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Objective: Treatment-emergent mania can have substantial negative impact on overall mood and psychosocial stability in patients receiving treatment for bipolar depression. This study examined the correlates associated with treatment-emergent mania in patients receiving adjunctive antidepressant treatment for bipolar depression. Method: A total of 176 adult outpatients with bipolar disorder in a 10-week trial of adjunctive antidepressant treatment for depression were categorized into three groups based on the Clinical Global Impression Scale for Bipolar Disorder: those who responded to antidepressant treatment (N-85), those who did not respond to antidepressant treatment (N=45), and those who had treatment-emergent mania or hypomania (N=46). Symptom se verity was measured with the Inventory of Depressive Symptomatology and the Young Mania Rating Scale (YMRS) at baseline and bimonthly intervals. Factor analysis was used to examine correlates of treatment-emergent mania. Results: Baseline YMRS scores were significantly different between groups. Otherwise, there were no significant between-group differences in demographic or clinical characteristics. Factor analysis showed that a subset of the YMRS items predicted treatment-emergent mania in this sample: increased motor activity, speech, and language-thought disorder. Conclusions: These data suggest that minimal manic symptoms at baseline coexisting with otherwise full syndromal bipolar depression are associated with antidepressant treatment-emergent mania or hypomania. A careful examination of motor activation, pressured speech, and racing thoughts is warranted before starting antidepressant treatment in bipolar depression.

Objective: The consensus cognitive battery developed by the National Institute of Mental Health's (NIMH's) Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative includes 10 independently developed tests that are recommended as the standard battery for clinical trials of cognitionenhancing interventions for schizophrenia. To facilitate interpretation of results from the MATRICS Consensus Cognitive Battery using a common scaling across tests, normative data were obtained from a single representative U.S. community sample with the battery administered as a unit. Method: The MATRICS Consensus Cognitive Battery was administered to 300 individuals from the general community at five sites in differing geographic regions. For each site, recruitment was stratified by age, gender, and education. A scientific survey sampling method was used to help avoid sampling bias. The battery was administered in a standard order to each participant in a single session lasting approximately 60 minutes. Descriptive data were generated, and age, gender, and education effects on performance were examined. Results: Prominent age and education effects were observed across tests. The results for gender differed by measure, suggesting the need for age and gender corrections in clinical trials. The MATRICS Consensus Cognitive Battery components were co-normed, with allowance for demographic corrections. Conclusions: Co-norming a battery such as the MATRICS Consensus Cognitive Battery, comprising tests from independent test developers each with their own set of norms, facilitates valid interpretation of test scores and communication of findings across studies. These normative data will aid in estimating the magnitude of change during clinical trials of cognition-enhancing agents and make it possible to derive more directly interpretable composite scores.

Objective: This study examined the short-term effects of first- and second-generation antipsychotic medications on social cognition and basic cognition. Method: One hundred patients with schizophrenia or schizoaffective disorder participated in an 8 week, double-blind study of risperidone, olanzapine, and haloperidol. Participants were administered multiple measures of social cognition, basic cognition, and clinical symptoms at baseline, the end of week 4, and the end of week 8. Seventy-three patients completed the baseline assessment and at least one other assessment. Data were analyzed with mixed-effects analyses of co-variance. For data reduction, the social cognitive measures were clustered into a summary score, and the cognitive measures were clustered into two summary scores: general cognitive ability and processing speed. (The effects on thinking of risperidone and olanzapine can be found at NCT00108368, www.clinicaltrials.gov.) Results: There were no treatment-related differences on any of the three summary scores. Social cognition did not show within-group changes over time either by itself or after control for the cognitive clusters. One cognitive score (general cognitive ability) increased during the study period for all three medication groups. Conclusions: The present study included a rather thorough assessment of social cognition and did not find any evidence of between-group or within-group effects of antipsychotic medication on social cognition.

