Deep brain stimulation of ventral internal capsule for refractory obsessive-compulsive disorder.

The main objective of this study is to assess the effectiveness of deep brain stimulation (DBS) of the ventral striatum (VS) of the anterior limb of internal capsule for patients suffering from refractory obsessive-compulsive disorder (OCD) and to compare its result with traditional anterior capsulotomy. The present study consisted of two patients subjected to stimulation of ventral capsule (VC)/VS region of internal capsule for refractory OCD. Leads were implanted on both sides stereotactically using fused images of magnetic resonance imaging and computed tomography scan brain and connected to pulse generator (Medtronic). Outcome of both the patients was measured by Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), Beck Depression Inventory (BDI), and Mini-Mental Status Examination. The first case was followed for 4 years and 6 months, while the second case was followed for 2 years and 6 months. Both the patients responded very well to stimulation with reduction of Y-BOCS from 38 to 12 (68.42% improvement) in the first patient and 38 to 10 (78.68% improvement) in the second patient after 1 year. BDI also improved in both the patients with no significant change in mental state. No adverse effect was seen in any of the patient. The beneficial effect of DBS persisted in both the patients till follow-up and was much superior to the beneficial effect of anterior capsulotomy. We conclude that DBS of VC/VS complex is very safe and effective in refractory OCD and shows considerable promise for the future. The result of two treated patients was much better as compared to lesioning (anterior capsulotomy) and the beneficial effect persisted for long time.

The role of personality disorders in obsessive-compulsive disorder.

Personality disorders are a common comorbidity in obsessive-compulsive disorder (OCD). The effect of comorbidity on the symptom presentation, course, and treatment outcome of OCD is being discussed here. OCD and obsessive-compulsive personality disorder (OCPD) though similar in their symptom presentation, are distinct constructs. Schizotypal disorder, OCPD, and two or more comorbid personality disorders have been found to be consistently associated with a poor course of illness and treatment response. Further research is needed to determine treatment strategies to handle the personality pathology in OCD.

Use of a relapse monitoring board: an independent assessment for determining relapse in clinical trials for bipolar disorder.

OBJECTIVE: Independent review boards can provide an objective appraisal of investigators' decisions and may be useful for determining complex primary outcomes, such as bipolar disorder relapse, in crossnational studies. This article describes the use of an independent, blinded relapse monitoring board to assess the primary outcome (relapse) in an international clinical trial of risperidone long-acting therapy adjunctive to standard-care pharmacotherapy for patients with bipolar disorder. DESIGN: The fully autonomous relapse monitoring board was composed of a chair and two additional members-all psychiatrists and experts in the diagnostic, clinical, and therapeutic management of bipolar disorder. The relapse monitoring board met six times during the study to review patient relapse data and was charged with the responsibility of determining if the events described by investigators qualified as relapses. Additionally, the relapse monitoring board reviewed data for all randomized patients to identify any relapse events not recognized by investigators. RESULTS: Primary efficacy results were similar and significant for investigator- and relapse monitoring board-determined relapses. Ten discrepancies were noted: two of the 42 investigator-determined relapses did not meet the intended clinical relapse threshold as determined by the relapse monitoring board; conversely, the relapse monitoring board confirmed eight relapse events not identified by investigators. The relapse monitoring board had no direct interactions with patients and had to rely on the accuracy of investigator assessments. Also, once an investigator determined a relapse and the patients discontinued the study, less information was available to the relapse monitoring board for relapse assessment. CONCLUSIONS: Use of the relapse monitoring board supported the validity of the study by incorporating a level of standardization to mitigate the risk that local practice in different cultures and medical systems at the sites would confound study results.

An overview of Indian research in obsessive compulsive disorder.

Obsessive-compulsive disorder (OCD) was considered a relatively rare disorder until about two decades ago. Since then, considerable advance has been made in understanding the various aspects of OCD that include epidemiology, clinical features, comorbidity, biology and treatment. In the last one decade, there has also been interest in a group of related disorders called obsessive-compulsive spectrum disorders. There is substantial research from India on various aspects of OCD, particularly from the National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore. We attempt to review all the relevant Indian data on OCD.

Anti-brain autoantibodies and altered excitatory neurotransmitters in obsessive-compulsive disorder.

