Unanticipated plasma concentrations in two clozapine-treated patients.

OBJECTIVE: To report two cases of lower than anticipated clozapine plasma concentrations despite near maximum recommended doses of clozapine 800-900 mg/d in two medication-compliant schizophrenic inpatients. CASE SUMMARIES: Clozapine therapy was initiated in two male schizophrenic inpatients for treatment of psychotic symptoms refractory to other typical and atypical antipsychotics. Despite receiving adequate doses of clozapine for at least two months, these patients remained symptomatic. Therapeutic drug monitoring was used to target a clozapine plasma concentration of > or =250 ng/mL, the minimum value reported in the literature to be associated with increased clinical response. Clozapine plasma concentrations remained at 200 ng/mL in one patient despite dosage increases from 600 to 800 mg/d. In the second patient, administration of the maximum recommended dose resulted in concentrations between 200 and 250 ng/mL. Increasing the clozapine dosage to 1000 mg/d did not increase the clozapine plasma concentration. Evaluation of the ratio of clozapine plasma concentration clozapine to dose yielded lower than expected values compared with those reported in the literature. DISCUSSION: These two patients exhibited lower than anticipated clozapine plasma concentrations despite receiving high doses of clozapine. Several studies evaluating clozapine serum concentrations and clinical response have suggested threshold concentrations of > or =350 ng/mL, > or =370 ng/mL, or > or =420 ng/mL. The only study that randomized patients to three concentration ranges found that patients who achieved a clozapine serum concentration in a medium range (mean 251 ng/mL) responded better than patients in a low range (mean 91 ng/mL) and similar to patients in a high range (mean 396 ng/mL). However, attaining plasma concentrations in this range for these patients proved difficult. Reasons for the low concentrations are unclear and may be related to increased metabolic activity at several cytochrome P450 isoenzymes involved in the metabolism of clozapine. CONCLUSIONS: These cases illustrate lower than anticipated clozapine plasma concentrations despite high-dose clozapine therapy. Strategies to increase clozapine plasma concentrations in such patients might include adding a drug to partially inhibit the metabolism of clozapine. If those strategies are unacceptable based on risk assessment, patient compliance, or other reasons, clinicians may consider addition of a low-dose typical or other atypical antipsychotic drug to augment clozapine response.

The visual backward masking deficit in schizophrenia.

1. Subjects with schizophrenia have an impairment very early in visual information processing, requiring a longer minimal stimulus duration than normal controls to identify a target stimulus. Subjects with schizophrenia have a deficit in visual backward masking, identifying fewer target stimuli than normal controls when the target is briefly obscured by a second visual stimulus When interstimulus interval is increased parametrically, subjects with schizophrenia have trouble identifying target stimuli at intervals that do not affect the performance of normal controls. 2. The visual backward masking deficit: is trait-related; is associated with negative symptoms but has also been associated with measures of thought disorder; may or may not be related to treatment with neuroleptic medication or other neurocognitive deficits of schizophrenia; is of unclear etiology, though researchers have speculated that it involves magnocellular channels and/or the cortical dorsal visual processing stream; has been shown to be heritable in one study. 3. If visual information processing deficits are observed in the unaffected siblings of schizophrenic patients, it may be a candidate intermediate phenotype.

The visual backward masking deficit in schizoaffective disorder.

1. Subjects with schizoaffective disorder have an impairment in early visual information processing known as backward masking. 2. Backward masking studies in schizoaffective disorder have not established if the deficit: is state- or trait-related; is associated with negative symptoms or neuroleptic treatment; or is partially attributable to lithium treatment. 3. Integration and interruption are mechanisms of backward masking in schizoaffective disorder, but experiments maximizing interruption only, have not been performed. 4. Studies isolating the transient visual channels have not been performed in patients with schizoaffective disorder.

Backward masking in bipolar affective disorder.

1. When an informational stimulus, the target, is followed closely in time by a non-informational stimulus, the mask, the visual system's processing of the informational stimulus is disturbed. This disturbance is known as backward visual masking. 2. Transient and sustained visual pathways detect different characteristics of a visual stimulus, at different times in early visual information processing, and have unique anatomic distribution with regard to retinal origin, thalamic and cortical projections. 3. Backward masking occurs by two mechanisms. Interruption occurs when activity in the transient channels of the mask disrupt activity in the sustained channels of the target. Integration occurs when activity in the sustained channels of the mask disrupt activity of the sustained channels of the target. 4. Characteristics of the mask--energy, location, or the time presented after the target--can be altered to enhance interruption or integration. Interruption is a bell-shaped function of, and integration is an exponential function of, visual performance and interstimulus interval. 5. An impairment in backward masking is present in bipolar subjects during manic episodes, is not related to the presence of psychotic symptoms, and persists when mania resolves. Lithium appears to have a detrimental effect on backward masking.

Phase II study of spirogermanium in patients with advanced colorectal carcinoma.

Twenty one evaluable patients with advanced colorectal carcinoma were treated with continuous infusion of spirogermanium at a median daily dose of 150 mg/m2 (range 120-210) for five consecutive days every 14 days. Treatments were accomplished by using outpatient infusion devices. Fifteen patients had not received any prior radiation therapy, immunotherapy, or chemotherapy. Nineteen patients were previously untreated with chemotherapy. Five patients had received prior immunotherapy with copovithane and only two patients had received radiation therapy prior to spirogermanium therapy. None of the patients achieved a complete or partial remission. Minor tumor regressions were observed in two patients, both were less than 12 weeks in duration. The major toxicities included nausea and vomiting and neurologic side effects; however, the toxicity was completely reversible. Spirogermanium is not effective in the treatment of patients with advanced colorectal carcinoma.