Objective: Modafinil is approved by the U.S. Food and Drug Administration for improving wakefulness in patients with excessive sleepiness associated with narcolepsy, obstructive sleep apnea, and shift-work sleep disorder. This study was conducted to evaluate the efficacy and safety of adjunctive modafinil in bipolar depression, which is often characterized by excessive sleepiness and fatigue. Method: Eighty-five patients with bipolar depression that was inadequately responsive to a mood stabilizer with or without concomitant antidepressant therapy were randomly assigned to receive adjunctive modafinil (N=41) or placebo (N=44) for 6 weeks. The primary outcome measure was baseline-to-endpoint change in score on the Inventory of Depressive Symptoms--Clinician Rated (IDS). Results: The baseline-to-endpoint change in IDS score was significantly greater in the modafinil group (mean dose, 177 mg/day) compared with the placebo group. Improvement in depressive symptoms was significantly greater in the modafinil group by week 2, and this greater improvement was maintained at weeks 4, 5, and 6. Both the response and remission rates were significantly higher in the modafinil group (44% and 39%) compared with the placebo group (23% and 18%). During the 6-week study period, there was no difference between groups in treatment-emergent hypomania or mania (six patients in the modafinil group and five in the placebo group) or hospitalization for mania (one in each group). Conclusions: These data suggest that adjunctive modafinil at doses of 100-200 mg a day may improve depressive symptoms in patients with bipolar disorder.

Objective: The authors evaluated the effects of prenatal antidepressant exposure and maternal depression on infant gestational age at birth and risk of preterm birth. Method: Ninety women were followed in a prospective, naturalistic design through pregnancy with monthly assessments of symptoms of depression and anxiety using the Structured Clinical Interview for DSM-IV mood module for depression, the Hamilton Depression Rating Scale, the Beck Depression Inventory, and the Perceived Stress Scale. Participants included 49 women with major depressive disorder who were treated with antidepressants during pregnancy (group 1), 22 women with major depressive disorder who were either not treated with antidepressants or had limited exposure to them during pregnancy (group 2), and 19 healthy comparison subjects (group 3). The primary outcome variables were the infants' gestational age at birth, birth weight, 1- and 5-minute Apgar scores, and admission to the special care nursery. Results: Groups 1, 2, and 3 differed significantly in gestational age at birth (38.5 weeks, 39.4 weeks, 39.7 weeks, respectively), rates of preterm birth (14.3%, 0%, 5.3%, respectively), and rates of admission to the special care nursery (21%, 9%, 0%, respectively). Birth weight and Apgar scores did not differ significantly between groups. Mild to moderate depression during pregnancy did not affect outcome measures. Conclusions: Prenatal antidepressant use was associated with lower gestational age at birth and an increased risk of preterm birth. Presence of depressive symptoms was not associated with this risk. These results suggest that medication status, rather than depression, is a predictor of gestational age at birth.

Objective: There is a clear need to develop psychosocial rehabilitation methods that compensate for neurocognitive deficits common to persons with severe and persistent mental illness. Errorless learning, a compensatory training intervention, has been successful in teaching entry-level job tasks. However, errorless learning's applicability to broader, more complex functions is unknown. The present study tested the extension of errorless learning for deficits in social problem-solving skills in patients with schizophrenia. Method: Sixty clinically stable outpatients with schizophrenia or schizoaffective disorder were stratified by gender and level of memory impairment before being randomly assigned to one of two training programs: errorless learning or symptom management. Groups were matched for training time, format and structure of training, and types of teaching aids used. Social problem-solving ability, measured by the Assessment of Interpersonal Problem-Solving Skills, was assessed at baseline, within 2 days of training completion, and after 3 months. Dependent measures were the scores for the receiving, processing, and sending skills areas from the Assessment of Interpersonal Problem-Solving Skills. Results: A repeated-measures analysis of covariance was conducted for each dependent measure with baseline Assessment of Interpersonal Problem-Solving Skills score entered as a covariate. For all three skills, there was a significant training group effect favoring errorless learning. Durability of errorless learning training effects extended to the 3-month follow-up assessment for processing and sending skills but not receiving skills. Conclusions: Results support the extension of errorless learning to complex functions such as social problem-solving skills in the rehabilitation of persons with schizophrenia.

