Biju Viswanath

Cognitive endophenotypes in OCD: a study of unaffected siblings of probands with familial OCD.

BACKGROUND Impairments in executive functions and non-verbal memory are considered potential endophenotype markers of obsessive-compulsive disorder (OCD). For the neuropsychological deficits to be considered endophenotypes, they should be demonstrable in unaffected family members. AIM To compare the neuropsychological performance in unaffected siblings of probands with familial OCD with that of individually matched healthy controls. METHODS Twenty-five unaffected siblings of OCD probands with familial OCD, and 25 individually matched healthy controls were assessed with tests of attention, executive function, memory and intelligence. RESULTS Unaffected siblings showed significant deficits in tests of decision making and behavioural reversal i.e., the Iowa Gambling Task (IGT) and the Delayed Alternation Test (DAT) respectively, but performed adequately in other tests. CONCLUSIONS Our study suggests that the deficits in decision making and behavioural reversal could be potential endophenotypes in OCD. These deficits are consistent with the proposed neurobiological model of OCD involving the orbitofrontal cortex. Future studies could couple cognitive and imaging strategies to identify neurocognitive endophenotypes in homogenous samples of OCD.

Neuropsychological performance in OCD: a study in medication-naïve patients.

BACKGROUND Obsessive-compulsive disorder (OCD) is associated with impairments in multiple neuropsychological domains but the findings are rather inconsistent across studies. One potential reason for poor replication is the confounding influence of medications. There is limited research on neuropsychological performance in medication-naïve, never treated OCD patients. METHODS In this study, we assessed 31 medication-naïve, never-treated, DSM-IV OCD patients free of comorbid major depression and 31 healthy controls individually matched for age, gender and years of education, with tests of attention, executive function, memory reasoning and visuo-spatial function. RESULTS Medication-naïve OCD patients did not significantly differ from healthy controls on most neuropsychological tests. Patients performed somewhat poorly only on the highest goal hierarchy of the Tower of London (TOL) test (p=0.001, effect size=0.68). CONCLUSIONS It is intriguing to find that symptomatic, drug-naïve OCD patients did not significantly differ from healthy controls on most neuropsychological tests. Our finding of medium effect size on TOL highest goal hierarchy test suggests that brain regions outside the affective orbitofrontal loop may also be perhaps involved in OCD. This finding however needs replication because of modest effect size. Future studies should focus on studying medication-naïve, co-morbidity-free patients and relatives using symptom dimensions for consistent and robust findings.

Impact of age of onset of illness on clinical phenotype in OCD

BACKGROUND This study aims to examine the demographic, clinical and comorbid patterns in a large sample of adult OCD subjects at a specialty OCD clinic in India. METHODS Consecutive patients (n=545) who consulted a specialty OCD Clinic over 5 years at a large psychiatric hospital in India were evaluated with the Mini International Neuropsychiatric Interview, the Yale-Brown Obsessive-Compulsive Scale, and the Clinical Global Impression scale. RESULTS Earlier age onset of OCD (years) was characterized by male preponderance (19.61±7.98 vs. 25.19±10.39, U=23453.5, p=<0.001), positive family history of OCD (19.60±10.02 vs. 22.27±9.20, U=16590.5, p<0.001) and presence of tic disorder (16.28±8.21 vs. 22.01±9.38, OR=0.86, p=0.001). In addition, early age of onset was associated with presence of sexual obsessions (18.92±7.49 vs. 22.88±9.82, OR=0.96, p=0.02), hoarding (19.61±9.32 vs. 22.21±9.36, OR=0.95, p=0.009), repeating rituals (19.76±8.37 vs. 23.29±9.84, OR=0.95, p=0.006) and need to touch compulsions (16.40±7.19 vs. 22.36±9.43, OR=0.89, p<0.001). CONCLUSIONS Our findings from a large sample not only confirm that early onset OCD could be a valid and distinct subtype of OCD but also support the cross-cultural similarity of early onset phenotype.

Cellular models to study bipolar disorder: a systematic review

BACKGROUND There is an emerging interest in the use of cellular models to study psychiatric disorders. We have systematically reviewed the application of cellular models to understand the biological basis of bipolar disorder (BD). METHOD Published scientific literature in MEDLINE, PsychINFO and SCOPUS databases were identified with the following search strategy: [(Lymphoblastoid OR Lymphoblast OR Fibroblast OR Pluripotent OR Olfactory epithelium OR Olfactory mucosa) AND (Bipolar disorder OR Lithium OR Valproate OR Mania)]. Studies were included if they had used cell cultures derived from BD patients. RESULTS There were 65 articles on lymphoblastoid cell lines, 14 articles on fibroblasts, 4 articles on olfactory neuronal epithelium (ONE) and 2 articles on neurons reprogrammed from induced pluripotent stem cell lines (IPSC). Several parameters have been studied, and the most replicated findings are abnormalities in calcium signaling, endoplasmic reticulum (ER) stress response, mitochondrial oxidative pathway, membrane ion channels, circadian system and apoptosis related genes. These, although present in basal state, seem to be accentuated in the presence of cellular stressors (e.g. oxidative stress--rotenone; ER stress--thapsigargin), and are often reversed with in-vitro lithium. CONCLUSION Cellular modeling has proven useful in BD, and potential pathways, especially in cellular resilience related mechanisms have been identified. These findings show consistency with other study designs (genome-wide association, brain-imaging, and post-mortem brain expression). ONE cells and IPSC reprogrammed neurons represent the next generation of cell models in BD. Future studies should focus on family-based study designs and combine cell models with deep sequencing and genetic manipulations.

