Chapter 18. Antipsychotic Drugs and Lithium

The antipsychotic agents, also known as neuroleptic drugs, are used in schizophrenia and are also effective in the treatment of some other psychoses and agitated states. Although schizophrenia is not cured by drug therapy, the symptoms, including thought disorder, emotional withdrawal, and hallucinations or delusions, may be ameliorated by antipsychotic drugs. Unfortunately, protracted therapy (years) is often needed and can result in severe toxicity in some patients.

In bipolar affective disorder, lithium has been the mainstay of treatment for many years. Recently, however, the use of newer antipsychotic agents and of several antiseizure drugs has been increasing.

The term psychosis denotes a variety of mental disorders. Schizophrenia is a particular kind of psychosis characterized mainly by a clear sensorium but a marked thinking disturbance. The pathogenesis of schizophrenia is unknown, although a genetic predisposition has been proposed that is based on the observed familial incidence of schizophrenia. The molecular basis of the disease is also unclear, but evidence suggests there is a link with abnormalities of amine neurotransmitter function, especially that of dopamine. For this reason, drug therapy for schizophrenia is directed at this group of neurotransmitters and their receptors.

Bipolar affective (manic-depressive) disorder is a frequently diagnosed and very serious psychiatric disorder characterized by cyclic attacks of mania with many symptoms of paranoid schizophrenia (grandiosity, bellicosity, paranoid thoughts, and overactivity) alternating with periods of severe depression.

Schizophrenia is by far the most common form of psychosis and although current drug therapy does not cure the disease, the number of patients requiring hospitalization in mental institutions has markedly decreased since the first neuroleptic drugs (reserpine and chlorpromazine) were found to be useful in the early 1950s. Because of the positive effects of drug therapy on the symptoms of the disease, psychiatric philosophy has shifted to a more biologic basis.

Physical therapists may encounter patients taking antipsychotic medications in several settings. Many psychiatric facilities employ therapists to provide direct care to their patients. Also, therapists may encounter patients outside the hospital setting, taking antipsychotic medications (Figure 18–1), who have been referred for rehabilitation for a diagnosis unrelated to their psychosis.

The major chemical subgroups of older antipsychoticdrugs are the phenothiazines (e.g., chlorpromazine, thioridazine, fluphenazine), the thioxanthenes (e.g., thiothixene), and the butyrophenones (e.g., haloperidol). Newer drugs (second-generation or atypical drugs) vary in their chemical structure but are also effective in schizophrenia. They include clozapine, loxapine, olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole. In some patients, these atypical drugs are more effective and less toxic than the older drugs. They are deemed atypical because they appear to have lower affinity for the dopamine D2 receptor and tend to be more selective in their pharmacologic effects with fewer adverse effects such as sedation and extrapyramidal symptoms (bradykinesia, rigidity, and tremor). However, they are much more costly than the older drugs, most of which are prescribed generically. Table 18–1 lists some antipsychotic agents, their clinical potencies, and the severity of some adverse effects.

The antipsychoticdrugs are well absorbed when given orally and, because they are lipid soluble, readily enter the central nervous system (CNS) and most other body tissues. Many are bound extensively to plasma proteins. These drugs require metabolism by liver enzymes before elimination and have long plasma half-lives that permit once-daily dosing. Parenteral forms of some agents are available for both rapid initiation of therapy and depot treatment, the latter helping to improve drug compliance, a major problem for patients who suffer from schizophrenia.

Mechanism of Action

The mechanism of action of antipsychotic agents most commonly related to the treatment of schizophrenia is based on the dopamine hypothesis of schizophrenia. This hypothesis proposes that the disorder is caused by a relative excess of functional activity of the neurotransmitter dopamine in specific neuronal tracts in the brain. The hypothesis is based on the observations that many antipsychotic drugs block brain dopamine receptors (especially D2 receptors) and dopamine agonist drugs (e.g., amphetamine, levodopa) exacerbate schizophrenia. Also, an increased density of dopamine receptors has been detected in certain brain regions of untreated patients diagnosed with schizophrenia. The dopamine hypothesis of schizophrenia is not fully satisfactory because antipsychotic drugs are only partially effective in most patients and because many effective drugs have a much higher affinity for other receptors than for D2 receptors.