Objective: The diagnosis of bipolar disorder in juveniles is controversial. This study was designed to compare proton magnetic resonance spectroscopy ([sup.1]H MRS) in patients with bipolar disorder or intermittent explosive disorder, two groups with symptomatic overlap but categorical distinction. Children with intermittent explosive disorder designate patients whose illness clinically resembles pediatric bipolar disorder but does not satisfy DSM-IV criteria for mania. Based on the authors' previous report of higher levels of [sup.1]H MRS cingulate myo-inositol/ creatine in youngsters with bipolar disorder than in normal comparison subjects, they hypothesized that patients with bipolar disorder would have higher cingulate myo-inositol/creatine-phosphocreatine measurements than patients with intermittent explosive disorder and normal comparison subjects. Method: Myo-inositol levels were measured with a 2x2x2 [cm.sup.3] voxel placed in the anterior cingulate for acquisition of [sup.1]H MRS in 10 patients with bipolar disorder, 10 patients with intermittent explosive disorder, and 13 normal comparison subjects. N-Acetylaspartate, choline moieties, creatine-phosphocreatine, and glutamate-glutamine metabolite levels were also measured. Results: The patients with bipolar disorder showed significantly higher anterior cingulate myo-inositol/creatine-phosphocreatine and myo-inositol (mmol/liter) levels than the patients with intermittent explosive disorder and the normal comparison subjects. No significant differences were found across groups for myo-inositol or other metabolites in the occipital cortex. Conclusions: These data provide evidence that differences in the concentration of myo-inositol (mmol/liter) in the anterior cingulate cortex in [sup.1]H MRS may differentiate these two populations. Follow-up studies involving larger samples may conclusively estimate the biological specificity between pediatric bipolar disorder and other disorders, which overlap clinically.

Objective: Most controlled studies comparing second-generation and conventional antipsychotics have focused on the acute treatment of schizophrenia. The authors compared symptom outcomes, side effects, and social adjustment in stable schizophrenia outpatients who received 2 years of maintenance treatment with risperidone or haloperidol. Method: This was a 2-year, randomized, double-blind comparison of 6 mg of risperidone versus haloperidol in 63 patients with stabilized DSM-IV schizophrenia. Study patients also received 15 months of standard behavioral skills training or enhanced training with a case manager who promoted patients' use of their skills in the community. Results: The risk of psychotic exacerbations and the risk of leaving the study were similar for both drug treatment groups. However, patients who received both risperidone and the enhanced community-based skills training were more likely to remain in the study than those in the other treatment groups. Patients demonstrated significant improvement in score on the Brief Psychiatric Rating Scale over time with both medications. There were no between-group differences in cluster scores for thought disturbance, hostile-suspiciousness, and withdrawal-retardation. A significant between-group difference favoring risperidone was found for the anxious-depression cluster. Risperidone resulted in significantly greater reductions in tremor and akathisia and greater improvements in most items on the SCL-90-R. Conclusions: When compared with patients given a low dose of haloperidol, risperidone-treated patients experienced similar improvements in positive and negative symptoms and similar risks of psychotic exacerbations. However, risperidone-treated patients appeared to feel subjectively better, as indicated by less anxiety and depression and fewer extra-pyramidal side effects.

Objective: Until recently, few training methods used in the psychosocial rehabilitation of persons with schizophrenia have taken into account the neurocognitive deficits common to this illness. The present study tested a training method called errorless learning (which theoretically compensates for neurocognitive impairments) for efficacy at teaching entry-level job tasks to persons with serious and persistent mental illness. Method: Sixty-five unemployed, clinically stable outpatients with schizophrenia or schizoaffective disorder were randomly assigned to training by means of either errorless learning or conventional instruction for two entry-level job tasks (index card filing and toilet tank assembly). Training was conducted in small groups of four subjects for 90-120 minutes in a simulated workshop. Efficacy--as measured by accuracy, speed, and overall productivity--was assessed immediately after training and at a 3-month follow-up evaluation. Results: Significant group differences in accuracy that favored errorless learning were found on both job tasks. In terms of productivity, the errorless learning group was superior to the conventional instruction group on the card filing task, and differences for the tank assembly task approached significance. There were no significant group differences in speed. Both groups showed significant drops in accuracy and productivity on the tank assembly task from immediately after training to the 3-month follow-up evaluation; performance levels were more stable for both groups on the card filing task. Conclusions: Errorless learning appears to be a useful training method for establishing introductory high levels of performance in the work rehabilitation of persons with schizophrenia. Future studies may wish to test its long-term durability by embedding it within supported employment programs.

