some depressed patients present with hypersomnia and increased appetite, referred to as atypical depression. Physical fatigue or loss of energy occurs independently of sleep disturbance and appetite changes. Although it can be very frustrating to patients and their partners, a common symptom that patients may be reluctant or embarrassed to report is the loss of sex drive.

Cognitive Symptoms

Patients with major depression often report difficulty concentrating or completing tasks. For example, patients frequently report that they do not know where their mind is when they are reading. They have to read the same page over and over again but still do not comprehend the page. Another common frustration reported by depressed patients is the loss of memory, especially immediate or recent memories. They feel they are unable to remember anything. This cognitive dysfunction is usually not a simple matter of having distracting thoughts. Some patients exhibit frank confusion, are disoriented as to the time and place, and do not recognize people they know. This phenomenon is also referred as “pseudodementia” because it is transient in nature and secondary to the untreated depression. Pseudodementia occurs more often in aging patients and usually resolves when the depression is treated and improved.

Psychomotor Symptoms

Psychomotor activity is usually reduced in depressed patients, which is known as psychomotor retardation. Psychomotor retardation involves a slowing down of thoughts and speech, as well as a reduction of physical movements in patients. Patients with psychomotor retardation have difficulty performing activities that normally require little effort, such as getting out of bed. If psychomotor retardation is severe and combined with poor oral intake, severe apathy, and overall self-neglect, a medical emergency can result, and admission to an inpatient service is indicated. In contrast, some depressed patients may exhibit psychomotor agitation, especially depressed patients with anxious features or children and adolescents. Psychomotor agitation can also be seen in patients who have just started taking antidepressants. However, it should subside in these patients over a few weeks, when they are more tolerant to the medication.

Severity of Major Depression

Depression can be categorized as mild, moderate, or severe. Besides clinical judgment, depression severity can be evaluated using standardized depression rating scales such as the Beck Depression Inventory (self-report) or the Hamilton Depression Rating Scale or the Montgomery-Asberg Depression Rating Scale (both administered by the physician). The assessment of depression severity is of clinical importance because it can guide the physician to select a treatment plan. Mild depression can be treated with psychotherapy alone. However, in moderate or severe depression, antidepressants are often part of the first-line treatment in adults, alone or in combination with psychotherapy, in order to stabilize patients rapidly to prevent or avoid adverse outcomes such as suicide.

Persistent Depressive Disorder

Persistent depressive disorder was previously called dysthymia before DSM-V. It is a mild but long-term form of depression that lasts at least 2 years. Its core symptom is a low, gloomy, or sad mood on most days for at least 2 years. In children or adolescents, the mood can be irritable instead of depressed and lasts for at least 1 year. In addition, 2 or more of the following symptoms are present almost all of the time: lost interest in normal activities, hopelessness, low self-esteem, low appetite, low energy, sleep disturbance, and poor concentration. Early morning awakening or worsening of mood in the morning, which are typical for major depression, are usually not present in patients with persistent depressive disorder unless patients also have an episode of major depressive disorder at some point in their lives. This coexistence of persistent depressive disorder and major depression is referred as double depression. Persistent depressive disorder tends to run in families and appear more frequently in women. Individuals with persistent depressive disorder often take a negative or discouraging view of themselves, their future, other people, and life events.

Premenstrual Dysphoric Disorder

Premenstrual dysphoric disorder is a mood disorder characterized by severe depressive symptoms, including irritability, extreme sadness, hopelessness, or anger, plus common premenstrual symptoms (breast tenderness, headache, and bloating) before menstruation. This specific condition causes extreme mood shifts that can disrupt work and damage relationships. Premenstrual dysphoric disorder follows a predictable and cyclic pattern. Symptoms begin in the late luteal phase of the menstrual cycle, remit within a few days of the follicular phase, and end in the week after menses.

Disruptive Mood Dysregulation Disorder

This is a fairly new diagnosis and was included for the first time in DSM-V. The diagnosis is only given to children between 6 and 18 years old. It is a childhood condition of extreme irritability, anger, and frequent outbursts that goes far beyond being a “moody” child. Patients often exhibit psychomotor agitation and suffer from severe functional impairments that warrant clinical attention. To be diagnosed with disruptive mood dysregulation disorder, patients must have the symptoms for at least 12 months in at least 2 settings with impaired quality of life and school performance and disrupted relationships with family and peers. Children with this diagnosis usually develop depressive disorders or anxiety disorders, rather than bipolar disorders, as they mature into adulthood.

BIPOLAR DISORDERS

Bipolar disorder is a mental disorder that causes unusual shifts in mood, energy, and activity levels and impairments in daily tasks. Patients with bipolar disorders have discrete periods of altered feeling, thought, and behavior. Most patients with bipolar disorders have manic or hypomanic (less severe form of mania) episodes as well as major depressive episodes. Depressive episodes in bipolar disorders are indistinguishable from those in major depression. The main types of bipolar disorders are presented in Figure 39–3, and all of them involve clear changes in mood, energy, and activity levels. Those who experience at least 1 manic episode are diagnosed with bipolar I disorder; however, an episode of major depression is not necessary to make a diagnosis of bipolar I disorder. Patients with episodes of both major depression and hypomania are diagnosed with bipolar II disorder. In the DSM-V, a diagnosis of bipolar disorder can be established if a full episode of mania or hypomania emerges during antidepressant treatment and persists at a fully symptomatic level beyond the immediate effects of the treatment.

Mania

A manic episode is defined by a distinct period of at least 1 week of abnormally elevated, expansive, or irritable mood accompanied by impairments in judgment and social and occupational function. Besides abnormal mood, at least 3 of the following symptoms should be present. If the person is only irritable, he or she must experience at least 4 of the following symptoms:

• Inflated self-esteem or grandiosity (ranges from uncritical self-confidence to a delusional sense of expertise)

• Decreased need for sleep

• More talkative than usual or pressure to keep talking

• Flight of ideas or subjective experience that thoughts are racing

• Distractibility (attention easily pulled away by irrelevant/unimportant things)

• Increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation (eg, pacing and hand-wringing)

• Excessive involvement in pleasurable activities that have a high potential for painful consequences.

Psychological Symptoms

Patients with manic episode describe their mood as euphoric; they feel they are “on top of the world” and are able to do or accomplish anything and that nothing can stop them (grandiosity). However, sometimes the mood can be irritable and even angry rather than elevated, especially if patients’ wishes are curtailed or denied. Along with euphoric mood and unrealistic grandiosity, patients usually engage in significant goal-directed activities that frequently contain high potential for negative consequences.

Behavioral Symptoms

During the manic episode, mood abnormality is often accompanied by the decreased need for sleep. Patients usually sleep <3 hours at night but still feel rested and have excess energy for all kinds of tasks. Sometimes patients describe themselves as “a motor that is going too fast.” Although patients may engage in multiple projects at the same time, often none of the projects are completed due to poor or no planning, resulting in frustrations. Their busy pace may also become unpleasant when patients have insomnia for several nights in a row. Mania can also manifest as increased sexual drive and indiscrete sexual behavior. Patients tend to have multiple partners and are more vulnerable to substance use, which may later result in feelings of shame and embarrassment.

Cognitive Symptoms

Many manic patients have significant changes in their speech, thoughts, and attention. Patients may experience pressured speech, racing thoughts, and distractibility, which is often noticed by their family and friends. When mania is severe enough, racing thoughts can progress to flight of ideas, which is characterized by a series of tenuously connected thoughts. Irritable mood combined with other cognitive symptoms can result in psychomotor agitation. The extreme form of psychomotor agitation is manic delirium, in which patients are disoriented, act chaotically, and have incoherent speech. Patients with manic delirium warrant immediate medical intervention.

Suicide

In addition to the adverse psychosocial and vocational impacts of bipolar disorders, patients with bipolar disorders are also at increased risk for suicide. The lifetime risk of suicide in individuals with bipolar disorders is estimated to be 15 times higher than that of the general population. Suicide rate is higher in bipolar disorders than in major depressive disorder. The highest risk of suicide is seen in patients with bipolar disorders during depressed or mixed states. Indeed, bipolar disorders account for approximately one-quarter of all completed suicides.

Hypomania

Hypomanic and manic symptoms are similar, but a hypomanic episode is less severe than mania. Because hypomanic symptoms are less severe, patients with hypomania may not suffer from significant impairment in the social and occupational functions and are able to have a relatively normal quality of life. If patients stay in the hypomanic stage, they may not need to be hospitalized. Instead, some patients may be more productive at work or at school and may even state, “I’ve never felt so good before in my life.” However, hypomanic patients can be “promoted” from hypomania to mania by the presence of 1 of the following 3 features: psychotic symptoms during the episode, severe symptoms warranting hospitalization, or marked social and occupational impairments. Of the 3 characteristics by which a patient is “promoted” from hypomania to mania, the presence of psychosis firmly indicates that the episode is mania rather than hypomania. Sometimes, hypomania may last for months, or it may occur for a few days before a full-blown manic episode develops.

Cyclothymia

As its name suggests, cyclothymia is a milder disorder or subsyndromal bipolar I or II disorder with cycling between depression and hypomania that lasts over several weeks to months. Patients experience emotional highs and lows alternating with normal or stable moods, but the highs and lows are much less extreme than those in bipolar I or II disorders. Due to its mild form, cyclothymic patients seek medical attention less frequently than those with full-blown bipolar I or II disorder. Although mood abnormalities in cyclothymia are less extreme, it is still critical to seek help managing these symptoms because they can interfere with patients’ daily function and increase the risk for full-blown bipolar I or II disorder.

COURSE OF MOOD DISORDERS

Major Depressive Disorder

Episodes of major depression usually start gradually, and they can be self-limited and last approximately 6 to 9 months from time of onset to full recovery if untreated. However, a number of studies have shown the potential for recovery to take much longer or to not occur at all (never asymptomatic). It appears that for each episode of depression, approximately 10% of individuals remain ill for at least 5 years. Risk factors for prolonged time to recovery or chronic depression include a longer duration of the current episode before treatment is started, a family history of major depression, lower economic status, and comorbidity with other psychiatric illness, including alcohol and substance abuse. Only 25% of patients have only 1 episode of major depression. Thus, the majority of depressed patients will have >1 episode in their lives.

Approximately 20% of patients relapse within 1 year of follow-up evaluation. Factors predicting relapse include multiple episodes of major depression and a history of other psychiatric illness. Although none of these risk factors can significantly predict the likelihood of recurrence, the rate and timing of recurrence seem to depend on the type of recovery. Patients with full recovery (ie, asymptomatic on follow-up evaluation) have a much lower rate of recurrence than those with some residual symptoms. The time to recurrence is also much longer in the asymptomatic group compared with the group with residual symptoms. Therefore, it is important for depressed patients to reach recovery in each episode to reduce the risk for recurrence.

Bipolar Disorders

The degree of recovery between bipolar episodes varies. Episodes of mania and depression typically recur across the life span. Between episodes, most people with bipolar disorders are free of symptoms, but as many as one-third of people have some residual symptoms. Besides episodes of full-blown mania and major depression, patients can have episodes of milder depression, hypomania, or mixed states characterized by simultaneous occurrence of both depressive and manic symptoms. The natural course of bipolar disorders is for episode frequency to gradually increase and for a high percentage of episodes to be characterized by depressive symptoms rather than mania or hypomania. Although many patients are able to resume their normal activities within several weeks to months, a small percentage of patients may experience chronic unremitting symptoms despite treatment and have significant social and professional dysfunction for up to 2 years. The median duration of bipolar I episodes is approximately 3 months, and >75% of patients recover from their episodes within 1 year of onset. Factors that reduce the probability of recovery from a mood episode include severe onset of the mood episode, rapid cycling from one pole to the other, and greater cumulative morbidity. Patients with bipolar disorders tend to deteriorate without appropriate treatment, but proper treatment can help reduce the frequency and severity of episodes. Thus, patients with bipolar disorders can lead normal and productive lives when their illness is well managed.

Bipolar Disorders with Rapid Cycling

An important clinical phenomenon in bipolar disorders is rapid cycling, which is defined as having 4 (any combination of manic, hypomanic, mixed, or depressed episodes) or more episodes of bipolar disorder within a 12-month period in a patient. Episodes are demarcated by either partial or full remission for at least 2 months or a switch from one pole to the other with no intervening period of recovery (eg, major depressive episode to manic episode without a normal period). The prevalence of rapid cycling is estimated at 12% to 24% of patients with bipolar disorder and is more common in females than in males. Some patients experience multiple episodes very briefly or even in a single day, which is called ultra-rapid cycling.

Rapid cycling is an important marker of outcome in bipolar disorders because it predicts a relatively poorer outcome and worse response to mood stabilizers including lithium. Rapid cycling may occur at any time during the disorder; however, it tends to develop later in the course of illness. Several specific risk factors may be associated with rapid cycling, including earlier age at onset, comorbid substance use, greater severity of depressive episodes, antidepressant use, and prior or current thyroid dysfunction.

DIAGNOSIS & DIFFERENTIAL DIAGNOSIS

According to the DSM-V, identification of individual mood episodes is the basis for the diagnosis of major depression and bipolar disorders. A careful interview is essential to establish an accurate diagnosis. Due to the illness itself, some patients may not be able to engage in a meaningful and informative interview. In this case, it is useful to obtain collateral information from the patient’s family and friends to understand patient’s illness and baseline function. Sometimes it is difficult to determine what diagnosis a patient may have from a single interview. Considering the course of symptoms over time, including the timing, duration, and recurrence of episodes, is critical to avoid diagnostic errors. In addition, individuals with recurrent major depression often do not recognize or report prior hypomanic or even manic episodes, so these must be asked about specifically. The same holds true for evaluating manic episodes in bipolar disorder because patients may not be able to recognize their altered mood and abnormal behavior.

Similar to other psychiatric disorders, underlying medical causes and adverse effects of medications must be ruled out. Medical conditions and medications have been associated with both major depression and bipolar disorders. Common medical illnesses that induce mood disorders include endocrine disorders (eg, hypothyroidism, hyperthyroidism, Cushing disease), neurologic disorders (eg, cardiovascular diseases, dementia, temporal lobe epilepsy), and some cancers. Medication history should include both prescribed and over-the-counter medications.

Substance use is another major cause of mood disorders, and approximately half of patients with either major depression or bipolar disorders are affected by legal or illegal drugs. Most patients tend to self-medicate their mood disorders using substances such as alcohol, cocaine, and amphetamines. However, self-medication with these drugs usually causes or exacerbates their mood symptoms. Acute intoxication with stimulants such as cocaine or amphetamines may produce the same symptoms as mania or hypomania, although they last only a few hours to a few days. In contrast, withdrawal symptoms from these stimulants can mimic depression. Chronic alcohol use may cause depressive symptoms, but alcohol may also cause disinhibition that resembles hypomania, such as irritability. Substance use may likely contribute to diagnostic uncertainty. Thus, reassessment after a few months of abstinence is indicated.

Other psychiatric disorders may also have mood symptoms, such as schizoaffective disorder and delusional disorder (see Chapter 38). Persistent psychosis during periods of normal mood would be characteristic of schizoaffective disorder. Although sometimes patients may have comorbid psychotic disorders, mood symptoms should be the most prominent features in patients with mood disorders. Another common differential diagnosis is between mood disorders and anxiety disorders. Predominance of either anxiety or mood symptoms usually helps establish the correct diagnosis. Differential diagnosis is simplified if discrete episodes (depression, mania, or hypomania) are noted. However, mood disorders have a high rate of comorbidity with different anxiety disorders.

Similarly, personality disorders, including borderline, histrionic, and narcissistic personality disorders, can have some of the same symptoms as mood disorders. For example, borderline personality disorder frequently involves mood lability, instability of interpersonal relationships, periodic feelings of emptiness, and episodes of self-harm. All of these symptoms can be present in bipolar disorders. Although psychodynamic formulation can frequently differentiate the former from the latter, temporal course and relationship features are able to clarify the diagnosis. Thus, it is critical to ask what the patient’s personality was like before the onset of mood symptoms. However, many patients may have comorbid mood disorders and personality disorders, both of which require treatment.

Medical Evaluation

Although the diagnosis of mood disorders is established primarily based on interview and collateral information, it is recommended that a thorough medical history, a physical examination, and laboratory tests be included to evaluate patients with mood disorders. There are several reasons to include this in routine evaluation. First, some medical conditions and substances can induce mood disorders. The management of these situations may lead to the resolution of the mood episodes. Second, medical evaluation is necessary to start some medications and to track medication-related adverse effects. Finally, for many patients with psychiatric illnesses, particularly chronic or severe illnesses, their first contact with a medical professional may be due to their psychiatric disorders. Thus, a thorough medical history and physical examination are necessary to provide appropriate and safe care for patients with mood disorders.

