Barry D. Jones

A Canadian multicenter placebo-controlled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients.

In a double-blind study, 135 inpatients with a diagnosis of chronic schizophrenia were randomly assigned to 8 weeks of treatment with one of six parallel treatments: risperidone (a new central 5-hydroxytryptamine2 and dopamine D2 antagonist), 2, 6, 10, 16 mg/day; haloperidol, 20 mg/day; or placebo, after a single-blind placebo washout period. Doses were increased in fixed increments up to a fixed maintenance dose reached after 1 week. On the Clinical Global Impression-Severity of Illness and Improvement, all active medications were superior to placebo except for risperidone (2 mg) on the Clinical Global Impression-Improvement. On the total Positive and Negative Syndrome Scale (PANSS) score and positive subscale, superiority to placebo was observed for all treatment groups except for haloperidol and risperidone (2 mg), which tended to be superior to placebo on total PANSS and the positive subscale, respectively. On the PANSS negative subscale, only risperidone (6 mg/day) was significantly better than placebo. Risperidone (6 mg) was superior to haloperidol on the total PANSS, General Psychopathology, and Brief Psychiatric Rating Scale subscales. Although there was a linear increase in parkinsonism with increasing risperidone dosage, there were no statistically significant differences between risperidone (2, 6, and 16 mg/day) and placebo. At doses of 6 to 16 mg, risperidone displayed a marked antidyskinetic effect compared with placebo. This effect was more pronounced in patients with severe dyskinesia. By contrast, haloperidol produced significantly more parkinsonism than placebo and risperidone (2, 6 and 16 mg), with no effect on tardive dyskinesia. These data suggest that risperidone, at the optimal therapeutic dose of 6 mg/day, produced significant improvement in both positive and negative symptoms without an increase in drug-induced parkinsonian symptoms and with a significant beneficial effect on tardive dyskinesia.

Risperidone in the treatment of pervasive developmental disorder.

Elevated concentrations of blood serotonin have been documented in autistic children and mentally retarded adults. Antiserotonergic pharmacotherapy has been partially effective in treating a subgroup of children with autistic disorder. Therefore, the possibility is raised that an antiserotonergic treatment may be of value to adult psychiatric patients with a history of pervasive developmental disorder. Two such cases are described where the patients underwent psychiatric and neuropsychological examination before and after treatment with risperidone, a potent 5-HT2 antagonist with additional D2 antagonistic properties. Particular improvements were documented in both patients, despite long histories of cognitive compromise and high likelihood of damage to the central nervous system.

A Canadian multicenter trial assessing memory and executive functions in patients with schizophrenia spectrum disorders treated with olanzapine.

Serial verbal learning task (explicit long-term memory) and verbal fluency (generation of a response) are tests that are usually severely impaired in schizophrenia. Despite the growing literature supporting the clinical efficacy of olanzapine, psychiatrists still question its cognitive consequences. This study assessed the efficacy of olanzapine on neurocognitive functioning. Patients (N = 134) meeting diagnostic criteria for schizophrenia, schizophreniform, or schizoaffective disorders began an 8-week, open-label olanzapine treatment at a dose of 5 mg/d, which was increased to 10 mg/d after 1 week. Daily dosage was subsequently adjusted between 5 and 20 mg/d based on individual clinical status. All previous antipsychotics were tapered and discontinued during the first 2 weeks of the study. Neuropsychologic assessments were carried out at baseline and at 4 and 8 weeks. Explicit long-term memory was assessed with the Rey Auditory-Verbal Learning Test: the average immediate recall score significantly improved (P < 0.001), as did the delayed recall score (P < 0.001). The average total score on category fluency improved from 34.6 words at baseline to 37.6 words at end point (P < 0.0001). Time on both Trail A and B making tasks significantly decreased (P < 0.0001). Lack of a control arm makes it impossible to exclude a practice effect as an explanation for the enhanced cognitive performance, although the Word List Recall test represents one of the better resources to avoid a practice effect. After switching to olanzapine, there was a statistically significant improvement of cognitive function in the 3 main domains tested and no significant worsening of any memory or executive function measure.