Objective: Although skills training is a validated psychosocial treatment for schizophrenia, generalization of the skills to everyday life has not been optimal. This study evaluated a behaviorally oriented method of augmenting clinic-based skills training in the community with the aim of improving opportunities, encouragement, and reinforcement for outpatients to use their skills in their natural environment. Method: Sixty-three individuals with schizophrenia were randomly assigned to 60 weeks of clinic-based skills training alone or of clinic-based skills training supplemented with manual-based generalization sessions in the community. Patients were also randomly assigned to receive either haloperidol or risperidone. Therapists' fidelity to the manuals was measured. Patients' acquisition of the skills from pre- to posttraining was evaluated. The primary outcome measures were the Social Adjustment Scale-II and the Quality of Life Scale. Results: Seventy-one percent of the patients completed the trial. Only six participants experienced psychotic exacerbations during the trial. There was no evidence of a differential medication effect on social functioning. Social functioning improved modestly in both psychosocial conditions over time; participants who received augmented skills training in the community showed significantly greater and/or quicker improvements. Conclusions: Given judicious and effective antipsychotic medication that limited exacerbations to less than 10% during the trial, a wide range of outpatients with schizophrenia demonstrated substantial learning of illness management and social skills in the clinic. When clinic-based skills training was augmented by in vivo training and consultation, transfer of the skills to everyday life was enhanced. These benefits were established regardless of the medications prescribed.

Objective: Neuroanatomical abnormalities have been identified in patients with late-life mood disorders by using magnetic resonance imaging. This study examined the biochemical correlates of late-life major depression in the frontal gray and white matter by using single-voxel proton spectroscopy. Method: Twenty elderly patients with major depression and 18 comparison subjects similar in age and gender to the patients were scanned on a 1.5-T magnetic resonance scanner with head coil. Voxels were placed in the left dorsolateral white matter and bilaterally in the anterior cingulate gray matter. Absolute levels of N-acetylaspartate, choline, myo-inositol, and creatine were estimated with the LC-Model algorithm. Ratios of metabolite to creatine levels were computed from the absolute values. Results: myo-Inositol/creatine and choline/crealine ratios were significantly higher in the frontal white matter in the major depression group than in the comparison group. The groups had no significant differences in the metabolite ratios in the gray matter. Conclusions: Biochemical changes in the white matter may provide some of the neurobiological substrates to late-life major depression.

Objective: Maintenance medication is critical in the prevention of psychotic relapse and rehospitalization among patients with schizophrenia. Given potential adverse effects, identification of the minimum effective dose is clinically important. Method: A multicenter, double-blind study was conducted to determine rates of symptomatic exacerbation and adverse effects in 105 outpatients with schizophrenia randomly assigned to four different fixed doses of haloperidol decanoate and treated for 1 year or until relapse. The doses used were 25, 50, 100, and 200 mg given intramuscularly once per month. Results: Rates of symptomatic exacerbation were 15% in the 200-mg group, 23% with 100 mg, 25% with 50 mg, and 60% with 25 mg. No significant differences in outcome were found between the groups treated with 200, 100, and 50 mg. Among the patients who completed the trial with no symptomatic exacerbation, there were no differences between close groups on measures of psychopathology at the final rating point. Conclusions: The results of this study suggest that the 200-mg/month close of haloperidol decanoate is associated with the lowest rate of symptomatic exacerbation (15%) with minimal increased risk of adverse effects or subjective discomfort in comparison to 100 or 50 mg. At the same time, the rates of worsening with 100 mg (23%) and 50 mg (25%) were not significantly greater than that seen with 200 mg. These results provide some guidance as to effective dose ranges of haloperidol decanoate.

Objective: The goal of this report was to examine the clinical course following neuroleptic discontinuation of patients with recent-onset schizophrenia who had been receiving maintenance antipsychotic treatment for at least 1 year. Method: Fifty-three volunteer patients with recent-onset schizophrenia who had been clinically stabilized on a maintenance regimen of fluphenazine decanoate for a mean of 16.7 months had their antipsychotic medications withdrawn under clinical supervision. Participants initially entered a 24-week, double-blind crossover trial in which fluphenazine and placebo were administered for 12 weeks each. For those who did not experience symptom exacerbation or relapse during this period, fluphenazine was openly withdrawn; participants were then followed for up to 18 additional months. Results: When a low threshold for defining symptom reemergence was used, 78% (N=39 of 50) of the patients experienced an exacerbation or relapse within 1 year; 96% (N=48 of 50) did so within 2 years. Mean time to exacerbation or relapse was 235 days. When hospitalization was used as a relapse criterion, only six of 45 of individuals (13%) experiencing an exacerbation or relapse who continued in treatment in the clinic were hospitalized, demonstrating the sensitivity of the psychotic exacerbation criterion. Conclusions: The vast majority of clinically stable individuals with recent-onset schizophrenia will experience an exacerbation or relapse after antipsychotic discontinuation, even after more than a year of maintenance medication. However, clinical monitoring and a low threshold for reinstating medications can prevent hospitalization for the majority of these patients. (Am J Psychiatry 2001; 158:1835-1842)