Routine laboratory tests include a complete blood count, basic metabolic profile, thyroid function panel, hepatic function panel, lipid profile, urine drug screening test, and urinalysis. An electrocardiogram may be ordered because of the cardiovascular effects of some medications, particularly QT_c prolongation with antipsychotic use. If it is the first onset of symptoms, brain imaging such as computed tomography or even MRI may be considered. Electroencephalography is considered in some patients with sedative abuse or suspected sedative abuse. Some workup results may indicate a need for consultation with other specialties.

TREATMENT

Major Depressive Disorder

What therapy to start first is determined by the severity of the depression. With mild or moderate major depression, especially mild depression, psychotherapy is usually the first option. If major depression is moderate or severe, the first-line therapy is to start and optimize an antidepressant, such as an SSRI or serotonin-norepinephrine reuptake inhibitor (SNRI; eg, bupropion and mirtazapine; Table 39–1). Most antidepressants act by increasing the amount of serotonin and/or norepinephrine (see Figure 39–2). Antidepressants are not rapidly effective medications, and it often takes 2 to 4 weeks to see an initial response (Figure 39–4). Patients may also experience adverse effects in the beginning before they see the benefits, so it is important to encourage patients to be compliant with antidepressants. However, if patients do not feel better by 4 to 6 weeks, it is probably better to switch antidepressants rather than maintain the current antidepressant. If there is a partial response at 4 to 6 weeks at the full therapeutic dosage, adding another antidepressant from a different class or considering an augmenting strategy is indicated. Augmenting strategies include psychotherapy, thyroid hormone, lithium, or an approved atypical antipsychotic. Due to unpleasant and potentially lethal adverse effects, the tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) are usually not the first-line therapy except when treating atypical depression or treatment-resistant depression.

Several well-controlled studies, including the National Institutes of Health–funded STAR-D study, have shown that approximately one-third of patients with major depression do not respond to 2 trials with adequate treatments (adequate treatment duration and adequate dosage). There are a few other options available. Both repetitive transcranial magnetic stimulation and electroconvulsive therapy (ECT) have been demonstrated to be effective (efficacy as high as 80%) as treatments for major depression. The American Psychiatric Association recommends ECT for patients who have had previous positive response to ECT or who are nonresponsive to antidepressants, as well as for patients who experience severe, psychotic, or acute suicidal depression. Although the mechanism for ECT remains unclear, ECT works rapidly and is relatively safe, even during pregnancy. In general, many patients feel better regarding their depression after 6 to 12 ECT sessions over a few weeks. After initial treatment, patients may still require maintenance ECT treatment (ie, weekly to monthly) and/or antidepressants to prevent relapse or reoccurrence. Another potential and promising therapy is ketamine; ketamine is experimental at present but may be a consideration in the future.

Another issue involves how long patients need to take antidepressants. If they have a single episode of major depression, continuation of treatment at the full dosage should be maintained for at least 6 months after the acute phase to prevent relapse. However, if patients have had >2 recurrent episodes of major depression with a family history of depression, treatment may need to be indefinite. If relapse occurs, the same medication is usually, but not always, effective.

For persistent depressive disorder and premenstrual dysphoric disorder, psychotherapy and antidepressants are usually effective treatments, and cognitive-behavioral therapy (CBT) may attenuate the functional impairments in patients.

Bipolar Disorders

Treating bipolar disorder is very different from treating major depression. Antidepressants appear to be much less effective for bipolar depression than major depression. The first step is starting mood stabilizers or optimizing current mood stabilizers. Medications commonly used in bipolar depression include olanzapine, olanzapine-fluoxetine combination (more effective than olanzapine alone), lamotrigine, quetiapine, and the recently approved drug lurasidone. Lithium and lamotrigine have antidepressant efficacy as well (Table 39–2). ECT should be considered in severe cases if it is available. As with major depression (see Figure 39–3), switching to a new drug is indicated if current mood stabilizers do not work in a few weeks.

It is often debated whether antidepressant therapy in bipolar depression has a risk of triggering mania. Recent studies have yielded inconsistent results, ranging from as high as 30% to 40% with the tricyclics to as low as placebo rates with SSRIs and other newer antidepressants. The natural switch rate from depression to mania in the absence of treatment may be as high as 40%, adding more variables to this discussion. On the whole, the benefit of antidepressant treatment appears to be low in patients with bipolar depression, and maximizing mood stabilizers appears to be the best intervention.

Lithium and anticonvulsants are the mood stabilizers that have generally been effective for acute mania (see Table 39–2). Lithium is widely used, with a 60% to 70% remission rate in patients with bipolar disorder, especially in patients with euphoric mania or few or infrequent episodes, but it does not work well for rapid cyclers. Lithium has a narrow therapeutic window and lithium toxicity is an important complication. Symptoms include tremor, ataxia, confusion, lethargy, and nausea or diarrhea. When severe, lithium toxicity requires hemodialysis to correct.

Anticonvulsants, divalproex in particular, are more effective for bipolar disorder with rapid cycling than lithium (see Table 39–2). Sometimes patients may need to take both lithium and anticonvulsants to achieve an acceptable effect. In addition, atypical antipsychotics are also approved by the US Food and Drug Administration for mood stabilization in patients with acute mania and for long-term prevention.

It can take a week or more for mood stabilizers to act, and mood stabilizers do not have much sedative effect. Therefore, in the first few weeks of treating mania, antipsychotics and/or benzodiazepines may be used in combination with mood stabilizers to stabilize patients to ensure their safety and that of others. Improvements in psychomotor activation, insomnia, grandiosity, and psychotic symptoms are usually seen in a few days. Antipsychotics can be very helpful in treating hallucinations and delusions in patients with acute mania.

Suicide

Dealing with suicidality is probably the greatest challenge in the treatment of psychiatric illness, particularly in major depression and bipolar disorders. Suicidality needs to be assessed at every contact with patients. Predictors of an elevated suicide risk include depression severity, history of suicide attempts, active suicidal ideation/intent, hopelessness, unemployment, comorbid psychotic disorders (eg, substance use and personality disorder), a family history of completed suicide, male gender, and living single due to being widowed or divorced. Suicide events are most common right before initiating treatment and during the interval before treatment becomes effective, as well as within 1 to 3 months when patients are discharged from the hospital. Thus, frequent follow-up visits should be planned during these periods. In addition, it is important to involve family, friends, and caregivers in patients’ treatment and recovery.

Psychotherapy in Managing Mood Disorders

In addition to the medication, psychotherapy is helpful in both major depression and bipolar disorders. CBT is well established, particularly in mild to moderate major depression. Evidence suggests that CBT is as good as any antidepressant and, in some cases, may even be more effective at preventing relapse. Interpersonal therapy also has strong evidence to support its efficacy. This therapy focuses on interpersonal interactions and how to improve those interactions, which leads to improvement in depression.

In bipolar disorders, CBT possesses a good evidence base. Interpersonal therapy, social rhythm therapy, and family-focused therapies have been shown to decrease relapse, improve function, and help with treatment compliance. They are all used in conjunction with mood stabilizers to manage patients with bipolar disorders.

OBJECTIVES

Although anxiety is a normal emotion experienced by essentially everyone at some point in their lives, patients with anxiety disorders experience prolonged or abnormally intense feelings of anxiety that cause significant distress or impairment. In the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V), these disorders are grouped into 3 categories. The first category, anxiety disorders, includes panic disorders, generalized anxiety disorder (GAD), and several disorders with anxiety caused by specific stimuli (including separation anxiety disorder, a childhood condition discussed in Chapter 44). The obsessive-compulsive disorders category includes obsessive-compulsive disorder, hoarding, and body dysmorphic disorder (the latter is discussed in Chapter 41 because it is considered a somatic disorder in the 10th revision of the International Statistical Classification of Diseases and Related Health Problems, ICD-10). The third category, trauma- and stressor-related disorders, includes posttraumatic stress disorder (PTSD).

PREVALENCE & BURDEN

Anxiety is a common feeling or emotion experienced by most people. In general, anxiety disorders have the highest prevalence of all psychiatric conditions, with a lifetime prevalence of approximately 25%. Phobias (specific phobia and social anxiety disorder/phobia) are the most common mental disorders in the United States. At least 5% to 10% of the population and possibly as much as 25% of the population may suffer from some type of a phobic disorder (eg, fear of needles, animals, heights). Prevalence estimates of anxiety disorders are generally higher in developed countries than in developing countries. Many anxiety disorders are more prevalent in women than in men, with a ratio of 2:1, except obsessive-compulsive disorder and social anxiety disorder, in which the female-to-male ratio is closer to 1:1. Most anxiety disorders start in childhood.

Studies have estimated the annual cost of anxiety disorders in the United States to be approximately $42.3 billion in the 1990s, a majority of which was due to nonpsychiatric medical treatment costs, per the Centers for Disease Control and Prevention. This estimate focused on short-term effects and did not include the effect of outcomes such as the increased risk of other disorders. Anxiety can be severely debilitating and can cause significant suffering and social isolation.

ANXIETY DISORDERS

Social Anxiety Disorder (Social Phobia)

Social anxiety disorder, also known as social phobia, is a marked fear or anxiety about 1 or more social situations in which the individual is exposed to possible scrutiny by others. The fear, anxiety, or avoidance is persistent and typically present for ≥6 months. Examples include fear of social interactions (eg, having a conversation, meeting unfamiliar people), fear of being observed (eg, eating or drinking), and fear of performing in front of others (eg, giving a speech). Of note, in children, the anxiety must occur in peer settings and not just during interactions with adults. Patients with social phobia fear displaying anxiety symptoms that will be seen by others in a negative way. Patients are preoccupied with the fear of being humiliated or embarrassed, and this fear leads to a worry that they will be rejected by or offend others. Social situations almost always provoke fear or anxiety. In children, the fear or anxiety may be expressed by crying, tantrums, freezing, clinging, shrinking, or failing to speak in social situations. Social situations are avoided or endured with intense fear or anxiety. Fear or anxiety is out of proportion to the actual threat posed by the social situation and to the sociocultural context. Patients suffer clinically significant distress or impairment in social, occupational, or other important areas of functioning. For occasional anxiety-inducing situations such as public speaking, β-blockers or benzodiazepines may be treatment options. Cognitive-behavior therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs) are the treatments of choice for most cases of social anxiety disorder.

Phobic Disorders

Phobias are common disorders that cause a marked fear or anxiety about specific objects or situations (eg, flying, heights, animals, receiving an injection, seeing blood). In children, the fear or anxiety may be expressed by crying, tantrums, freezing, or clinging. The phobic object or situation almost always provokes immediate fear or anxiety. The phobic object or situation is actively avoided or endured with intense fear or anxiety. Fear or anxiety is out of proportion to the actual danger posed by the specific object or situation and to the sociocultural context. The fear, anxiety, or avoidance is persistent, typically lasting for ≥6 months, and causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. When discussing phobias, it is important to describe the phobic stimulus. Systematic desensitization or graded exposure is considered first-line treatment for phobias. A short course of benzodiazepines or β-blockers may be helpful initially during desensitization to blunt autonomic hyperarousal.

Panic Disorder

Panic disorder consists of recurrent unexpected panic attacks with an average age of onset between 20 and 24 years old; it affects 2% to 3% of the population. A panic attack is an abrupt surge of intense fear or intense discomfort that reaches a peak within minutes and during which time ≥4 of the following symptoms occur (Table 40–1): palpitations, pounding heart, or accelerated heart rate; sweating; trembling or shaking; sensations of shortness of breath or smothering; feelings of choking; chest pain or discomfort; nausea or abdominal distress; feeling dizzy, unsteady, light-headed, or faint; chills or heat sensations; paresthesias (numbness or tingling sensations); derealization (feelings of unreality) or depersonalization (being detached from oneself); fear of losing control or “going crazy”; and fear of dying. Of note, the abrupt surge of these symptoms during a panic attack can occur from a calm state or an anxious state. At least 1 of the attacks must be followed by 1 month (or more) of 1 or both of the following: persistent concern or worry about additional panic attacks or their consequences (eg, losing control, having a heart attack, “going crazy”), and significant maladaptive change in behavior related to the attacks (eg, behaviors designed to avoid having panic attacks, such as avoidance of exercise or unfamiliar situations). Panic attacks may occur with other mental disorders such as depression or PTSD.

Agoraphobia

Agoraphobia is a condition of intense fear or anxiety related to anticipating or actually being in a situation where escape would be unlikely or help unavailable if panic or embarrassing or incapacitating symptoms were to occur. Patients report marked fear or anxiety about ≥2 of the following 5 situations: using public transportation (eg, automobiles, buses, trains, ships, planes); being in open spaces (eg, parking lots, marketplaces, bridges); being in enclosed places (eg, shops, theaters, cinemas); standing in line or being in a crowd; or being outside of the home alone. Patients fear or avoid these situations because of thoughts that escape might be difficult or help might not be available if they develop panic-like symptoms or other incapacitating or embarrassing symptoms (eg, fear of falling in the elderly; fear of incontinence).

Agoraphobic situations almost always provoke fear or anxiety, and patients will actively avoid agoraphobic situations and/or require the presence of a companion unless they choose to endure the situation with intense fear or anxiety. The level of fear or anxiety is out of proportion to the actual danger posed by the agoraphobic situations and to the sociocultural context. The anxiety associated with the situations must occur over the course of ≥6 months. If another medical condition (eg, inflammatory bowel disease, Parkinson disease) is present, the fear, anxiety, or avoidance is noticeably excessive.

It is important to be aware of the following medical conditions that are known to cause symptoms of panic disorders: hyperthyroidism, hyperparathyroidism, pheochromocytomatous, vestibular dysfunctions, seizure disorders, cardiopulmonary conditions (eg, arrhythmias, mitral valve prolapse), chronic obstructive pulmonary disease, asthma, and hypoglycemia.

Generalized Anxiety Disorder

Generalized anxiety disorder is a condition of uncontrollable worry, fear, or preoccupation about everyday situations and possibilities. Prevalence of GAD is 3% in adults, with an average age of onset at 30 years old; it effects females more than males at a rate of 2:1. Parental overprotection and childhood adversities play a role in the future development of GAD. Patients may report excessive anxiety and worry (apprehensive expectation), occurring more days than not for at least 6 months, about a number of events or activities (eg, work or school performance). Patients report great difficulty with trying to control the worry. In GAD, the anxiety and worry are associated with ≥3 of the following 6 symptoms (Table 40–2), with at least some symptoms being present more days than not over the past 6 months: restlessness or feeling keyed up or on edge; being easily fatigued; difficulty concentrating or mind going blank; irritability; muscle tension; and sleep disturbance (difficulty falling or staying asleep or restless, unsatisfying sleep). Of note, in children, only 1 item is required to make the diagnosis. First-line treatment includes CBT, SSRIs, or a serotonin-norepinephrine reuptake inhibitor (SNRI) such as venlafaxine.

Substance-Induced Anxiety Disorder

In patients who suffer from a substance-induced anxiety disorder, panic attacks or anxiety is predominant in the clinical picture along with evidence from the history, physical examination, or laboratory findings of symptoms developing during or soon after substance intoxication or withdrawal or after exposure to a medication and evidence that the involved substance or medication is capable of producing the panic or anxiety symptoms. The disturbance described by the patient is not better explained by an anxiety disorder that is not substance or medication induced. Evidence of an independent anxiety disorder may include the following: the symptoms precede the onset of substance or medication use; the symptoms persist for a substantial period of time (eg, about 1 month) after the cessation of acute withdrawal or severe intoxication; or there is other evidence suggesting the existence of an independent non–substance or non–medication-induced anxiety disorder (eg, a history of recurrent episodes not related to substance or medication use). The patient’s symptoms do not occur exclusively during the course of a delirium. The disturbance caused by reported substance-induced anxiety or panic attacks leads to clinically significant distress or impairment in the patient’s social, occupational, or other important areas of functioning. Agents that may induce a clinical picture of substance-induced anxiety include, but are not limited to, the following: anesthetics and analgesics, sympathomimetics or other bronchodilators, anticholinergics, insulin, thyroid preparations, oral contraceptives, antihistamines, antiparkinsonian medications, corticosteroids, antihypertensive and cardiovascular medications, anticonvulsants, lithium carbonate, antipsychotics, antidepressants, and heavy metals and toxins (eg, organophosphate insecticide, nerve gases, carbon monoxide, carbon dioxide, volatile substances such as gasoline and paint). Identifying and avoiding exposure to the substance should lead to improvement in symptoms.

