After studying this chapter, the student should be able to:
Define the term psychosis.
Understand the symptoms of schizophrenia and related disorders.
Describe common pathophysiologic abnormalities associated with schizophrenia.
Outline current available treatments for schizophrenia and related disorders.
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.
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.
Affective flattening: Lack of range and intensity of emotional expression.
Akathisia: Extreme restlessness. May include pacing, rocking back and forth, or an inability to sit still.
Alogia: Synonym for poverty of speech.
Catalepsy: Passive induction of a posture held against gravity.
Catatonia: Unusual motor behavior, typically with lack of reactivity to the environment.
Delusion: A belief that is firmly maintained despite being contradicted by reality.
Dyskinesia: Abnormal, involuntary movement.
Dystonia: Abnormal muscle tone resulting in muscular spasm and abnormal posture.
Echolalia: Mimicking another’s speech.
Echopraxia: Mimicking another’s movement.
Extrapyramidal: Referring to the motor systems involving the basal ganglia, as opposed to the corticospinal tracts that pass through the medullary pyramids. Often used in the context of parkinsonian side effects of antipsychotic medications.
Formal thought disorder: A disturbance in the organization and expression of thoughts.
Hallucination: A sensory experience of something that is not present.
Ideas of reference: An unfounded belief that objects, events, or people are of personal significance.
Mannerisms: Odd caricature of normal actions.
Mutism: No or very little verbal response.
Negative symptoms: Normal behaviors or thought patterns lost as a feature of disease, such as apathy or social withdrawal.
Negativism: Opposing or not responding to instructions or external stimuli.
Positive symptoms: Abnormal behaviors or thought patterns that emerge as a feature of disease, such as delusions or hallucinations.
Posturing: Spontaneous and active maintenance of a posture against gravity.
Poverty of speech: Inability to start or take part in a conversation, mostly “small talk.”
Stereotypy: Repetitive, abnormally frequent, non–goal-directed movements.
Stupor: A condition in which a person is immobile, mute, and unresponsive, but appears to be fully conscious.
Tardive: Appearance late in the treatment of a disease.
Thought broadcasting: The belief that one’s thoughts are being made known to others.
Thought insertion: The belief that thoughts are put into one’s mind.
Waxy flexibility: Slight and even resistance to positioning by examiner.
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 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 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.
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.
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 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.
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.
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.
Magnetic resonance imaging (MRI) in a patient with limbic encephalitis. Coronal axial fluid-attenuated inversion recovery (FLAIR) images demonstrate abnormal hyperintensities involving the mesial temporal lobes (arrowhead) including the hippocampi (arrows) without significant mass effect. (Reproduced with permission from Jameson JL, Fauci AS, Kasper DL, et al: Harrison’s Principles of Internal Medicine, 20th ed. New York, NY: McGraw Hill; 2018.)
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 illness trajectory of schizophrenia. The premorbid stage represents the stage of risk or genetic vulnerability, with no clinical signs or symptoms of the illness. The prodromal stage ushers in mild symptoms such as social isolation, functional decline, unusual thoughts, and suspicion. The stage of onset/deterioration is the stage of the manifest disease and usually involves multiple hospitalizations and gradual decline. The residual/stable stage is marked by deficit and cognitive symptoms, typically without full-blown psychotic episodes.
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.
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.
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.
The N-methyl-D-aspartate receptor (NMDAR) hypofunction hypothesis of schizophrenia. Reduced NMDAR activation leads to reduced output from inhibitory γ-aminobutyric acid (GABA)-ergic interneurons, especially those that contain parvalbumin (PV+ interneurons). This then results in disinhibition of excitatory pyramidal neurons (PyR). (Reproduced with permission from Paoletti P, Bellone C, Zhou Q: NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease, Nat Rev Neurosci. 2013 Jun;14(6):383-400.)
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.
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.
The 3 major dopaminergic projections in the central nervous system. 1. The nigrostriatal pathway. Neurons in the substantia nigra pars compacta (SNc) project to the dorsal striatum (upward dashed blue arrows). 2. Neurons in the ventral tegmental area project to the ventral striatum (nucleus accumbens), olfactory bulb, amygdala, hippocampus, orbital and medial prefrontal cortex, and cingulate gyrus (solid blue arrows). 3. Neurons in the arcuate nucleus of the hypothalamus project by the tuberoinfundibular pathway in the hypothalamus, from which dopamine is delivered to the anterior pituitary (red arrow). (Reproduced with permission from Brunton LL, Hilal-Dandan R, Knollmann BC: Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13th ed. McGraw Hill; 2018.)
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.
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.
Algorithm for the pharmacologic treatment of patients with schizophrenia or schizoaffective disorder. First-line options include amisulpride (AMI; not available in the United States), aripiprazole (ARIP), olanzapine (OLZ), quetiapine (QTP), risperidone (RISP), paliperidone (PALI), or ziprasidone (ZIP). Clozapine (CLOZ) should be considered if a patient does not respond to 2 or more adequate medication trials. ECT, electroconvulsive therapy; NMS, neuroleptic malignant syndrome; TD, tardive dyskinesia. Adapted from the International Psychopharmacology Algorithm Project (IPAP) schizophrenia treatment algorithm, available online at www.ipap.org. (Adapted with permission from the International Psychopharmacology Algorithm Project (IPAP) algorithm for the treatment of schizophrenia, available at www.ipap.org.)
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.
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 GABAA 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.