Schizophrenia typical antipsychotics

Lee, C. et al. (2006). Treatment with olanzapine, risperidone or typical antipsychotic drugs in Asian patients with schizophrenia. Aust. N. Z. J. Psychiatry, 40, 437-45. 

Kaiser etal. (2000) DRD4 (48-bp repeat) Typical antipsychotic drugs, clozapine No association. Schizophrenia Caucasian... 

Joober etal. (1999) HTR2A (T102C) Typical antipsychotic drugs Trend toward association between C/C genotype and poor response among Schizophrenia Caucasian... 

Clozapine is the prototype of atypical antipsychotic drugs, and it has been used effectively to treat patients with schizophrenia who are unresponsive or intolerant to typical antipsychotics [7]. Clozapine is characterized as atypical by its preferential binding to serotonin (5-HT2) and dopamine D4 receptors (D4) relative to dopamine D2 receptors [8]. A recent body of work also suggests that atypicality may be defined by the rate at which clozapine dissociates from D2 receptors. Specifically, clo-... 

The positive symptoms are the most responsive to antipsychotic medications, such as chlorpromazine or halo-peridol. Initially, these drugs were thought to be specific for schizophrenia. However, psychosis is not unique to schizophrenia, and frequently occurs in bipolar disorder and in severe major depressive disorder in which paranoid delusions and auditory hallucinations are not uncommon (see Ch. 55). Furthermore, in spite of early hopes based on the efficacy of antipsychotic drugs in treating the positive symptoms, few patients are restored to their previous level of function with the typical antipsychotic medications [2]. 

The typical antipsychotic drugs, which for 50 years have been the mainstay of treatment of schizophrenia, as well as of psychosis that occurs secondary to bipolar disorder and major depressive disorder, affect primarily the positive symptoms[10]. The behavioral symptoms, such as agitation or profound withdrawal, that accompany psychosis, respond to the antipsychotic drugs within a period of hours to days after the initiation of treatment. The cognitive aspects of psychosis, such as the delusions and hallucinations, however, tend to resolve more slowly. In fact, for many patients the hallucinations and delusions may persist but lose their emotional salience and intrusiveness. The positive symptoms tend to wax and wane over time, are exacerbated by stress, and generally become less prominent as the patient becomes older. 

Clozapine (Clozaril). Clozapine was introduced over 30 years ago but has only been available in the United States since 1990. It remains the medication of choice for treatment-resistant schizophrenia. Since its introduction, it has been used to treat acute mania with excellent results. Furthermore, it avoids the potential for tardive dyskinesia posed by haloperidol and the other typical antipsychotics. 

Chlorpromazine (Thorazine). The first of the modem antipsychotics was developed in the early 1950s, not as an antipsychotic but as an antihistamine that could be used during surgery to minimize the amount of anesthesia needed. It was hoped that this would lessen the danger of shock (dangerously low blood pressure) during surgery. It was actually quite successful, but it was soon found to have other benefits. Of key importance, it could relieve the positive symptoms of schizophrenia. In the years to follow, this led to the production of other similar antipsychotics collectively known as the typical antipsychotics. 

In admittedly oversimplified terms, it is believed that hyperactivity of dopamine neurons in the mesolimbic pathway contribute to the positive symptoms of schizophrenia. All the typical antipsychotics are believed to work by reducing the activity of the mesolimbic dopamine pathway. More specifically, they do this by blocking dopamine receptors on the nerve cells. Over a period of 1-3 weeks, the dopamineblocking effect of the typical antipsychotic begins to relieve the positive symptoms of schizophrenia. 

In contrast, it is often hypothesized that the negative symptoms of schizophrenia are a result of decreased activity of the mesocortical dopamine pathway. Unfortunately, dopamine blocking by typical antipsychotics in the mesocortical pathway does not improve the negative symptoms, and may even worsen them. 

Molindone (Moban). Molindone is another of the medinm potency antipsychotics. There are two featnres that set it apart. First, it is less prone to cansing weight gain than other antipsychotics. As a result, it is sometimes preferred for obese schizophrenia patients. Second, although typical antipsychotics do not necessarily cause seizures, they may make them more likely to occur in people who are already prone to seizures. There is some evidence to suggest that molindone may be the least likely antipsychotic to increase the vulnerability to seizures. For this reason, molindone is frequently used to treat patients with schizophrenia who also have epilepsy. 

In the era of modern psychiatry, the treatment of schizophrenia has undergone two revolutions. The first revolution began in the 1950s with the debut of the typical antipsychotics, the first proven effective treatments for psychosis. These medications enabled patients who in years past would have been relegated to long-term hospitalization to return to the community. 