Impact of depressive and anxiety disorder comorbidity on the clinical expression of obsessive-compulsive disorder.

BACKGROUND The identification of distinct subtypes based on comorbidity offers potential utility in understanding variations in the clinical expression of obsessive-compulsive disorder (OCD). Hence, we examined the hypothesis whether patients with OCD with major depressive disorder (MDD) or anxiety disorder comorbidity would differ from those without in terms of phenomenology. METHODS A total of 545 consecutive patients who consulted a specialty OCD clinic during the period 2004 to 2009 at a psychiatric hospital in India formed the sample. They were evaluated with the Yale-Brown Obsessive-Compulsive Scale (YBOCS), the Mini International Neuropsychiatric Interview, and the Clinical Global Impression scale. RESULTS Among 545 patients, 165 (30%) had current MDD, and 114 (21%) had current anxiety disorder comorbidity. Patients with OCD with MDD were mostly women who had a greater severity of OCD symptoms, more of obsessions (especially religious), greater occurrence of miscellaneous compulsions (need to confess or need to touch), higher suicidal risk, and past suicidal attempts. Patients with OCD with anxiety disorder had an earlier onset of illness that was associated with prior life events, less of compulsions, more of aggressive and hoarding obsessions, pathologic doubts, checking, and cognitive compulsions. CONCLUSIONS Obsessive-compulsive disorder, when comorbid with MDD, is more severe and is associated with higher suicidal risk. On the other hand, anxiety disorder comorbidity seems to influence not so much the morbidity but the phenotypic expression of OCD.

Relationship between sunlight and the age of onset of bipolar disorder: an international multisite study.

BACKGROUND The onset of bipolar disorder is influenced by the interaction of genetic and environmental factors. We previously found that a large increase in sunlight in springtime was associated with a lower age of onset. This study extends this analysis with more collection sites at diverse locations, and includes family history and polarity of first episode. METHODS Data from 4037 patients with bipolar I disorder were collected at 36 collection sites in 23 countries at latitudes spanning 3.2 north (N) to 63.4 N and 38.2 south (S) of the equator. The age of onset of the first episode, onset location, family history of mood disorders, and polarity of first episode were obtained retrospectively, from patient records and/or direct interview. Solar insolation data were obtained for the onset locations. RESULTS There was a large, significant inverse relationship between maximum monthly increase in solar insolation and age of onset, controlling for the country median age and the birth cohort. The effect was reduced by half if there was no family history. The maximum monthly increase in solar insolation occurred in springtime. The effect was one-third smaller for initial episodes of mania than depression. The largest maximum monthly increase in solar insolation occurred in northern latitudes such as Oslo, Norway, and warm and dry areas such as Los Angeles, California. LIMITATIONS Recall bias for onset and family history data. CONCLUSIONS A large springtime increase in sunlight may have an important influence on the onset of bipolar disorder, especially in those with a family history of mood disorders.

DRD4 gene and obsessive compulsive disorder: Do symptom dimensions have specific genetic correlates?

INTRODUCTION The dopamine D4 receptor (DRD4) is a promising candidate gene in obsessive compulsive disorder (OCD). A 48-bp variable number of tandem repeats (VNTR) sequence in exon 3 has been studied previously, and alleles containing 2-11 repeats (2R-11R) have been identified. We investigated the association of DRD4 VNTR polymorphism with OCD and its relationship with various clinical parameters (age of onset, gender, family history, co-morbidity, factor-analyzed symptom dimensions and insight). METHODOLOGY One hundred and seventy three South Indian OCD patients (DSM-IV) recruited from a specialty OCD clinic were evaluated using the Yale-Brown obsessive compulsive scale (YBOCS), YBOCS item-11 for insight, Mini International Neuropsychiatric Interview (MINI) plus, tic disorder subsection of the MINI-KID and Clinical Global Impression scale. 201 healthy controls were evaluated using MINI plus. All subjects were genotyped for the DRD4 VNTR polymorphism. RESULTS Genotype frequencies did not deviate significantly from the Hardy-Weinberg equilibrium. Case-control association analysis revealed that the 7R allele frequency was significantly greater in OCD patients than controls. This difference was restricted to the women subsample when performing the gender sub-analysis. Among other clinical variables examined, factor 3 (symmetry) was associated with presence of 2R allele. Linear regression analysis confirmed the association of symmetry dimension with the 2R allele (Beta=0.23, t=2.96, p=0.004, CI=0.19-0.95). CONCLUSIONS Our data provides further evidence that DRD4 VNTR polymorphism is associated with OCD. Furthermore, the presence of the 2R allele was significantly associated with the symmetry dimension. This dimension may represent a more homogeneous subtype of OCD with a genetic etiology.

