A prospective study of predictors of poststroke depression.

OBJECTIVE: To investigate the association between early depressive behavior after stroke onset and occurrence of poststroke depression (PSD) at 3- and 12-month follow-up evaluations. METHODS: The study prospectively included 273 patients with first-ever single uncomplicated ischemic stroke. In the stroke unit, nurses scored crying, overt sadness, and apathy daily using an observational method to include patients with comprehension deficits. The Barthel Index was used to assess disability. Follow-up evaluation at months 3 and 12 included psychiatric assessment based on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition. RESULTS: Crying (19.8%), overt sadness (50.5%), and apathy (47.6%) were observed. Of the patients observed crying, 4 showed pathologic crying, 19 emotionalism, and 12 catastrophic reactions. Crying and overt sadness, but not apathy, were associated with a subjective experience of depression (p < 0.05). Thirty of 52 (58%) patients observed crying, 12 of 19 (63%) patients with emotionalism, and 5 of 12 (41%) patients with catastrophic reactions developed PSD within the first year. Multiple logistic regression analysis showed that only severe functional disability (odds ratio [OR], 4.31; 95% CI, 2.41 to 7.69), crying behaviors (OR, 2.66; 95% CI, 1.35 to 5.27), and an age <68 years (OR, 2.32; 95% CI, 1.30 to 4.13) were (p < 0.05) predictors of late PSD development (13% of the variance). CONCLUSIONS: In the stroke unit, crying and overt sadness are more reliable indicators of depressed mood than apathy. In patients with first-ever stroke, crying behaviors soon after stroke, a younger age, and severe disability are predictors of poststroke depression occurrence within the first year after stroke onset.

Secretion of melatonin in healthy elderly subjects: a longitudinal study.

UNLABELLED: We report on a 10-year longitudinal study on 24-h serum melatonin secretion (AUC) in healthy human subjects. Fifty women and 53 men (aged 42-83 yr) participated in the study initially. Of these, 18 women and 15 men were followed for 6 consecutive years. RESULTS: (a) Cross-sectional analysis (n = 103): A significant (R = -.49, P =.0001) decline in AUC melatonin with age was found in women, but not in men. (b) Longitudinal analysis (n = 33): Repeated-measure ANOVAs for women (n = 18): Time: linear F(1,17) = 5.14, P =.037. The AUC increased by about 40% over the six-year period. In men, there were no significant changes. CONCLUSION: In agreement with most cross-sectional studies, an inverse relationship was found between melatonin secretion and age. However, the longitudinal study showed an increase in melatonin secretion, indicating the presence of putative compensatory mechanisms during healthy aging. Changes in melatonin secretion were gender specific, occurring in women only.

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 subject's and partner's 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.

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.

A placebo-controlled study of the effects of L-tryptophan in patients with premenstrual dysphoria.

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 given under double-blind conditions for 17 days, from the time of ovulation to the third day of menstruation, during three consecutive cycles. Visual Analog Mood Scales revealed a significant (p = 0.004) therapeutic effect of L-tryptophan relative to placebo for the cluster of mood symptoms comprising the items dysphoria, mood swings, tension and irritability. These results suggest that increasing serotonin synthesis during the late luteal phase of the menstrual cycle is therapeutic in patients with premenstrual dysphoric disorder.

Moclobemide versus fluoxetine in the treatment of major depressive disorder in adults.

The objective of the present study was to compare the safety and efficacy of moclobemide versus fluoxetine in adult patients with major depressive disorder. The design of the study was a multicenter, double-blind, comparative, and randomized trial. A 1- to 2-week single-blind placebo washout phase was followed by 6 weeks of double-blind treatment with moclobemide or fluoxetine. A total of 150 patients were enrolled in the study. There were 128 patients eligible to be randomized, with 66 patients receiving moclobemide and 62 patients receiving fluoxetine. At the termination of the study, patients in the moclobemide group were receiving a mean dose of 440 mg +/- 123 mg, while the mean dose in the fluoxetine group was 35 mg +/- 8 mg. No significant treatment differences were found for any of the efficacy parameters. Headache and nausea were the most frequently reported adverse events in both treatment groups. Headache and blurred vision were reported significantly more often (P < 0.05) in the fluoxetine group, whereas significantly more dry mouth was reported (P < 0.05) in the moclobemide group. These results provide supporting evidence of the comparable efficacy of moclobemide and fluoxetine and the better tolerability of moclobemide when used in the treatment of major depressive disorder.