Anxiety Disorder Due to Another Medical Condition

The critical feature of anxiety disorder due to another medical condition is clinically significant anxiety that is best attributed to be a physiologic effect of another medical condition. The presence of panic attacks or anxiety is predominant in the clinical picture. There is evidence from the history, physical examination, or laboratory findings that the disturbance is the direct pathophysiologic consequence of another medical condition. The disturbance cannot occur exclusively during the course of a delirium. The patient’s disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of daily functioning. In determining whether the anxiety symptoms are attributable to another medical condition, it is important to first establish the presence of the medical condition that may be causing the physiologic symptoms described by the patient. A number of medical conditions are known to include anxiety as a symptomatic manifestation (Table 40–3). Examples include endocrine disease (eg, hyperthyroidism, pheochromocytoma, hypoglycemia, hyperadrenocorticism), cardiovascular disorders (eg, congestive heart failure, pulmonary embolism, atrial fibrillation), respiratory illness (eg, chronic obstructive pulmonary disease, asthma, pneumonia), metabolic disturbances (eg, vitamin B₁₂ deficiency, porphyria), and neurologic illness (eg, neoplasms, vestibular dysfunction, encephalitis, seizure disorders).

OBSESSIVE-COMPULSIVE DISORDERS

Obsessive-Compulsive Disorder

Obsessive-compulsive disorder (OCD) includes the presence of either obsessions or compulsions that cause significant impairment in daily functioning or that are time consuming and interfere with routines, work, and interpersonal relationships. Obsessions are recurrent, intrusive thoughts or impulses that increase anxiety and are not simply excessive worries about real problems. Patients try to suppress the thoughts but are overpowered by them. Patients are able to realize that the thoughts are products of their own mind (patients have insight). Compulsions are repetitive behaviors that the patient feels compelled to perform to decrease anxiety. The compulsive behavior is intended to decrease distress, but there is no realistic link between the behavior and the distress. The person is aware that the obsessions and compulsions are unreasonable and excessive. Patients may have contamination obsessions followed by compulsive washing or avoidance; obsessional doubt, such as wondering if the doors are locked with compulsive checking to avoid potential danger; or intrusive thoughts (often violent or sexual in nature) without compulsions.

Hoarding was previously considered a form of OCD but is now a separate DSM-V diagnosis. A diagnosis of OCD requires the presence of obsessions and/or compulsions occurring for >1 hour a day that cause major distress and impair work, social, or other important function. Approximately 1.2% of Americans have OCD, and among adults, slightly more women than men are affected. OCD often begins in childhood, adolescence, or early adulthood; the average age of onset is 19 years old. There is increased risk in patients with first-degree relatives who have Tourette syndrome.

TRAUMA- & STRESSOR-RELATED DISORDERS

Posttraumatic Stress Disorder

The essential feature of posttraumatic stress disorder (PTSD) is the development of characteristic symptoms following exposure to 1 or more traumatic events. Additional criteria focus on the presence of intrusion symptoms, avoidance behavior, negative effects on cognition or mood, and altered arousal (Table 40–4).

PTSD may develop after exposure to life-threatening events, serious injury, or sexual violence that is directly experienced, is witnessed in person, or affects a close friend or relative. The stressor (criterion A) can be repeated firsthand exposure to the aftermath of trauma (eg, by first responders); however, exposure through media does not qualify. Intrusion symptoms (criterion B) include recurrent, unwanted memories or thoughts related to the trauma, nightmares or distressing dreams, brief reliving of events (flashbacks), and psychological distress in response to cues. In children, this can manifest as repetitive play with traumatic themes. Avoidance (criterion C) includes efforts to avoid memories or cues related to the trauma or behavioral avoidance of trauma-related places, people, or objects. Persistent negative alterations in cognition or mood (criterion D) include inability to remember parts of the trauma (dissociative amnesia), exaggerated negative beliefs about self or others, distorted cognitions about causes of the trauma (self-blame), loss of interest in activities, feeling of detachment or estrangement from others, or inability to experience positive emotions. Alterations in arousal and reactivity (criterion E) include angry outbursts, reckless or self-destructive behavior, sleep problems, exaggerated startling, vigilance toward possible threats or repetition of the trauma, or impaired concentration. The PTSD symptoms must cause clinically significant distress or impairment in social, occupational, or other important areas of functioning for >1 month.

In the United States, the projected lifetime risk for PTSD is 8%. Rates of PTSD are higher among veterans and others whose vocation increases the risk of traumatic exposure (eg, police, firefighters, emergency medical personnel). Highest rates (ranging from one-third to more than one-half of those exposed) are found among survivors of rape, military combat and captivity, and ethnically or politically motivated internment and genocide. Symptoms usually begin within the first 3 months after the trauma, although there may be a delay of months, or even years, before criteria for the diagnosis are met. Often, an individual’s reaction to a trauma initially meets criteria for acute stress disorder in the immediate aftermath of the trauma. Although the severity of a trauma is predictive of PTSD, the lasting impression of the stressor depends of the survivor’s appraisal of its meaning. First-line treatment for PTSD includes trauma-focused CBT, SSRIs, or venlafaxine (SNRI). Studies have shown that prazosin may aid in reducing nightmares.

Acute Stress Disorder

Acute stress disorder describes symptoms exhibited in the early period following traumatic exposures. As such, the primary distinction between acute stress disorder and PTSD is the duration of symptoms, with acute stress disorder being limited to between 3 days and 1 month. Acute stress disorder is diagnosed when ≥9 symptoms emerge from the following 5 categories: intrusion, negative mood, dissociation, avoidance, and arousal.

Acute stress disorder is a strong predictor of PTSD. Prospective studies have found that 72% to 83% of individuals with acute stress disorder go on to develop PTSD 6 months after trauma and that 63% to 80% of those with acute stress disorder meet criteria for PTSD 2 years after trauma. CBT is considered first-line treatment for acute stress disorder, and in the majority of cases, psychopharmacologic treatment is not indicated.

TREATMENT OF ANXIETY DISORDERS

For most anxiety disorders, first-line treatment includes therapy or psychotropic medications or a combination of both. Medication options can be divided between those that are fast acting, including benzodiazepines and β-blockers, and those that are anxiolytic only with chronic treatment, including SSRIs, SNRIs, and buspirone.

At serotonergic synapses, signaling is terminated by reuptake of serotonin into the presynaptic terminal by the serotonin transporter (SERT). SSRIs inhibit SERT, reducing presynaptic reuptake and enhancing serotonergic neurotransmission. SSRIs are effective for the treatment of GAD, OCD, panic disorder, PTSD, and social anxiety disorder. They may also be helpful for select cases of specific phobias. They are also fairly easy to dose and inexpensive. In most cases, treatment of OCD requires higher doses of SSRIs. SSRIs are generally very well tolerated, with the most common side effects including mild gastrointestinal upset or decreased libido. Severe side effects may include serotonin syndrome, usually when multiple serotonergic drugs are combined. Serotonin syndrome manifests with hyperthermia, agitation, sweating, diarrhea, and miosis. There is a US Food and Drug Administration black box warning against using SSRIs or SNRIs for patients under the age of 18 years due to suicidal thoughts and behavior.

SNRIs, such as venlafaxine and duloxetine, are similar to SSRIs but also act at noradrenergic synapses, inhibiting the norepinephrine transporter that mediates reuptake of norepinephrine. Thus, SNRIs enhance both serotonergic and noradrenergic neurotransmission. They have similar indications and side effects to SSRIs.

Buspirone is a serotonin partial agonist that acts at serotonin 1A (5-HT_1A) receptors. It is primarily used in patients with GAD. It is well tolerated and does not cause sedation, addiction, or tolerance. Buspirone generally takes 1 to 2 weeks to take effect and does not interact with alcohol.

Tricyclic antidepressants include amitriptyline, nortriptyline, imipramine, desipramine, clomipramine, doxepin, and amoxapine. Their mechanism of action involves blockade reuptake of norepinephrine and 5-hydroxytryptophan. They are used in the treatment of major depressive disorder, OCD (clomipramine), and anxiety.

Benzodiazepines (alprazolam, lorazepam, clonazepam, and diazepam) are generally considered second-line medications for anxiety due to the potential side effects and their great potential for abuse, but they have the advantage of more rapid action. Benzodiazepines may serve as a bridge while patients wait the 4 to 6 weeks for SSRIs to reach therapeutic efficacy. Generally, they are most effective for panic disorder and can also be used with social anxiety disorder related to performance stressors. In most cases, benzodiazepines are not indicated for other anxiety disorders. There is evidence to indicate relative contraindication in PTSD due to potential for abuse. After taking benzodiazepines daily for 2 weeks, patients become physiologically dependent, leading to withdrawal symptoms in the absence of medication. Withdrawal from benzodiazepines may include severe anxiety, tremor, hypertension, tachycardia, diaphoresis, seizures, and hallucinations. Overdose from benzodiazepines may lead to respiratory depression and death.

β-Blockers, most commonly propranolol, are often used in the treatment of panic disorder and social anxiety disorder. Their mechanism of action aids in preventing the autonomic hyperarousal associated with symptoms of anxiety.

Psychological treatments used for anxiety disorder include various therapies. CBT is best suited to address symptoms of anxiety disorder and depressive disorders. CBT assists the patient in identifying and modifying cognitive distortions. Patients identify and examine cognitive distortions and replace anxious thoughts with more realistic helpful and positive thoughts. Cognitive interventions can be very helpful in the treatment of GAD. Other behavioral interventions include exposure response prevention for the treatment of OCD and graded exposure or systemic desensitization for the treatment of specific phobias, panic disorder, or PTSD. Other therapies include trauma processing therapy and prolonged exposure therapy for the treatment of PTSD and flooding for the treatment of specific phobias.

OBJECTIVES

PREVALENCE & BURDEN

Somatic symptom disorder and related conditions such as conversion disorder present with physical symptoms that cause significant distress or impairment. A summary of somatic symptom disorder and related disorders is provided in Table 41–1. Individuals with these disorders commonly seek care in medical settings, such as primary care or emergency department settings, as opposed to psychiatric settings. Many patients with these disorders experience a chronic course, and they are often high utilizers of the medical system. Although these disorders are not often discussed, the prevalence is significant. Somatic symptom disorder occurs in 5% to 7% of the adult population, and conversion disorder is the second most common diagnosis in neurology clinics. In addition, previous estimates of hypochondriasis were as high as 10% of the population. These patients frequently seek medical care for their symptoms and are often significantly limited by their condition. Symptoms significantly interfere with many patients’ ability to complete activities of daily living such as maintaining employment or living independently.

MIND–BODY CONNECTION

The Diagnostic and Statistical Manual of Mental Disorders (DSM), Fourth Edition, Text Revision (DSM-IV-TR, 2000), focused on medically unexplained symptoms in the diagnosis of somatic symptom and related disorders, which emphasizes mind–body dualism, or the idea that the mind and body are separable. However, our thoughts, feelings, and beliefs have been found to positively and negatively affect biological functioning, suggesting a significant mind–body connection. Over the past decade, it has become clear that the mind and body are not separate from each other but instead are closely connected. The placebo effect, which is when symptoms are improved or worsened (nocebo effect) by a patient’s expectations about symptoms, has been found to significantly impact physical symptoms. Functional neuroimaging studies have demonstrated that the placebo effect and unexplained medical occurrences involve similar cerebral mechanisms. Studies using positron emission tomography found increased activation in the right orbitofrontal and anterior cingulate cortices, as well as an absence of activity in the right primary motor cortex, in both a case of unexplained (functional) paralysis of the leg and a case of hypnotic left leg paralysis. This indicates that suggested paralysis and conversion paralysis may both involve the inhibition of primary motor activity in the prefrontal cortex, emphasizing that these symptoms are not “fake” and are being experienced by the patient.

Having a medical diagnosis does not exclude the presence of a mental health disorder, including a diagnosis of somatic symptom and related disorders, and it is not appropriate to diagnosis a mental health disorder based solely on the absence of a medical explanation. The emphasis on the absence of a medical diagnosis has historically been understood by patients to mean that doctors believe their symptoms are fake or “in their head,” often angering and alienating patients and resulting in the patient searching for a different doctor to diagnose their symptoms. These diagnostic criteria were also difficult for doctors in primary care settings to use, which is where most patients with somatic symptom disorders initially present. Therefore, the fifth edition of the DSM (DSM-V, 2013) revised this section of disorders to make the diagnostic criteria clearer and more practical for use in medical settings. The current criteria no longer emphasize the presence of medically unexplained symptoms and instead focus on positive symptoms, such as distress and abnormal thoughts, feelings, and behaviors about symptoms, and/or the incompatibility of symptoms with recognized medical disorders.

As demonstrated in Figure 41–1, all physical symptoms, regardless of etiology, have many factors that may contribute to or exacerbate physical symptoms. These include biological, psychological, social, and behavioral factors and activities of daily living. In addition, physical symptoms may also affect these factors. For example, a patient with arthritis may experience increased joint pain during a time of increased stress, such as after an argument with his or her spouse. At the same time, joint pain associated with arthritis may increase a patient’s stress level. This bidirectional explanation may increase patients’ acceptance of their somatic symptom disorder diagnosis. To effectively treat these symptoms, each of these factors should be addressed in treatment, and using Figure 41–1 to explain the diagnosis may help patients understand why they are being referred to a psychologist and/or physical therapist for treatment.

SOMATIC SYMPTOM DISORDER

Somatic symptom disorder, previously called somatization disorder (in 10th revision of the International Statistical Classification of Diseases and Related Health Problems [ICD-10]), is characterized by 1 or more physical symptoms that are distressing to the individual and/or disrupt the patient’s daily life and are present for at least 6 months. Commonly reported somatic symptoms include general pain, headaches, fatigue, chest pain, stomachaches, dizziness, and insomnia. In the previous version of the DSM, a diagnosis of somatization disorder required that the physical symptoms could not be explained by a medical diagnosis. Under current criteria, somatic symptom disorder can occur with or without a medical explanation for the somatic symptoms, but patients must exhibit inappropriate thoughts, feelings, or behaviors in response to the somatic symptoms. This change was due in part to the understanding that the disorder is characterized not by the somatic symptoms, but instead by an individual’s expectation and interpretation of symptoms and the individual’s response to the symptoms. This can include thoughts about the symptoms that are disproportionate to the severity of the symptom (eg, interpreting normal bodily sensations as a sign of serious illness), excessive anxiety related to one’s health or symptoms (eg, increased attention to physical symptoms, worry about becoming ill, fear of physical activity causing harm to one’s body), or spending excessive time or energy on one’s symptoms or health concerns (eg, body-focused attention, seeking frequent medical care, or avoiding physical activity). Brief somatic symptom disorder may be diagnosed when a patient exhibits symptoms that meet the criteria for somatic symptom disorder but that have been present for <6 months.

Given the recent shift in diagnostic criteria, the prevalence of somatic symptom disorder is unknown. Its predecessor, somatization disorder, had a prevalence of <1%, but it is suggested that the prevalence of somatic symptom disorder is higher, at an estimated 5% to 7% of the adult population. Typically, individuals with somatic symptom disorder are more likely to present for treatment in a medical setting than a mental health setting. In general, females report more somatic symptoms than males; therefore, it follows that the prevalence of somatic symptom disorder is also likely to be higher in females than males.

CONVERSION DISORDER (FUNCTIONAL NEUROLOGIC SYMPTOM DISORDER)

Conversion disorder, also called functional neurologic symptom disorder, is a disorder in which a person experiences neurologic symptoms that are not due to a neurologic condition, as confirmed by a medical professional. Conversion disorder is found in approximately 5% of referrals to neurology clinics, making it the second most common diagnosis in these clinics. Onset of conversion disorder is found throughout the life span, and symptoms may present in various ways and can change over time. Short duration of symptoms, childhood onset, and acceptance of the diagnosis are positive prognostic factors. Conversion disorder is 2 to 3 times more common in females than males. If they do not obtain timely diagnosis and treatment, these patients can experience significant disability, often similar to those with medical disorders.

Symptoms can include physical weakness, abnormal gait, paralysis, dystonic movements, tingling, dizziness, syncope, or episodes of seizures or tremors. Other symptoms may include impaired hearing or vision, diplopia, dysarthria, dysphonia, and aphonia, and it must be determined that the presenting symptoms are not associated with a neurologic disorder. However, confirming this may be difficult. Although psychogenic nonepileptic seizures (PNES) can be confirmed through electroencephalography (EEG), other symptoms, such as paralysis or syncope, do not have a gold standard test to definitively rule out a neurologic disorder. Therefore, absence of positive test results does not automatically indicate a diagnosis of conversion disorder.