There are five recognized dopaminereceptors (D1 to D5). Each is a member of the G protein–coupled receptor class. The D2 receptor, found in the caudate putamen, nucleus accumbens, cerebral cortex, and hypothalamus, is negatively coupled to adenylyl cyclase via a Gi protein. The therapeutic efficacy of most of the older antipsychoticdrugs correlates with their relative affinity for the D2 receptor. Unfortunately, blockade of D2 receptors also correlates strongly with extrapyramidal dysfunction. Most of the newer atypical antipsychotic agents have higher affinities for other receptors than for the D2 receptor. For example, α adrenoceptor-blocking action correlates well with antipsychotic effect for several of the drugs (Table 18–2). Clozapine, a drug with significant D4 and serotonin (5-HT) type 2 receptor-blocking actions, has low affinity for D2 receptors. Several of the newer atypical drugs (e.g., olanzapine, aripiprazole, and risperidone) have high affinity for 5-HT2A receptors, although they may also interact with D2 and other receptors. Ziprasidone is an antagonist at the D2, 5-HT2A, and 5-HT1D receptors and an agonist at the 5-HT1A receptor. The newest antipsychotic agent, aripiprazole, is a partial agonist at D2 and 5-HT1A receptors, but is a strong antagonist at 5-HT2A receptors. Most of the atypical drugs cause less extrapyramidal dysfunction than standard drugs. With the exception of haloperidol, all antipsychotic drugs block H1 histamine receptors to some degree.

Dopaminereceptor blockade is the major effect that correlates with therapeutic benefit for older antipsychoticdrugs. Dopaminergic tracts in the brain include the mesocortical-mesolimbic pathways (regulating mentation and mood), nigrostriatal tract (extrapyramidal function), tuberoinfundibular pathways (control of prolactin release), and chemoreceptor trigger zone (emesis). Mesocortical-mesolimbic dopamine receptor blockade presumably underlies antipsychotic effects, and a similar action on the chemoreceptor trigger zone leads to the useful antiemetic properties of some antipsychotic drugs. Adverse effects resulting from receptor blockade in the other dopaminergic tracts, a major problem with older antipsychotic drugs, include extrapyramidal dysfunction and hyperprolactinemia (see section on Adverse Effects below).

Clinical Use

The primary clinical use of antipsychoticdrugs is for the treatment of schizophrenia. These agents reduce some of the positive symptoms of schizophrenia, including hyperactivity, bizarre ideation, hallucinations, and delusions. Consequently, antipsychotic drugs can facilitate functioning in individual activity and social participation in both inpatient and outpatient environments. Beneficial effects may take several weeks to develop. Newer atypical drugs also improve some of the negative symptoms of schizophrenia, including emotional blunting and social withdrawal. Older drugs are still commonly used; in part because of their low cost in comparison with newer agents. However, none of the traditional drugs has much effect on these negative symptoms. A representative group of antipsychotic drugs, both older typical agents and newer atypical agents, with selective advantages and disadvantages is presented in Table 18–3.

Antipsychoticdrugs are often used with lithium in the initial treatment of mania (discussed below). Olanzapine has been used as the sole agent in the manic phase and acts as a mood stabilizer in bipolar disorder. The antipsychotic drugs are also used in the management of psychotic symptoms of schizoaffective disorders, in Tourette’s syndrome, and for management of toxic psychoses caused by overdosage of certain CNS stimulants. Molindone, although rarely used in schizophrenia, is effective in treating Tourette’s syndrome. The newer atypical antipsychotics have been used to allay psychotic symptoms in patients with Alzheimer’s disease or Parkinson’s disease.

In addition, most phenothiazines have antiemetic actions related to D2 and H1 receptor blockade. The latter also contributes to their use as antipruritics and sedatives.

Adverse Effects

Most of the unwanted effects of antipsychotics are extensions of their known pharmacologic actions (Tables 18–1 and 18–4). A few are due to allergic and idiosyncratic reactions.