The use of placebos in psychiatry: a response to the draft document prepared by the Tri-Council Working Group. Canadian College of Neuropsychopharmacology.

This article is a position paper of the Canadian College of Neuropsychopharmacology (CCNP). It was approved unanimously at a meeting of the CCNP Council on June 2, 1996, and at the CCNP Annual General Business Meeting on June 4, 1996.

A cross-sectional study of parkinsonism and tardive dyskinesia in lithium-treated affective disordered patients.

BACKGROUND: The purpose of this study was to investigate the prevalence of extrapyramidal symptoms (EPS) and tardive dyskinesia (TD) in affective disordered patients treated with lithium and to study the association of these symptoms with medication and other factors. METHODS: This cross-sectional study was carried out in all consenting outpatients attending an affective disorders clinic in a psychiatric hospital. The study sample consisted of 130 stable outpatients: 110 with bipolar disorder, 18 with unipolar (major) depression, and 2 with atypical affective disorder. At the time of evaluation, 110 patients were receiving lithium, 37 in combination with antidepressants and 19 with neuroleptics, and 40 had a history of neuroleptic treatment during the previous 6 months. The patients were assessed with the Extrapyramidal Symptom Rating Scale (ESRS) for parkinsonism, akathisia, dystonia, and TD. The prevalence of these symptoms was calculated for all patients and by current lithium and neuroleptic intake. Multiple linear regression analysis was used to investigate the relationship between the ESRS subscale scores and gender, age, diagnosis, and medication type. RESULTS: The prevalence of tremor was 20.8%; hypokinetic parkinsonism, 7.7%; akathisia, 4.6%; dystonia, 3.8%; and TD, 9.2%. Tremor was associated with lithium and neuroleptic intake; hypokinesia was associated with neuroleptic treatment and age; and TD was associated with neuroleptic, lithium, and tricyclic intake and age. Seven of 51 patients taking lithium but without a history of neuroleptic treatment during the previous 6 months presented symptoms of TD. CONCLUSION: The combination of lithium and neuroleptics was associated with a high prevalence of EPS. The presence of TD in lithium-treated patients not treated with neuroleptics for at least 6 months is consistent with the hypothesis that lithium may exacerbate the vulnerability of affective disordered patients to dyskinesias.

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. Flesinoxan (7 and 14 micrograms/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.

Antianginal efficacy and safety of controlled-delivery diltiazem QD versus an equivalent dose of immediate-release diltiazem TID.

Controlled-delivery once-daily diltiazem (qd), 180 mg and 360 mg, was assessed in two multicenter, randomized, double-blind, placebo-controlled trials using a 3 x 3 Latin square design. Both studies compared the controlled-delivery dosage form to the same total daily dose of immediate-release diltiazem administered three times daily (tid) and to placebo. The primary measure of efficacy was the time to termination of the exercise tolerance test (ETT) at 2, 8, and 24 hours after the morning dose. There were no significant differences in time to ETT termination between the qd and tid formulations at any time, except at 24 hours with 180 mg qd versus 60 mg tid. The comparison to placebo showed that diltiazem 180 mg qd, 360 mg qd, and 120 mg tid significantly lengthened the time to ETT termination (p < 0.05) at all time points, while diltiazem 60 mg tid did not differ from placebo at any time point. The qd formulation also increased the time to 1-mm ST-segment depression and reduced the number of angina attacks and the amount of nitroglycerin used when compared to placebo. No new or unusual adverse events were noted. Diltiazem controlled-release capsules administered once daily are safe and effective for the treatment of patients with chronic stable angina.

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.

Tryptophan in the treatment of late luteal phase dysphoric disorder: a pilot study.

Thirteen patients diagnosed during two menstrual cycles as suffering from late luteal phase dysphoric disorder were then followed in an open pilot study for a further three cycles. During one complete cycle, baseline levels of symptoms were obtained. During the next three cycles, the patients were treated with L-tryptophan, six grams per day. L-tryptophan treatment was associated with a significant amelioration of symptoms with only mild side effects. These data suggest that L-tryptophan should be tested at a dose of six grams of L-tryptophan per day in a placebo-controlled study in patients with late luteal phase dysphoric disorder who suffer from symptoms such as depression, irritability, insomnia and carbohydrate craving, which may respond to potentiation of serotonin function.

A double-blind randomized clinical trial of rapid tranquilization with I.M. clonazepam and I.M. haloperidol in agitated psychotic patients with manic symptoms.