Objective: Atypical antipsychotic medications have generally been found to be more effective than conventional antipsychotics in the treatment of negative symptoms. Whether the benefits derived from the atypical agents are the result of improvements in primary versus secondary negative symptoms is unclear. The authors examined the effects of olanzapine on primary and secondary negative symptoms for patients with severe negative symptoms who did or did not have the deficit syndrome. Method: Thirty-nine outpatients with schizophrenia and severe negative symptoms were assessed for the presence of the deficit syndrome and entered into a 12-week, open-label study of olanzapine. Positive and negative symptoms, extrapyramidal side effects, quality of life, and level of functioning of the patients were assessed at baseline and endpoint. Results: All 39 patients completed the 12-week protocol; 13 of the patients had deficit negative symptoms, and 26 had nondeficit negative symptoms. Patients who had nondeficit negative symptoms demonstrated improvements in positive and negative symptoms, level of functioning, and extrapyramidal side effects over baseline. In contrast, patients meeting criteria for the deficit syndrome improved significantly over baseline only in extrapyramidal side effects. Conclusions: The results of this study suggest that olanzapine is efficacious for secondary negative symptoms in schizophrenia but fail to support the contention that olanzapine has a direct beneficial effect on primary negative symptoms.

Objective: The purpose of this study was to evaluate the clinical safety and efficacy of risperidone compared to haloperidol in patients with treatment-refractory schizophrenia. Method: Sixty-seven medication-unresponsive subjects were randomly assigned to treatment with risperidone (N-34) or haloperidol (N-33). After a 3-7 day-placebo washout period, there was a 4-week, double-blind, fixed-dose comparison trial that was followed by a 4-week, flexible-dose phase. Measures of clinical change were quantified by standard psychopathologic and neuromotor instruments. Results: Risperidone demonstrated clinical efficacy superior to that of haloperidol on the total Brief Psychiatric Rating Scale (BPRS) after the first 4 weeks of treatment. Risperidone did not show any advantage over haloperidoi after an additional 4 weeks. Overall improvement on the BPRS at 4 weeks was significantly better for the risperidone group (24%) than for the haloperidol group (11%). Risperidone-treated subjects were significantly less likely than haloperidol-treated subjects to require concomitant anticholinergic medication after 4 weeks (20% versus 63%); they also had significantly less observable akathisia (24% versus 53%) and significantly less severe tardive dyskinesia. Baseline characteristics that correlated significantly with risperidone response were positive symptoms, conceptual disorganization, akathisia, and tardive dyskinesia. Conclusions: Risperidone was better tolerated and more effective in a subset of patients with treatment-refractory schizophrenia. Positive psychotic symptoms and extrapyramidal side effects at baseline appear to be powerful predictors of subsequent response to risperidone.

Objective: Patients with schizophrenia consistently show performance deficits on measures of visual backward masking, but the nature of these deficits is not well understood. Performance deficits on backward masking tasks may indicate an underlying predisposition instead of the presence of illness, because deficits are present in unaffected first-degree relatives. Performance deficits in remitted patients would constitute converging support for this hypothesis. Method: Eleven patients with recent-onset schizophrenia who were in a period of no medication use during remission of psychosis were compared with a matched normal group on three visual masking conditions. These conditions included target identification tasks with a high-energy mask, a low-energy mask, and a blurred target. Results: Patients in psychotic remission showed significant deficits across all conditions. In addition, trend analyses revealed significant group differences in the shape of the masking functions: the comparison group showed an oscillating performance pattern across all masking conditions, whereas the patients did not exhibit this pattern on any condition. Conclusions: These data from patients in well-documented psychotic remission add converging support for the hypothesis that deficits on backward masking procedures are indicators of vulnerability to schizophrenia. Because visual masking procedures may reflect underlying neural oscillations of 30 to 70 Hz in the visual cortex, the pattern of results is consistent with the theory that visual masking deficits in schizophrenia stem from an underlying failure to establish cortical oscillations.

