Lawrence Annable

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.

The effect of tryptophan on social interaction in everyday life: a placebo-controlled study.

In monkeys increasing serotonin function enhances affiliative interactions and promotes the acquisition of dominance. To examine whether similar effects occur in humans, we treated 98 subjects for 12 days with the serotonin precursor tryptophan (1g TID) and for 12 days with placebo in a double-blind, cross over study. Agreeableness/quarrelsomeness and dominance/submission were measured using an event-contingent method, in which subjects reported on various behaviors during important social interactions throughout their day. Tryptophan decreased quarrelsome behavior, but only when placebo was given first, suggesting that a decrease in quarrelsomeness when tryptophan was given first may have carried over into the subsequent placebo period. Tryptophan increased dominant behavior, an effect that was independent of the order of treatment, the broad social context, and the subjects and partners sex. Our results suggest that serotonin may enhance dominance in humans, as in monkeys, and illustrate the advantages of the event contingent methodology in studying the associations between biology and human social interaction.

Serotonin1A receptor activation by flesinoxan in humans: Body Temperature and Neuroendocrine Responses

The effects of the selective 5-HT1A receptor agonist flesinoxan on neuroendocrine function, temperature, and behavior were assessed in male healthy volunteers using a double-blind, placebo-controlled crossover design. Flexinoxan (7 and 14 μg/kg), administered intravenously in 11 healthy volunteers, elicited a dose-related decrease in body temperature and increases in growth hormone, adrenocorticotropic hormone (ACTH), cortisol, and prolactin plasma levels. In a second independent study, 12 healthy volunteers were pretreated sequentially, at one-week intervals, with either the 5-HT1A antagonist pindolol (30 mg, PO), the nonselective 5-HT1 2 antagonist methysergide (4 mg, PO), or placebo, prior to being administered flesinoxan (1 mg, IV). The growth hormone response to flesinoxan was blocked by pindolol but not by methysergide, whereas the prolactin response was blocked by methysergide but not by pindolol. The ACTH and cortisol responses to flesinoxan were potentiated by methysergide. The flesinoxan-induced hypothermia was attenuated by both methysergide and pindolol, although the latter effects did not reach statistical significance. The present results suggest that the growth hormone response and the hypothermic response to the intravenous infusion of flesinoxan may serve as a valid index of 5-HT1A receptor function in humans.

A 5-year prospective longitudinal study of tardive dyskinesia: factors predicting appearance of new cases.

In a 5-year longitudinal study in a cohort of 169 schizophrenic outpatients treated with neuroleptics, we found a twofold increase (from 22% to 44%) in prevalence of tardive dyskinesia (TD) meeting the Schooler and Kane research diagnostic criteria. If we include cases of TD that were considered definite but did not meet the research criteria, the prevalence increased from 31% to 58%. In the cohort of 131 patients who did not present with the disorder in 1975, we found parkinsonism and increase in parkinsonism to be the best predictors of subsequent development of the disorder. Poor schizophrenic prognosis and long treatment duration also appeared to be risk factors. Another finding was the importance of changes in neuroleptic and antiparkinsonian dosage in both covering and uncovering TD.

A dose-ranging study of the behavioral and cardiovascular effects of CCK-tetrapeptide in panic disorder ☆

Recent animal studies have shown that pretreatment with centrally active cholecystokinin (CCK) antagonists blocks the anxiogenic effects of CCK-tetrapeptide (CCK-4). In order to determine whether pretreatment with these antagonists can block the anxiogenic effects of CCK-4 in patients with panic disorder, a suitable challenge dose of CCK-4 must be selected. Thus, we conducted a dose range study in which patients with panic disorder (n = 29) were challenged with CCK-4 (10, 15, 20, or 25 micrograms) or placebo on two separate occasions, in a balanced incomplete block design. Patients received in random order 10 micrograms (n = 12), 15 micrograms (n = 11), 20 micrograms (n = 12), or 25 micrograms (n = 12) of CCK-4 or placebo (n = 11). CCK-4 induced anxiety and panic responses in a dose-dependent fashion. The incidence of panic attacks following the CCK-4 challenge was 17% (10 micrograms), 64% (15 micrograms), 75% (20 micrograms), and 75% (25 micrograms). None of the patients panicked with placebo. Moreover, a strong linear relationship between CCK-4 and increases in heart rate and diastolic blood pressure was found. The findings of this study suggest that a dose of 20 micrograms of CCK-4 (ED75) might be suitable for efficacy studies of CCKB antagonists and other potential antipanic drugs in patients with panic disorder.

