Clozapine studies/trials

Clozapine Longitudinal Trials. In a naturalistic study design, Banov et al. (300) found clozapine was an effective long-term treatment in mood disorders, particularly nondepressed affective patients. After a chart review, the authors identified 193 treatment-resistant patients, including the following ... 

To date, clozapine remains the only drug with proven and superior efficacy in treatment-resistant patients, and it is currently the only drug approved for the treatment-resistant schizophrenic. Studies have shown a response of approximately 30% to 50% in these well-defined treatment-resistant patients. Clinical trials have consistently found clozapine to be superior to traditional antipsychotics for treatment-refractory patients, and it is efficacious even after nonresponse to other SGAs and in partially responsive patients. It is often rapidly effective even in those who have had a poor response to other medication for years. Recent studies have demonstrated that it has a beneficial effect for aggression and suicidality, which led to the Food and Drug Administration (FDA) approval for the treatment of suicidal behavior in people with psychosis.41... 

Finally, an intriguing possible future therapy arises from a radical idea of Horrobin (2001) that schizophrenia is a nutritional disorder linked to a decreased intake of essential polyunsaturated fatty acids. Recent 31P-MRS studies have shown changes in plasma membrane phospholipids in the neocortex of unmedicated schizophrenics, which would have deleterious consequences on synaptic neurotransmission (Fukuzako, 2001). A clinical trial with the co6 fatty acid derivative ethyleicosa-pentaenoic acid (LAX-101) in patients who had been unresponsive to clozapine, reported that a daily dose of 2g LAX-101 gave a 26% improvement in symptoms over 12 weeks compared with 6% with placebo (Peet and Horrobin, 2001). Maybe in... 

Of the atypical antipsychotics, clozapine, olanzapine, and risperidone have been studied the most. Clozapine was used to treat 10 treatment refractory acutely manic patients and 15 schizomanic patients. Using reduction in the YMRS score as the outcome measure, 72% improved (non-rapid cycling, bipolar patients). Comparison of olanzapine (5-20 mg) with placebo showed significant reduction of the YMRS in 49% vs. 24% of subjects by 3 weeks, with significant change evident by the first week. In a trial comparing risperidone at 6 mg with haloperidol at 10 mg and low-dose lithium (800-1200 mg/day) efficacy was similar over the 28 days of the trial. 

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. 

There have been numerous trials of use of the atypical antipsychotics in patients with developmental disabilities, but most of these trials were uncontrolled open-labeled studies or case reports (Aman and Madrid, 1999). Findings were reported for 86 adults and 1 child with prominent self-injury. The reports of adults assessed clozapine (1 report) and risperidone (4 reports). Improvement was observed for a majority of participants in all of these trials. The patients presented with a multitude of conditions, ranging from nonspecific MR and associated behavior problems, to pervasive developmental disorders (including autism), to various psychiatric disorders, including schizophrenia and manic disorder. Self-injury appeared to respond to treatment regardless of concomitant condition. In the only clozapine report with a child (who had autistic disorder), a mean dose of 283 mg/day caused a transient reduction in self-injury. 

The previous course of a disorder and its resolution with treatment can be a key element of patient selection. Investigation of the effects of a drug in de novo diagnosed, first-episode patients will lead to different conclusions than a trial in mainly chronic, multitreatment-exposed patients. Some key inclusion criteria can be defined according to the treatment response history of patients a study with clozapine in treatment resistant schizophrenic patients (Kane et ah. 1988 see Chapter 2) is an example for this. 

Remembering that when a large number of patients are studied, a relatively small effect can become statistically significant, this evidence seems to establish that clozapine is more effective than conventional agents. Because clozapine is marketed in over 20 countries, there has been wide clinical experience and several open trials supporting its efficacy as well. 

In 1996, Pilowsky and coworkers (111) found that olanzapine-treated patients showed significantly lower occupancy of striatal D 2 receptors compared with neuroleptic-treated patients. In support of the clinical trial data, PET studies have shown that 5-HT 2 and D2 receptor occupancies with olanzapine and clozapine are comparable, and that olanzapine should have a low propensity to evoke acute EPS (112). 

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. 

Whether diabetes is associated, and to what extent, with a particular antipsychotic drug or a particular type of antipsychotic drug is a matter of debate since the two most commonly used atypical antipsychotic drugs are risperidone and olanzapine, comparison of these two drugs has been a recent focus of attention. There are more case reports for clozapine and olanzapine, but the studies discussed below have reached conflicting results further information from clinical trials is needed. 

There has been one comprehensive meta-analysis including over 80 studies and over 30 000 patients (814). A meta-analysis of trials of neuroleptic drugs showed the following mean weight gains in kg after 10 weeks of treatment clozapine, 4.5 olanzapine, 4.2 thioridazine, 3.2 sertindole, 2.9 chlorpromazine, 2.6 risperidone, 2.1 haloperidol, 1.1 fluphenazine, 0.43 ziprasidone 0.04 molindone, —0.39 placebo, —0.74... 

Experiences in uncontrolled open studies in Chinese patients have been summarized (7). The most common adverse effect of clozapine was hypersalivation, followed by sedation. Mandatory blood monitoring is considered an obstacle in persuading some patients to undergo a trial of clozapine, mainly for cultural reasons, summed up by the Chinese proverb that a hundred grains of rice make a drop of blood. ... 

The combination of clozapine and lithium has been studied in a randomized controlled trial in 10 patients with schizophrenia and 10 with a schizoaffective disorder taking clozapine with either lithium or placebo for 4 weeks (299). The combination was well tolerated, except for reversible neurotoxic reactions in two patients with schizophrenia, and safety measures showed no significant variations. The authors concluded that the lithium added to clozapine appears to afford potential benefit in schizoaffective disorders without harmful effects for schizophrenia, however, it did not afford improvement but posed a risk of lithium toxicity. 

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