Adel Wassef

GABA and schizophrenia: a review of basic science and clinical studies.

Background: A converging body of evidence implicates the γ-aminobutyric acid (GABA) neurotransmitter system in the pathogenesis of schizophrenia. Methods: The authors review neuroscience literature and clinical studies investigating the role of the GABA system in the pathophysiology of schizophrenia. First, a background on the GABA system is provided, including GABA pharmacology and neuroanatomy of GABAergic neurons. Results from basic science schizophrenia animal models and human studies are reviewed. The role of GABA in cognitive dysfunction in schizophrenia is then presented, followed by a discussion of GABAergic compounds used in monotherapy or adjunctively in clinical schizophrenia studies. Results: In basic studies, reductions in GABAergic neuronal density and abnormalities in receptors and reuptake sites have been identified in several cortical and subcortical GABA systems. A model has been developed suggesting GABA’s role (including GABA-dopamine interactions) in schizophrenia. In several clinical studies, the use of adjunctive GABA agonists was associated with greater improvement in core schizophrenia symptoms. Conclusions: Alterations in the GABA neurotransmitter system are found in clinical and basic neuroscience schizophrenia studies as well as animal models and may be involved in the pathophysiology of schizophrenia. The interaction of GABA with other well-characterized neurotransmitter abnormalities remains to be understood. Future studies should elucidate the potential therapeutic role for GABA ligands in schizophrenia treatment.

Maintenance efficacy of divalproex in the prevention of bipolar depression

Breakthrough depression is a common problem in the treatment of bipolar disorder. Only one, recently published, double-blind, placebo-controlled trial has examined the efficacy of divalproex in the prevention of depressive episodes in bipolar patients. This report describes, in further detail, the findings from that trial of the effect of divalproex on multiple dimensions of depressive morbidity in bipolar disorder. A randomized, double-blind, parallel-group, multicenter study was conducted over a 52-week maintenance period. Bipolar I patients, who may have been treated with open-label lithium or divalproex and who met recovery criteria within 3 months of onset of an index manic episode, were randomized to maintenance treatment with divalproex, lithium, or placebo in a 2 : 1 : 1 ratio. Adjunctive paroxetine or sertraline for breakthrough depression was allowed in maintenance phase. Outcome measures were the rate of early discontinuation for depression, time to depressive relapse, proportion of patients with depressive relapse, mean change in Depressive Syndrome Scale score, proportion of patients receiving antidepressants, and time in the study. Among patients taking an antidepressant, a higher percentage of patients on placebo than divalproex discontinued early for depression. Patients who were previously hospitalized for affective episodes or took divalproex in the open period relapsed later on divalproex than on lithium during the maintenance period. Divalproex-treated patients had less worsening of depressive symptoms than lithium-treated patients during maintenance. Indices of severity of prestudy illness course predicted worse outcome in all treatment groups. Divalproex improved several dimensions of depressive morbidity and reduced the probability of depressive relapse in bipolar disorder, particularly in patients who had responded to divalproex when manic, and among patients with a more severe course of illness.

New subscales for an anchored version of the Brief Psychiatric Rating Scale: construction, reliability, and validity in acute psychiatric admissions.

Attending psychiatrists completed an anchored version of the 18-item Brief Psychiatric Rating Scale (BPRS-A) based on admission and evaluation information on a total of 2,921 adult patients treated at 1 public sector acute psychiatric teaching hospital. Exploratory factor analysis was applied to a 6-month sample to construct 4 nonoverlapping subscales: Resistance, Positive Symptoms, Negative Symptoms, and Psychological Discomfort. Confirmatory factor analysis compared these new subscales to 3 other published subscale models using a second 6-month sample. Internal consistency, rater influence, and interrater agreement were estimated in separate studies. Discriminant validity was explored by comparison of diagnosis-based samples. Application of the BPRS-A as a debriefing instrument in the study of symptomatic change and the multiple challenges inherent in psychometric study of such a rating scale in realistic hospital practice are discussed.

Randomized, placebo-controlled pilot study of divalproex sodium in the treatment of acute exacerbations of chronic schizophrenia.

