Guy Chouinard

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.

Manual for the Extrapyramidal Symptom Rating Scale (ESRS)

The Extrapyramidal Symptom Rating Scale (ESRS) was developed to assess four types of drug-induced movement disorders (DIMD): Parkinsonism, akathisia, dystonia, and tardive dyskinesia (TD). Comprehensive ESRS definitions and basic instructions are given. Factor analysis provided six ESRS factors: 1) hypokinetic Parkinsonism; 2) orofacial dyskinesia; 3) trunk/limb dyskinesia; 4) akathisia; 5) tremor; and 6) tardive dystonia. Two pivotal studies found high inter-rater reliability correlations in both antipsychotic-induced movement disorders and idiopathic Parkinson disease. For inter-rater reliability and certification of raters, >or=80% of item ratings of the complete scale should be +/-1 point of expert ratings and >or=70% of ratings on individual items of each ESRS subscale should be +/-1 point of expert ratings. During a cross-scale comparison, AIMS and ESRS were found to have a 96% (359/374) agreement between TD-defined cases by DSM-IV TD criteria. Two recent international studies using the ESRS included over 3000 patients worldwide and showed an incidence of TD ranging from 10.2% (2000) to 12% (1998). ESRS specificity was investigated through two different approaches, path analyses and ANCOVA PANSS factors changes, which found that ESRS measurement of drug-induced EPS is valid and discriminative from psychiatric symptoms.

Placebo-controlled study of gabapentin treatment of panic disorder.

A randomized, double-blind, placebo-controlled, parallel-group study was conducted to evaluate the efficacy and safety of gabapentin in relieving the symptoms of panic disorder. One hundred three patients were randomly assigned to receive double-blind treatment with either gabapentin (dosed flexibly between 600 and 3,600 mg/day) or placebo for 8 weeks. No overall drug/placebo difference was observed in scores on the Panic and Agoraphobia Scale (PAS) (p = 0.606). A post hoc analysis was used to evaluate the more severely ill patients as defined by the primary outcome measure (PAS score > or = 20). In this population, the gabapentin-treated patients showed significant improvement in the PAS change score (p = 0.04). In patients with a PAS score of 20 or greater, women showed a greater response than men regardless of treatment. Adverse events were consistent with the known side effect profile of gabapentin and included somnolence, headache, and dizziness. One patient experienced a serious adverse event during the study. No deaths were reported. The results of this study suggest that gabapentin may have anxiolytic effects in more severely ill patients with panic disorder.

Sexual dysfunction and plasma prolactin levels in neuroleptic-treated schizophrenic outpatients.

A random sample of 55 schizophrenic outpatients, 26 men and 29 women, treated with neuroleptics was selected from our long term follow-up clinic. The patients rated their current sexual functioning on specially designed scales. Fifty-four per cent of male and 30 per cent of female patients reported impaired sexual functioning during neuroleptic treatment. Ninety-one per cent of female patients reported changes in menstruation. Partial correlation coefficients were calculated between sexual dysfunction score and plasma prolactin level adjusting for age. Sexual dysfunction was found to be associated with high plasma prolactin levels in male patients but not in female patients. High prolactin tended also to be associated with menstrual disturbances. Antiparkinsonian medication was not found to be correlated with either sexual dysfunction or menstrual disorder score.

Risperidone in the treatment of tourette syndrome: a double-blind, placebo-controlled trial.

A double-blind, placebo-controlled trial was performed to determine the efficacy and tolerability of 8 weeks of treatment with risperidone in the management of 48 adolescent and adult patients with Tourette syndrome. Twenty-four patients were randomly assigned to treatment with risperidone in doses of 0.5 to 6.0 mg/day, and 24 were assigned to placebo. The dosage of medication was increased in fixed increments during the first week of double-blind treatment and thereafter in a flexible dose regimen according to clinical response. Risperidone, at a median dose of 2.5 mg/day (range, 1 to 6 mg/day), was found to be significantly (p < 0.05) superior to placebo on the Global Severity Rating of the Tourette Syndrome Severity Scale. The proportion of patients who improved by at least one point on this seven-point scale was 60.8% in the risperidone group and 26.1% in the placebo group. Treatment with risperidone was accompanied by an improvement in global functioning in patients with average to above-average impairment at baseline as measured by the Global Assessment of Functioning scale. With respect to extrapyramidal symptom scores measured on the Extrapyramidal Symptom Rating Scale, hypokinesia and tremor increased in the risperidone group, but the effect on tremor was largely confined to subjects with higher baseline tremor scores. There were no significant differences in dystonic reactions, dyskinetic movements, subjective parkinsonism, or akathisia. Risperidone did not increase obsessive-compulsive symptoms. Fatigue and somnolence were the most common adverse events associated with risperidone.

A path-analytical approach to differentiate between direct and indirect drug effects on negative symptoms in schizophrenic patients. A re-evaluation of the North American risperidone study.

The hypothesis that differences in drug effects of risperidone and haloperidol on negative symptoms in schizophrenia are secondary to effects on positive, extrapyramidal, and depressive symptoms was investigated by means of an analysis of the data from the USA-Canada risperidone double-blind randomized clinical trial of 523 chronic schizophrenic patients. Regression analyses in the total sample and within treatment groups confirmed a strong relationship between changes in negative symptoms and the other variables studied (R2=0.50−0.51,p<0.001). Only depressive symptoms did not contribute significantly to these results (p>0.10). Path analysis showed that the greater mean change (p<0.05) of negative symptoms with risperidone compared to haloperidol could not be fully explained by correlations with favourable effects on positive and extrapyramidal symptoms. The relationship between shift in extrapyramidal symptoms and shift in negative symptoms failed to reach statistical significance; however, there was a clear tendency in the expected direction in both treatment groups.