This double-blind clinical trial studied 16 acutely agitated psychotic patients with manic or manic-like symptoms who needed rapid tranquilization and were therefore on maintenance treatment. They were randomized to receive intramuscular preparations of clonazepam (1 to 2 mg) or haloperidol (5 to 10 mg) at 0, 0.5, and 1.0 hours. Both medications produced significant reduction of manic symptoms within two hours of initial treatment; however, haloperidol produced beneficial results more rapidly than clonazepam. All patients completed the study, with the exception of one haloperidol-treated patient who developed severe parkinsonism. It was concluded that I.M. clonazepam is an effective, safe, but slower-acting alternative to I.M. haloperidol in the treatment of agitated psychiatric patients in need of rapid tranquilization.

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.

Lithium, benzodiazepines, and sexual function in bipolar patients.

OBJECTIVE: Lithium and benzodiazepines are widely used in the treatment of bipolar patients. Yet studies of the effect of these drugs on sexual function are scarce. This study surveyed sexual function in bipolar patients treated with lithium, either alone or in combination with other drugs. METHOD: Sexual function was assessed by self-rating scale in 104 outpatients (45 men and 59 women) with a DSM-III diagnosis of bipolar disorder who were attending an affective disorders clinic. All patients were under treatment with lithium, either alone (35%) or in combination with benzodiazepines (49%), tricyclic antidepressants (17%), neuroleptics (17%), tryptophan (10%), or carbamazepine (1%). The patients were in a stable and euthyroid state at the time of the assessment. Serum lithium and plasma prolactin concentrations were measured at the same time. RESULTS: Multiple regression analysis revealed an association between concomitant benzodiazepine administration and sexual dysfunction scores. Difficulties in sexual functioning were significantly more common in patients treated with a combination of lithium and benzodiazepines (49%) than in those treated with either lithium alone (14%) or lithium in combination with other drugs (17%). No relationship was found between serum lithium or plasma prolactin levels and sexual dysfunction scores. CONCLUSIONS: Lithium, when given alone, did not appear to have a major effect on sexual function, whereas its combination with benzodiazepines was associated with sexual dysfunction in about half of the patients. More attention should be given to drug-induced sexual dysfunction, since its presence can have important consequences for clinical management and compliance.

Vitamin E in the treatment of tardive dyskinesia: a double-blind placebo-controlled study.

The authors compared vitamin E with placebo in a double-blind randomized crossover study of 27 patients with tardive dyskinesia. Each treatment period lasted for 6 weeks. Vitamin E showed no differences from placebo in the treatment of tardive dyskinesia.

Usefulness of sustained-release diltiazem for stable angina pectoris.

Sustained-release diltiazem, 120 and 180 mg twice daily, was assessed in a multicenter, double-blind, randomized, placebo-controlled trial in 65 stable angina patients with exercise-induced ST depression. Exercise testing was performed 12 +/- 1 hours after the last dose at the end of each of the 3 treatment weeks. Both dose levels of drug reduced spontaneous angina (p less than 0.001) and increased exercise duration (p less than 0.01) and time to 1-mm ST depression (p less than 0.001). No differences were noted between the 2 dose levels. Rate-pressure product at maximal exercise was similar for the 3 groups. Only 1 patient terminated the study because of adverse drug effects; severe adverse effects occurred in 1 placebo and 1 low-dose period. Sustained-release diltiazem is safe and efficacious monotherapy for patients with stable angina.

A randomized clinical trial of haloperidol decanoate and fluphenazine decanoate in the outpatient treatment of schizophrenia.

We carried out an 8-month double-blind clinical trial comparing haloperidol decanoate with fluphenazine decanoate in the maintenance treatment of 72 schizophrenic outpatients. A parallel-groups design was used with stratification by sex and injection interval (2, 3, or 4 weeks). The initial injection interval was based on pretrial maintenance treatment with fluphenazine esters. The dosage equivalency of haloperidol decanoate (1.5 cc or 75 mg) to fluphenazine decanoate (1 cc or 25 mg) used was 3:1. This remained approximately the same throughout a 2-month titration period with a flexible dose regimen, and a further 6-month period with a fixed dose regimen. No statistically significant differences in therapeutic effect were found between the drugs. Both drugs had a similar profile for drug-induced parkinsonism, but there was a trend for differences in masking tardive dyskinesia. Haloperidol and prolactin plasma concentrations were well correlated with dosage, with the exception of haloperidol concentrations in patients receiving injections at 2-week intervals.

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.