Does insight have specific correlation with symptom dimensions in OCD

OBJECTIVE To study relationship between insight and clinical characteristics in subjects with obsessive-compulsive disorder (OCD). METHOD Sample included 545 consecutive patients with a primary diagnosis of DSM-IV OCD who consulted a specialty OCD Clinic at a tertiary psychiatric hospital in India between January 2004 and December 2009. They had been evaluated with the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) symptom checklist, severity rating scale and the item 11 for insight, the Mini International Neuropsychiatric Interview (MINI) and the Clinical Global Impression scale (CGI). Regression analyses were performed to identify predictors of insight. RESULTS The sample had 498 (91%) subjects with good insight (score≤2) and 47 (9%) subjects with poor insight (score>2) as per the Y-BOCS item11. Poor insight group had a significantly higher score on the Y-BOCS compulsions (p<0.001) and total score (p=0.001), the CGI-Severity (p=0.001) and a higher rate of contamination fears (p<0.001) and washing compulsions (p<0.001). Good insight group had a significantly higher frequency of aggressive obsessions (p<0.001). In linear regression, contamination dimension (p=0.007) and Y-BOCS total score (p<0.001) predicted poorer insight and presence of forbidden thoughts (p=0.006) predicted better insight. LIMITATIONS Study sample is from a specialty OCD clinic of a major psychiatric hospital in India and therefore, generalizability to other clinical settings may be limited. CONCLUSION Poor insight is associated with severe form of OCD, and is associated with contamination dimension. That degree of insight has specific correlation with certain symptom dimensions adds to the growing knowledge on the dimensional aspect of OCD. Insight has to be systematically assessed in all OCD subjects particularly in those with contamination fears. Failure to systematically assess insight may have treatment implications.

Influence of light exposure during early life on the age of onset of bipolar disorder

BACKGROUND Environmental conditions early in life may imprint the circadian system and influence response to environmental signals later in life. We previously determined that a large springtime increase in solar insolation at the onset location was associated with a younger age of onset of bipolar disorder, especially with a family history of mood disorders. This study investigated whether the hours of daylight at the birth location affected this association. METHODS Data collected previously at 36 collection sites from 23 countries were available for 3896 patients with bipolar I disorder, born between latitudes of 1.4 N and 70.7 N, and 1.2 S and 41.3 S. Hours of daylight variables for the birth location were added to a base model to assess the relation between the age of onset and solar insolation. RESULTS More hours of daylight at the birth location during early life was associated with an older age of onset, suggesting reduced vulnerability to the future circadian challenge of the springtime increase in solar insolation at the onset location. Addition of the minimum of the average monthly hours of daylight during the first 3 months of life improved the base model, with a significant positive relationship to age of onset. Coefficients for all other variables remained stable, significant and consistent with the base model. CONCLUSIONS Light exposure during early life may have important consequences for those who are susceptible to bipolar disorder, especially at latitudes with little natural light in winter. This study indirectly supports the concept that early life exposure to light may affect the long term adaptability to respond to a circadian challenge later in life.

Comorbid obsessive compulsive disorder in patients with bipolar-I disorder

BACKGROUND Limited numbers of studies have examined the prevalence of OCD systematically in consecutively sampled adult bipolar disorder type I (BD-I) patients. We examined the frequency of OCD in a large number (n=396) of consecutively hospitalized patients with BD-I and identified socio-demographic and clinical correlates of BD-I with and without OCD. METHOD BD-I patients (n=396) were assessed using the Mini International Neuropsychiatric Interview for Bipolar Disorder Studies, the Structured clinical interview for (Axis II) DSM-IV, the Family interview for genetic studies, the Yale-Brown Obsessive-Compulsive Scale, the Young Mania Rating Scale, the Hamilton Rating Scale for Depression, the Global Assessment of Functioning (GAF) and the Clinical Global Impression scale. Patients with and without OCD were compared in terms of various socio-demographic and clinical variables. RESULTS Thirty (7.6%) of the 396 inpatients studied had OCD and 15 (3.8%) had subclinical OCD. BD-OCD group had significantly lower GAF scores, higher rates of unemployment, and lower incidence of psychotic symptoms. In addition, BD-OCD group had higher rates of comorbid social anxiety and anxious avoidant personality disorder (AAPD) and OCD in first-degree relatives. Those with clinical and subclinical OCD did not differ on functioning and severity measures. LIMITATIONS Retrospective design and recruitment of patients from inpatient services of a tertiary psychiatric hospital. CONCLUSION OCD is not an uncommon comorbid disorder in BD-I and appears to be associated with greater functional disability. BD-I with comorbid OCD is associated with greater family history of OCD, comorbidities of social phobia and AAPD and less of psychotic symptoms.