Extrapyramidal Symptoms

A Parkinson-like syndrome with bradykinesia, rigidity, and tremor is an extremely common adverse effect occurring early during treatment with older agents. These dose-dependent extrapyramidal effects are reversible by decreasing the dose of the drug or by treating the symptoms with conventional antiparkinsonism drugs of the antimuscarinic type (Chapter 17). Extrapyramidal toxicity occurs most frequently with haloperidol and the more potent phenothiazines (e.g., fluphenazine, trifluoperazine). Pseudoparkinsonism occurs infrequently with clozapine and the newer drugs. Other reversible neurologic dysfunctions that occur more frequently with older agents include akathisia and dystonias; these usually respond to treatment with diphenhydramine or muscarinic-blocking agents.

Tardive dyskinesia is a disorder characterized by choreoathetoid movements of the muscles of the lips, tongue, and jaw. This important toxicity may be irreversible. Tardive dyskinesias tend to develop after several years of antipsychoticdrug therapy but have appeared as early as 6 months. Antimuscarinic drugs that usually ameliorate other extrapyramidal effects generally increase the severity of tardive dyskinesia symptoms. There is no effective drug treatment for tardive dyskinesia. Switching to clozapine does not exacerbate the condition. Tardive dyskinesia may be attenuated temporarily by increasing neuroleptic dosage; this suggests that tardive dyskinesia may be caused by dopaminereceptor sensitization.

Autonomic Effects

Autonomic effects result from blockade of peripheral muscarinic receptors and α adrenoceptors and are more difficult to manage in elderly patients. Tolerance to some of the autonomic effects occurs with continued therapy. Thioridazine has the strongest autonomic effects and haloperidol the weakest. Clozapine and most of the atypical drugs have intermediate autonomic effects (Table 18–2).

Muscarinic receptor blockade, with atropine-like effects (dry mouth, constipation, urinary retention, and visual problems), are often pronounced with the use of thioridazine and phenothiazines (e.g., chlorpromazine). These effects also occur with clozapine and most of the atypical drugs but not with ziprasidone or aripiprazole. Antimuscarinic CNS effects may include a toxic confusional state similar to that produced by atropine and the tricyclic antidepressants (Table 18–4).

Alpha receptor blockade, which manifests as postural hypotension, is a common adverse effect of many of these drugs, especially phenothiazines. In the elderly, measures must be taken to avoid falls resulting from postural fainting. All of the atypical drugs can cause orthostatic hypotension. Failure to ejaculate is common in men treated with the phenothiazines (Table 18–4).

Metabolic and Endocrine Effects

Weight gain is very common, especially with several of the atypical agents including clozapine and olanzapine. Monitoring of food intake, especially carbohydrates, may be necessary. Hyperglycemia may develop, but whether secondary to weight gain–associated insulin resistance or due to other potential mechanisms remains to be clarified. Hyperprolactinemia in women results in the amenorrhea-galactorrhea syndrome and infertility; in men, loss of libido, impotence, and infertility may result.

Most of these endocrine side effects are predictable manifestations of dopamine D2 receptor blockade in the pituitary; dopamine is the normal inhibitory regulator of prolactin secretion.

Neuroleptic Malignant Syndrome

Patients who are particularly sensitive to the extrapyramidal effects of antipsychoticdrugs may develop a life-threatening malignant hyperthermic syndrome. The symptoms include muscle rigidity, impairment of sweating, hyperpyrexia, and autonomic instability. Drug treatment involves the prompt use of dantrolene and perhaps dopamineagonists.

Sedation

The sedative properties of antipsychoticdrugs are variable (Table 18–1). They are more marked with phenothiazines (especially chlorpromazine) than with other antipsychotics. Although it was previously thought that sedation enhanced the efficacy of these drugs, current practice indicates that these effects offer no benefit and can be detrimental in withdrawn patients with psychosis. Fluphenazine and haloperidol are the least sedating of the older drugs; aripiprazole appears to be the least sedating of the newer agents.

Miscellaneous Effects

Visual impairment caused by retinal deposits has occurred with thioridazine. At high doses, thioridazine may also cause severe conduction defects in the heart resulting in fatal ventricular arrhythmias. Ziprasidone prolongs the QT interval of the electrocardiogram, which may lead to cardiac arrhythmias (e.g., torsade de pointes). Clozapine causes a small but important (1 to 2%) incidence of agranulocytosis, and at high doses has caused seizures.