Objective: Treatment efficacy in schizophrenia is typically defined in terms of symptom reduction. However, new antipsychotic medications could potentially have an impact on aspects of disability, such as neurocognitive deficits. The authors evaluated the effects of risperidone on verbal working memory, a memory component of theoretical interest because of its link to prefrontal activity and of practical interest because of its link to psychosocial rehabilitation. Method: Verbal working memory of 59 treatment-resistant schizophrenic patients was assessed as part of a randomized, double-blind comparison of treatment with risperidone and haloperidol. Verbal working memory was measured under both distracting and nondistracting conditions at baseline and after 4 weeks of both fixed- and flexible-dose pharmacotherapy. Results: Risperidone treatment had a greater beneficial effect on verbal working memory than haloperidol treatment across testing conditions (with and without distraction) and study phases (fixed and flexible dose). The treatment effect remained significant after the effects of benztropine cotreatment, change in psychotic symptoms, and change in negative symptoms were controlled. Neither benztropine status nor symptom changes were significantly related to memory performance. Conclusions: Treatment with risperidone appears to exert a more favorable effect on verbal working memory than treatment with a conventional neuroleptic. The beneficial effect appears to be due, at least partially, to a direct effect of the drug, possibly through antagonism of the 5-H[T.sub.2A] receptor. Results from this study suggest that pharmacotherapeutic efficacy in schizophrenia treatment could be broadened to include impact on neurocognitive abilities.

Objective: The authors evaluated the effectiveness of behaviorally oriented social skills training and supportive group therapy for improving the social adjustment of schizophrenic patients living in the community and for protecting them against psychotic relapse. Method: Eighty male outpatients with schizophrenia were stabilized with a low dose of fluphenazine decanoate (5 to 10 mg every 14 days), which was supplemented with oral fluphenazine (5 mg twice daily) or a placebo when they first met criteria for a prodromal period. (Half of the patients did so at some time during the study.) Patients were randomly assigned to receive either social skills training or supportive group therapy twice weekly for 6 months and then weekly for the next 18 months. Rates of psychotic exacerbation were monitored, as were scores on the Social Adjustment Scale II. Results: There were significant main effects favoring social skills training over supportive group therapy on two of the six Social Adjustment Scale II cluster totals examined (personal well-being and total) and significant interactions between psychosocial treatment and drug treatment for three items (external family, social and leisure activities, and total). In each case, these interactions indicated that the advantage of social skills training over supportive group therapy was greatest when it was combined with active drug supplementation. Social skills training did not significantly decrease the risk of psychotic exacerbation in the full group, but an advantage was observed (post hoc) among patients who received placebo supplementation. Conclusions: These findings suggest that social skills training resulted in greater improvement in certain measures of social adjustment than supportive group therapy. The greatest improvement in social outcomes occurred when social skills training was combined with a pharmacological strategy of active drug supplementation at the time prodromal worsening of psychotic symptoms was first observed. However, these improvements were modest in absolute terms and confined to certain subgroups of patients.

Objective: Given concerns about use of psychotropic medication during pregnancy, the authors reviewed the literature regarding the effects of prenatal exposure to psychotropic medications on fetal outcome. Method: A MEDLINE search of all articles written in English from 1996 to 1995 was performed to review information on the effects of psychotropic drug use during pregnancy on fetal outcome. Where sufficient data were available and when methodologically appropriate, meta-analyses were performed to assess risk of fetal exposure by psychotropic medication class. Results: Three primary effects are associated with medication use during pregnancy: 1) teratogenicity, 2) perinatal syndromes (neonatal toxicity), and 3) postnatal behavioral sequelae. For many drug classes there are substantial data regarding risk for teratogenicity. Tricyclic antidepressants do not seem to confer increased risk for organ dysgenesis. The available data indicate the first-trimester exposure to low-potency phenothiazines, lithium, certain anticonvulsants, and benzodiazepines may increase the relative risk for congenital anomalies. However, the absolute risk of congenital malformations following prenatal exposure to most psychotropics is low. Conclusions: Exposure to certain psychotropic drugs in utero may increase the risk for some specific congenital anomalies, but the rate of occurrence of these anomalies even with the increased risk remains low. Use of psychotropic medications during pregnancy is appropriate in many clinical situations and should include thoughtful weighing of risk of prenatal exposure versus risk of relapse following drug discontinuation. The authors present disorder-based guidelines for psychotropic drugs use during pregnancy and for psychiatrically ill women who wish to conceive.