A placebo-controlled clinical trial of l-tryptophan in premenstrual dysphoria

BACKGROUND Antidepressant drugs, including specific serotonin reuptake inhibitors, have been shown to be beneficial in the treatment of premenstrual dysphoric disorders. The present study tests the efficacy of L-tryptophan, which acts specifically on serotonergic neurons, in this disorder. METHODS In a randomized controlled clinical trial, 37 patients with premenstrual dysphoric disorder were treated with L-tryptophan 6 g per day, and 34 were given placebo. The treatments were administered under double-blind conditions for 17 days, from the time of ovulation to the third day of menstruation, during three consecutive menstrual cycles. RESULTS The Visual Analogue Scales (VAS) revealed a significant (p = .004) therapeutic effect of L-tryptophan relative to placebo for the cluster of mood symptoms comprising the items of dysphoria, mood swings, tension, and irritability. The magnitude of the reduction from baseline in maximum luteal phase VAS-mood scores was 34.5% with L-tryptophan compared to 10.4% with placebo. CONCLUSIONS These results suggest that increasing serotonin synthesis during the late luteal phase of the menstrual cycle has a beneficial effect in patients with premenstrual dysphoric disorder.

Tryptophan-nicotinamide, imipramine and their combination in depression. A controlled study.

In a double‐blind controlled study lasting 4 weeks 25 newly admitted severely depressed patients were randomly assigned to tryptophan‐nicotinamide or imipramine or tryptophan‐nicotinamideimipramine combination. Nicotinamide was given to reduce peripheral breakdown of tryptophan. Although there were no substantial differences between the three treatments, the efficacy of tryptophannicotinamide tended to diminish after 2 weeks when the dose of tryptophan was increased from 4 g/day to 6 g/day and that of nicotinamide from 1.0 g/day to 1.5 g/day. The therapeutic response of patients treated with tryptophan‐nicotinamide was significantly correlated with the rise in plasma tryptophan. For the tryptophannicotinamide‐imipramine group, however, therapeutic response and rise in plasma tryptophan were negatively correlated, implying that tryptophan levels were too high in some patients. The data suggest that tryptophan‐nicotinamide may be as effective as imipramine in unipolar patients providing the dose is kept within the therapeutic window, and that at low doses it could also potentiate the action of tricyclic antidepressants. Bipolar patients seem to require higher doses of tryptophan than unipolar patients.

Neuropsychological impairments in neuroleptic-responder vs. -nonresponder schizophrenic patients and healthy volunteers.

To determine whether two groups of schizophrenic patients representing the two extremes of the neuroleptic response-spectrum (consistent responders vs. consistent nonresponders) differ with respect to their neuropsychological profile. Neuroleptic-responder (R; n=36) and -nonresponder (NR; n=39) schizophrenic patients were recruited according to a priori defined criteria of responsiveness to typical neuroleptics. Seven neuropsychological domains were assessed and compared between groups: attention-vigilance, abstraction-flexibility, spatial organization, visual-motor processing, visual memory, verbal abilities, and verbal memory and learning. All measures were standardized using the scores of 36 healthy volunteers. NR schizophrenic patients performed worse in all neuropsychological domains compared to normal controls and R schizophrenic patients. However, only performances on visual memory, verbal abilities, and verbal memory and learning were significantly poorer in NR compared to R patients. Only the latter domain significantly differentiated NR patients from the other two groups. R patients performed at an intermediate level in all domains. This report of differences in neuropsychological profile between neuroleptic-responder and -nonresponder schizophrenic patients adds to the growing evidence supporting the value of distinguishing schizophrenic patients on the basis of their therapeutic response to neuroleptics.

Clonazepam in the treatment of panic disorder: a double-blind, placebo-controlled trial investigating the correlation between clonazepam concentrations in plasma and clinical response.

Thirty-two outpatients with a DSM-III diagnosis of panic disorder or agoraphobia with panic attacks were randomly assigned to 4 weeks of treatment with clonazepam or placebo, after a 1-week placebo washout period. Twenty-nine patients entered the double-blind phase of the study and were eligible for intent-to-treat analysis. Clonazepam-treated patients experienced significantly fewer panic attacks, and these were of lesser intensity and short duration than those in placebo-treated patients (p < 0.001). Clonazepam was also superior to placebo with respect to symptoms of anxiety and depression (p < 0.001). The mean dose of clonazepam at week 4 was 2.2 mg (standard deviation, 0.7 mg). There was significant (p < 0.05) correlation between drug concentration in plasma and decrease in the global measure of the severity of panic disorder (r = 0.68); similar trends were seen for the decreases in frequency (r = 0.60) and severity (r = 0.55) of panic attacks, but not between concentration in plasma and decline in generalized anxiety. The most common adverse event was drowsiness, which occurred in 9 of 13 clonazepam-treated patients.