Experimental and clinical data suggest that GABA-ergic drugs such as valproate may have a potential role in the treatment of schizophrenia. The authors designed a 21-day prospective, double-blind, randomized, placebo-controlled pilot study of divalproex sodium as add-on treatment to haloperidol in 12 hospitalized patients with acute exacerbations of chronic schizophrenia. All patients received haloperidol 10 mg/day for 3 days and 15 mg/day for the remaining 18 days. In addition, five patients were randomly assigned to receive divalproex augmentation and seven to receive placebo. The divalproex dose was adjusted to a target serum concentration of 75 microg/mL for 2 weeks; placebo replaced divalproex during the third and last weeks to determine any carryover effect. Psychiatric rating scales were administered at baseline and on days 7, 14, and 21. Although the placebo group improved with haloperidol treatment, the divalproex group demonstrated greater improvement. On day 21, the divalproex group had greater improvement from baseline on the Clinical Global Impression Scale (p < or = 0.04), Brief Psychiatric Rating Scale (p < or = 0.13), and Schedule for Assessment of Negative Symptoms scores (p < or = 0.007). After divalproex withdrawal on day 15, a carryover effect was observed during week 3. The authors concluded that the addition of divalproex sodium to standard antipsychotic drugs may prove effective in relieving the symptoms of acute schizophrenia. Future studies may benefit from the design of this pilot study. However, it is premature to apply this augmentation strategy in the clinical setting just yet because of the small sample size and the likely heterogeneity of the disorder.

Divalproex sodium augmentation of haloperidol in hospitalized patients with schizophrenia : Clinical and economic implications

Divalproex sodium has been approved for use in treating bipolar disorder. Its usefulness in schizophrenia has yet to be adequately assessed. Three days after initiating haloperidol treatment, patients who were hospitalized for an acute exacerbation of schizophrenia received either valproate augmentation (early-augmentation group) or continued to receive haloperidol alone (no-augmentation group). Patients in the no-augmentation group who failed to respond 14 days after the dose of haloperidol reached 20 mg/day received valproate augmentation (delayed-augmentation group). By day 14, the early-augmentation group improved 32.4% more than the no-augmentation group. Fifty percent of the patients in the no-augmentation group failed to respond to haloperidol alone for 2 weeks. They improved by 29% upon the addition of valproate. Compared with those who received no or delayed augmentation, the early-augmentation group required 44.8% fewer inpatient days from the initiation of haloperidol treatment. Patient response to treatment was particularly noted in suspiciousness, hallucinations, unusual thought content, and emotional withdrawal. Early augmentation with valproate may reduce the length of inpatient stays and provide substantially better therapeutic outcomes. It is, however, premature to recommend changes in the standard clinical management of schizophrenia on the basis of the data provided herein, in view of the small sample and open-label nature of the report.

Neuroleptic-Valproic Acid Combination in Treatment of Psychotic Symptoms: A Three-Case Report

Valproic acid is infrequently used for treatment of psychosis. Three consecutive patients with severe neuroleptic-resistant psychotic symptoms responded dramatically to the combination of valproic acid and neuroleptics. All three had normal EEGs and CT scans. Outpatient follow-up showed that the combination was effective in maintaining remissions.

Immediate versus delayed visual memory task performance among schizophrenic patients and normal control subjects

In an exploratory study, 10 schizophrenic patients and 10 normal control subjects performed immediate and delayed memory tasks, which were variants of previously developed continuous performance tests. Both tasks required participants to identify five-digit numbers which were repeated. Numbers were presented in series for 500 ms each and separated by a 500-ms time-out period. In the immediate memory task, subjects were to respond if a number was identical to the one that had immediately preceded it. The delayed memory task differed from the first task in that a longer delay (3.5 s) between stimuli was introduced, and during this delay distracter stimuli appeared. While normal control subjects performed accurately on both tasks (exceeding 80% correct detections), schizophrenic patients performed poorly, performing worse on the delayed memory task than on the immediate memory task. Rates of commission errors (responses made to similar, but not identical numbers) were nearly equal between groups on the immediate memory task, but on the delayed memory task normal control subjects made relatively more commission errors while schizophrenic patients made fewer commission errors. No differences in response latencies were observed between subject groups or tasks. This paradigm may prove useful in discriminating subtle differences in immediate and delayed memory capability among psychiatric populations and normal control subjects.

