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OBJECTIVE Schizophrenia patients show executive function (EF) impairments in voluntary orienting as measured by eye-movements. We tested 14 inpatients to investigate the effects of the antipsychotic olanzapine on EF, as measured by antisaccade eye-movement performance. METHODS Patients were tested at baseline (before olanzapine), 3-5 days post-medication, and 12-14 days post-medication. Patients were also assessed on the Positive and Negative Syndrome Scale (PANSS) to measure the severity of schizophrenia-related symptoms, and administered the Stroop task, a test of EF. Nine matched controls were also tested on the antisaccade and Stroop. RESULTS Both groups showed improvement on Stroop and antisaccade; however, the schizophrenia group improved significantly more on antisaccade, indicating an additional benefit of olanzapine on EF performance. Patients with poorer baseline antisaccade performance (High-Deficit) showed significantly greater improvement on the antisaccade task than patients with better baseline performance (Low-Deficit), suggesting that baseline EF impairment predicts the magnitude of cognitive improvement with olanzapine. These subgroups showed significant and equivalent improvement on PANSS scores, indicating that improvement on the antisaccade task with olanzapine was not a result of differences in magnitude of clinical improvement. CONCLUSIONS This preliminary study provides evidence that olanzapine may be most advantageous for patients with greater baseline EF deficits.

Background Long-term outcomes are often poor in patients with bipolar disorder despite treatment; more effective treatments are needed to reduce recurrences and morbidity. This study compared the efficacy of divalproex, lithium, and placebo as prophylactic therapy. Methods A randomized, double-blind, parallel-group multicenter study of treatment outcomes was conducted over a 52-week maintenance period. Patients who met the recovery criteria within 3 months of the onset of an index manic episode (n = 372) were randomized to maintenance treatment with divalproex, lithium, or placebo in a 2:1:1 ratio. Psychotropic medications were discontinued before randomization, except for open-label divalproex or lithium, which were gradually tapered over the first 2 weeks of maintenance treatment. The primary outcome measure was time to recurrence of any mood episode. Secondary measures were time to a manic episode, time to a depressive episode, average change from baseline in Schedule for Affective Disorders and Schizophrenia–Change Version subscale scores for depression and mania, and Global Assessment of Function scores. Results The divalproex group did not differ significantly from the placebo group in time to any mood episode. Divalproex was superior to placebo in terms of lower rates of discontinuation for either a recurrent mood episode or depressive episode. Divalproex was superior to lithium in longer duration of successful prophylaxis in the study and less deterioration in depressive symptoms and Global Assessment Scale scores. Conclusions The treatments did not differ significantly on time to recurrence of any mood episode during maintenance therapy. Patients treated with divalproex had better outcomes than those treated with placebo or lithium on several secondary outcome measures. Arch Gen Psychiatry. 2000;57:481–489

Objective Valproic acid (VPA) has been suggested as a potential adjunct therapy in schizophrenia for the treatment of clinical symptoms and cognitive deficits. Here, we investigate the effects of VPA on clinical symptoms and saccadic eye movements while controlling for multiple medication effects. Methods Remitted and first-episode schizophrenia patients taking haloperidol were given adjunct VPA for approximately 2weeks and tested using a measure of clinical symptoms (Positive and Negative Syndrome Scale) and saccadic eye movement tasks over three testing periods. The effects of VPA were compared with schizophrenia patients medicated with equivalent doses of haloperidol alone (HAL group) and normal controls. Results Schizophrenia patients had higher error rates on the antisaccade task (AS task) compared with normal controls. Adjunct VPA did not affect AS task error rates but was associated with an increase in response times for both saccade and AS tasks, with a significantly greater and dose-dependent increase in response times for the AS task. There were no differences in clinical improvement between VPA and HAL schizophrenia patient groups when controlling for haloperidol medication state. Conclusions These results suggest that adjuvant VPA therapy results in both sensorimotor and cognitive slowing but does not either help or further impair inhibitory control in schizophrenia, as measured by the elevated AS task errors. Copyright © 2011 John Wiley & Sons, Ltd. key words—saccade; antisaccade; valproic acid; schizophrenia; haloperidol