Instead of relying on the absence of a medical diagnosis alone, the DSM-V diagnostic criteria now focus on the incompatibility between the patient’s symptoms and a recognized neurologic or medical disorder. There are several ways to examine patients’ symptoms and determine if they are consistent with a medical disorder (Table 41–2). For example, patients with PNES often present with closed eyelids and pelvic thrusting during episodes, which are both rare in epilepsy. Although physicians are sometimes hesitant to make this diagnosis, research has demonstrated that neurologists’ impression of conversion disorder based on clinical presentation is commonly confirmed with further medical examination, such as EEG. Although physicians should not rely solely on the incompatibility of symptoms, when paired with reasonable medical tests, an accurate diagnosis can be made.

Traditionally, conversion disorder was believed to be the direct result of trauma or stress. However, it is important to note that although conversion disorder is more common in people who have a history of trauma or stress, trauma or stress is not the direct cause of conversion disorder, and not all of those with conversion disorder have a history of trauma or stress. Due to recent research demonstrating this, the DSM-V removed the requirement that psychological factors need to be associated with the symptoms to make the diagnosis. Instead, trauma and stress are considered risk factors for, but not required contributors to, the development of conversion disorder. In addition, the presence of a neurologic disease with similar symptom presentation in either the patient or the patient’s family members is also a risk factor. For example, patients with epilepsy or a family history of epilepsy are at greater risk of developing PNES. Previous exposure to neurologic disorders may have created symptom expectations for these patients, consistent with the idea that the placebo effect may be a causal mechanism for conversion disorder.

Neurobiological evidence has demonstrated abnormal brain activity during conversion movements despite employing voluntary motor pathways. One study compared brain activity in conversion patients during their functional tremors and while mimicking their tremor. Results showed hypoactivity in the right temporoparietal junction during functional tremors, which is associated with discerning between self-generated and externally generated sensations, suggesting symptoms are perceived to be involuntary despite the use of voluntary motor pathways.

ILLNESS ANXIETY DISORDER

Illness anxiety disorder, previously called hypochondriasis, is characterized by excessive concern surrounding currently having or developing a serious illness. Notably, to be diagnosed with illness anxiety disorder, patients cannot have any somatic symptoms or their somatic symptoms must be mild in intensity. Often, the somatic symptoms that are present are normal physiologic sensations (eg, dizziness upon standing) or symptoms not typically indicative of a medical condition (eg, belching). If the individual has a current medical condition or is at high risk for a medical condition, the worry must be excessive or disproportionate to the severity. In illness anxiety disorder, an individual’s distress stems not from the somatic symptom, if present, but instead from what that symptom might mean (eg, serious illness). In addition, individuals with illness anxiety disorder either perform excessive health-related behaviors (eg, body-focused attention) or display avoidance (eg, avoiding hospitals or individuals who are ill). Individuals with illness anxiety disorder typically do not experience relief from their health-related anxiety as a result of negative test results or reassurance from physicians about their health. The preoccupation with health must last for at least 6 months to merit a diagnosis of illness anxiety disorder. Individuals who have symptoms for <6 months are diagnosed with brief illness anxiety disorder. Similarly, individuals who meet criteria for most symptoms but do not engage in excessive health-related behaviors are diagnosed with illness anxiety disorder without excessive health-related behaviors.

The primary change between the fourth edition DSM (DSM-IV) and DSM-V definitions is that a DSM-IV diagnosis of hypochondriasis also involved significant somatic symptoms, whereas the DSM-V definition specifies that individuals with illness anxiety disorder cannot have somatic symptoms or the symptoms must be mild in nature. With the changes in diagnostic criteria between DSM-IV and DSM-V, approximately 75% of individuals who would have previously been diagnosed with hypochondriasis now meet criteria for somatic symptom disorder instead. Estimates of the prevalence of illness anxiety disorder are not available because the diagnostic criteria have changed significantly. However, previous estimates of hypochondriasis ranged from 1.3% to 10%.

FACTITIOUS DISORDER & MALINGERING

Factitious disorder is a disorder in which an individual falsely reports physical or psychological symptoms or purposefully induces injury or disease. Individuals with factitious disorder may lie about medical history, falsify medical records, or induce symptoms in themselves. The individuals present themselves as ill or injured to others and often seek medical treatment. Deception is the key element of factitious disorder, and the deception must occur without any obvious external rewards (eg, disability income). Individuals with factitious disorder may have an existing medical condition, but to merit a diagnosis of factitious disorder, the individuals must present themselves in such a way that makes them appear more ill or impaired to others.

An individual may also receive the diagnosis of factitious disorder imposed on another (factitious disorder by proxy in DSM-IV). This diagnosis would be merited if an individual falsely presents another person as ill or disabled or induces illness or injury in another person. Notably, the individual who is falsifying information receives this diagnosis, not the individual who is presented as ill.

Malingering is similar to factitious disorder but differs in that there is an external motivation for the falsification of symptoms. This could include monetary gain, avoiding school or work, avoiding criminal prosecution, or obtaining drugs.

The prevalence of factitious disorder is particularly hard to determine due to the element of deception. However, within the hospital setting, it is estimated that 1% of individuals meet criteria for diagnosis. Factitious disorder often develops after a hospitalization for a medical or mental disorder or, in the case of factitious disorder imposed on another, the hospitalization of a family member.

BODY DYSMORPHIC DISORDER

DSM-V moved body dysmorphic disorder from under the category of somatic symptom disorders and into the category of obsessive-compulsive and related disorders. However, the ICD-10 currently classifies it under somatoform disorders, and therefore, it has been included in this chapter.

Body dysmorphic disorder involves individuals having an irrational preoccupation with what they believe to be a defect or a flaw in their physical appearance. Common areas of preoccupation include the skin (eg, acne, scars, wrinkles), hair (eg, thinning hair or unwanted body or facial hair), and nose. However, the preoccupation can focus on any part of the body. These preoccupations are unwanted, difficult for the individual to control, and often very time consuming. On average, individuals with body dysmorphic disorder spend 3 to 8 hours per day thinking about their perceived flaw or defect. Notably, these flaws or defects are not noticed by others, or the individual’s concerns about a flaw are disproportionate to what others perceive. Individuals with body dysmorphic disorder also engage in repetitive behaviors or thoughts at some point during their disorder. Examples of these thoughts and behaviors include excessive mirror checking, excessive grooming, repeatedly applying makeup, seeking reassurance from peers, or comparing him- or herself to others. These repetitive behaviors are the basis for moving body dysmorphic disorder from the somatoform disorders classification into the obsessive-compulsive and related disorders classification in the DSM-V. Individuals with body dysmorphic disorder often receive cosmetic treatment such as dermatologic treatment or cosmetic surgery to try to fix their perceived flaws. However, cosmetic treatment rarely relieves the symptoms of body dysmorphic disorder and may instead worsen the severity of the preoccupation.

Body dysmorphic disorder with muscle dysmorphia is a specific form of body dysmorphic disorder that occurs primarily in males. This form of body dysmorphic disorder involves the preoccupation with the idea that their body is not muscular enough, despite being normal looking or very muscular. Individuals with muscle dysmorphia often diet and exercise excessively and may use steroids or other substances to compensate for their perceived flaws.

The prevalence of body dysmorphic disorder in the United States is 2.4% overall, 2.5% in females, and 2.2% in males. The prevalence in dermatology and cosmetic surgery patients is higher, with a prevalence of 9% to 15% and 7% to 8% in those settings, respectively. The majority of individuals with body dysmorphic disorder have an onset in adolescence, with two-thirds of individuals with the disorder having onset prior to the age of 18 years.

PSYCHOLOGICAL FACTORS AFFECTING OTHER MEDICAL CONDITIONS

The defining characteristic of psychological factors affecting other medical conditions is the existence of psychological or behavioral factors that have a negative effect on an existing medical condition. Psychological factors may include psychological distress (eg, depression or anxiety), poor coping skills, current life stressors, and interpersonal relationships. Behavioral factors include poor health behaviors such as symptom denial or difficulty with adherence to medical recommendations. These factors may exacerbate symptoms, resulting in nonadherence to or avoidance of treatment, or may be a well-established health risk. To receive a diagnosis of psychological factors affecting other medical conditions, the individual’s psychological or behavioral factors must significantly affect either the course or outcome of the medical condition. In addition, the factors must exist prior to diagnosis of the medical condition. If an individual develops psychological or behavioral symptoms following the diagnosis of a medical condition, a diagnosis of adjustment disorder is likely more appropriate.

The prevalence of psychological factors affecting other medical conditions is unknown. However, based on insurance billing within the United States, it is more commonly diagnosed than somatic symptom disorder.

OTHER SPECIFIED & UNSPECIFIED SOMATIC SYMPTOM & RELATED DISORDERS

A diagnosis of other specified somatic symptom and related disorder is appropriate when an individual exhibits symptoms of a somatic symptom and related disorder but does not meet all diagnostic criteria for a diagnosis. These diagnoses include brief somatic symptom disorder, brief illness anxiety disorder, and illness anxiety disorder without excessive health-related behaviors, all of which have been discussed previously in this chapter. Pseudocyesis is also encompassed in the other specified category. Pseudocyesis is the incorrect belief that one is pregnant without any objective signs or symptoms of pregnancy. Similarly, unspecified somatic symptom and related disorder is an appropriate diagnosis when an individual does not meet full criteria for a diagnosis of a somatic symptom and related disorder. However, this diagnosis should only be given when information is lacking for a more specific diagnosis.

DIAGNOSIS & TREATMENT

Providing an accurate diagnosis and explanation of the diagnosis to the patient is the first step to providing appropriate treatment for these patients. Physicians often avoid officially diagnosing somatic symptom disorder or conversion disorder, and instead opt to diagnose the symptoms, such as “tremor” or “pain.” However, providing an accurate diagnosis is important for patients. This prevents them from continuing to search for a medical explanation and reduces their risk for obtaining improper medical treatment and iatrogenic illness.

After making the diagnosis, providing a clear explanation is crucial to helping the patient understand the diagnosis and treatment. It is important to emphasize that the symptoms are real and not “in their head” or “fake.” Most patients do not respond well to psychiatric explanations for their symptoms, such as “stress-related” or “depression-related,” and as discussed earlier, stress and depression are usually exacerbating factors or risk factors, not causal factors. Instead, patients have been found to prefer the word “functional” to describe the symptoms, meaning affecting physiologic or psychological functions but not organic structure. This suggests that although medical tests were negative, there is a functional issue, such as a miscommunication between the brain and nerves, that is not detected by diagnostic tests. In addition, use of Figure 41–1 can be helpful in explaining how symptoms can be exacerbated by many factors and can aid in patients’ understanding as to why they are being referred to a psychologist, psychiatrist, or physical therapist.

Pharmacologic Treatment

A number of pharmacologic treatments (eg, antidepressants, antiepileptic drugs, and antipsychotics) have been proposed for somatic symptom disorders. However, research indicates they generally are not effective. Antidepressants have several proposed underlying mechanisms of action for the treatment of somatic symptom disorders. Individuals with somatic symptom disorders have been found to have abnormal brain activity in areas of the brain associated with serotonin and norepinephrine, and some have postulated that serotonin and norepinephrine may suppress somatic symptoms. Antidepressants may also directly affect organ systems. For example, they may slow the gastrointestinal tract, providing symptom relief for individuals with irritable bowel syndrome. Furthermore, antidepressants have immunoregulatory effects that are speculated to decrease symptoms of fatigue, sleep disturbance, and psychomotor retardation. Finally, antidepressants may reduce comorbid psychiatric conditions, including anxiety and depressive disorders, possibly resulting in a decrease in functional symptoms. Antiepileptic drugs are thought to treat somatic symptom disorders through their analgesic, anxiolytic, and sedative effects. Similarly, antipsychotics have been used in the treatment of somatic symptom disorders for their analgesic effects.

Randomized controlled trials of pharmacologic treatment for somatic symptom disorders have demonstrated very little support for pharmacology as an effective treatment. There is limited evidence for new-generation antidepressants, with some studies showing a reduction in depressive symptoms and functional disability. However, this evidence is inconsistent across studies.

Nonpharmacologic Treatment

Systematic reviews of randomized controlled trials for the treatment of somatic symptom and related disorders show cognitive-behavioral therapy (CBT) to be the most effective treatment. CBT has been found to be consistently effective in treating the range of somatic symptom and related disorders, including somatic symptom disorder, conversion disorder, illness anxiety disorder, and body dysmorphic disorder.

CBT treatment may focus on a number of aspects of somatic symptom disorders, including reducing attention to symptoms, cognitive reframing of catastrophic thinking related to symptoms (eg, “I’m going to die!”), behavioral modifications (eg, reduction in seeking medical help for somatic symptom disorder and reduction in mirror checking for body dysmorphic disorder), and reducing functional disability (eg, returning to work or school). Secondary to direct reduction in symptoms, CBT is also effective at treating comorbid anxiety or depression, which may exacerbate or be related to symptoms.

Most somatic symptom and related disorders respond to general CBT techniques, but some require specific treatments. Specifically, illness anxiety disorder is effectively treated with exposure and response prevention techniques used in CBT. Typically, this includes imaginal exposure and in vivo exposure (eg, visiting a hospital), as well as relaxation techniques and cognitive reframing of thoughts related to illness. Conversion disorder often requires an interdisciplinary approach to CBT, including physicians, psychologists, and physical therapists. Physical therapists are involved with the rehabilitation process for functional gait disorders, tremors, and paralysis, using techniques similar to those used for organic neurologic conditions, and research has found this approach to improve symptoms in both inpatient and outpatient settings. Similarly, physical therapists treat pain symptoms with techniques that increase functionality and mobility and desensitization techniques for relief of pain.

OBJECTIVES

Personality disorders are characterized by trait-like, inflexible, and unhealthy patterns of thought and behavior that deviate from cultural norms and are associated with significant distress or impaired social or occupational function. A key feature is that they are enduring, with typical onset in adolescence or early adulthood and persistence over a long duration and across a variety of contexts.

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) classifies personality disorders into 3 categories. Cluster A is the odd or eccentric group, and includes paranoid, schizoid, and schizotypal personality disorders. Cluster B is the dramatic, emotional, or erratic group, and includes antisocial, borderline, histrionic, and narcissistic personality disorders. Cluster C is the anxious or fearful group, and includes avoidant, dependent, and obsessive-compulsive personality disorders. In practice, patients do not usually present with a single, clearly defined personality disorder, and the lines between these syndromes are not precise. In fact, the majority of personality disorders probably go undiagnosed, often until some predisposing event or other medical or psychiatric issue brings them into the healthcare system.

Prior editions of the DSM classified personality disorders as Axis II disorders, in contrast to Axis I disorders such as major depressive disorder or schizophrenia. Although DSM-5 does not use this axis categorization, personality disorders are still sometimes referred to as Axis II disorders.

PREVALENCE & BURDEN

Personality disorders are common, affecting a little under 10% of the adult population. On the whole, they are equally common in men and women, although certain personality disorders are more common in one sex or the other. The most common personality disorder varies by country. In the United States, the most common personality disorders are obsessive-compulsive, narcissistic, and borderline personality disorder.

By definition, personality disorders are associated with impaired functioning in work, relationships, and society. Personality disorders are often comorbid with other psychiatric diagnoses. Anxiety disorders are particularly common (over half of patients with personality disorders), and substance use disorders occur in approximately 25% of patients with personality disorders. The suicide rate in borderline personality disorder, in particular, is much higher than that of the general population.

CLUSTER A: ODD OR ECCENTRIC PERSONALITY DISORDERS

Paranoid personality disorder is characterized by a pervasive and enduring distrust and cynical view of the world. Furthermore, the disorder is also characterized by hypervigilance to physical, verbal, or interpersonal threats. As a result, individuals with paranoid personality tend to have few if any close or intimate connections. Their interpersonal style is best described as detached and distrustful. They often appear guarded and secretive, as well as inflexible. Moreover, any perceived criticism typically elicits a response of hostility and defensiveness.

Paranoid personality disorder is a nonpsychotic disorder involving dysfunctional and maladaptive personality characteristics, rather than a thought or mood disorder. Individuals with paranoid personality disorder may develop brief psychotic reactions under stress, but these episodes do not endure. However, paranoid personality disorder is characterized by genuine belief that others have hidden motives or are out to harm them. Similarly, depressive disorders may present with paranoid ideation, often with an underlying focus on persecution. However, a detailed longitudinal history of illness will differentiate between paranoid personality disorder and ideation that only occurs in the presence of a concurrent mood disorder.

Schizoid personality disorder is characterized by a lack of close personal relationships or even a desire for such relationships. People with this personality disorder are described as cold, aloof, detached, or withdrawn. They display a restricted range of emotions and affect. They do not seek or enjoy close relationships with family or friends, and instead prefer solitary activities and are often seen as loners. People with this disorder are able to function in everyday life but may prefer solitary jobs that involve little interaction with others. This disorder generally appears by early adulthood and is more common in males than females.