A comparison of venlafaxine, trazodone, and placebo in major depression.

A double-blind, placebo-controlled trial was undertaken to compare the safety and efficacy of venlafaxine and trazodone in patients with major depression. Two hundred twenty-five patients entered an initial 6-week treatment phase, and 149 completed it. Ninety-six patients who were responders continued in a 1-year, double-blind, long-term phase during which they received the same medication and doses they had during the short-term phase. Both active treatments were significantly more effective than placebo on some measures during the short-term study, but venlafaxine produced more improvement in the cognitive disturbance and retardation factors on the Hamilton Rating Scale for Depression. Trazodone was more effective against the sleep disturbance factor. Patients on venlafaxine were most likely to enter the long-term phase and to remain in the trial longest. The side effect profiles of the three treatment groups were compared. Venlafaxine was most likely to cause nausea, whereas trazodone was associated with the most dizziness and somnolence.

A 1 year double-blind placebo-controlled fixed dose study of sertraline in the treatment of obsessive-compulsive disorder.

The objective of this study was to evaluate the safety and efficacy, over a 1 year treatment period, of three dose levels of sertraline and placebo in the treatment of non-depressed adult out-patients with obsessive-compulsive disorder (OCD). Following 1 week of single-blind placebo washout, patients (n = 325) from 11 sites following identical protocols were randomly assigned to 12 weeks of double-blind treatment with one of three fixed doses of sertraline (50, 100 or 200 mg) or placebo. At the end of 12 weeks, treatment responders (including placebo patients) were offered an additional 40 weeks of double-blind treatment at their assigned doses. Efficacy measures were the Vale-Brown Obsessive Compulsive Scale, the NIMH Global Obsessive Compulsive Scale, Clinical Global Impressions of Severity of Illness and Global Improvement and the Maudsley Obsessive Compulsive Inventory. Patients in the pooled sertraline group showed greater improvement than placebo-treated patients on all efficacy measures, based on the endpoint analyses. Moreover, pairwise comparisons at endpoint revealed a significant effect on all three investigator-rated scales in patients receiving 50 or 200 mg of sertraline; in the 100 mg group, there was a significant effect on the NIMH Global Obsessive Compulsive Scale only. Patients completing 3 months of sertraline treatment exhibited excellent toleration and sustained improvement during an additional 40 weeks of therapy. Results support the safety, efficacy and tolerability of daily doses of 50–200 mg of sertraline in the long-term treatment of patients with OCD.

Loss of striatal cholinergic neurons as a basis for tardive and L-dopa-induced dyskinesias, neuroleptic-induced supersensitivity psychosis and refractory schizophrenia

In the first section of this paper several aspects of tardive dyskinesia (TD) (clinical, epidemiological, pharmacological) are reviewed. We propose that this syndrome is not the consequence of dopamine receptor proliferation, but results from damage or degeneration of striatal cholinergic interneurons. We suggest that this cellular damage is caused by prolonged overactivation of these neurons, which occurs when they are released from dopaminergic inhibition following neuroleptic administration. Overactivity of central cholinergic systems during akinetic and motor retarded depression could be a contributory cause. The predisposition to L-DOPA-induced peak-dose dyskinesia in Parkinsons disease may depend on the same type of striatal neuronal loss. In the second part of the paper, the subject of supersensitivity psychosis and drug-resistant schizophrenia is reviewed. These two syndromes, are commonly associated with TD, have similar predisposing factors and pharmacology to TD, and are potentially persistent. We suggest that these conditions also result from degeneration of cholinergic striatal interneurons following chronic neuroleptic administration. The efficacy of clozapine for such treatment-refractory psychoses is explained in terms of its blockade of D-1 dopamine receptors. Other drugs effective against refractory psychoses (e.g. risperidone) are predicted to reduce activation at D-1 receptors.

effects of Risperidone in Tardive Dyskinesia: An Analysis of the Canadian Multicenter Risperidone Study*

&NA; In the Canadian multicenter, double‐blind clinical trial of risperidone, 135 hospitalized chronic schizophrenic patients were randomly assigned to one of six parallel treatment groups for 8 weeks: risperidone, 2, 6, 10, or 16 mg/day; haloperidol, 20 mg/day; or placebo. Risperidone (6 to 16 mg)treated patients showed significantly (p < 0.05) lower dyskinetic scores than those receiving placebo, whereas in haloperidol‐ and placebo‐treated patients, no significant differences for dyskinetic symptoms were noted. To explore the antidyskinetic effect of risperidone, a post hoc analysis was performed on two selected patient samples: (1) patients meeting Research Diagnosis Criteria (RDC) for tardive dyskinesia (TD) at baseline or during double‐blind treatment (N = 49) and (2) patients with RDC TD and with a Clinical Global Impression (CGI) Severity of dyskinesia score ≥ 5 (at least moderately severe) (N = 48). The composition of the two subsamples was found to be almost identical because all but one of the patients with RDC TD (N = 49) were members of the group with at least moderately severe TD (N = 48). Analysis of four parameters (Extrapyramidal Symptom Rating Scale‐dyskinesia total score, CGI severity of dyskinesia, buccolinguomasticatory ?[BLM] factor score, and extremities [choreoathetoid factor] score confirmed the antidyskinetic effect that was noted in the intent‐to‐treat analysis, which included all patients, whether they had RDC TD or not. Results indicated that risperidone at 6 mg/day had the most beneficial effect on TD, especially on the BLM syndrome, without inducing significant parkinsonism while treating psychotic symptoms. This antidyskinetic effect was greater than with either placebo or haloperidol.