The purpose of this study was to examine characteristics associated with prescribing antidepressants in major depression and the utility of such antidepressants in an acute-care, inpatient setting. Demographic and clinical (self-report and clinician-rated scales) were obtained for 111 inpatients diagnosed with major depression. Three comparison sets were made: (1) all patients prescribed antidepressants versus those who were not; (2) those in the top quartile for length of stay (LOS) versus those in the bottom quartile; and (3) patients discharged in less than one week who were prescribed versus not prescribed, antidepressants. Overall, minimal differences were found in the three comparison sets. Those prescribed antidepressants had higher admission BDI scores, longer LOS, more previous episodes, higher education levels, and were more likely to be admitted voluntarily. At admission, there were no clear predictors of LOS. Regardless of differences between groups at admission or discharge (antidepressant versus no antidepressant, short versus long LOS), no differences were found in the length of time before patients were readmitted. These findings suggest that the traditional practice of avoiding immediate medication at hospitalization appears to have some validity.

Ratings of change in MDD severity during a brief psychiatric hospitalization were examined across informant sources to determine the extent of change from admission to discharge and if specific symptoms are especially likely to change. Study participants were 137 inpatients with a primary diagnosis of MDD. Symptom data were collected at admission and discharge from attending psychiatrists, nurses, and patients. Global ratings of MDD severity and specific MDD symptoms significantly decreased during the course of hospitalization. This effect held across informant sources. All symptoms were equally likely to change. Females were rated as more depressed at admission and discharge by psychiatrists, but no gender differences were seen in self-report or nurse ratings. Shorter length of stay and involuntary admission status were associated with greater reduction in MDD severity. The temporal course and magnitude of the symptom reduction may result in part from unique aspects of an inpatient setting or from an underreporting of symptoms. The association between a shorter length of stay and greater symptom reduction may reflect a distinction between treatment responders and nonresponders.

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.

This double-blind, randomized, multicenter study investigated the use of divalproex with an antipsychotic agent in patients hospitalized for acute exacerbation of schizophrenia. Patients (n = 249) who met DSM-IV criteria for schizophrenia were randomly assigned to receive olanzapine monotherapy, risperidone monotherapy, divalproex plus olanzapine, or divalproex plus risperidone for 28 days. Divalproex was initiated at 15 mg/kg/day and titrated over 12 days to a maximum dosage of 30 mg/kg/day. Olanzapine and risperidone, were, respectively, initiated at 5 and 2 mg/day and were titrated over the first 6 days to respective target fixed daily dosages of 15 and 6 mg/day. Improvements from baseline were observed at all evaluation points throughout the 28-day treatment period in the two combination therapy and the two antipsychotic monotherapy groups, with statistically significant treatment differences favoring combination therapy as soon as day 3 for Positive and Negative Syndrome Scale (PANSS) total score, derived Brief Psychiatric Rating Scale (BPRSd) total score, as well as PANSS and BPRSd subscales. These findings were confirmed in post hoc repeated-measures analyses of variance in which treatment differences favoring combination therapy were observed for PANSS total (p = 0.020) and PANSS positive scale scores (p = 0.002). Both combination therapy and antipsychotic monotherapy were well tolerated. Treatment with divalproex in combination with an atypical antipsychotic agent resulted in earlier improvements in a range of psychotic symptoms among acutely hospitalized patients with schizophrenia. Further evaluation is warranted to confirm these findings.

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.

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.

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.

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.

This study analyzed the perceptions of 136 mental health providers toward the consideration ofculturalfactors in the evaluation of Hispanic children and adolescents. Results show that the providers overwhelmingly perceived that cultural issues are important and need to be considered in their evaluations. However, only 54% considered themselves as highly successful in assessing the degree of acculturation, and a higher percentage (69%) reported a high degree of needfor more culturally focused training. The results suggest that a lack of cultural training might be more related to an inability to access training than a lack of understanding of the importance of cultural issues.

