Drug Treatment Of Psychoses

SHORT-TERM TREATMENT The antipsychotic drugs are effective in acute psychoses of unknown etiology, including mania, acute idiopathic psychoses, and acute exacerbations of schizophrenia. The best studied indications are for the acute and chronic phases of schizophrenia and in acute mania. Antipsychotic drugs also are used empirically in many other neuromedical and idio-pathic disorders with prominent psychotic symptoms or severe agitation.

Neuroleptic agents are effective antipsychotics and are superior to sedatives (e.g., barbiturates and benzodiazepines), or alternatives (e.g., ECT, other medical or psychological therapies). The "target" symptoms for which antipsychotic agents are especially effective include agitation, com-bativeness, hostility, hallucinations, acute delusions, insomnia, anorexia, poor self-care, negativism, and sometimes withdrawal and seclusiveness. More variable or delayed are improvements in motivation and cognition, including insight, judgment, memory, orientation, and functional recovery. The most favorable prognosis is for patients with acute illnesses of brief duration who had functioned relatively well prior to the illness.

No one drug or combination of drugs selectively affects a particular symptom complex in groups of psychotic patients. Drug responses in individual patients can be determined only by trial and error. Generally, "positive" (irrational thinking, delusions, agitated turmoil, hallucinations) and "negative" symptoms tend to respond (or not) together with overall clinical improvement, a tendency well documented with typical neuroleptics and modern atypical antipsychotic agents. Aripiprazole, clozapine, quetiapine, and ziprasidone induce less bradykinesia and other parkinsonian effects than do typical neuroleptics, and aripiprazole and ziprasidone are minimally sedating. Minimizing such side effects is sometimes interpreted clinically as specific improvement in impoverished affective responsiveness and energy level.

The short-term clinical superiority of modern antipsychotic agents over older neuroleptics has been particularly hard to prove. Nevertheless, in the U.S., the modern atypical agents dominate clinical practice, owing mainly to their perceived superior tolerability and acceptability.

It is important to simplify the treatment regimen and to ensure that the patient is receiving the drug. In cases of suspected severe and dangerous noncompliance or with failure of oral treatment, the patient can be treated with injections of fluphenazine decanoate, haloperidol decanoate, or other long-acting preparations, including risperidone microspheres.

Because the choice of an antipsychotic drug cannot be made reliably on the basis of anticipated therapeutic effect, drug selection often depends on likely tolerability of specific side effects, the need for sedation, or on a previous favorable response. If the patient has a history of cardiovascular disease or stroke and the threat from hypotension is serious, a modern atypical agent or a potent older neuroleptic should be used in the smallest dose that is effective (Table 18—1). For minimizing the risk of acute extrapyramidal symptoms, aripiprazole, clozapine, quetiapine, ziprasidone, or a low dose of olanzapine or risperidone should be considered. If the patient would be seriously discomfited by interference with ejaculation or if there are serious risks of cardiovascular or other autonomic toxicity, low doses of a potent neuroleptic might be preferred. If sedative effects are undesirable, a potent agent (aripiprazole or ziprasidone) is preferable. Small doses of antipsychotic drugs of high or moderate potency may be safest in the elderly, in whom the possible risk of stroke with risperidone and olanzapine must be considered. If hepatic function is compromised or there is a potential threat of jaundice, low doses of a high-potency agent may be used. The physician's experience with a particular drug may outweigh other considerations. Skill in the use of antipsychotic drugs depends on selection of an adequate but not excessive dose, knowledge of what to expect, and judgment as to when to stop therapy or change drugs.

A substantial minority of psychotic patients do poorly with any antipsychotic medicine, including clozapine. If a patient does not improve after a course of seemingly adequate treatment and fails to respond to another drug given in adequate dosage, the diagnosis should be reevaluated.

Usually 2-3 weeks or more are required to demonstrate obvious beneficial effects in schizophrenia patients; maximum benefit in chronically ill patients may require several months. In contrast, improvement of some acutely psychotic or manic patients can be seen within 48 hours. Aggressive dosing with high doses of an antipsychotic drug at the start of an acute episode of psychosis has not been found to increase either the magnitude or the rate of therapeutic responses. However, parenteral agents in moderate doses can bring about rapid sedation and may be useful in acute behavioral control. After the initial response, drugs usually are used in conjunction with psychological, supportive, and rehabilitative treatments.

There is no convincing evidence that combinations of antipsychotic drugs offer clear or consistent advantages. A combination of an antipsychotic drug and an antidepressant may be useful in some cases, especially in depressed psychotic patients or in cases of agitated major depression with psychotic features. The first combination antipsychotic/antidepressant (olanzapine/fluoxetine; symbyax) was approved in the U.S. for treatment of depressive episodes associated with bipolar disorder. However, antidepressants and stimulants are unlikely to reduce apathy and withdrawal in schizophrenia, and they may induce clinical worsening in some cases. Adjunctive addition of lithium or an antimanic anticonvulsant may add benefit in some psychotic patients with prominent affective, aggressive, or resistant symptoms.

Optimal dosage of antipsychotic drugs requires individualization to determine doses that are effective, well tolerated, and accepted by the patient. Dose-response relationships for antipsy-chotic and adverse effects overlap, and it can be difficult to determine an end-point of a desired therapeutic response. To achieve control of symptoms in the treatment of acute psychoses, the dose of antipsychotic drug is increased as tolerated during the first few days. The dose is then adjusted during the next several weeks as the patient's condition warrants. Severe and poorly controlled agitation usually can be managed safely by use of adjunctive sedation (e.g., with a benzodiazepine such as lorazepam) and close supervision in a secure setting. One must remain alert for acute dys-tonic reactions, which are especially likely to appear early with aggressive use of potent neu-roleptics, and for side effects such as hypotension. After an initial period of stabilization, regimens based on a single daily dose often are effective and safe. The time of administration may be varied to minimize adverse effects.

Table 18—3 gives the usual and extreme ranges of dosage for antipsychotic drugs used in the U.S. The ranges have been established for the most part in the treatment of young and middle-aged adult patients diagnosed with schizophrenia or mania. Acutely disturbed hospitalized patients often require higher doses of an antipsychotic drug than do more stable outpatients. However, the concept that a low or flexible maintenance dose often will suffice during follow-up care of a partially recovered or chronic psychotic patient is well supported by controlled trials.

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