The “schiz” in the term schizoid personality disorder comes from “schizophrenia,” with the suffix “-oid” meaning schizophrenia-like, based on symptoms such as the detachment from others and flat affect. However, unlike people with schizophrenia, people with schizoid personality disorder do not have active psychotic symptoms such as paranoia or hallucinations, nor do they have disorganized speech (ie, they generally make sense in conversation). Schizoid personality disorder is often associated with depression but generally is not a precursor to schizophrenia.

Schizotypal personality disorder, like schizoid personality disorder, is characterized by difficulty forming relationships. The key difference is that those with schizotypal personality disorder, unlike those with schizoid personality disorder, may desire and seek personal relationships. However, their odd beliefs, eccentric appearance, peculiar behavior, and discomfort with other people make forming such relationships difficult. In other words, someone with schizotypal personality disorder may try and fail to form relationships and has anxiety and discomfort around others, whereas someone with schizoid personality disorder is indifferent and does not even desire to form relationships.

Strange beliefs are an important aspect of schizotypal personality disorder. Those affected often believe in special powers such as clairvoyance or telepathy or in aliens or witchcraft. Patients are likely to misperceive social cues or take offense at inoffensive things. The word schizotypal comes from schizophrenic phenotype because, like schizoid personality disorder, there are some similarities to schizophrenia. One way to think about the difference between schizoid and schizotypal personality disorders is that those with schizoid personality disorder exhibit some negative symptoms of schizophrenia (flat affect, restricted emotional range, indifference to others), whereas those with schizotypal personality disorder exhibit some positive symptoms of schizophrenia (magical thinking, delusions, odd speech, paranoia). (Mnemonic hint: Associate the “p” in schizotypal with positive symptoms.) Both of these personality disorders may share some of the same genetic predispositions as schizophrenia and be part of a schizophrenia spectrum.

CLUSTER B: DRAMATIC, EMOTIONAL, OR ERRATIC PERSONALITY DISORDERS

Narcissistic personality disorder is characterized by a pervasive pattern of grandiosity, lack of empathy for others, and a need for admiration (narcissism is defined as excessive interest in oneself). Individuals with narcissistic personality disorder are often described as arrogant, self-absorbed, and manipulative, with fantasies of success and attractiveness. Moreover, these individuals perceive themselves as deserving of special treatment. People with narcissistic personality disorder believe they are superior and often try to associate with other people who they believe are unique or gifted in some way. This association enhances their self-esteem, which is typically quite delicate. Individuals with narcissistic personality disorder have difficulty tolerating criticism or defeat and may feel humiliated or empty following criticism or rejection. Narcissistic personality disorder may present as either a grandiose, attention-seeking, entitled, or arrogant subtype or a hypersensitive, inhibited, chronically envious, and anxious subtype. Individuals with narcissistic personality disorder can also fluctuate between grandiose and vulnerable states.

The differential diagnosis for narcissistic personality disorder includes bipolar illness and other mood disorders, substance abuse, and anxiety disorders.

Histrionic personality disorder is characterized by excessive emotionality and attention seeking. People with this disorder need to be the center of attention and, as a result, may be overly dramatic, theatrical, flirtatious, or seductive. They tend to focus on their physical appearance as a way to draw attention to themselves (eg, dressing provocatively) and are uncomfortable when they are not the focus. They are usually very social and vivacious and often seen as the “life of the party.” Their emotional states can shift rapidly.

Histrionic personality disorder shares some features with narcissistic personality disorder, particularly the fact that people with both conditions seek the admiration and attention of others. However, what lies behind these traits is quite different: Whereas narcissists are convinced of their own superiority and do not need the approval of others to be convinced of their special qualities, histrionics are often very suggestible, easily influenced, and sensitive to criticism; histrionics lack a sense of self-worth and seek reassurance and others’ approval through their dramatic appearance or behavior. Narcissistic personality disorder is diagnosed more commonly in males, whereas histrionic personality disorder is more commonly found in females.

Borderline personality disorder is characterized by instability in interpersonal relationships and impulsive behavior. People with this condition tend toward emotional extremes and can swing suddenly between them. For example, they may quickly develop a close, intimate relationship, which tends to be intense but stormy, and then may suddenly turn on the partner, considering them an enemy and cutting off the relationship. They have intense bouts of anger, depression, or anxiety that can last hours to days. They tend to act impulsively and without considering the consequences, and given the tendency toward bouts of depression, they are at risk of self-injurious behavior and suicidal thoughts or threats. Many of these behaviors can be seen as efforts to avoid abandonment, whether real or imagined.

Borderline personality disorder is one of the more common personality disorders in both women and men. Those affected have a high rate of hospitalization, accounting for about 20% of psychiatric admissions. The term borderline dates back to when neurosis and psychosis were considered the 2 main types of mental disorders; people with this disorder had features of both and thus were considered as occupying the “border” between the 2 types.

Borderline personality disorder has similarities to histrionic personality disorder in the tendency to display provocative or intensely emotional behavior, and these 2 disorders overlap to some extent, but the driving force is different. The key feature of borderline personality disorder is extreme difficulty with emotional regulation and erratic behavior, lacking the goal-directed nature in histrionic personality disorder, which is driven by a desire to temporarily enhance self-esteem.

Antisocial personality disorder is characterized by disregard for moral or ethical standards and the rights of others. Those with the disorder often violate rules or laws and have no guilt or remorse for doing so. They may be superficially charming but are manipulative and aggressive and tend to exploit others for their own purposes. Affected individuals are often hostile, callous, disrespectful, and/or deceitful. Their behavior is impulsive, reckless, and without concern for others.

Antisocial personality disorder is much more common in males than females and is prevalent among those in prison.

CLUSTER C: ANXIOUS OR FEARFUL PERSONALITY DISORDERS

Obsessive-compulsive personality disorder is characterized by preoccupation with rules, orderliness, and a need for control. People with this disorder tend toward perfectionism, even to the point of interfering with task completion due to rigid adherence to an unrealistically high standard. This can be exacerbated by unwillingness to delegate, because of the associated loss of control and fear that things will be done incorrectly. They can be workaholics, with a fixation on their vocation at the expense of relationships. People with obsessive-compulsive personality disorder are often overly adherent to rules and inflexible about moral or ethical standards. They can be miserly, with tight control over spending, and they can be reluctant to part with old items and thus have a tendency to hoard.

Obsessive-compulsive personality disorder is one of the most common personality disorders, with a prevalence between 2% and 8%, and it is more common in males. There are obvious similarities to obsessive-compulsive disorder (OCD), but there are several differences that distinguish the 2 conditions. First, obsessive-compulsive personality disorder lacks true obsessions (uncontrollable intrusive thoughts) or compulsions (irresistible urges to repeatedly perform purposeless behaviors). Second, and perhaps more importantly, whereas people with OCD are distressed by their condition and aware of its negative effects on them and those around them and thus usually seek treatment, people with obsessive-compulsive personality disorder tend to think that their inflexible behaviors are adaptive and appropriate and see no need to change or seek treatment.

Avoidant personality disorder is characterized by social anxiety and isolation, with feelings of inadequacy. People with this disorder fear embarrassment or rejection, are easily hurt by any criticism, and feel socially inept. They tend to be preoccupied with their own weaknesses and suspect that they are unappealing to others. As a result, those affected cope with these feelings of inferiority by isolating themselves socially and avoiding intimate relationships. People with avoidant personality disorder may be perceived as shy and risk averse, with low self-esteem.

Although both avoidant and schizoid personality disorders have social isolation as a defining feature, the key difference is that those with avoidant personality disorder have a great deal of anxiety and distress about what might happen in a relationship, whereas those with schizoid personality disorder simply have no interest in forming relationships.

Dependent personality disorder is characterized by a pervasive and abnormal need for the approval and assistance of others. People with this disorder find it difficult to make even simple decisions like what to wear, let alone major choices such as where to live or work, without input from others. They require constant reassurance. They do not trust their own instincts and put themselves in need of caregiving from others. They may be viewed as passive, clingy, naïve, oversensitive to criticism, and submissive, with low self-confidence. People with dependent personality disorder fear abandonment and do not like to be alone; they often place their own needs below those of others and even tolerate mistreatment.

Borderline personality disorder is also associated with a fear of abandonment, but the difference with dependent personality disorder lies in how the individual responds: A person with borderline personality disorder is likely to lash out, rage, and be highly demanding, whereas someone with dependent personality disorder tends toward submissiveness and appeasement to maintain the relationship. The similarity between patients with dependent personality disorder and those with histrionic personality disorder is that both seek approval from others; however, those with histrionic personality disorder do so in a highly outgoing, flamboyant, or seductive way, whereas those with dependent personality disorder do so in a meek, childlike way. Finally, although both avoidant and dependent personality disorders feature feelings of inadequacy, the response is quite different, with the former avoiding social relationships and the latter strongly seeking them, even to the point of sacrificing their own autonomy.

CAUSES & RISK FACTORS

The factors that influence the development of personality disorders are not well understood, but both genetic vulnerability and childhood experiences are thought to underlie the risk for personality disorders. They are more common when there is a family history of personality disorders or other psychiatric disorders, which could be due to either genetic or environmental influences. Twin studies indicate fairly high genetic heritability, estimated at 30% to 60%, which is consistent with growing evidence for genetic determinants of personality traits in general, apart from personality disorders. Approaches such as genome-wide association studies are beginning to identify some candidate genes, including several involved in neuronal development and differentiation or neurotransmitter pathways. In many cases, the genetic risk factors for personality disorders are related to those for related psychiatric disorders. For example, there are shared factors between schizophrenia and Cluster A personality disorders and between bipolar disorder and Cluster B borderline personality disorder.

Environmental factors in childhood also likely contribute to many personality disorders. Abuse (eg, sexual, physical, verbal, or psychological abuse or neglect) is associated with higher rates of personality disorders in all 3 clusters. Childhood abuse is particularly associated with borderline personality disorder, but it is also associated with most other personality disorders.

Given evidence that both genetics and experience substantially contribute to the development of personality disorders, there is increasing interest in gene–environment interactions. That is, adverse childhood experiences may have a particularly detrimental effect on those with certain genetic backgrounds, whereas others with a less vulnerable genetic susceptibility may have more resilience after abuse.

TREATMENT OF PERSONALITY DISORDERS

Because by definition personality disorders reflect a long-standing pattern of behavior, often since young adulthood, they can be difficult to treat or modify. Because of their enduring nature, the prognosis for spontaneous remission is rather low. Furthermore, given the symptoms of many personality disorders, particularly the ones associated with social isolation, those affected may not even seek treatment because they may not believe there is anything wrong them. Because it is among the most common personality disorders and because it engenders behavior such as suicidal gestures that may drive hospitalization, borderline personality disorder has the most literature on treatment.

The mainstay of treatment is psychotherapy. Cognitive-behavioral therapy (CBT) addresses ingrained thought patterns (rather than life events) that may drive problematic behaviors. A type of CBT that has been well-studied for borderline personality disorder is dialectical behavioral therapy. Dialectical refers to integrating opposite ideas, such as accepting patients as they are while simultaneously emphasizing the need for change. Randomized controlled trials indicate that these approaches can reduce some of the frequency of self-injurious behavior or other symptoms, although they probably do not reduce the number of patients meeting diagnostic criteria for the disorder. Psychodynamic therapy, which focuses on discussing past experiences and increasing insight, is another evidence-based approach for borderline personality.

Pharmacotherapy is viewed as an adjunct treatment for personality disorders, particularly during periods of decompensation or acute behavior changes. Guidelines recommend treatment aimed at 3 symptom clusters: neuroleptics for cognitive/perceptual symptoms, selective serotonin reuptake inhibitors (SSRIs) for affective symptoms, and SSRIs or low-dose neuroleptics for impulsivity and irritability.

OBJECTIVES

PREVALENCE & BURDEN

Approximately 20.2 million adults (8.4%) had a substance use disorder in the past year, making substance use disorders one of the most prevalent mental health disorders in the United States. Nicotine use disorder is the most prevalent, with an estimated lifetime prevalence of 27%. Alcohol use disorder is also common, with an estimated 8% of adults meeting criteria during their lifetime. Lifetime prevalence of an illicit drug use disorder is approximately 2% to 3%. The National Institute on Drug Abuse estimates the total cost of substance use to our country to be $740 billion annually. This includes not only associated healthcare cost, but also lost productivity and crime-related costs.

SUBSTANCE USE DISORDERS & THE REWARD PATHWAY

It is important to understand the role of the reward pathway and the effects of drugs on this part of the brain. The reward pathway of the brain increases pleasurable behaviors that enhance our survival. For example, on a more basic level, drinking a bottle of water after a run or eating meal when hungry activates the reward pathway to create the feeling of satiation. The reward pathway also plays a role in more complex behaviors such as forming relationships, sexual intercourse, and child rearing.

The reward pathway is also known as the mesolimbic pathway. It originates in a portion of the midbrain called the ventral tegmental area (VTA). From the VTA, dopaminergic neurons project into an area of the ventral striatum called the nucleus accumbens (NAcc) (Figure 43–1). When dopamine is released at the NAcc, it causes pleasure, partially through the release of endorphins. Generally, the more dopamine a given stimulus releases at the NAcc, the more pleasurable is the experience. The NAcc is able to assign various stimuli differing amounts of salience. This stimulus–reward phenomenon plays a vital role in both classical and operant conditioning (Figure 43–2).

In some individuals, the reward pathway is able to be “highjacked” through a variety of substances. The very nature of the reward system itself can lead to substantial changes in behavior through the salience phenomena. In some circumstances, this system, which developed as a means to ensure survival, can lead to destructive behaviors that all too frequently increase morbidity and mortality.

Individuals develop what is known as a substance use disorder, when through repeated use of a given substance, physiologic and psychologic changes occur, leading to maladaptive behaviors. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) lists 11 criteria for substance use disorder, with the severity of the disorder determined by the number of criteria met as follows: 2 to 3 for mild, 4 to 5 for moderate, and ≥6 for severe substance use disorder. These criteria can be thought of as occurring in 1 of 4 domains, as shown in Table 43–1.

SUBSTANCE USE DISORDERS

This section reviews common drugs of abuse (Table 43–2), including the associated neurotransmitters and neural pathways, symptoms of intoxication and withdrawal, and common treatment modalities, including pharmacotherapies. Although this chapter is focused specifically on substance use disorders, it is important to realize that these disorders often have many other substance, psychiatric, and medical comorbidities. For example, it is common to see patients who meet criteria for multiple substance use disorders with comorbid psychiatric disorders. Many patients will have comorbid medical problems directly due to their use of substances.

Alcohol

Humans have consumed alcohol for thousands of years, beginning somewhere between 3000 and 2000 B.C. Alcohol is produced during the process of fermentation in which yeast breaks down sugar into alcohol and carbon dioxide. The antiseptic properties of alcohol allowed for potable beverages prior to modern water sanitation systems.

Unlike the other substances of abuse, there is no “alcohol receptor” in the human brain. Alcohol exerts its effect primarily due to the molecule’s interactions at the amino acids level. The net result leads to a general decrease in the amount of glutamate transmission and general increase in the amount of γ-aminobutyric acid (GABA). In addition, alcohol has been shown to cause the release of endorphins at the NAcc, leading to the phenomenon of alcohol-induced cravings.

Alcohol is primarily metabolized in the body by 2 enzymes: alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). ADH breaks alcohol down into acetaldehyde, which ALDH further degrades into acetate. Acetaldehyde is a known carcinogen, and higher concentration of this chemical are known to cause flushing and nausea. A mutation in the gene for ADH (ADH1B*2) is commonly found in people of East Asian descent and is thought to be protective against developing alcohol use disorder.

At low levels of consumption, alcohol reduces anxiety. As the amount of alcohol consumed increases, intoxication occurs, leading to symptoms of ataxia, slurred speech, and cognitive impairment. As the concentration of alcohol increases in the blood, a transient anterograde amnesia (blackout) can occur. Coma and respiratory depression are signs of alcohol poisoning.

Alcohol withdrawal occurs in individuals who have become physiologically dependent on alcohol. Its symptoms commonly include anxiety, nausea, tremor, sweating, hypertension, and tachycardia. Withdrawal symptoms may begin as early as 6 hours after consumption, but generally, they begin within 24 hours and, in most people, subside within 2 days. Individuals who consume large amounts of alcohol for long periods of time may experience withdrawal symptoms before the blood alcohol concentration reaches zero. Life-threatening complications of alcohol withdrawal include seizures and delirium tremens (DT). DT is the most severe form of alcohol withdrawal and is a medical emergency. It occurs in the context of the previously mentioned alcohol withdrawal symptoms, but also includes confusion, disorientation, fever, agitation, and hallucinations (visual, auditory, and tactile). Generally, DT begins within 3 to 4 days after the last alcohol consumption and typical resolves after 3 days. If untreated, the DT mortality rate may reach 40%.