Valproic acid (VPA) has been suggested as a potential adjunct therapy in schizophrenia for the treatment of clinical symptoms and cognitive deficits. Here, we investigate the effects of VPA on clinical symptoms and saccadic eye movements while controlling for multiple medication effects.Remitted and first-episode schizophrenia patients taking haloperidol were given adjunct VPA for approximately 2 weeks and tested using a measure of clinical symptoms (Positive and Negative Syndrome Scale) and saccadic eye movement tasks over three testing periods. The effects of VPA were compared with schizophrenia patients medicated with equivalent doses of haloperidol alone (HAL group) and normal controls.Schizophrenia patients had higher error rates on the antisaccade task (AS task) compared with normal controls. Adjunct VPA did not affect AS task error rates but was associated with an increase in response times for both saccade and AS tasks, with a significantly greater and dose-dependent increase in response times for the AS task. There were no differences in clinical improvement between VPA and HAL schizophrenia patient groups when controlling for haloperidol medication state.These results suggest that adjuvant VPA therapy results in both sensorimotor and cognitive slowing but does not either help or further impair inhibitory control in schizophrenia, as measured by the elevated AS task errors.

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.

A difficult case in psychotherapy can be defined in many ways. This study proposes a model for that definition, in which three domains (patient characteristics, case characteristics, and therapist characteristics) are considered to impact on that definition. A total of 264 professionals received a questionnaire to assess the relative importance of a series of variables within and across these domains. Wilcoxon Matched-Pairs Signed-Ranks tests indicated that patient characteristics were considered more important than therapist or case characteristics in defining a difficult case. Case characteristics were considered more important than therapist characteristics. Pearson correlations, however, suggested that the three domains in the model are related. Correlations (for years of experience) and Kruskal-Wallis one-way ANOVA for ranks (for professions) also indicated that participants were able to identify variables within domains as important in that definition regardless of years of experience or professions. Across domains, the most important variables included the motivation of the client (a patient characteristic), dropout/attrition and multiple diagnoses (case characteristics), and the degree of therapist-client racial similarity (a therapist characteristic).

The authors examined clinical differences between divalproex sodium and generic immediate-release valproic acid.This 6-year prospective, quasi-experimental clinical trial compared the effectiveness and tolerability of divalproex and valproic acid. The dependent variables were length of hospital stay, rehospitalization rate, and adverse drug reactions in 9,260 psychiatric admissions.Inpatients who initially received divalproex sodium had a 32.7% longer hospital stay and 3.8% higher readmission rate than did patients who initially received valproic acid. Initial treatment with divalproex prolonged length of stay by 30.3% in patients treated with divalproex and valproic acid during different admissions. After other variables were controlled by multiway analysis of variance, the hospital stay of patients who continued the initial medication was 15.2% longer (2.0 days) for divalproex than valproic acid. Switching medications was more common for valproic acid, partly because of study design. Medication intolerance occurred in approximately 6.4% more patients taking valproic acid than divalproex. However, switching from valproic acid to divalproex did not significantly prolong length of stay, over that for continuous divalproex, or increase the rehospitalization rate.Lower peak valproate concentrations with divalproex sodium may have enhanced tolerability but may also explain the lower effectiveness. Extended-release divalproex could lower effectiveness further and require higher doses. Thus, inpatients are better served by beginning with generic valproic acid and by changing to delayed-release divalproex only if intolerance occurs. This would save up to one-third of inpatient costs and two-thirds of a billion dollars yearly in medication costs.

A total of 423 health professionals, including physicians, psychologists, counselors, social workers, and nurses, attended a two-day program to increase awareness, recognition, and treatment of depression. In a preprogram opinion survey, nurses and social workers reported less perceived ability to recognize mood disorders compared with physicians and psychologists. In a group of 274 respondents who took a 20-item test of their knowledge about depression before and after attending the program, scores for all professions increased after the program and pretest differences in scores between professions decreased. The results suggest that training was successful in increasing knowledge about depression among a diverse group of health professionals.

A converging body of evidence implicates the gamma-aminobutyric acid (GABA) neurotransmitter system in the pathogenesis of schizophrenia.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.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.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.

GABA-ergic medications may have a potential role in the treatment of schizophrenia. Laboratory evidence has generally supported the ability of gamma-aminobutyric acid (GABA) to reduce dopaminergic activity and has suggested that GABA may be effective in combating hypofrontality by acting on mesoprefrontocortical tracts in patients resistant to treatment with antipsychotic drugs. Although the results of clinical trials of several GABA-ergic compounds have been inconclusive because of methodologic limitations and drug toxicity, benzodiazepines and valproate seem to be associated with favorable treatment outcomes, especially when combined with typical antipsychotic agents. This study concludes that further investigation of the use of GABA in schizophrenia is likely to improve the understanding of the psychopathology of this illness and to expand our treatment alternatives. Also provided are suggestions to enhance the design of future studies, improve the potential for favorable treatment outcomes, and assist in predicting patients' responses to GABA-ergic medications.