Objective: Accumulating evidence suggests a greater number of [T.sub.2] abnormalities in the brains of patients with bipolar I disorder. The authors sought to evaluate the presence of signal 'hyperintensities' in both bipolar I and II subjects and systematically review the existing literature. Method: Magnetic resonance images of the brain were obtained prospectively for 29 patients with bipolar I disorder, 26 patients with bipolar II disorder, and 20 normal comparison subjects. The presence and location of signal hyperintensities in three brain regions (periventricular white matter, subcortical gray matter, and deep white matter) were evaluated. Results: No significant differences were found between groups for the presence of subcortical gray or deep white matter hyperintensities. Periventricular hyperintensities were more common in bipolar I patients (62%) than in bipolar II patients (38%) and normal comparison subjects (30%). Within patient groups, medication use was not significantly different for those with or without the presence of white matter hyperintensities. The literature on bipolar disorder and signal hyperintensities is reviewed. A meta-analysis of the pooled data in the literature on bipolar illness and signal hyperintensities revealed that the odds of having a [T.sub.2] hyper-intensity are significantly greater for bipolar I than for normal comparison subjects. Conclusions: Having bipolar I disorder significantly increases the chance of having white matter changes in the brain. This study suggests that bipolar II patients may be more similar than bipolar I patients to comparison subjects on [T.sub.2] measures. The possible pathophysiological significance of hyperintensities is discussed.

Thirteen treatment-refractory schizophrenic patients (10 men and three women) who were receiving more than 50 mg/day of haloperidol and who had been hospitalized for more than 1 year successfully tolerated a mean dose reduction of 63% with consequent improvement in psychopathology and side effects. The addition of intensive behavior therapy to the optimal dose of haloperidol yielded further improvements in functional behavior, such as self-care and social interaction.

Objective: To determine whether schizophrenic outpatients receiving low-dose neuroleptic therapy could learn and retain complex information and skills related to self-management of their illness, a novel technique of teaching, using cognitive and behavioral methods, was designed to compensate for the patients' learning disabilities. Method: The subjects were 41 patients with DSM-III-R schizophrenia who were receiving constant maintenance neuroleptic drug therapy. They were randomly assigned to structured, modularized skills training or to supportive group psychotherapy. Results: The patients who received skills training made significant gains in each of the areas taught, while those participating in group therapy did not. The skills learned during training were retained without significant erosion over a 1-year follow-up period. Conclusions: The effectiveness of modularized teaching of illness self-management skills to schizophrenic patients appears to be largely independent of baseline psychopathology and symptom improvement. Such an approach is useful for overcoming or compensating for the enduring cognitive and information processing deficits commonly found in schizophrenia. (Am J Psychiatry 1992; 149:1549-1555)

Objective: The purpose of the study was to assess the relationship between plasma haloperidol and clinical response. Method: Sixty-nine newly admitted drug-free schizophrenic men were randomly assigned to receive haloperidol, 5, 10, or 20 mg daily for 4 weeks, and clinical response was measured at the end of the fixed-dose period. Haloperidol was assayed by a sensitive and specific radioimmunoassay. Results: The authors found a curvilinear relationship between clinical response and plasma haloperidol during fixed-dose treatment, with an apparent optimum between 5 and 12 ng/ml. When plasma levels above 12 ng/ml were lowered to the 5-12 ng/ml range, all patients improved to varying degrees and no patient deteriorated. When plasma levels of nonresponders within this therapeutic window were raised above 12 ng/ml (as in routine practice), they, on balance, deteriorated in that they became more dysphoric. With the 20-mg dose, half the patients had plasma levels above 12 ng/ml. Conclusions: In this sample of newly admitted schizophrenic men, optimal clinical response occurred with a plasma haloperidol range of 5-12 ng/ml. (Am J Psychiatry 1992; 149:500-505)