Bipolar affective (manic-depressive) disorder is a very serious psychiatric condition characterized by cyclic attacks of mania with many symptoms of paranoid schizophrenia. The episodes of mood swings characteristic of this condition are generally unrelated to life events. Although the exact biologic disturbance has not been identified, a preponderance of catecholamine-related activity is thought to be present during the manic phase. Drugs that increase this activity tend to exacerbate mania, whereas those that reduce activity of dopamine or norepinephrine relieve mania. Acetylcholine or glutamate may also be involved. The nature of the abrupt switch from mania to depression experienced by some patients is uncertain. Bipolar disorder has a strong familial component, and genetic studies have identified at least three possible linkages to different chromosomes.

Lithium is often referred to as an “antimanic” drug, but is more properly considered a “mood-stabilizing” agent because its primary action is to prevent mood swings. Carbamazepine has also been recognized as effective in some manic-depressive patients despite not being formally approved for such use. Valproic acid has recently been approved for the treatment of mania, and is being evaluated as a mood stabilizer. Atypical antipsychotics, beginning with olanzapine, are being investigated and approved as antimanic agents and potential mood stabilizers (Figure 18–1).

Lithium is absorbed rapidly and completely from the gut. The drug is distributed throughout the body water. Lithium is not metabolized and is cleared by the kidneys at a rate one-fifth that of creatinine. The half-life of lithium is about 20 hours. Plasma levels should be monitored, especially during the first weeks of therapy, to establish an effective and safe dosage regimen. Major problems can arise with lithium use if it accumulates within the body. The therapeutic plasma concentration range is 0.6 to 1.4 mEq/L. Plasma levels of the drug may be altered by changes in body water. Dehydration, or treatment with thiazide diuretics, may result in an increase of lithium in the blood to toxic levels. Theophylline increases the renal clearance of lithium. The pharmacokinetics of lithium are characterized in Table 18–5.

Mechanism of Action

The mechanism of action of lithium is not well defined. Three major possibilities exist: (1) an effect on electrolyte and ion transport, (2) an effect on neurotransmitters and their release, and (3) an effect on second messengers and intracellular enzymes that mediate transmitter actions.

Lithium is closely related to sodium in its properties and can substitute for sodium in generating action potentials and in Na+-Na+ exchange across membranes, inhibiting this process. Lithium also appears to enhance some of the actions of serotonin and may decrease norepinephrine and dopamine turnover. It may also augment the synthesis of acetylcholine. However, one of the best-defined actions of lithium is its effect on inositol phosphates. The drug inhibits the recycling of neuronal membrane phosphoinositides involved in the generation of inositol trisphosphate (IP3) and diacylglycerol (DAG). These second messengers are important in amine neurotransmission, including that mediated by central adrenoceptors and muscarinic receptors (Figure 18–2). It is hypothesized that the activity in phosphatidylinositol 4,5-bisphosphate (PIP2)–dependent pathways is abnormally increased in manic episodes and that lithium causes a selective depression of the overactive circuits.

Clinical Use

Lithium carbonate is used in the treatment of bipolar disorder. Maintenance therapy with lithium decreases manic behavior and reduces both the frequency and the magnitude of mood swings. Neuroleptics or benzodiazepines are commonly required at the initiation of treatment because lithium has a slow onset of action. Antidepressant drugs are often required concurrently during maintenance. Alternative drugs of value in bipolar disorder include olanzapine and valproic acid and several other antiseizure drugs (e.g., clonazepam, gabapentin, lamotrigine).

Lithium may also be used in conjunction with antipsychotic agents for the treatment of schizophrenia in patients who might otherwise be treatment resistant with regular antipsychotic agents. Another interesting application of lithium is as an adjunct to tricyclic antidepressants and selective serotonin reuptake inhibitors in patients with unipolar depression who do not respond fully to monotherapy with the antidepressant. For this application, concentrations of lithium at the lower end of the recommended range for manic depressive illness appear to be adequate.

