Clozapine comparative studies

Zarate and his collaborators (301) conducted a systematic follow-up study, evaluating the number of hospitalizations in the 5 years before clozapine compared with the rehospitalization rate while on this agent. These authors found that monotherapy with clozapine reduced both the number of episodes and rehospitalizations in 17 previously severely ill affective patients. The yearly rate before clozapine was 0.8 1.2 and after clozapine 0.4 1.2, a difference that was statistically significant. Rehospitalization rates were lowest in the schizophrenic, schizoaffective bipolar, and schizoaffective depressed patients, whereas unipolar and bipolar depressed patients had the highest relapse rate. 

Comparative studies In a meta-analysis of 48 studies clozapine produced statistically significantly more weight gain (from baseline to end-point, 2-6 months) than risperidone (mean difference=2.86 kg n = 459 in... 

Comparative studies Olanzapine and clozapine The efficacy and safety of clozapine (300 mg/day = 18) and olanzapine (up to 30 mg/day n = 21) have been evaluated in a 12-week double-blind study of treatment-refractory children and adolescents with schizophrenia aged 10-18 years [73 ]. 

Idonije O, Festus O, Akpamu U, Okhiai O, Iribhogbe O, lyalomhe GA. Comparative study of the effects of clozapine and risperidone monotherapy on Hpid profile in Nigerian patients with schizophrenia. Int J Pharmacol 2012 8(3) 169-76. 

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. 

Therapeutic Efficacy. Early evidence supporting clozapine s efficacy came from one double-blind, placebo-controlled study and six other neuroleptic-controlled, random-assignment studies (43, 57, 58, 59 and 60 Novartis, unpublished data). When compared with neuroleptics such as CPZ and haloperidol, clozapine was found to be more effective (i.e., three studies found clozapine significantly superior and two others found a trend favoring clozapine ( p = 0.10)). When the results of these studies were combined, the probability that clozapine is superior to neuroleptic antipsychotics was highly statistically significant ( p = 1 x 1CT °) (Table 5-11 and Table 5-12). 

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). 

Recently, a study was conducted to compare the MDF method to PIS and NLS methods in finding oxidative metabolites in biological fluids (Zhu et al., 2004, 2006). In this study, diclofenac and clozapine (Fig. 6.8) were incubated with human liver microsomes and the metabolites generated were then spiked into pooled rat urine and bile followed by analyses using either high-resolution LC- MS -based MDF or triple-quadmpole LC-MS with NLS and PIS. 

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