Dissolution profile, tolerability, and acceptability of the orally disintegrating olanzapine tablet in patients with schizophrenia.

Objectives: This pilot study investigates the dissolution profile, tolerability, and acceptability of an orally disintegrating olanzapine tablet in patients with schizophrenia. Method: Eleven patients with schizophrenia stabilized on oral olanzapine (mean dosage 12.7 mg daily [SD5.2]) were given an orally disintegrating olanzapine tablet, rather than their usual tablet, daily for 7 days. At each visit, visual assessments were made for elapsed time to initial disintegration (every 15 seconds) and complete disintegration (every 1 minute). At the end of the study, patients completed a drug-acceptance questionnaire. Results: The mean time to initial disintegration was 15.78 seconds, and mean time to complete disintegration was 0.97 minutes. All patients found the orally disintegrating tablet acceptable and expressed positive comments. Nonserious clinically significant adverse events, asthenia, purpuric rash, headache, depression, and insomnia (preexisting, except for asthenia and insomnia) were reported in 3 patients. Conclusion: The orally disintegrating olanzapine tablet disintegrates rapidly and is a well-tolerated and acceptable alternative to standard olanzapine tablets in patients with schizophrenia.

Evidence of Brain Dopamine Deficiency in Schizophrenia

Summary It is proposed that the increased dopamine function suggested by the dopamine hypothesis of schizophrenia is a dopaminergic postsynaptic receptor supersensitivity resulting from a dopamine deficiency. In support of this, three double-blind controlled studies conducted on drugs which alter brain dopaminergic activity in a manner different from that of classic neuroleptics are reported. 1) α-methyldopa-neuroleptic interaction proved efficacious for schizophrenic positive symptoms but only on a short-term basis. 2) Rubidium improved negative symptoms rapidly, and in contrast has a late onset of action on positive symptoms of schizophrenia. 3) Tryptophan-benserazide was efficacious in controlling both negative and positive symptoms of schizophrenia (although less so than chlorpromazine). It is concluded that currently accepted modes of pharmacological therapy (classical neuroleptics) are in the short-term controlling the dopamine supersensitivity secondary to a deficiency, but contributing in the long-term to increase the dopamine deficiency, and so exacerbate the supersensitivity. More effective forms of treatment may involve the use of agents which alter dopamine activity without inducing dopamine supersensitivity.

Tardive dyskinesia: legal and preventive aspects.

Tardive dyskinesia is a complication associated with long term neuroleptic drug treatment that can be the object of litigation. Such litigation has occurred recently in the United States, where awards of considerable value have been granted to plaintiffs. Circumstances that can lead to TD litigation are presented as well as guidelines for the prescription of neuroleptics, the prevention of litigation and of the syndrome itself. Five lawsuits associated with TD serve as a backdrop for the discussion.

RISPERIDONE TREATMENT FOR SEVERE NEGATIVE SYMPTOMS

We have recently managed the care of a severely ill treatment refractory patient with life-threatening schizophrenia for whom a variety of conventional therapeutics were attempted prior to successive treatment with clozapine then successful treatment with risperidone. This case highlights a possible course of action to clinicians who may confront a similar treatment dilemma with implications to the survival of the patient.

Withdrawal symptoms after long-term treatment with low-potency neuroleptics

Twenty-six chronic schizophrenic outpatients receiving low-potency anticholinergic neuroleptics were switched over periods of up to 2 years to an equivalent dose of high-potency neuroleptics. Of these patients, 85% experienced withdrawal symptoms, mainly insomnia, anxiety, and tensional restlessness. Complete withdrawal of low-potency medication was achieved during the study period in 9 patients only. The mean duration of treatment with low-potency neuroleptics was 15 years and the mean dose was 147 mg chlorpromazine equivalents/day. It is suggested that new symptoms associated with withdrawal of low-potency neuroleptics may lead to overcompliance by patients and difficulty in achieving the minimum therapeutic dosage. Thus, low-potency neuroleptics would not appear suitable for the long-term treatment of most schizophrenic patients.