Adverse Effects

Adverse neurologic effects of lithium at therapeutic levels include tremor, sedation, ataxia, and aphasia. Any marked changes in mental behavior such as confusion or withdrawal or bizarre motor movements may indicate drug toxicity and serum concentrations should be evaluated. Thyroid enlargement may occur, but thyroid dysfunction is rare. Reversible nephrogenic diabetes insipidus occurs commonly at therapeutic drug levels. Edema is a frequent adverse effect of lithium therapy and may be related to some effect of lithium on sodium retention. Transient acneiform skin eruptions have been noted early in lithium treatment. Leukocytosis is always present during lithium treatment. The use of lithium during pregnancy may increase the incidence of congenital cardiac anomalies (Ebstein’s anomaly). Lithium is contraindicated in nursing mothers.

Antipsychoticdrugs have had a major impact on psychiatric treatment over the last 50 years. They have shifted the care of patients from mental institutions to the community. For many patients, this shift has provided a better quality of life. As a result, many physical therapists will have the opportunity to treat such patients. Regardless of the reason for which they have been referred for rehabilitation, they will benefit from these agents by improved behavior and reality perception, which will ultimately improve their rehabilitation outcomes.

The medical staff must always weigh the risk of side effects with the benefits of the antipsychoticdrugs. Some adverse effects such as sedation, dry mouth, and constipation are only symptomatic and can usually be tolerated. Physical therapists must be aware of orthostatic hypotension and the potential risk of falls and should educate the patient regarding such events. The major adverse effects associated with the use of the older antipsychotic agents are the extrapyramidal effects of bradykinesia, tremor, and rigidity. Therapists should be aware of any changes in balance, posture, or involuntary movements and report these to the attending physician.

Adverse Drug Reactions

• Sedation
• Orthostatic hypotension
• Extrapyramidal effects

Effects Interfering with Rehabilitation

• Sedation
• Bradykinesia, tremor, rigidity
• Balance and posture problems
• Tardive dyskinesia

Possible Therapy Solutions

• Orthostatic hypotension: compressive garments, tilt table, allow sufficient time for the patient’s blood pressure to adjust to postural changes; monitor response to exercise.

Potentiation of Functional Outcomes Secondary to Drug Therapy

• In many cases, these medications can help with functional outcomes at both the activity and participation levels.

Brief History: The patient is a 56-year-old male who was referred to rehabilitation by his family physician after several reported falls and increasing problems with balance as per his wife’s observation. The patient has a history of schizophrenia that has been well controlled with medication. Hesitantly, the patient also reports several recent episodes of being lightheaded. He states he has begun to feel extremely stiff at times and has a hard time moving.

Current Medical Status and Drug Therapy: The patient has no current medical problems. Recent neurologic diagnostic tests have ruled out any CNS pathology. The patient is currently taking pantoprazole (a proton pump inhibitor) and risperidone. The patient states that his prescribing practitioner recently increased his dose of risperidone after a recent psychotic episode.

Rehabilitation Setting: The patient presented in no acute physical distress. Evaluation revealed that the patient suffered from orthostatic hypotension evident by a rapid fall in blood pressure with positional changes. The patient also presented with postural rigidity evident by resistance to passive stretch in both the upper extremities and lower extremities; it was more severe in the lower extremities. The patient did not demonstrate a resting tremor. Balance testing using the Clinical Test for Sensory Integration and Balance revealed increased sway in conditions with absent or impaired vision and impaired somatosensory input.

Problem/Clinical Options: Consultation between the physical therapist and the patient’s prescribing health-care provider determined that the patient may be experiencing adverse effects of postural hypotension and extrapyramidal system dysfunction that can be associated with the use of risperidone at high doses. Since this dose of medication was controlling the patient’s psychosis, the prescribing practitioner was reluctant to make any abrupt changes in the patient’s medication. Therefore, the physical therapist educated the patient and his wife about postural hypotension and how to prevent episodes of syncope. The patient also began a program of stretching and functional balance training. The patient, the physical therapist, and prescribing practitioner agreed to follow the patient’s symptoms closely. The patient’s condition would be reevaluated in 3 months.