Benzodiazepines are commonly used to treat alcohol withdrawal symptoms. Longer acting forms such as chlordiazepoxide, clonazepam, and diazepam allow for less frequent dosing in addition to a smoother detoxification course and are especially useful in the outpatient setting. For patients who are hospitalized, lorazepam is a common choice to treat withdrawal symptoms. Lorazepam is available in a variety of formulations (oral, intramuscular, and intravenous) and does not require oxidation, but only glucuronide, to be excreted. This may be of use in patients whose alcohol use has led to liver disease, and its shorter half-life reduces the chance of accumulation in the plasma.

Several pharmacotherapies have US Food and Drug Administration (FDA) approval for the treatment of alcohol use disorders. These medications include disulfiram, acamprosate, and naltrexone. Disulfiram produces sensitivity to alcohol by inhibiting the enzyme acetaldehyde dehydrogenase, such that ingestion of even a small amount of alcohol causes flushing, throbbing in the head and neck, headache, respiratory difficulty, nausea, vomiting, sweating, thirst, chest pain, dyspnea, tachycardia, hypotension, syncope, weakness, blurred vision, and confusion. These unpleasant effects generally prevent individuals from drinking alcohol. However, disulfiram is not widely used because adherence to the medication is generally poor. Acamprosate is believed to be an N-methyl-D-aspartate (NMDA) receptor antagonist and modulator of GABA_A receptors that helps regulate chemical signaling in the brain. However, the efficacy of acamprosate is limited, and the pill burden (2 pills taken 3 times daily) often makes adherence to the medication problematic. However, acamprosate is metabolized through the kidneys and may be the best option for alcohol treatment among patients with severe liver disease. Naltrexone, an opioid antagonist, is available in both oral and monthly intramuscular injectable formulations. Naltrexone is believed to reduce the rewarding effects of alcohol and reduce cravings. Naltrexone cannot be used for patients who are prescribed chronic opioids because it will precipitate withdrawal. Although these medications are all FDA approved for alcohol use disorders, none has shown strong efficacy or is widely used in practice.

Caffeine

Caffeine is a legal and unregulated central nervous system stimulant that belongs to the methylxanthine class. It is an antagonist for adenosine receptors and therefore blocks the lethargic effects of adenosine. Caffeine is found in several South American and East Asian native plants and is typically sourced from Coffea plants. It is most typically consumed through drinking beverages such as coffee, tea, and carbonated drinks. Although >85% of adults and children consume caffeine, only about 7% of caffeine users experience ≥5 symptoms and functional impairment indicating caffeine intoxication.

Caffeine use disorder is included in the Conditions for Further Study section of the DSM-V, because additional research is needed to determine a consistent manner of identifying cases with adequate severity to warrant the diagnosis of a disorder. A strict diagnostic threshold needs to be determined due to the high rate of nonproblematic daily use in the general population. Current research has provided enough evidence supporting the establishment of a proposed disorder, and the World Health Organization recognized caffeine dependence in the 10th revision of the International Statistical Classification of Diseases and Related Health Problems.

Caffeine intoxication usually occurs with doses >250 mg and is characterized by restlessness, nervousness, excitement, insomnia, flushed face, diuresis, gastrointestinal disturbance, muscle twitch, rambling thought and speech, tachycardia or arrhythmia, and psychomotor agitation. Given the short half-life of caffeine (4 to 6 hours), caffeine intoxication usually ends within a day and generally does not produce any long-term negative effects. Abrupt cessation of caffeine used regularly usually results in withdrawal symptoms of headache, fatigue or drowsiness, difficulty with concentration, and the flulike symptoms of nausea, vomiting, and muscle aches or stiffness. Onset of withdrawal is usually within 12 to 24 hours of last caffeine use; withdrawal peaks after 1 to 2 days and can last between 2 and 9 days, although the caffeine headache can persist up to 21 days after discontinuation of caffeine.

Cannabis

Cannabis is a genus of flowering plant that has been used by humans for thousands of years (Figure 43–3). The plant can be used to form hemp fibers used in rope and textiles. The plant also contains a variety of chemicals known as cannabinoids. These chemicals have been shown to interact with the endocannabinoid system in various ways. Tetrahydrocannabinol (THC) is the most psychoactive of these substances, at least in terms of addiction. Marijuana is the dried leaves and flowers from the plant and is typically smoked. More concentrated amounts of THC can be found in hashish (a dried resin), with an even greater concentration found in hash oil.

THC has endogenous receptors in the brain, the CB1 and CB2 endocannabinoid receptors. Through its binding action, it is able to cause a variety of effects throughout the body, including appetite stimulation, suppression of nausea, and analgesia. It is also known to cause euphoria, in addition to impairing both motor function and memory. Cannabis use, particularly during adolescence, is associated with a higher risk of schizophrenia and may also worsens its symptoms.

Cannabis intoxication is associated with dry mouth, tachycardia, euphoria, hunger, and relaxation in lower amounts. In some individuals, cannabis may cause lightheadedness and paranoia; in higher amounts, it may heighten anxiety or cause panic. Chronic, heavy use has been shown to induce tolerance. Upon cessation, prominent withdrawal symptoms include anorexia, nausea, insomnia, irritability, and anxiety.

Although the use, possession, and sale of cannabis remain illegal under federal law, approximately half of the states in the United States have passed laws allowing for some medical use of marijuana, whereas 8 states allow medical as well as recreational use of marijuana. Two FDA-approved medications available in oral form, dronabinol and nabilone, contain cannabinoids and are prescribed for nausea and to increase appetite. Cannabidiol (CBD) oil, which does not contain THC or produce psychoactive effects, has also shown promise for seizure disorders that do not respond to conventional medications. CBD oil does not have FDA approval for any medical condition.

Hallucinogens

Hallucinogens or psychedelics represent a classification of drugs that produce changes in perceptual experiences. These changes may be associated with short-term alterations in cognition and mood that may produce lasting changes in cognitive beliefs. Hallucinogens span a wide range of drugs including phencyclidine (PCP), ketamine, psilocybin (mushrooms), lysergic acid diethylamide (LSD), and 3,4-methylenedioxy-methamphetamine (MDMA). Serotonergic psychedelics such as LSD and psilocybin cause more hallucinogenic and less stimulatory effects. Serotonergic hallucinogens alter thinking and produce illusions and visual hallucinations. Glutamatergic NMDA receptor antagonists, such as PCP and ketamine, were first developed as anesthetic drugs for humans or large animals and produce a dissociative state of being. Interestingly, MDMA (catecholamine-like psychedelic) is chemically similar to both stimulants and hallucinogens, which causes this drug to produce mixed subjective effects including increased energy, pleasure, and emotional warmth as well as distorted sensory and time perception.

Although hallucinogens may produce varied subjective effects and act on several different receptors, all hallucinogen-related disorders are classified as either PCP use or other hallucinogen use. PCP intoxication is characterized by vertical or horizontal nystagmus, hypertension or tachycardia, numbness or diminished responsiveness to pain, ataxia, dysarthria, muscle rigidity, seizures or coma, and hyperacusis. These symptoms are typically present within 1 hour of use. Repetitive, uncontrolled movements of the eyes coupled with bizarre and violent behavior may help distinguish individuals suffering from PCP intoxication versus intoxication with other substances. Symptoms of other hallucinogen intoxication occur shortly after ingestion and include pupillary dilation, tachycardia, sweating, palpitations, blurring of vision, tremors, and incoordination. Although suicide is rare among hallucinogen users, hallucinogen intoxication may lead to increased suicide risk or death due to secondary effects (eg, increased severity of visual hallucinations may cause individuals to place themselves in dangerous situations).

Although some hallucinogens produce tolerance, not all hallucinogens have been associated with physical withdrawal symptoms, and most withdrawal symptoms are likely experienced psychologically rather than physically. One notable exception is with repeated use of PCP, which often produces cravings, headaches, and sweating withdrawal symptoms upon abrupt cessation.

On rare occasions, the use of hallucinogens has been associated with long-term effects. Hallucinogen persisting perception disorder is the reexperiencing of perceptual distortions (eg, hallucinations, false perceptions of movement, flashes of color, images of moving objects, positive afterimages, halos around objects, macropsia, and micropsia) after the cessation of hallucinogen use. Similarly, there are anecdotal accounts of flashbacks from hallucinogen users. A flashback is the reexperience of a hallucinogen’s subjective effects that can happen a few day or years after drug use and often occurs without warning.

Although hallucinogens are commonly considered drugs of abuse, some hallucinogens have been studied as pharmacotherapeutic agents. For example, recent research has investigated the use of ketamine to treat severe depression. Some studies have shown that a single dose of ketamine can decrease depression for up to 2 weeks, and therapeutic benefits begin immediately. This is especially important considering that it takes approximately 2 weeks before individuals begin to experience any benefit from most antidepressant medications. Similarly, a recent pilot study among individuals with terminal cancer demonstrated that a single-dose session of psilocybin significantly reduced patients’ end-of-life anxiety and improved their depressed mood, which was maintained for up to 3 and 6 months, respectively.

Inhalants

Inhalant use (also known as huffing, sniffing, or bagging) is the intentional inhalation of chemical vapors to achieve a short-acting altered mental state. Inhalants include commonly found household products, such as solvents (paint thinners or removers, gasoline, lighter fluid), aerosols (spray paints, hair or deodorant sprays, aerosol computer cleaning products), gases (butane lighters, propane tanks, whipped cream aerosols), adhesives (glue), and nitrates (room odorizer, leather cleaner, liquid aroma). Inhalants affect the central nervous systems to produce short-term effects that are similar to the effects of alcohol, including slurred or distorted speech, lack of coordination, euphoria, and dizziness. Inhalants are predominately used by youths, with 2017 trends revealing that >8% of adolescents age 12 to 17 years reported having used an inhalant. In particular, nitrates are primarily used among older adolescents as sexual enhancers. Nitrates produce vasodilatation, which is thought to increase sexual satisfaction.

Inhalant intoxication is characterized by the experience of the following symptoms shortly after inhalant use: dizziness, nystagmus, incoordination, slurred speech, unsteady gait, lethargy, depressed reflexes, psychomotor retardation, tremor, generalized muscle weakness, blurred vision or diplopia, stupor or coma, and euphoria. Abusers of inhalants may be particularly susceptible to overdose because solvents and aerosol sprays may be highly concentrated. Inhaling the high volume of chemicals can cause sudden sniffing death syndrome. Butane and propane are particularly associated with sudden sniffing death syndrome due to rapid-onset, potentially fatal cardiac arrhythmias.

Although inhalants do not have significant withdrawal symptoms, chronic abuse of inhalants is associated with serious damage to the heart, lungs, liver, and kidneys. Other serious complications include peripheral and central nervous system damage, dementia, loss of cognitive functioning, gait disturbances, and loss of coordination. Due to these possible cognitive impairments, psychotherapies and other standard approaches to substance abuse treatment must be adapted to accommodate the short attention span and poor impulse control associated with chronic inhalant abuse.

Opioids

The opium poppy, Papaver somniferum (Figure 43–4), is native to the eastern Mediterranean, and its uses were known to ancient civilizations. The term opiate is reserved for naturally occurring alkaloids found in the latex of the poppy plant (eg, codeine, morphine, and thebaine). Originally, the term opioid was used to describe the semisynthetic (eg, buprenorphine, hydrocodone, oxycodone) and fully synthetic (eg, methadone, fentanyl) chemicals with similar clinical effects, but now, it is commonly used to describe any chemical in this class.

Although multiple opioid receptors and subtypes have been discovered, this chapter will primarily focus on the effects of the mu (µ) opioid receptor, because it is the most relevant to substance use disorders. The µ receptors are present in the NAcc, cortex, and thalamus, in addition to others areas of the central nervous system and body. Its endogenous ligands are endorphins and enkephalins. Depending on the area in the brain in which the receptor is found, activation may cause euphoria, analgesia, or respiratory depression. The µ receptors are also found in the gastrointestinal tract, where activation causes a decrease in motility, leading to constipation.

Opioid intoxication is characterized by a decrease in heart rate, respirations, and blood pressure, in addition to pupillary constriction and euphoria. As serum levels increase, respiratory suppression occurs and leads to death. Opioid overdose can be reversed by naloxone, a µ-receptor antagonist that can be given by nasal spray or by injection, either intramuscular or intravenous.

Opioid withdrawal is often described as a flulike syndrome. Common symptoms include alternating hot and cold sweats, body aches, diarrhea, nasal congestion, rhinorrhea, sweating, restless legs, and pupillary dilation. It is important to note that withdrawal symptoms can occur in some individuals after as little as a 2-week course of pain medication. As a result, symptoms of tolerance and withdrawal cannot be counted as criteria used to make the diagnosis of opioid use disorder in individuals who have been taking medications as prescribed by their physician. Opioid withdrawal is generally not life threatening; however, these are cases where extreme caution should be used due to the vasoconstrictive effects of opioid withdrawal. Individuals with severe coronary artery disease should be closely monitored during withdrawal to avoid myocardial infarction. In addition, uterine artery constriction can cause fetal distress in pregnant females, and current practice is to maintain these women on opioids such as buprenorphine or methadone throughout the duration of the pregnancy.

Treatment of Opioid Use Disorder

Unlike other substances discussed so far in this chapter, pharmacotherapy treatment for opioid use disorder is to maintain individuals on long-acting opioids while under the supervision of a physician, following federal guidelines. Patients with opioid use disorder who meet certain criteria may be able to participate in methadone treatment programs. Methadone is a long-acting µ-receptor agonist that can be titrated to a dose sufficient to alleviate not only cravings, but also withdrawal symptoms. Initially, methadone is dispensed daily from the treatment program in liquid form under direct observation to prevent diversion and ensure adherence. The titration schedule is set by federal regulation. Individuals are also required to meet with an individual counselor and establish a treatment plan and are monitored with urine drugs screens. Over time, individuals who adhere to their treatment plan may earn “take-home” doses of up to 1 month of medication. Methadone can prolong the QTc interval, and electrocardiograms should be obtained periodically to reduce the chance of torsades de pointes.

Another maintenance treatment option for opioid use disorder is buprenorphine. Unlike methadone, buprenorphine is a partial agonist for the µ receptor. This characteristic causes a ceiling effect, such that dosages >24 mg show little to no effect in regard to respiratory suppression, analgesia, or cravings when taken sublingually. In addition, buprenorphine has a very high affinity for the µ receptor, and thus, it can prevent the euphoria caused by full µ agonists if a full µ agonist is taken after buprenorphine (eg, heroin). Conversely, individuals must be in moderate to severe opioid withdrawal (12 hours since last use of an opioid) prior to being induced on buprenorphine, because its displacement of lower affinity, full µ agonists (eg, heroin) would cause a precipitated withdrawal. An additional benefit of buprenorphine is that federal law allows for its use in an office-based practice as opposed to an opioid treatment center. This allows for a physician who has been trained and has a waiver on their Drug Enforcement Administration license to see patients in their regular practice. The physician can determine the amount of medication prescribed and the interval indicated for follow-up for an individual patient, as opposed to following a strict federally mandated schedule for dosing adjustments and visits. Buprenorphine is typically prescribed in a form that includes a coating of naloxone in a 4:1 ratio of buprenorphine to naloxone. Naloxone, a µ-receptor antagonist, was added to the formulation to prevent dissolving buprenorphine in saline and injecting it intravenously. When taken as directed in sublingual form, very little naloxone is absorbed into the bloodstream, and there is no clinically relevant effect.

Patients who are abstinent from opioids for at least 7 to 10 days but who are at high risk for opioid relapse could be prescribed naltrexone. Naltrexone is an opioid antagonist and blocks opioid effects if opioids are administered after naltrexone. Naltrexone requires detoxification from all opioids prior to administration to avoid precipitating withdrawal. This medication may be a particularly good choice for individuals at high risk for opioid relapse who are leaving a controlled environment such as a drug treatment program, inpatient treatment program, or a correctional facility. Naltrexone comes in both oral and monthly intramuscular formulations, which can increase adherence.

Withdrawal can occur after the discontinuation of opioids that are being abused or taken as prescribed for analgesia or maintenance. Although withdrawal symptoms can be reduced by tapering the opioid over time, it is virtually impossible to eliminate them completely through tapering. Withdrawal is managed symptomatically, that is, by giving medications targeted at relieving the individual symptoms, such as loperamide for diarrhea and ibuprofen for muscle aches. The α₂-adernergic agonist clonidine is useful for symptoms related to sympathetic outflow from the central nervous system, such as sweating and tachycardia.