Although serum autoantibodies directed against basal ganglia (BG) implicate autoimmunity in the pathogenesis of obsessive-compulsive disorder (OCD), it is unclear whether these antibodies can cross the blood-brain barrier to bind against BG or other components of the OCD circuit. It is also unclear how they might lead to hyperactivity in the OCD circuit. We examined this by investigating the presence of autoantibodies directed against the BG or thalamus in the serum as well as CSF of 23 OCD patients compared with 23 matched psychiatrically normal controls using western blot. We further investigated CSF amino acid (glutamate, GABA, taurine, and glycine) levels and also examined the extent to which these levels were related to the presence of autoantibodies. There was evidence of significantly more binding of CSF autoantibodies to homogenate of BG as well as to homogenate of thalamus among OCD patients compared with controls. There was no significant difference in binding between patient and control sera except for a trend toward more bands to BG and thalamic protein corresponding to 43 kD among OCD patients compared with controls. CSF glutamate and glycine levels were also significantly higher in OCD patients compared with controls, and further multivariate analysis of variance showed that CSF glycine levels were higher in those OCD patients who had autoantibodies compared with those without. The results of our study implicate autoimmune mechanisms in the pathogenesis of OCD and also provide preliminary evidence that autoantibodies against BG and thalamus may cause OCD by modulating excitatory neurotransmission.

EEG power spectra differentiate positive and negative subgroups in neuroleptic-naive schizophrenia patients.

Electroencephalogram spectral power was estimated at 30 scalp locations in 28 neuroleptic-naive, recent-onset schizophrenia (NRS) patients and 25 healthy comparison subjects in the resting eyes closed condition. Weighted relative power values in the various bandwidths were initially compared between NRS subjects and comparison subjects and subsequently between the positive symptom subgroup, negative symptom subgroup, and comparison subjects, to look for characteristic spectral power profiles of the homogeneous symptom subgroups. Significant differences were noted especially in alpha2, delta, and theta bands between NRS patients and healthy comparison subjects, while the positive symptom and negative symptom subgroups showed characteristic spectral power profiles in alpha1, alpha2, delta, and theta bands.

Ziprasidone in treatment-resistant schizophrenia: a 52-week, open-label continuation study.

OBJECTIVE: To evaluate the efficacy, safety, and tolerability of long-term ziprasidone therapy in treatment-resistant schizophrenia. METHOD: This prospective, 1-year, open-label study of ziprasidone (40-160 mg/day) was conducted in subjects who had participated in a previous randomized 12-week comparison of ziprasi-done and chlorpromazine in treatment-resistant schizophrenia (DSM-III-R criteria). The clinical response of 62 subjects was evaluated (32 subjects had been on ziprasidone treatment and 30 had been on chlorpromazine treatment prior to enrollment in the continuation study). Assessments included the Positive and Negative Syndrome Scale total and subscale scores, movement disorder scales, body weight, and laboratory measures. This study was conducted from May 2000 to April 2002. RESULTS: Thirty-three subjects (53%) completed 1 year of open-label ziprasidone therapy. Ziprasidone maintained clinical improvement (no significant symptom exacerbation) in 30 of 41 subjects (73%) who responded to the initial 12-week double-blind treatment with either ziprasidone or chlorpromazine. Ziprasidone did not increase body weight and was associated with a favorable metabolic profile during the continuation study period. There were no significant changes in standard movement disorder measures from the core study baseline during long-term ziprasidone treatment. CONCLUSION: Ziprasidone was effective and well tolerated in the long-term therapy of patients with treatment-resistant schizophrenia.

Efficacy and tolerability of ziprasidone in patients with treatment-resistant schizophrenia.

This multicentre, parallel-group study compared the efficacy and tolerability of ziprasidone and chlorpromazine in treatment-resistant schizophrenia (at least three treatment periods of at least 6 weeks each with two or more antipsychotic agents during the past 5 years without significant response) that was unresponsive to 6 weeks of open-label haloperidol (

Risperidone in the treatment of acute mania: double-blind, placebo-controlled study.

BACKGROUND: Severe mania is life-threatening, carries an increased risk of suicide and has a serious impact on patients and their families. Efficient and rapid control of episodes of acute mania is needed. AIMS: To evaluate the safety and efficacy of risperidone monotherapy for acute mania. METHOD: In a 3-week, randomised, double-blind trial, 290 in-patients with bipolar I disorder with current manic or mixed episode and a baseline Young Mania Rating Scale (YMRS) score of 20 or more received flexible doses of risperidone (1-6 mg per day) or placebo. RESULTS: Risperidone was received by 146 patients and placebo by144. Their mean baseline YMRS score was 37.2 (s.e.=0.5). Significantly greater improvements were observed with risperidone than with placebo at weeks 1 and 2 and at end-point (total YMRS: P <0.01). Extrapyramidal symptoms were the most frequently reported adverse events in the risperidone group. CONCLUSIONS: In patients with severe manic symptoms, risperidone produced significant improvements in YMRS scores as early as week 1 and substantial changes at end-point. Treatment was well tolerated.