The second revolution began in the past 10 years with the arrival of the atypical antipsychotics. Although the atypicals are no panacea for schizophrenia, they represent an advance in at least three areas. First, they lessen the burden of antipsychotic side effects and therefore frequently increase adherence dramatically. Second, the atypicals may treat all of the schizophrenia symptom clusters (positive, negative, mood, cognitive), whereas the typical antipsychotics chiefly treat the positive symptoms. Third, atypical antipsychotics sometimes benefit patients whose schizophrenia is unresponsive to typical antipsychotics. 

In the residual phase, the patient is unlikely to have an acute exacerbation even if (s)he stops taking an antipsychotic. Nevertheless, (s)he may still require treatment for residual symptoms. If medications are continued during a residual phase of schizophrenia, an atypical antipsychotic is preferred. Because positive symptoms are no longer a prominent aspect of the illness, there is usually little justification for using a typical antipsychotic and thereby exposing a patient to the risk of tardive dyskinesia. Moreover, atypical antipsychotics likely better treat the remaining negative symptoms of residnal schizophrenia. 

Schizoid Personaiity Disorder (SPD). Again, there is very little research to guide in the selection of medications to treat the schizoid patient. If we conceptualize the symptoms of SPD as most resembling the negative symptoms of schizophrenia, the choice of agents would tend to favor the atypical antipsychotic drugs as opposed to the older typical antipsychotics. Consequently, we also recommend low doses of an atypical antipsychotic as a first-line treatment for SPD. 

Antipsychotics in a few small studies have been shown to be helpful. To date this research is limited to typical antipsychotics. Nevertheless, the excellent track record of atypical antipsychotics in treating schizophrenia and the lower burden of side effects lead us to recommend atypical antipsychotics as a first-line treatment for STPD as well. Low doses of risperidone, olanzapine, quetiapine, ziprasidone, or aripiprazole are all reasonable options. If no therapeutic effect is observed, doses should be increased. 

Hunter RH, Joy CB, Kennedy E, Gilbody SM, Song F. Risperidone versus typical antipsychotic medication for schizophrenia. Cochrane Database Syst Rev 2003. Issue 2. 

Efficacy in short-term treatment. From studies in adult schizophrenia, it is evident that clozapine treatment has at least the same or superior antipsychotic effect, compared to typical antipsychotics. In some studies, clozapine was superior with regard to symptom reduction in severe and acute schizophrenic patients. As the guidelines do not allow the use of clozapine as a first-choice drug, most patients have been treated before with at least two atypical or typical antipsychotics. Only one controlled trial has assessed the efficacy of clozapine in child and adolescent psychiatry. In this study (Kumra et ah, 1996), clozapine was found to be superior to haloperidol in all measures of psychosis, and showed a striking superiority for both positive and negative symptoms. 

Investigators have attempted to assess the impact of antipsychotics on the cognitive and the behavioral disturbances characteristic of schizophrenia. The antipsychotics decrease typical, but nonspecific, positive symptoms such as hallucinations and delusions ( Table 5-4). Thus, labeling them as antischizophrenic agents is too restrictive inasmuch as they also benefit such disparate disorders as psychotic depression or mania, iate-onset paraphrenia, and organic-induced psychosis. As the symptoms reduced by neuroleptics are typical of psychosis in general, these agents are best conceptualized as a type of antipsychotic. 

Younger patients with schizophrenia may be less responsive to pharmacotherapy than adult patients ( 164, 165). Nonresponse to typical antipsychotics is as high as 40% to 50% in some reports. Thought disorder is the most drug-refractory of the classic psychotic symptoms in children and adolescents with schizophrenia. Thus, even when the more florid symptoms (e.g., hallucinations and delusions) abate following treatment with antipsychotics, these patients frequently continue to have substantial impairment in social functioning and scholastic performance. 

Among the atypical antipsychotics, clozapine has the most convincing evidence of efficacy in children and adolescents with schizophrenia ( 166,167, 170). Kumar and colleagues (171) conducted a double-blind, randomized trial of clozapine versus haloperidol in 21 children and adolescents (mean age = 14 years) whose psychosis had been previously unresponsive to typical antipsychotics. Clozapine at a mean dose of 176 mg per day was superior to haloperidol for both positive and negative symptoms. These results are consistent with an open-label study by Remschmidt and colleagues (172). This group found that clozapine at a mean dose of 154 mg per day produced notable improvement in 27 of 36 (75%) adolescents with schizophrenia previously unresponsive to at least two trials of typical antipsychotics. 

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