Sedatives, Hypnotics, & Anxiolytics

For the purpose of this chapter, sedatives refer to medications commonly used for their sedating effects, namely benzodiazepines and barbiturates. In clinical practice, these medications are often used to treat panic disorder, anxiety, insomnia, and seizures. These medications typically act as agonists at the GABA receptor, although they have different binding sites.

Barbiturates were first used clinically in 1904. They can be divided into short-, intermediate-, and long-acting groups. They act by binding to the GABA_A receptor at locations between the individual subunits. Barbiturates tend to increase the duration of chloride channel opening. Tolerance develops with regular use; however, the lethal dose varies greatly between individuals. There is no antidote to barbiturate overdose. As such, barbiturates began to fall out of favor clinically after the development of benzodiazepines in the 1960s, although phenobarbital, due to its very long half-life, is sometimes used as treatment for alcohol withdrawal and for some cases of epilepsy.

Benzodiazepines were first marketed in the 1960s for the treatment of anxiety. Like barbiturates, they can be divided into short-, intermediate-, and long-acting forms. They act by binding to GABA_A receptors at the benzodiazepine site. Benzodiazepines tend to increase the frequency of chloride channel opening.

Sedative use initially causes relaxation and a reduction in anxiety. As serum concentrations rise, slurred speech, ataxia, and nystagmus can be seen. At still higher levels, coma and respiratory depression occur. An important point is that although tolerance may develop to the therapeutic effects of sedatives, there is no increase in the levels required to cause coma or respiratory depression. Flumazenil is a GABA/benzodiazepine receptor antagonist that can be used to reverse the effects of benzodiazepine overdose, but it must be used with caution because use can precipitate a seizure. No maintenance pharmacotherapy exists to treat sedative, hypnotic, or anxiolytic use disorder.

Sedative withdrawal symptoms may occur after as little as 2 months of continuous use. Anxiety, tremor, tachycardia, hypertension, irritability, and insomnia are common when withdrawing from lower dosages. When higher dosages are abruptly discontinued, seizures and delirium can occur. Thus, alcohol and sedative intoxication and withdrawal syndromes have similarities due to these substances acting in similar ways at the GABA_A receptor.

Detoxification from sedatives typically requires a prolonged taper over weeks to months, depending on the substance that had been abused. Generally speaking, higher dosages or shorter acting agents cause more severe withdrawal symptoms. As with alcohol, longer acting benzodiazepines are typically used because they are able to better control withdrawal symptoms and require less frequent dosing.

Stimulants (Cocaine & Amphetamines)

Cocaine is a stimulant derived from the leaves of the coca plant, Erythroxylum coca. It is native to South America, where the leaves have been chewed by the local population as a mild stimulant for perhaps 8000 years. Cocaine is clinically useful due to its anesthetic and vasoconstrictive properties. This makes it especially useful for surgeries involving the face and nasopharynx. It is not uncommon to find perforations of the nasal septum in individuals who chronically insufflate cocaine due to these vasoconstrictive properties. Illicit cocaine is found in 2 forms: a salt that is nasally insufflated or intravenously injected and a base (crack cocaine) that is typically smoked. When consumed in the presence of alcohol, the chemical cocaethylene is formed, which has significant cardiotoxic effects.

Cocaine affects the brain by increasing the amount of neurotransmitters in the synaptic cleft (Figure 43–5). Primarily, it blocks presynaptic reuptake of dopamine by binding to the dopamine reuptake transporter. It also affects norepinephrine and serotonin reuptake.

Cocaine use initially causes feeling of euphoria, increased energy, and pupillary dilation. As serum levels increase, symptoms of tachycardia, hypertension, anorexia, and agitation become apparent. Paranoia and hallucinations may also occur; however, it should be noted these are typically of the nonbizarre type. Death may occur through the sequelae of seizures, strokes, or arrhythmias.

Cocaine withdrawal is noted to cause fatigue, hypersomnia, increased appetite, psychomotor retardation, and dysphoria. Withdrawal is not life threatening. Unfortunately, there are no proven pharmacotherapeutic agents effective for the treatment of stimulant disorders. Behavioral treatment approaches, such as cognitive-behavioral therapy and contingency management, are the most effective for stimulant disorders.

Amphetamines were first discovered in the late 19th century. Current medicinal uses include the treatment of attention-deficit/hyperactivity disorder (ADHD), narcolepsy, and obesity. Amphetamine and the more potent methamphetamine are structurally related to bupropion and MDMA (ecstasy). Amphetamine is taken orally when used for approved purposes, but it is often crushed into a powder and nasally insufflated when abused. Although methamphetamine does come in an oral preparation for treatment of ADHD, its use is uncommon. The vast majority of methamphetamine that is abused is manufactured outside of the pharmaceutical industry, either by drug cartels or by individuals, using various household chemicals.

Like cocaine, amphetamines also cause an increase of neurotransmitters in the synaptic cleft, but via different mechanisms (see Figure 43–5). Although amphetamines block reuptake of synaptic dopamine via the dopamine transporter, they are able to cause the dopamine transporter to work in reverse, effectively pumping cytoplasmic dopamine into the synaptic cleft. This effect is compounded by the intracellular effects of amphetamines, which result in dopamine release from intracellular storage vesicles through its effects on the vesicular monoamine transporter.

Due to the similar mechanisms of action, the intoxication and withdrawal syndromes for amphetamines are similar to those of cocaine. Feelings of euphoria and a state of alertness progress to anxiety, agitation, and paranoia as serum levels rise. Insomnia is another side effect especially prominent with methamphetamine, causing binge users to remain awake for days at a time, exacerbating hallucinations and paranoia. Skin picking also may occur. This may be evident as sores or scabs, typically on the face or arms. Unlike amphetamine, methamphetamine is a neurotoxin.

Tobacco (Nicotine)

Nicotiana tabacum is a plant native to Central and South America from which the stimulant nicotine is derived. Commonly known as the tobacco plant, it has been smoked by indigenous people for thousands of years for a variety of purposes. It was introduced to Europe in the 1500s. Nicotine can be inhaled in cigarettes, cigars, or pipes or can be chewed by placing it between the gums and oral mucosa.

Nicotine is active at the nicotinic acetylcholine receptor. The receptors are found throughout the brain and not surprisingly affect dopamine in the reward pathway. When consumed via smoking, additional chemicals are inhaled, many of which are carcinogenic. Interestingly, some of these inhaled chemicals are also monoamine oxidase inhibitors (MAOIs). These MAOIs are the reason many people report that smoking has an antidepressant effect. Although there is no nicotine intoxication syndrome, nicotine is known to cause relaxation and to have anxiolytic properties despite being a mild stimulant.

Nicotine replacement therapy (NRT) is often the first pharmacologic method used for smoking cessation. The FDA has approved gum, lozenges, and patches as over-the-counter medications, whereas an inhaler and nasal spray are available with a prescription. The patch is long acting and applied daily. The patch can be worn for 24 hours, and common side effects include irritation at the patch site and vivid dreams. The patch can be removed before bed if the patient finds the vivid dreams unpleasant or has insomnia. The other shorter acting forms or NRT are used to substitute for cigarettes when cravings occur. The patch and a short-acting form of NRT can be used together for optimal effectiveness.

Bupropion is a norepinephrine-dopamine reuptake inhibitor that is most commonly used as an antidepressant, although it now has a second indication for smoking cessation treatment under the trade name of Zyban. It also has nicotine receptor antagonist properties that have been shown to decrease both nicotine withdrawal symptoms and cravings. Patients are allowed to continue smoking after starting the medication and commonly report “losing the taste” or experiencing a “bad taste” for cigarettes between 1 and 2 weeks of therapy. Bupropion has been shown to be effective alone or in combination with NRT to improve cessation outcomes.

Varenicline functions as both a partial agonist and antagonist at the nicotine receptor. As such, it is able to prevent nicotine from binding to the receptors, while activating the receptor itself, but at lower levels of activity. Because varenicline is cleared through the kidneys, this medication may be preferred for patients with severe liver disease. Studies have shown varenicline to be the most effective single-medication treatment, and its effectiveness is comparable to that of combination NRT for smoking cessation.

OBJECTIVES

PREVALENCE & BURDEN

Almost 1 in 5 children either currently or at some point during their life will have a severe mental disorder. Mental and substance use disorders are the leading cause of disability in children and youth worldwide, and depression is the number 1 cause of loss of disability-adjusted life-years. These conditions can affect children’s development, educational attainment, and potential to live fulfilling and productive lives.

DISORDERS

In this chapter, psychiatric disorders prevalent in child and adolescent years are discussed. Some disorders will gradually improve with maturation, some will persist through adulthood, and some will worsen without adequate intervention. We will also note the different presentations of some common psychiatric disorders in children and adolescents. Eating disorders are also included in this chapter because their onset often occurs in adolescence.

Neurodevelopmental Disorders

Neurodevelopmental disorders are characterized by developmental deficits of the central nervous system, which can have prominent effects on personal, social, academic, or occupational functioning. These can vary from very specific impairments (eg, communication disorder) to global impairments (eg, intellectual disability). It is common for these disorders co-occur (eg, intellectual disability with autism spectrum disorder, or attention-deficit/hyperactive disorder [ADHD] with a specific learning disorder). Because the etiology of these conditions varies, their presentation is also heterogeneous. There are few pharmacologic treatments indicated specifically for neurodevelopmental disorders, other than stimulants for ADHD. However, nonpharmacologic interventions such as speech therapy, occupational therapy, educational support, and psychotherapy can improve overall prognosis and daily functioning.

Intellectual disabilities are the result of a variety of prenatal, perinatal, and postnatal etiologies. Congenital causes include fetal alcohol syndrome (FAS), genetic conditions such as trisomy 21 and fragile X syndrome, and infections during pregnancy such as toxoplasmosis. In some cases, intellectual disability may result from severe head injury, infection, or other acquired factors after birth. Intellectual disability is characterized by deficits in general mental abilities and impairment in everyday adaptive functioning, compared with an individual’s age-, gender-, and socioculturally matched peers. Examples of areas of impaired functioning may include reasoning, problem solving, planning, abstract thinking, judgment, academic learning, and learning from experience. With severe intellectual disability, delay in major milestones in the motor, language, and social aspects can be identified within 2 years of life, but mild cases may not be diagnosed until school age. Approximately 1% of the general population is affected by intellectual disabilities, and severe intellectual disability is estimated to be present in approximately 6 per 1000 population. Males are more likely than females to be diagnosed with intellectual disabilities. After childhood, the disorder is lifelong. When a delay in development is suspected either from caregiver’s report or during routine screening, a child can be assessed for the possibility of intellectual disability through comprehensive evaluation of intellectual capacity and adaptive functioning. Further workup to identify genetic and nongenetic etiologies should be considered. Given their various etiologies, there is no single pharmacologic treatment identified to treat intellectual disabilities. Early and ongoing nonpharmacologic treatment and intervention may improve adaptive functioning.

Speech sound disorder, a communication disorder, is defined as persistent difficulty with speech sound production that interferes with speech intelligibility. The disturbance causes limitation in effective communication. The onset of symptoms occurs in the early developmental period. Most children master mostly intelligible speech by 3 years of age, and other misarticulation should be corrected by 8 years of age. However, children with speech sound disorder continue to use immature misarticulation past community norm. When the diagnosis is suspected, regional, social, or cultural/ethnic variations of speech should be considered. Most children respond well to speech therapy, and speech difficulties improve over time.

In the United States, approximately 1 in 68 children has been diagnosed with autism spectrum disorder (ASD). It is reported to occur in all racial, ethnic, and socioeconomic groups. ASD is about 4.5 times more common among boys (1 in 42) than among girls (1 in 189). Worldwide prevalence is estimated to be between 1% and 2%. Heritability is estimated to be between 37% and 90% based on twin studies. Symptoms are typically recognized during the second year of life (12 to 24 months of age). Patients often initially present with delayed language development with lack of interest in social interaction, odd play patterns, and unusual communication patterns. Its key features include persistent impairment in reciprocal social communication and social interaction and restricted, repetitive patterns of behavior, interests, or activities. These symptoms are present from early childhood, and the impairments limit everyday functioning. ASD is not a degenerative disorder, and learning and compensation continue throughout life. It is a spectrum disorder, which means the severity of symptoms and level of functioning vary greatly, and early detection and intervention are thought to be the key to a better prognosis. The Modified Checklist for Autism in Toddlers (M-CHAT) is applied to screen for ASD during pediatric check-ups between 16 and 30 months of age. The final diagnosis is made clinically based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) criteria that emphasize clinical features; there is no biomarker or imaging study that is diagnostic. Standardized behavioral diagnostic instruments (eg, Autism Diagnostic Observation Schedule) are also available to improve the reliability of diagnosis. After a diagnosis is made, structured educational and behavioral interventions including Picture Exchange Communication System, pragmatic language skills training, applied behavioral analysis, and structured educational approaches have been shown to be effective and are associated with better outcomes.

ADHD has been reported in approximately 5% of children and 2.5% of adults in population surveys, but recent data show a higher prevalence in the United States. Its key features include a persistent pattern of inattention and hyperactivity-impulsivity that interferes with functioning or development. The dysfunction of brain areas for executive function and inhibitory control (frontal-striatal regions), catecholaminergic dysregulation, and delays in cortical maturation are all associated with ADHD. Before the age of 4 years, the symptoms of ADHD are difficult to distinguish from highly variable normative behaviors. In preschool, the main symptom is hyperactivity, which becomes less obvious in adolescence and adulthood. Restlessness, inattention, poor planning, and impulsivity may remain problematic. Some symptoms improve over time. Diagnosis can be made based on DSM-V criteria if there is consistent information from at least 2 separate contexts. Rating scales can be helpful to obtain an objective report from informants other than the primary caregiver. Prior to making the diagnosis, other causes of inattention, hyperactivity, or impulsivity such as ASD, anxiety disorder, depressive disorder, and substance use disorder should be evaluated.

The first-line pharmacologic treatments for ADHD are methylphenidate and amphetamine. These are stimulants medications and have been proven to be effective in the treatment of core symptoms. Both increase norepinephrine and dopamine in the synaptic cleft by inhibiting reuptake and increasing release from presynaptic neurons. Prior to treatment with these drugs, a physical exam and careful family history should be obtained because they may have serious adverse effects on the cardiovascular system. Insomnia and decreased appetite are common and problematic side effects. Other possible side effects include hypertension, tachycardia, psychosis, anxiety, nausea, and headache. Other nonstimulant pharmacologic treatments such as clonidine and guanfacine can also be considered. Clonidine is a nonselective α₂-adrenergic agonist, and guanfacine is a selective α_2A-adrenergic agonist. They both decrease activity of the locus coeruleus, which may have increased basal activity in individuals with ADHD. Side effects of an α₂ agonist include rebound hypertension and tachycardia, sedation, dizziness, constipation, headache, and fatigue. Atomoxetine can be used for ADHD patients with comorbid anxiety disorder who report worsening anxiety with stimulants. Atomoxetine is a norepinephrine reuptake inhibitor that can cause decreased appetite, dizziness, dyspepsia, and sedation as side effects.

Specific learning disorder is defined as persistent difficulties learning keystone academic skills including the reading of single words, reading comprehension, written expression and spelling, arithmetic calculation, and mathematical reasoning. The individual with a specific learning disorder has well-below-average skill for age, that is not due to lack of opportunity of learning or inadequate instruction. The disorder is apparent in the early school years in most individuals, and the prevalence is estimated to be 5% to 15% of school-age children. Diagnosis of a specific learning disorder usually occurs when children are required to learn to read, spell, write, and learn mathematics. Psychological testing, neuropsychological testing, and projective testing can be applied to support the diagnosis. Symptoms typically persist into adulthood, but the course is variable. Educational support using accommodation modification such as an individualized education plan is important.