A family genetic study of clinical subtypes of obsessive-compulsive disorder.

OBJECTIVE: The results of various family studies of obsessive-compulsive disorder have varied widely, possibly because of heterogeneity in the obsessive-compulsive disorder phenotype. The current study was conducted to determine familiality of checker and washer subtypes of obsessive-compulsive disorder compared with normal controls. METHODS: In this study, all available first-degree relatives of 25 checker, 34 washer and 40 psychiatrically normal control probands were interviewed directly, using structured interviews. RESULTS: The morbid risk of syndromal and subsyndromal obsessive-compulsive disorder was significantly greater among the relatives of checker probands (19.4%) than in the relatives of washer (8.7%) or control probands (5.4%), while the morbid risk for the relatives of washer and control probands was not significantly different. In all, 67% of the checker relatives with syndromal and subsyndromal obsessive-compulsive disorder were checkers, while 54% of the washer relatives with syndromal and subsyndromal obsessive-compulsive disorder were washers. CONCLUSIONS: Our study provides preliminary evidence of familiality of the checker subtype of obsessive-compulsive disorder. Future studies using patients subtyped on the basis of symptom dimensions, in larger obsessive-compulsive disorder samples, are needed, to further validate the genetic basis of obsessive-compulsive disorder.

Glutamatergic dysfunction in OCD.

The role of glutamatergic dysfunction in the pathophysiology of OCD has hardly been explored despite recent reports implicating glutamatergic dysfunction in OCD. We decided to investigate CSF glutamate levels in adult OCD probands compared to psychiatrically normal controls. In total, 21 consenting psychotropic drug-naïve adult OCD patients, diagnosed using SCID-IV-CV, and 18 consenting psychiatrically normal controls with age within 10 years of age of the patients, who did not have any history of head injury or neurological illness, were included into the study. Aseptically collected and stored CSF samples obtained from the patients and control subjects were used for glutamate estimation, which was carried out by a modification of the procedure described by Lund (1986). CSF glutamate (micromol/l) level was found to be significantly higher [F(1,31)=6.846, p=0.014] in OCD patients (47.12+/-4.25) compared to control subjects (41.36+/-3.63) on analysis of covariance. There was no effect of gender, age, duration of illness, Y-BOCS score, or CGI-S score on CSF glutamate levels. Our study provides preliminary evidence implicating glutamatergic excess in the pathophysiology of OCD, which needs to be further explored by studies from other centers involving larger sample sets from different age groups.

Acute and continuation risperidone monotherapy in bipolar mania: a 3-week placebo-controlled trial followed by a 9-week double-blind trial of risperidone and haloperidol.

In a randomized, double-blind trial, patients with acute bipolar mania received 1-6 mg/day of risperidone, 2-12 mg/day of haloperidol, or placebo for 3 weeks, followed by double-blind risperidone or haloperidol for 9 weeks. Of 438 patients, 154 were randomized to risperidone, 144 to haloperidol, and 140 to placebo. The mean+/-S.D. modal doses were 4.2+/-1.7 mg/day of risperidone and 8.0+/-3.6 mg/day of haloperidol during the initial 3-week phase and 4.1+/-1.8 and 7.4+/-3.7 mg/day during the 12-week period. At week 3, mean Young Mania Rating Scale (YMRS) score reductions from baseline were significantly greater in patients receiving risperidone than placebo (p<0.001). Differences between risperidone and haloperidol on this efficacy measure were not significant. Further reductions in YMRS scores were seen in patients receiving risperidone or haloperidol during the subsequent 9 weeks. No unexpected adverse events were reported. Extrapyramidal disorder and hyperkinesias, the most commonly reported adverse events with antipsychotic use, occurred less frequently with risperidone than haloperidol. We conclude that risperidone monotherapy was an effective and well-tolerated treatment for bipolar mania and that efficacy was maintained over the long term.

Exploration of dimensions of psychopathology in neuroleptic-naïve patients with recent-onset schizophrenia/schizophreniform disorder.

