Placebo-controlled trial of D-cycloserine added to conventional neuroleptics, olanzapine, or risperidone in schizophrenia.

OBJECTIVE: The authors investigated the clinical effects of D-cycloserine when added to treatment with conventional neuroleptics, olanzapine, or risperidone for treatment-resistant schizophrenia. METHOD: Twenty-four patients participated in a double-blind, placebo-controlled, 6-week crossover trial with D-cycloserine, 50 mg/day, added to their fixed dose of antipsychotic medication. Clinical ratings were performed every 2 weeks. RESULTS: D-Cycloserine treatment was well tolerated and resulted in a significant reduction in negative symptoms (mean=15%). The degree of improvement did not differ between patients treated with conventional neuroleptics and those treated with olanzapine or risperidone. CONCLUSIONS: These data support the efficacy of the addition of 50 mg/day of D-cycloserine to treatment with conventional neuroleptics and suggest that therapeutic benefits may also be attained when D-cycloserine is added to olanzapine or risperidone.

Angiotensin converting enzyme gene insertion/deletion polymorphism: case-control association studies in schizophrenia, major affective disorder, and tardive dyskinesia and a family-based association study in schizophrenia.

Angiotensin converting enzyme (ACE) is a candidate gene for psychiatric disorders. We examined the frequency of a functional insertion/deletion (I/D) polymorphism in the 16th intron of the ACE gene (located on chromosome 17q23) in groups of patients with schizophrenia (n = 104 and 113), major depression (n = 55), and bipolar disorder (n = 87) compared to healthy control subjects (n = 87). There was no evidence for allelic or genotypic association of the polymorphism with any of the disorders or with tardive dyskinesia (TD) in patients with schizophrenia. In a sample of nuclear families (n = 61) made up of one or more patients with schizophrenia recruited with their parents, there was no evidence for biased transmission of ACE I/D alleles. Particularly in the case of schizophrenia, these findings do not support an association of the ACE I/D polymorphism with the phenotypes examined.

Evaluation of central serotonergic function in affective and related disorders by the fenfluramine challenge test: a critical review.

Plasma prolactin levels following oral administration of the serotonin (5-HT) releasing agent, fenfluramine hydrochloride, have been extensively used to evaluate central serotonergic function in affective and related disorders. Cortisol responses to fenfluramine have generally been a less informative measure. In healthy subjects, prolactin release by fenfluramine is dose-dependent, blocked by antagonists of serotonin receptors of the 5-HT-2a/2c type, negatively correlated with age and increased in young females. In major depression, a preponderance of studies have found blunted prolactin responses compared to matched normal controls. Although a significant minority of studies have not found blunting, increased prolactin release has not been observed. The blunted prolactin release is not due to a deficient secretory capacity of pituitary lactotrophs and is congruent with other evidence for reduced central serotonergic function in major depression. Blunting of the prolactin response may be associated with severity of depression and with elevated baseline cortisol levels. Treatment with antidepressant drugs and electroconvulsive therapy has been reported to increase the prolactin response but this has not been replicated in all studies. Blunted prolactin responses to fenfluramine have been fairly consistently associated with impulsive aggression in different personality disorders and with severity of suicide attempts in depressed patients. A number of studies employing the fenfluramine challenge test (FCT) have been conducted in obsessive compulsive disorder but their results have been variable. Prolactin responses to fenfluramine may be enhanced in panic disorder and chronic fatigue syndrome but the number of studies in these conditions is small as is the case for seasonal affective disorder. Since the therapeutic administration of fenfluramine as an appetite suppressant has been suspended because of reports of cardiac complications, further use of this compound as a challenge agent is not anticipated. Future studies are likely to employ agents acting on specific serotonin receptors and should apply methodological insights from the use of the FCT, which are considered in this review. Use of concomitant brain imaging to evaluate the central effects of challenge agents directly is likely to become more prevalent and may supplant neuroendocrine challenge paradigms such as the FCT which have been remarkably heuristic but are limited in scope and methodologically complex.

Age-Dependent Effects of Electroconvulsive Therapy on Memory.

We examined the relation between age and recovery of memory functions after electroconvulsive therapy (ECT). In a group of patients 20-65 years of age, older depressed patients treated with ECT experienced more severe and longer lasting memory deficits than did younger patients. Testing conducted 24-72 h after a course of ECT showed more severe deficits in older patients for verbal and visuospatial anterograde memory, and for retrograde memory. The difference between younger and older subjects was marginal at 1 month follow-up, seen only in differences in verbal anterograde memory. At 6 months follow-up, no difference in memory test scores between older and younger patients was observed. Older patients are more vulnerable to cognitive effects of ECT, and these effects last longer.