Tic disorders are characterized by a sudden, rapid, recurrent, nonrhythmic motor movement or vocalization. Simple motor tics include eye blinking, shoulder shrugging, and extension of the extremities. Simple vocal tics include throat clearing, sniffing, and grunting. Complex motor tics are a stereotyped combination of movements. Examples of complex vocal tics are repeating sounds or words, repeating the last heard word of the phrase, or uttering socially unacceptable words. Patients report a premonitory urge before a tic and a feeling of tension reduction after the expression of the tic. Tics are often suppressible for a period of time. The diagnosis of a tic disorder can be made when there are motor and vocal tics and the symptoms are present for >1 year. If the symptoms are present for <1 year, provisional tic disorder is an appropriate diagnosis. Tourette syndrome is diagnosed when both multiple motor tics and 1 or more vocal tics have been present at some time during the illness, although not necessarily concurrently. Tics are common in childhood but transient in most cases. The estimated prevalence of Tourette syndrome is 3 to 8 per 1000 school-age children. Males are 2 to 4 times more likely to be diagnosed with tic disorder than females. Onset is typically between ages 4 and 6 years, and peak onset occurs between ages 10 and 12 years; severity then declines during adolescence. Many adults with tic disorders experience diminished symptoms, but a small number of patients will have persistent or worsening symptoms in adulthood. Tics wax and wane in severity and change in affected muscle groups and vocalizations over time. ADHD, obsessive-compulsive disorder, and anxiety disorders are common comorbidities with tic disorders (Figure 44–1).

Effective nonpharmacologic treatment options include habit reversal training, where individuals are trained to replace a tic with a competing response that is a more comfortable or acceptable movement or sound. Pharmacologic treatment is recommended only when tics result in significant subjective discomfort, pain, or ongoing social problems. α₂-Adrenergic agonists such as clonidine and guanfacine reduce symptoms by decreasing sympathetic nerve impulses. Atypical antipsychotic agents, such as risperidone, and high-potency, first-generation antipsychotics such as haloperidol can also be considered if the benefit outweighs the risk. Significant and possibly life-threatening side effects can occur with antipsychotics, including neuroleptic malignant syndrome, extrapyramidal symptoms including tardive dyskinesia, sedation, increased appetite, and weight gain.

Mood Disorders in Children & Adolescents

Mood disorders are common in childhood and adolescence. Major depressive disorder (MDD) is estimated to be present in approximately 2% of children and 4% to 8% of adolescents. There is no significant difference in prevalence between males and females during childhood, but in adolescence, females have a higher prevalence compared to males. The cumulative prevalence of MDD is 20% by age 18 years. Children and adolescents with MDD often report irritability rather than depressed mood. They also exhibit poor concentration that affects academic performance. Depression in children is associated with childhood neglect, parental mental illness (eg, depression, substance use disorder), domestic violence, marital conflict, or persistent parental conflict following separation, divorce, or child abuse. Some children and adolescents who experience a major depressive episode may eventually develop bipolar disorder. Children with bipolar disorder are more likely to have a family history of this illness. In individuals with bipolar disorder, mood usually alternates between high mood (mania) and low mood (depression) more rapidly than in adults. This rapid and severe cycling between moods may produce a type of chronic irritability with few clear periods of peace between episodes. Patients may also experience symptoms of mania and depression at the same time, which is defined as a mixed episode. See Chapter 39 for further information on mood disorders.

Anxiety Disorders in Children & Adolescents

Anxiety can be normal for children and adolescents when faced with an unfamiliar or especially stressful situation. It becomes pathologic or problematic when it is excessive or persists beyond developmentally appropriate periods.

Separation anxiety disorder is the most prevalent anxiety disorder in children younger than age 12 years. The 6- to 12-month prevalence is estimated to be approximately 4% in children and 1.6% in adolescents. Increased anxiety related to separation from attachment figures is normal in early development. However, the anxiety can be viewed as problematic if it is excessive for the child’s age or cultural norm. Children who are diagnosed with separation anxiety disorder have exacerbations and remissions, although in some cases, symptoms may persist through adulthood. The disorder is characterized by excessive fear or anxiety concerning separation from home or attachment figures. Younger children are more reluctant to go to school or may avoid school altogether. As children age, they often worry about specific dangers (eg, accidents, kidnapping, or death) or not being reunited with attachment figures. Repeated nightmares about separation or physical symptoms may occur when separation is anticipated. To meet the diagnostic criteria, fear, anxiety, or avoidance needs to be persistent, lasting at least 4 weeks in children and adolescents and 6 months or more in adults. See Chapter 40 for further information on anxiety disorders.

Trauma- & Stress-Related Disorders

Traumatic events such as neglect, physical or sexual abuse, natural or manmade disasters, violent crimes such as kidnapping or school shooting, and motor vehicle accidents can lead to the development of posttraumatic stress disorder (PTSD). It is estimated that approximately 5% of adolescents will meet criteria for PTSD in their lifetime, whereas the number of children exposed to traumatic events is much higher. Children and adolescents experience symptoms of PTSD that are similar to those of adults, including intrusion symptoms, negative alterations in cognition and mood, avoidance and numbing, and hyperarousal symptoms. Some school-age children may experience visual flashbacks or amnesia, but others will have time skew and omen formation, symptoms that are not typically seen in adults. Time skew refers to a child mis-sequencing trauma-related events when recalling the memory. Omen formation is a belief that there were warning signs that predicted the trauma. The child’s trauma is often exhibited in play, drawings, or verbalization. Adolescents tend to engage in traumatic reenactment, in which they incorporate aspects of the trauma into their daily lives. Adolescents are also more likely to exhibit impulsive and aggressive behaviors compared to children and adults with PTSD. Due to these distinctive features of PTSD in children, play therapy can help children process the traumatic memories. Other therapies and pharmacologic treatment that are effective in adults with PTSD can also be applied in children and adolescents.

Reactive attachment disorder is seen in children who have absent or underdeveloped attachment with putative caregiving adults. When distressed, they show no consistent effort to obtain comfort, support, nurturance, or protection from caregivers. It often co-occurs with delays in cognition and language. The clinical features include absent to minimal attachment behaviors in children between the ages of 9 months and 5 years. There is also a consistent pattern of inhibited, emotionally withdrawn behavior toward adult caregivers, which causes persistent social and emotional disturbance. Without a normative caregiving environment to remediate, symptoms may persist for several years.

Feeding & Eating Disorders

Feeding and eating disorders are characterized by a persistent disturbance of eating or eating-related behavior that results in the altered consumption or absorption of food. These behaviors significantly impair physical and psychological health and functioning. Abnormal eating behaviors seem to develop as a way of handling stress and anxieties. Although many disorders under this category share some features, there are substantial differences in clinical course, outcome, and treatment needs. In brief, anorexia is a form of self-starvation, bulimia nervosa is related to repetitive cycles of binge eating alternating with self-induced vomiting or starvation, and binge-eating disorder is when an individual has binge-eating behaviors without compensatory behaviors. Some individuals with these disorders report symptoms such as craving and compulsion, which are typical symptoms of substance use disorders.

Anorexia nervosa (AN) commonly begins during adolescence and young adulthood. The onset is often associated with a stressful life event, and the course is variable. The 12-month prevalence among young females is approximately 0.4%, and lifetime prevalence is 0.5% to 1%. It is 10 times more prevalent in females compared to males. After the onset of symptoms, many patients exhibit a fluctuating pattern, and some experience a chronic course over many years. Long-term follow-up shows a mortality rate of 7% at 10-year follow-up and 18% to 30% at 30-year follow-up, which is higher than any other mental illness. Individuals with AN report fear of gaining weight or of becoming fat and exhibit persistent behavior that interferes with weight gain. These behaviors include restriction of energy intake relative to requirements, leading to a significantly low body weight in the context of age, sex, developmental trajectory, and physical health. Body mass index (BMI) for adults or BMI percentile for children and adolescents can be used to determine a healthy weight for each patient. In the restricting type of AN, weight loss is accomplished primarily through dieting, fasting, and excessive exercise. The binge-eating/purging type of AN involves recurrent episodes of binge eating or purging behavior during the past 3 months. Binge eating is defined as eating an amount of food that is greater than what most individuals would consume. It is also accompanied by a sense of lack of control. Examples of purging behavior include self-induced vomiting; misuse of laxatives, diuretics, or other medications; fasting; or excessive exercise. Treatment consists of nutritional rehabilitation to restore weight, normalizing eating patterns, reestablishing normal perception of hunger, and correction of malnutrition. With severe malnutrition, hospitalization with close monitoring for refeeding syndrome is recommended. Psychotherapy has shown utility in adults, especially family-based therapy. However, medications are not generally effective for AN.

Bulimia nervosa is characterized by recurrent episodes of binge eating without abnormally low body weight. The 12-month prevalence among young females is 1% to 1.5%. After binge-eating behavior, recurrent inappropriate compensatory behaviors follow to prevent weight gain. Patients are often ashamed of their eating problems and attempt to conceal their symptoms. There is also excessive emphasis on body shape or weight, which affects self-esteem. The course may be chronic or intermittent, with periods of remission. The crude mortality rate for bulimia nervosa is nearly 2% per decade. The pharmacologic treatment fluoxetine is effective in decreasing binge and purge episodes. Because it is an antidepressant that works by selectively inhibiting reuptake of serotonin, it also treats comorbidities such as depression and obsessive-compulsive disorder. The most effective treatment strategy is combining antidepressant medication and cognitive-behavioral therapy. Other forms of therapy such as family-based therapy and dialectical behavioral therapy can also be helpful.

In contrast to bulimia nervosa, binge-eating disorder is not accompanied by compensatory behaviors. This disorder typically begins in adolescence or young adulthood but can also begin in later adulthood. Like bulimia, recurrent episodes of binge eating occur, but they are not associated with the recurrent compensatory behavior such as purging after binge eating. It can occur in normal-weight or overweight/obese individuals, and the remission rates are higher for binge-eating disorder than for bulimia or AN. For pharmacologic treatment, antidepressants (eg, selective serotonin reuptake inhibitors) have been shown to improve symptoms of binge-eating behavior. Antiepileptic drugs (eg, topiramate) can decrease appetite and overall improve binge-eating behavior. However, topiramate has side effects such as cognitive impairment, paresthesia, and somnolence. Stimulants (eg, lisdexamfetamine) also decrease appetite and weight, but there are side effects including anorexia, gastrointestinal distress, headaches, insomnia, and sympathetic nervous system arousal. Nonpharmacologic treatment, including cognitive-behavioral therapy, interpersonal therapy, dialectical behavioral therapy, and family therapy, can also be considered to improve symptoms.

Pica is defined as eating 1 or more nonnutritive, nonfood substances on a persistent basis over a period of at least 1 month. This abnormal eating must be developmentally, culturally, and socially inappropriate. It is important to recognize that pica may be caused by vitamin or mineral deficiencies, particularly iron and zinc. Pica can cause medical complications such as intestinal obstruction, intestinal perforation, toxoplasmosis, toxocariasis, and lead poisoning.

Elimination Disorders

Elimination disorders involve the inappropriate elimination of urine or feces. In infancy and toddler years, lack of continence is developmentally appropriate. Therefore, these diagnoses have minimal age requirements based on the level of development, not chronologic age. Both enuresis and encopresis can be voluntary or involuntary.

Enuresis is defined as repeated voiding of urine in inappropriate places. Primary enuresis is when urinary continence was never established and the developmental level is at least 5 years, and secondary enuresis is when the disturbance develops after a period of established urinary continence. In the United States, 30% of children achieve continence by age 2, and both primary and secondary enuresis have a spontaneous remission rate of 5% to 10% per year. Most children become continent by adolescence, but 1% of cases continue into adulthood. The nocturnal-only subtype is the most common, with the incontinence occurring only during nighttime sleep. Diurnal-only subtype is the absence of nocturnal enuresis and may be referred as to as urinary incontinence. Workup should rule out a physical cause of incontinence, especially if a child presents with repeated urinary tract infections. Ultrasounds and voiding cystourethrograms can help reveal underlying physical abnormalities such as detrusor hypertrophy and overactive bladder. Other evaluations including electroencephalogram or sleep study can be considered if there are other symptoms concerning for seizure or obstructive sleep apnea, which also can cause incontinence. Education for the family and patient and watchful waiting should be tried prior to considering interventions. Bell-and-pad therapy is a nonpharmacologic treatment that relies upon classical and operant conditioning. A child sleeps on the pad, which triggers an alarm when the child begins to urinate. It takes a few months to work and the success rate is 80% to 90%, but the relapse rate can be up to 40%. Other interventions such as bladder volume alarm, timed night awakening, and bladder training exercises can be considered. In terms of pharmacologic treatment, desmopressin is a long-acting arginine vasopressin (antidiuretic hormone [ADH]) that increases water reabsorption at the renal collecting duct, which results in reduced urine output. The success rate is between 10% and 65%, with a relapse rate as high as 80%. When desmopressin is used, sodium should be monitored due to risk for hyponatremia. Imipramine is a tricyclic antidepressant, and its anticholinergic properties cause relaxation of the bladder detrusor muscle and increase sphincter tone. It also increases the release of ADH, which results in free water retention and suppresses rapid eye movement sleep, which helps the child to wake up. The partial success rate is around 50%, but complete remission occurs in only about 25% of patients. Imipramine also has significant side effects including lethality in overdose, suicidal ideation, cardiac dysrhythmias, convulsions, and coma. In addition, 10% of patients report more common side effects related to its anticholinergic properties including drowsiness, dry mouth, dizziness, constipation, blurred vision, difficulty starting urine stream, and palpitation.

Encopresis is defined as repeated passage of feces in inappropriate places, which can be involuntary or intentional. When the passage of feces is involuntary, it is often related to constipation, impaction, or retention with subsequent overflow. Its prevalence is approximately 1% of 5-year-old children, and it occurs more often in males than females. Inadequate, inconsistent toilet training and psychosocial stress may be predisposing factors. Primary encopresis is when a child has never established fecal continence, and secondary encopresis is when the disturbance develops after a period of established fecal continence. When the diagnosis is suspected, physical exam and gastrointestinal imaging may be informative to assess stool burden. Other medical conditions, such as Hirschsprung disease, should be ruled out by barium enema and anorectal manography. Education for the family and patient including encouraging high-fiber food, increased fluid intake, and regular bathroom times should be provided. If encopresis is the retentive type, laxatives and stool softeners can be given to assist in emptying of the bowel.

Disruptive, Impulse-Control, & Conduct Disorders

Disruptive, impulse-control, and conduct disorders include conditions involving problems in the self-control of emotions and behaviors. These disorders are unique in that these behaviors violate the rights of others and bring the individual into significant conflict with societal norms and authority figures. They all tend to be more common in males than in females, although the relative degree of male predominance may differ. Although there is a developmental relationship between oppositional defiant disorder (ODD) and conduct disorder, not every child with ODD develops conduct disorder later in life.

Usually, ODD first appears during the preschool years and rarely after early adolescence. Angry or irritable mood, argumentative or defiant behavior, and vindictiveness characterize this disorder. Patients often justify their behavior as a response to unreasonable demands or circumstances. Children with defiant, argumentative, and vindictive symptoms develop a conduct disorder. Those with angry, irritable mood symptoms carry the risk of developing anxiety disorder or depression. Parent–child interaction therapy is a useful nonpharmacologic treatment option. There is no medication indicated for ODD, but it is important to identify and treat comorbidities such as ADHD, depression, PTSD, and bipolar disorder.

Diagnosis of conduct disorder can be made when there are symptoms of aggression to people and animals, destruction of property, deceitfulness or theft, and serious violations of rules. The onset may occur as early as the preschool years, but it occurs mostly in childhood and adolescence and rarely after the age of 16 years. The early-onset type has a poor prognosis and has more risk for criminal behavior and substance-related disorders. The 12-month prevalence is anywhere from 2% to >10%, and it is higher among males. Multisystemic therapy involving the individual, family, peers, school, and neighborhood can be effective and helpful.

Other Conditions

Fetal alcohol syndrome is a consequence of prenatal alcohol exposure, but not all exposure leads to FAS. Individuals affected by FAS can have facial anomalies including short palpebral features, flat or indistinct philtrum, and a thin vermillion border of the upper lip (Figure 44–2). There is also growth retardation that affects height more than weight. Central nervous system dysfunction is also significant. Microcephaly, structural brain abnormalities, and other neurologic problems occur. In terms of psychiatric symptoms, cognitive impairments, developmental delay, executive functioning deficits, learning disabilities, poor academic achievement, language problems, visual-spatial impairment, and memory impairment are all observed.

Rett syndrome is a postnatal neurologic disorder that is caused by mutations on the X chromosome in a gene called MECP2. It occurs worldwide in 1 in 10,000 female births and only rarely in males because the mutation in Rett syndrome is almost exclusively on the paternally derived X chromosome. Symptoms appear after an early period of apparently normal or nearly normal development until 6 to 18 months of life. After this period, there is stagnation following regression of development. The course and severity of Rett syndrome are determined by the location, type, and severity of the mutation as well as X-inactivation. The main symptoms include stereotypic hand movements, gait disturbances, and slowing of head growth. Psychiatric symptoms include inconsolable cries, irritability, lack of social/emotional reciprocity, impaired use of nonverbal communication, sensory problems, extreme tantrums, and language impairments.