1. In order to further understand the apparent glucocorticoid resistance in major depressive disorder, circadian variation in cortisol concentration, dexamethasone suppression and glucocorticoid receptor binding in mononuclear leukocytes, polymorphonuclear leukocytes and cultured skin fibroblasts were measured in rigidly defined major depressive disorder patients and non-depressed psychiatric controls. 2. Mononuclear leukocytes binding to glucocorticoid correlated significantly with polymorphonuclear leukocytes binding to glucocorticoid, but both determinations failed to differentiate major depressive disorder and control subjects. 3. Initial and post-dexamethasone in vitro fibroblast binding to glucocorticoid was not different between major depressive disorder and non-depressed control subjects. 4. The phenomenon of glucocorticoid resistance in major depressive disorder remains unexplained.

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.

Valproic Acid Induces Manifestations of Simultaneous Dopamine Enhancement and Reduction in Schizophrenia

Unbalanced Statistical Analysis of Combined Divalproex and Antipsychotic Therapy for Schizophrenia

Background Long-term outcomes are often poor in patients with bipolar disorder despite treatment; more effective treatments are needed to reduce recurrences and morbidity. This study compared the efficacy of divalproex, lithium, and placebo as prophylactic therapy. Methods A randomized, double-blind, parallel-group multicenter study of treatment outcomes was conducted over a 52-week maintenance period. Patients who met the recovery criteria within 3 months of the onset of an index manic episode (n=372) were randomized to maintenance treatment with divalproex, lithium, or placebo in a 2:1:1 ratio. Psychotropic medications were discontinued before randomization, except for open-label divalproex or lithium, which were gradually tapered over the first 2 weeks of maintenance treatment. The primary outcome measure was time to recurrence of any mood episode. Secondary measures were time to a manic episode, time to a depressive episode, average change from baseline in Schedule for Affective Disorders and Schizophrenia–Change Version subscale scores for depression and mania, and Global Assessment of Function scores. Results The divalproex group did not differ significantly from the placebo group in time to any mood episode. Divalproex was superior to placebo in terms of lower rates of discontinuation for either a recurrent mood episode or depressive episode. Divalproex was superior to lithium in longer duration of successful prophylaxis in the study and less deterioration in depressive symptoms and Global Assessment Scale scores. Conclusions The treatments did not differ significantly on time to recurrence of any mood episode during maintenance therapy. Patients treated with divalproex had better outcomes than those treated with placebo or lithium on several secondary outcome measures.

A subgroup of individuals with major depressive disorder have an impaired thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH). The molecular relationship between the mechanism of this "blunted" TSH response and depression is unknown. Numerous recent studies have characterized similarities and interactions between the immune and neuroendocrine systems. As the immune system both produces and responds to TSH, we utilized a peripheral blood leukocyte system to compare immunoreactive (ir)-TSH responsiveness in 10 adult patients (1 man, 9 women) with Research Diagnostic Criteria for major depressive disorder to that of 9 control subjects. All subjects had normal baseline serum TSH and T4 concentrations. Isolated mononuclear leukocytes were treated in vitro with either 0.5 micrograms/ml staphylococcal enterotoxin A (SEA), 50 micrograms/ml TRH, or no stimulant. After incubation, the cells were monitored for ir-TSH production by indirect immunofluorescence and reverse hemolytic plaque assay using antisera to TSH-beta. The culture supernates were analyzed by TSH radioimmunoassay. SEA- and TRH-treated cell cultures from depressed individuals had significantly fewer immunofluorescent positive cells, as well as significantly fewer and smaller plaques, than did similarly treated leukocytes from control subjects. The increase in supernatant ir-TSH was significantly less in TRH-treated cultures from depressed patients as compared to normals (p less than 0.05). These results suggest that examination of mononuclear leukocyte TSH production may reflect an altered state of neuroendocrine function and may thus be a useful marker for major depressive disorder.

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.