Mononuclear leukocyte glucocorticoid receptor binding characteristics and down-regulation in major depression

Some patients with major depressive disorder (MDD) have elevated plasma cortisol concentrations and show failure to suppress cortisol secretion upon administration of dexamethasone (DEX), yet they do not have Cushingoid features. To study whether this represents glucocorticoid (GC) resistance, [3H]-DEX-binding assays were used to measure, in vitro, the GC receptor affinity (1/Kd) and number (Bmax) in mononuclear leukocytes of 11 MDD patients and 15 control subjects. No receptor abnormalities were detected in the MDD group; thus any cellular defect leading to a lack of responsiveness to GC in the MDD patients, if present, probably lies beyond the initial receptor binding. DEX (1.0 mg orally) was administered to study in vivo GC receptor down-regulation. Compared to the control group, fewer depressed subjects down-regulated Bmax after DEX. By paired t-test, Bmax decreased significantly in the control group but not in the depressed group. Receptor number on the control day did not correlate significantly with the degree of receptor down-regulation, severity of depression or cortisol concentrations across all the subjects. These results do not lend support to previous reports suggesting that GC resistance in MDD results from a GC receptor-binding abnormality, and they emphasize the importance of considering receptor studies in the context of GC-mediated cell processes in order to identify the exact cellular defect(s) leading to GC resistance.

Lengthened temporal integration in schizophrenia.

Research in schizophrenia has tended to emphasize deficits in higher cognitive abilities, such as attention, memory, and executive function. Here we provide evidence for dysfunction at a more fundamental level of perceptual processing, temporal integration. On a measure of flicker fusion, patients with schizophrenia exhibited significantly lower thresholds than age and education matched healthy controls. We reasoned that this finding could result from a longer window of temporal integration or could reflect diminished repetition suppression: if every frame of the repeating stimulus were represented as novel, its perceived duration would be accordingly longer. To tease apart these non-exclusive hypotheses, we asked patients to report the number of stimuli perceived on the screen at once (numerosity) as they watched rapidly flashing stimuli that were either repeated or novel. Patients reported significantly higher numerosity than controls in all conditions, again indicating a longer window of temporal integration in schizophrenia. Further, patients showed the largest difference from controls in the repeated condition, suggesting a possible effect of weaker repetition suppression. Finally, we establish that our findings generalize to several different classes of stimuli (letters, pictures, faces, words, and pseudo-words), demonstrating a non-specific effect of a lengthened window of integration. We conclude that the visual system in schizophrenics integrates input over longer periods of time, and that repetition suppression may also be deficient. We suggest that these abnormalities in the processing of temporal information may underlie higher-level deficits in schizophrenia and account for the disturbed sense of continuity and fragmentation of events in time reported by patients.

Effects of Haloperidol on Cognition in Schizophrenia Patients Depend on Baseline Performance: A Saccadic Eye Movement Study

Schizophrenic patients are heterogeneous with respect to voluntary eye movement performance, with some showing impairment (e.g., high antisaccade error rates) and others having intact performance. To investigate how this heterogeneity may correlate with different cognitive outcomes after treatment, we used a prosaccade and antisaccade task to investigate the effects of haloperidol in schizophrenic subjects at three time points: baseline (before medication), 3-5 days post-medication, and 12-14 days post-medication. We also investigated changes on the Stroop Task and the Positive and Negative Syndrome Scale (PANSS) in these same subjects. Results were compared to matched controls. When considered as a single patient group, haloperidol had no effects across sessions on reflexive and voluntary saccadic eye movements of schizophrenic patients. In contrast, the performance of the Control group improved slightly but significantly across sessions on the voluntary eye movement task. When each subject was considered separately, interestingly, for schizophrenic patients change in voluntary eye movement performance across sessions depended on the baseline performance in a non-monotonic manner. That is, there was maximal worsening of voluntary eye movement performance at an intermediate level of baseline performance and the worsening decreased on either side of this intermediate baseline level. When patients were divided into categorical subgroups (nonimpaired and impaired), consistent with the non-monotonic relationship, haloperidol worsened voluntary eye movement performance in the nonimpaired patients and improved performance in the impaired patients. These results were only partially reflected in the Stroop Test. Both patient subgroups showed clinically significant improvement over time as measured by the PANSS. These findings suggest that haloperidol has different effects on cognitive performance in impaired and nonimpaired schizophrenic patients that are not evident in clinical ratings based on the PANSS. Given that good cognitive function is important for long-term prognosis and that there is heterogeneity in schizophrenia, these findings are critical for optimal evaluation and treatment of schizophrenic patients.