Antipsychotic Agents

Aripiprazole (Abilify)

Oral: 10-, 15-, 20-, 30-mg tablets

Chlorpromazine (generic, Thorazine, others)

Oral: 10-, 25-, 50-, 100-, 200-mg tablets; 10 mg/5 mL syrup; 30, 100 mg/mL concentrate

Oral sustained release: 30-, 75-, 150-mgcapsules

Rectal: 25-, 100-mg suppositories

Parenteral: 25 mg/mL for IM injection

Clozapine (generic, Clozaril)

Oral: 25-, 100-mg tablets

Fluphenazine (generic, Permitil, Prolixin)

Oral: 1-, 2.5-, 5-, 10-mg tablets; 2.5 mg/5 mL elixir; 5 mg/mL concentrate

Parenteral: 2.5 mg/mL for IM injection

Fluphenazine esters (generic [decanoate only], Prolixin Enanthate, Prolixin Decanoate)

Parenteral: 25 mg/mL

Haloperidol (generic, Haldol)

Oral: 0.5-, 1-, 2-, 5-, 10-, 20-mg tablets; 2 mg/mL concentrate

Parenteral: 5 mg/mL for IM injection

Haloperidol ester (Haldol Decanoate)

Parenteral: 50-, 100-mg/mL for IM injection

Loxapine (Loxitane)

Oral: 5-, 10-, 25-, 50-mg capsules; 25 mg/mL concentrate

Parenteral: 50 mg/mL for IM injection

Mesoridazine (Serentil)

Oral: 10-, 25-, 50-, 100-mg tablets; 25 mg/mL concentrate

Parenteral: 25 mg/mL for IM injection

Molindone (Moban)

Oral: 5-, 10-, 25-, 50-, 100-mg tablets; 20-mg/mL concentrate

Olanzapine (Zyprexa)

Oral: 2.5-, 5-, 7.5-, 10-, 15-, 20-mg tablets;5-, 10-, 15-, 20-mg orally disintegrating tablets

Perphenazine (generic, Trilafon)

Oral: 2-, 4-, 8-, 16-mg tablets; 16 mg/5 mL concentrate

Parenteral: 5 mg/mL for IM or IV injection

Pimozide (Orap)

Oral: 1-, 2-mg tablets

Prochlorperazine (generic, Compazine)

Oral: 5-, 10-mg tablets; 5 mg/5 mL syrup

Oral sustained release: 10-, 15-mg capsules

Rectal: 2.5-, 5-, 25-mg suppositories

Parenteral: 5 mg/mL for IM injection

Promazine (generic, Sparine)

Oral: 25-, 50-mg tablets

Parenteral: 25-, 50-mg/mL for IM injection

Quetiapine (Seroquel)

Oral: 25-, 100-, 200-, 300-mg tablets

Risperidone (Risperdal)

Oral: 0.25-, 0.5-, 1-, 2-, 3-, 4-mg tablets; 1 mg/mL oral solution

Thioridazine (generic, Mellaril, others)

Oral: 10-, 15-, 25-, 50-, 100-, 150-, 200-mg tablets; 30, 100-mg/mL concentrate; 25, 100 mg/5 mL suspension

Thiothixene (generic, Navane)

Oral: 1-, 2-, 5-, 10-, 20-mg capsules; 5 mg/mL concentrate

Trifluoperazine (generic, Stelazine)

Oral: 1-, 2-, 5-, 10-mg tablets; 10 mg/mL concentrate

Parenteral: 2 mg/mL for IM injection

Triflupromazine (Vesprin)

Parenteral: 10, 20 mg/mL for IM injection

Ziprasidone (Geodon)

Oral: 20-, 40-, 60-, 80-mg capsules

Parenteral: 20-mg/mL for IM injection

Mood Stabilizers

Carbamazepine (generic, Tegretol, others)

Oral: 200-mg tablets, 100-mg chewable tablets; 100 mg/5 mL oral suspension.

Oral extended release: 100-, 200-, 400-mg tablets; 200-, 300-mg capsules

Divalproex (Depakote)

Oral: 125-, 250-, 500-mg delayed-release tablets

Lithium Carbonate (generic, Eskalith)

(Note: 300-mg lithium carbonate = 8.12 mEq Li+)

Oral: 150-, 300-, 600-mg capsules; 300-mg tablets; 8 mEq/5 mL syrup

Oral sustained release: 300-, 450-mg tablets

Valproic acid (generic, Depakene)

Oral: 250-mg capsules; 250 mg/5 mL syrup