Clozapine enhances neurocognition and clinical symptomatology more than standard neuroleptics.

Neurocognition and clinical symptomatology were evaluated in 27 patients with schizophrenia during a double-blind, placebo-controlled, cross-over study involving clozapine, an atypical antipsychotic agent, and haloperidol, a conventional neuroleptic. Patients were assessed 5 to 6 weeks after initiation of each phase. Clinical symptomatology, based on Brief Psychiatric Rating Scale and Scale for the Assessment of Negative Symptoms ratings, markedly improved after treatment with both haloperidol and clozapine. The beneficial effects of clozapine were statistically significantly greater than the effects from the haloperidol treatment. Regarding neurocognition, both agents proved efficacious in improving performance on nearly all measures compared with placebo. In addition, as compared with haloperidol, clozapine significantly improved performance on Trails B, Verbal Fluency, and measures of delayed verbal memory, and it tended to increase performance on most measures. Additional analyses indicated that the improvement on neurocognitive measures was not because of symptom amelioration; rather, neurocognitive deficits seem to be an intrinsic enduring feature of schizophrenia. The superiority of clozapine over haloperidol may be related to clozapine's unique psychopharmacologic profile.

Effect of clozapine and adjunctive high-dose glycine in treatment-resistant schizophrenia.

OBJECTIVE: The focus of this study was the systematic evaluation of the clinical effects of glycine as an adjunct to the atypical antipsychotic clozapine in the treatment of schizophrenia. METHOD: In a double-blind, placebo-controlled study, 19 patients with chronic, treatment-resistant schizophrenia who were maintained on optimal doses of clozapine (400-1200 mg/day) were administered either 30 g/day of glycine (N=9) or placebo (N=10) for 12 weeks. Clinical evaluations with the Brief Psychiatric Rating Scale, the Scale for the Assessment of Negative Symptoms, and the Simpson-Angus movement scale were completed biweekly. RESULTS: The use of glycine as an adjunct to clozapine was not effective in decreasing positive or negative symptoms. In contrast, the patients treated with clozapine without glycine had a 35% reduction in positive symptoms. CONCLUSIONS: These preliminary data suggest that glycine may interfere with the antipsychotic efficacy of atypical neuroleptics such as clozapine.

Plasma clozapine concentrations predict clinical response in treatment-resistant schizophrenia.

Steady-state blood clozapine concentrations in 58 schizophrenic patients varied more than 45-fold (40-1911 ng/mL) after fixed-dose treatment (400 mg/day). Discriminant function analysis determined that a blood clozapine concentration of 420 ng/mL optimally distinguished responders from nonresponders. After 4 weeks of treatment, only 8% of those patients with a blood clozapine concentration < 420 ng/mL responded compared with 60% of those who had a blood clozapine concentration > 420 ng/mL. When plasma concentrations were increased above 420 ng/mL (by a double-blind random assignment procedure), nonresponders increased their response rate to 73% if their plasma concentrations at Week 12 exceeded 420 ng/mL compared with a response rate of 29% if their Week 12 levels remained below 420 ng/mL (chi 2 = 4.2, p < .04).

Clozapine effects on glucose metabolic rate in striatum and frontal cortex.

Eighteen patients with schizophrenia had cerebral metabolic rates assessed with positron emission tomography during a double-blind, placebo-controlled crossover study of clozapine treatment. Relative metabolic rates were increased in the basal ganglia, especially on the right side. In the frontal lobe, metabolic rates were lowered, more on the left than on the right. The anterior nuclei of the thalamus also showed lower metabolic rates after clozapine. We have previously observed patients with schizophrenia to have low metabolic rates in the basal ganglia and to lack the normal right > left asymmetry; in this study, clozapine normalized striatal activity. In the frontal lobe, asymmetry was normalized, but hypofrontal function was, if anything, exaggerated. This effect in the frontal lobe was not observed with haloperidol in earlier studies. The cortical effects of clozapine may be related to its unique clinical properties and suggest important differences between typical and atypical antipsychotic drugs.

Striatal metabolic rate and clinical response to neuroleptics in schizophrenia.

A low metabolic rate in the caudate nucleus and putamen in schizophrenic patients while they were not receiving medication was found to predict a favorable clinical response to haloperidol. Twenty-five patients (21 men and four women) entered a double-blind crossover trial of haloperidol and placebo; to our knowledge, this is the first such trial with positron emission tomography to be reported. Patients received either placebo or medication for the first 5 weeks, and they received the other treatment for the second 5 weeks. Positron emission tomographic scans were obtained at weeks 5 and 10. Patients with low relative metabolic rates in the caudate nucleus and putamen while they were receiving placebo were more likely to show decreases in their Brief Psychiatric Rating Scale scores with haloperidol treatment than individuals with normal or high metabolic rates. Among responders, haloperidol treatment had a "normalizing" effect on metabolic activity in the striatum, with the metabolic rate while they were receiving haloperidol being higher than that while they were receiving placebo. Nonresponders were more likely to show a worsening of hypofrontality while they were receiving medication and an absence of change in the striatum.