Previous studies have suggested that schizophrenic psychopathology segregates into three orthogonal dimensions, viz., psychosis, negative and disorganization. Most of these reports were based on studies on medicated patients with varying degrees of chronicity. The present study aimed at exploring the dimensionality of psychopathology rated on the Scale for the Assessment of Negative Symptoms (SANS) and the Scale for the Assessment of Positive Symptoms (SAPS) in a sample of 43 neuroleptic-naïve patients with recent-onset schizophrenia/schizophreniform disorder. Principal Components Analysis (PCA) of SANS and SAPS global ratings, excluding inattention but including inappropriate affect as a separate global rating, revealed that the symptoms segregated into three dimensions, viz., negative (affective flattening, alogia, avolition anhedonia and inappropriate affect), psychosis (delusions and hallucinations) and disorganization (positive formal thought disorder and bizarre behavior). Cumulatively these three dimensions explained 74.07% of the variance. The results suggest that the three dimensions of schizophrenic psychopathology are valid even in neuroleptic-naïve, recent-onset patients with schizophrenia/schizophreniform disorder. PCA of the SANS and SAPS individual items revealed similar findings, but psychotic symptoms loaded under two components, thus yielding a four-factor solution; however, this observation needs to be confirmed in a larger sample of neuroleptic-naïve schizophrenic patients.

EEG alpha coherence and psychopathological dimensions of schizophrenia.

The aim of this study was to evaluate the correlation between psychopathological dimensions in recent-onset neuroleptic-naive schizophrenic patients and EEG alpha coherence in the resting state. 37 neuroleptic-naive recent-onset schizophrenic patients were assessed on the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms, and psychopathological dimension scores on reality distortion, psychomotor poverty and disorganization were calculated. EEG alpha coherence was computed across 14 intra-hemispheric and 8 interhemispheric electrode pairs in the resting eyes closed and eyes open conditions. The relationship between the psychopathological dimension scores and coherence values was assessed using Pearson's product moment correlation with Bonferroni correction for levels of significance. Significant associations between higher psychomotor poverty scores and lower inter-hemispheric coherence values were found across the central and parietal regions in the eyes closed condition and across central regions in the eyes open condition. Reality distortion and disorganization dimensions were not significantly correlated with intra- or inter-hemispheric coherences in both eyes closed and eyes open conditions. However there was a trend for an inverse correlation between disorganization dimension and intra-hemispheric coherence across left frontal, left temporo-parietal and right parieto-occipital regions in the eyes open condition. These findings suggest a possible differential pattern in the extent of brain involvement across the three psychopathological dimensions of schizophrenia in neurolepticnaive patients with recent-onset illness.

Csf amines and their metabolites in first episode drug naive schizophrenic patients and their correlations with dimensions of schizophrenia.

There has been great interest in the neurobiological substrate of the different dimensions of schizophrenia. This has largely focused on structural and functional changes while it has been acknowledged that there is a relation between pharmacological response and neurotransmitter alteration on these dimensions. Atypical anti psychotics which affect both positive and negative symptoms mediate their action predominantly through dopaminergic and serotonergic receptors. The current study extends this further looking at CSF amines. 37 drug naive first episode psychosis patients with the duration of illness less than 2 years were included. Patients were assessed with SAPS (Scale for Assessment of Positive Symptoms) and SANS (Scale for Assessment of Negative Symptoms). Lumbar puncture was done under sterile conditions and CSF was analyzed by HPLC for dopamine, serotonin and their metabolites. Mean CSF 5- HIAA was 25.35ng/dl. Mean CSF 5 HT was 7.72 ng/dl. Mean CSFHVA was 36.99 ng/dl. Mean CSF 5-DA was 3.06 ng/dl. There was significant positive correlation between CSF5-HIAA and Negative and Disorganization dimensions. There was significant negative correlation between CSF HVA and Psychosis dimension. There is evidence to support that the implication of serotonin in Negative and Disorganization dimensions and the Serotonin- Dopamine interaction and dimensions of schizophrenia.

A clinical genetic study of adult obsessive compulsive disorder from India.

OBJECTIVE: The current study aims to replicate western reports of a familial excess of syndromal and sub-syndromal Obsessive Compulsive Disorder (OCD) in OCD probands in an Indian population. METHOD: 148 relatives of OCD probands were compared with 151 normal subjects, based on evaluation on Schedule for Clinical Assessment for Neuropsychiatry (SCAN). RESULTS: There were no clinically significant differences in the prevalence of psychiatric disorders between the two samples. CONCLUSION: In an Indian setting, the absence of familial loading in adult OCD is being reported. Whether subgroups of OCD are familial, or other factors play a role in the pathogenesis of OCD in India needs to be explored.