Options in the Treatment of Schizophrenia

By Roger W Sommi | Drug Topics, April 1997 | Go to article overview

Options in the Treatment of Schizophrenia


Roger W Sommi, Drug Topics


The treatment of schizophrenia and other psychotic disorders has been significantly changed with the advent of the newer, so-called atypical antipsychotic drugs: clozapine, risperidone, olanzapine, and-soon to be approved-sertindole. Arguably, antipsychotics have been the single most important advance in the treatment of schizophrenia, allowing patients to return to society and adapt to life outside of institutions. The atypical antipsychotics are a further refinement of this treatment.

The term atypical describes the lower potential of this class of drugs to produce extrapyramidal symptoms (EPS) (dystonia, pseudoparkinsonism, and akathisia) and to cause hyperprolactinemia (mediated by dopamine-2 receptor blockade). These atypical agents show increased efficacy in treatment-refractory schizophrenia and an enhanced effect on negative symptoms of schizophrenia, such as alogia (poverty of speech), anhedonia (inability to experience pleasure), blunted effect, apathy, attentional impairment, and avolition (impairment of mobility and speech). The use of atypical antipsychotic agents has thereby brought renewed hope for improved response and tolerability in the treatment of psychoses.

Psychosis is associated with many psychiatric illnesses, including schizophrenia, bipolar disorder, and depression. Psychosis can also be associated with endocrine and other metabolic disorders, dementia, seizure disorders, drug intoxication, and as an adverse effect of several medications. Economically, psychosis is estimated to cost more than $78 billion in morbidity and mortality in persons with schizophrenia and bipolar disorders combined.

Conventional antipsychotics are effective in controlling many of the symptoms of psychosis, allowing patients to function at a higher level. However, noncompliance due to side effects is common and accounts for a high rate of recidivism. Approximately 20% to 40% of persons with schizophrenia fail to respond to conventional drugs, and there is a 4% per year incremental risk of tardive dyskinesia in patients taking typical antipsychotics. In addition, 20% to 30% of all prescriptions for antipsychotics are for elderly individuals who are at particular risk for falls, cognitive dysfunction associated with anticholinergic effects, cardiovascular effects, and tardive dyskinesia. These adverse effects significantly limit the usefulness of conventional agents. Clearly, the atypical agents are welcome due to their greater efficacy and tolerability.

The development of the newer, atypical antipsychotic agents has focused on minimizing anticholinergic, cardiovascular, extrapyramidal, and sedative effects. Overall, the newer agents have been relatively successful in achieving a more focused pharmacologic profile. This has led to a greater degree of patient acceptance, increased compliance, and reduced recidivism and cost of care.

Insights into the role of serotonin (5-HT) in diseases such as schizophrenia have also led to the development of agents with relatively potent 5-HT antagonist effects. Conventional agents were developed based on the premise that dopamine-2 receptor (D-2) blockade was essential for antipsychotic effects. This premise led to the development of several agents of varying potency at this receptor. The atypicals, on the other hand, have a relatively higher ratio of -HT-2/D-2 antagonist effects.

Following is a discussion of the newer agents and clinical guidelines for use. Table 1 lists the atypical agents and their daily dosages. Table 2 is a comparison of efficacy and side effects of conventional versus atypical antipsychotics.

CLOZAPINE

Clozapine is a dibenzodiazepine antipsychotic drug with actions at several major neurotransmitter sites. Clozapine has antagonist action at 54-HT-2 and 1) 2 and I-2 receptors. Antagonist effects of dopamine-3, D4, and antimuscarinic effects also may play a role in its unique effects. Clozapine also has relatively potent alpha-1, alpha-2, beta-adrenergic, and histamine-1 (rl) antagonist effects that account for its cardiovascular and sedative properties. …

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