Symptoms of depression are not uncommon in schizophrenic patients. A study examined the course of both depressive and psychotic symptoms in 27 patients in the early stages of schizophrenia. Ratings were taken every two weeks for each patient for at least one year. The temporal relationship of these psychotic or depressive episodes was examined for patterns that were specific to early-onset schizophrenia. The ratings, which were made by using Brief Psychiatric Rating Scales, indicated that during the first eight-week period that followed the end of a psychotic episode, there was no increase in episodes of depression. Although periods of depression did occur in the postpsychotic period, no increase of depressive episodes was observed during periods of psychosis. These results run contrary to the popular idea that there are specific postpsychotic episodes of depression that occur in schizophrenics. The results do support the concept that the onset of depression occurs at the same time as the onset of psychosis, although with varying magnitudes. Depression may also occur before or after the psychotic episodes, but no specific patterns were detected. (Consumer Summary produced by Reliance Medical Information, Inc.)

Objective: Schizophrenia patients consistently demonstrate performance deficits on visual masking procedures. The present study examined whether attentional manipulation would improve subjects' performance on visual masking. Method: A metacontrast task was administered to 105 schizophrenia patients and 52 healthy comparison subjects. Attention was manipulated by associating selected trials of the task with monetary reward. Results: Schizophrenia patients exhibited poorer performance than the comparison subjects across conditions. Patients demonstrated modest, but statistically significant, improvement in performance with the attentional manipulation. This improvement was not significant for the comparison subjects. Conclusions: These findings suggest that early visual processes in schizophrenia are responsive to attentional manipulation but that the degree of improvement is relatively small, suggesting that these processes are not easily altered.

Objective: This study sought to investigate neural activity in the amygdala during episodes of mania. Method: Nine manic subjects and nine healthy comparison subjects underwent functional magnetic resonance imaging (fMRI) while performing a neuropsychological paradigm known to activate the amygdala. Subjects viewed faces displaying affect (experimental task) and geometric forms (control task) and matched them to one of two simultaneously presented similar images. Results: Manic subjects had significantly increased activation in the left amygdala and reduced bilateral activation in the lateral orbitofrontal cortex relative to the comparison subjects. Conclusions: Increased activation in the amygdala and decreased activation in the orbitofrontal cortex may represent disruption of a specific neuroanatomic circuit involved in mania. These brain regions may be implicated in disorders involving regulation of affect.

Objective: This study evaluated a brief educational video designed to enhance the informed consent process for people with serious mental and medical illnesses who are considering participating in treatment research. Method: Individuals with schizophrenia who were being recruited for ongoing clinical trials, medical patients without self-reported psychiatric comorbidity, and university undergraduates were randomly assigned to view either a highly structured instructional videotape about the consent process in treatment research or a control videotape that presented only general information about bioethical issues in human research. Knowledge about informed consent was measured before and after viewing. Results: Viewing the experimental videotape resulted in larger gains in knowledge about informed consent. Standardized effect sizes were large in all groups. Conclusions: The videotape was thus an effective teaching tool across diverse populations, ranging from individuals with severe chronic mental illness to university undergraduates.

Objective: The delayed onset of therapeutic response to antidepressants remains a major problem in the treatment of depression. Among the strategies to accelerate response to treatment, the early addition of thyroid hormone to antidepressants has been suggested as a viable method. The authors performed a meta-analysis of the literature on the use of thyroid hormone supplementation to accelerate the treatment of depression to determine whether there is sufficient evidence to support the clinical efficacy of this strategy. Method: Both a computer-aided search of the National Library of Medicine MEDLINE and an intensive search by hand were conducted to identify all double-blind, placebo-controlled studies assessing the concomitant administration of thyroid hormone and antidepressant to accelerate clinical response in patients with nonrefractory depression. Results: Six studies were identified. All were conducted with triiodothyronine ([T.sub.3]) and a tricyclic antidepressant. Five of the six studies found [T.sub.3] to be significantly more effective than placebo in accelerating clinical response. The pooled, weighted effect size index was 0.58, and the average effect was highly significant. Further, the effects of [T.sub.3] acceleration were greater as the percentage of women participating in the study increased. Conclusions: This meta-analysis supports the efficacy of [T.sub.3] in accelerating clinical response to tricyclic antidepressants in patients with nonrefractory depression. Furthermore, women may be more likely than men to benefit from this intervention. (Am J Psychiatry 2001; 158:1617-1622)