Atropine and Cognitive Performance After Electroconvulsive Therapy.

Two groups of patients receiving bilateral, moderately suprathreshold electroconvulsive therapy (ECT) were compared in their cognitive functions after receiving either 0.5 mg atropine i.v. or no atropine before ECT. The patients were tested for cognitive functions after four treatments using various measures, including orientation; retrograde (verbal and visuospatial) memory for information acquired about 15 minutes pretreatment and tested for about 1 hour posttreatment; anterograde (verbal and visuospatial) memory for information acquired about 1 hour, 30 minutes posttreatment and tested for both immediately after learning and 20 minutes later; and retrieval from semantic memory as assessed by word fluency. We found no effect of 0.5 mg atropine on cognitive performance, even though anticholinergic drugs that cross the blood brain barrier might be expected to affect cognition after ECT.

Disorientation and Bilateral Moderately Suprathreshold Titrated ECT.

Thirty-seven inpatients with major depression were assessed for postictal and interictal disorientation after they received 8 of 12 ECTs. In 20 patients, four of the eight assessments were after simulated ECT only. Only real, but not simulated, ECT produced postictal disorientation. Postictal disorientation was greatest after the first treatment, less after the second, and did not change in later assessments. It was shortest for person, longer for place, and longest for time, and showed a temporal time gradient. Interictal disorientation increased with the number of treatments. Two electrical stimulus variables (seizure duration and electrical stimulus intensity) correlated with the length of postictal disorientation. The influence of seizure duration and stimulus variables were independent of each other. The influence of the electrical stimulus variables was independent of the influence of demographic variables. These, however, did affect the length of postictal disorientation.

Change in Attitude Toward Electroconvulsive Therapy: Effects of Treatment, Time Since Treatment, and Severity of Depression.

Attitudes toward electroconvulsive therapy (ECT) of patients with major depressive episodes who are treated with ECT were evaluated before the beginning of treatment, 1 to 2 days after completion of the 12th treatment, and 6 months after the termination of the series using a questionnaire (adapted from Freeman and Kendall, 1980). Attitudes toward ECT become more positive after treatment, and remain so at the 6-month follow-up. Attitude changes correlate with changes in depressive symptoms and with subjective side effects during treatment. Patients who had a prior course of ECT had more knowledge of ECT but not a more positive attitude.

Factors Influencing Response to Bilateral Electroconvulsive Therapy in Major Depression.

The records of 52 patients with major depression who were treated with bilateral electroconvulsive therapy (ECT) were reviewed. Responders and nonresponders were compared on demographic, clinical, and treatment parameters. ECT nonresponders had a longer duration of current depressive episode as well as a greater initial severity of depression. The groups did not differ in age, sex, polarity, presence of psychosis, pre-ECT pharmacotherapy, and treatment parameters other than total electrical charge administered. Patients with long episode duration and greater severity of illness may represent a subgroup of major depressives relatively refractory to ECT and warranting novel therapeutic approaches.

Medication Outcome in ECT-Resistant Depression.

The outcome of antidepressant treatment in 12 cases of electroconvulsive therapy (ECT)-resistant depression is presented. Eight patients had been refractory to a clinically adequate course of ECT (Hamilton Depression Scale improvement <20%) and four were partial responders (improvement 20-49%). All remitted completely on antidepressant medication within 2.2 +/- 1.1 (mean +/- SD) months of the ECT course. Remission was associated with clomipramine treatment (139 +/- 49.7 mg/day) in seven cases and maprotiline (125 mg/day) in one case. Four patients who did not respond to a tricyclic antidepressant alone remitted following supplementation (of clomipramine in 2 cases, clomipramine + haloperidol in 1 case, and imipramine in 1 case) with lithium carbonate. Although a delayed therapeutic response to ECT cannot be excluded, the results suggest that ECT may alter the sensitivity of refractory patients to antidepressant medication.

Potentiation of Seizure Length and Clinical Response to Electroconvulsive Therapy by Caffeine Pretreatment: A Case Report.

A patient with a history of nonresponse to electroconvulsive therapy (ECT) was treated with ECT modified by i.v. caffeine before electrical stimulation for some of the seizures. Seizures preceded by i.v. caffeine were longer, and led to marked clinical improvement. Caffeine pretreatment may be a method to enhance seizure length and efficacy in resistant patients.