Clozapine observational studies

Observational studies Beneficial effects have been reported in patients with schizophrenia (n = 10) and schizoaffective disorder (n = 10) who were treated with a combination of clozapine and lithium (68). When lithium (serum lithium concentration titrated to at least 0.5 mmol/1) was added to clozapine 100—800 mg/day there was a positive effect in the patients with treatment-resistant schizoaffective disorder, but not in the patients with schizophrenia. 

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. 

For example, withdrawal of haloperidol in one patient revealed little change in either mental status or involuntary movements 3 weeks after discontinuation ( 478). In contrast, there was a marked deterioration in mental status and involuntary movements in this same patient 1 week after clozapine withdrawal. This rebound psychosis was attributed to increased dopamine release, a mechanism suggested by earlier observations made after withdrawal studies in humans and animals. For example, a study of the effects of abrupt withdrawal in rats showed increased and decreased striatal basal dopamine release with discontinuation of clozapine and haloperidol, respectively ( 479). The exacerbation of dyskinesia after clozapine withdrawal suggests that human nigrostriatal dopamine receptors (putatively involved in the emergence of dyskinetic movements) may be altered pharmacologically by this drug. 

There has been one comprehensive meta-analysis including over 80 studies and over 30 000 patients (489). 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 (490,491). In one study, excessive appetite was a more frequent adverse event in patients treated with olanzapine versus haloperidol (24 versus 12%) (185). Loss of weight has been observed after withdrawal of neuroleptic drugs (492). 

Suicide, suicidality, and suicidal ideation are very serious problems in patients with schizophrenia. Based on general observations that 1-2% of patients with schizophrenia complete suicide within 1 year after initial attempts, the authors of a retrospective study of 295 neuroleptic drug-resistant patients with schizophrenia who had taken clozapine monotherapy for at least 6 months would have expected as many as 10 or 11 successful suicides or suicide attempts, but none was observed (107). 

It is unquestionable that current antipsychotic therapy is comparatively effective and at the same time disappointingly insufficient. These drugs can treat the symptoms of the disorder but certainly do not provide a cure. The great majority of patients will have between 20 and 50% reduction in symptom severity. Some will have marked improvement beyond these figures, although this is rare, and a small minority of patients will be entirely refractory to all forms of treatment currently available. Full results from antipsychotic therapy take considerable time (although initial effects on some positive symptoms can be seen in a few days). Whereas the effect of benzodiazepines on anxiety and sleep can be measured in hours, and that of antidepressants in weeks, the full impact of antipsychotic therapy is measured in months. A study by Robinson et al. (1999) showed that only 20% of patients responded after 4 weeks of treatment with conventional antipsychotics, whereas after 26 weeks the number of responders had grown to about 70%. Similar results were reported with clozapine treatment, where a response was observed in 40% of subjects after 4 weeks and in 60% of subjects by week 17 (Kane et al., 2001). Clinical observations clearly show that improvement in... 

Olanzapine and clozapine have been compared in a double-blind study by Lilly Research Laboratories for 18 weeks in 220 patients with schizophrenia conclusions were based on the one-sided lower 95% confidence limit of the treatment effect observed from the primary efficacy... 

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