[Show abstract][Hide abstract] ABSTRACT: Background:
Variable responses to clozapine in patients with schizophrenia are complex and poorly understood phenomena. The findings of pharmacogenetic studies on the use of this drug are poorly replicated. Effects of individual polymorphisms have rarely proved explanatory. One possible explanation may be multi-factorial involvement of genetic and environmental influences.
To evaluate the role of possible second and third order genetic interactions (epistasis) between polymorphisms in CYP1A2 (*1F, *1D, *1E, *1C), HTR3A (rs1062613 and rs2276302), DRD4 (120-bp duplication) and COMT (Val158Met) genes in clinical response, serum levels and adverse effects of clozapine in patients with treatment-resistant schizophrenia (TRS).
The model-based multidimensionality reduction (MB-MDR) method has recently been shown to be superior to traditional parametric regression methods in detecting higher order gene-gene interactions. We used this approach in a sample of 93 patients with TRS to explore the epistatic effects of the polymorphisms of interest on clinical phenotypes of clozapine. Data on genotypes and phenotypes of the patients that was available from a previous pharmacogenetic study was used for the analysis.
The MB-MDR analysis showed a significant interaction between Val158Met, CYP1A2*1D and rs1062613 polymorphisms and clinical response to clozapine (p=0.002). In addition, multiple significant second and third order interactions were observed with regard to the adverse effects of clozapine (p<0.05). No significant interactions were observed between the polymorphisms and serum levels of clozapine. All the reported interactions were found to be significant after 1000 permutations.
Epistatic analysis showed significant associations of several polymorphisms with clinical phenotypes of clozapine that were not previously found on isolated analysis. This emphasizes the importance of epistatic analysis in pharmacogenetic studies of clozapine. Such an approach may be useful in predicting a patient’s response to clozapine therapy.
World Congress of Psychiatric Genetics, Copenhagen, Denmark; 10/2014
[Show abstract][Hide abstract] ABSTRACT: The use of clozapine, an effective antipsychotic drug used in treatment-resistant schizophrenia, is associated with adverse effects. Sialorrhea is one such effect, which can be distressing for many patients. Studies on the pharmacogenetics of the adverse effects of clozapine are limited. The aim of the present study was to determine whether clozapine-induced sialorrhea is associated with a 120 base-pairs (bp) tandem duplication polymorphism in the dopamine receptor subtype D4 (DRD4) gene. Ninety-five patients, mean age 35.43±9.43 years, with treatment-resistant schizophrenia and on clozapine were included in the study. Development of sialorrhea in response to the drug, as manifested by drooling of saliva, was documented in 45 (47.4%) patients. Genotyping of the patients was carried out to detect the presence of the polymorphism of interest. Clozapine-induced sialorrhea was found to be associated significantly with the 120-bp duplication in DRD4. The association was found to fit a log-additive model with an odds ratio of 2.95 (95% confidence interval 1.51-5.75; P=0.0006). Thus, the presence of the 120-bp duplication in DRD4 appears to confer a risk for sialorrhea in response to clozapine therapy. The underlying pathophysiology and clinical significance of this phenomenon warrant further investigation.
[Show abstract][Hide abstract] ABSTRACT: Background:
Genetic factors explaining phenotypes in psychiatric genetics were always characterised by significant heterogeneity and non-reproducibility. Even understanding genetic basis of highly heritable diseases such as schizophrenia, was challenging. Contribution of environmental factors in terms of its interaction with genetic factors were recently implicated in addressing the unexplained heterogeneity of schizophrenia genetics.
Aims and Objectives:
The present study explored the possible associations of polymorphisms in genes: DRD4 (120-bp duplication) and COMT (Val158Met), with clinical response to clozapine in patients with treatment resistant schizophrenia (TRS). We tried to identify the associations of gene-gene interaction( DRD4XCOMT) and gene-environmental interactions with clinical phenotypes of c!lozapine.
A cohort of 95 participants with diagnosis of TRS was studied. The patients, were genotyped for the polymorphisms of interest using polymerase chain reaction and restriction fragment polymorphism (RFLP) method. Clozapine response were defined a priori. Appropriate statistical analysis were employed.
The polymorphisms were not found to associate statistically with clozapine response when analysed individually. However, interestingly we found a statistically significant DRD4XCOMT interaction over clozapine response. We also found significant gene-environmental interactions
over clozapine response. A logistic regression model (Response ~ (COMTXDRD4)+age+smoking habit + maximum dose of clozapine + Abnormal involuntary movements scale + Adden’s cognitive examination scale) that proved most explanatory was derived.
Gene-gene interaction between DRD4 and COMT and their gene-environment interactions play a significant role in predicting clinical response to clozapine therapy. Future studies were suggested to replicate our findings before it could be translated to clinical practice.
International Conference on Schizophreni(ICONS) VI, Hyatt hotel, Chennai, TN, India; 08/2014
[Show abstract][Hide abstract] ABSTRACT: Anejaculation is an uncommon clinical entity that may result from a variety of causes, both organic and psychological. Psychogenic anejaculation is influenced by relationship, behavioral, and psychological factors. We present a clinical case of situational anejaculation, which was managed with a combination of techniques that addressed these factors including changes in masturbatory technique, improved marital communication and quality, and reduction of anxiety using cognitive behavioral techniques. It is suggested that the standard techniques of sex therapy be modified and tailored to manage the specific problems of the individual patient.
Indian Journal of Psychological Medicine 07/2014; 36(3):329-31.
[Show abstract][Hide abstract] ABSTRACT: While the traditional view within psychiatry is that insight is independent of psychopathology and predicts the course and outcome of psychosis, recent data from India argues that insight is secondary to interaction between progression of illness on one hand and local culture and social environment on the other. The findings suggest that “insight” is an Explanatory Model (EM) and may reflect attempts at coping with the devastating effects of mental disorders.
Most societies are pluralistic and offer multiple, divergent and contradictory explanations for illnesses. These beliefs systems interact with the trajectory of the person's illness to produce a unique personal understanding, often based on a set of complex and contradictory EMs. Like all EMs, insight provides meaning to explain and overcome challenges including disabling symptoms, persistent deficits, impaired social relations and difficult livelihood issues. The persistence of distress, impairment, disability and handicap, despite regular and optimal treatment, call for explanations, which go beyond the simplistic concept of disease. People tend to choose EMs, which are non-stigmatizing and which seem to help explain and rationalize their individual concerns. The frequent presence of multiple and often contradictory EMs, held simultaneously, suggest that they are pragmatic responses at coping.
The results advocate a non-judgmental approach and broad based assessment of EMs of illness and their comparison with culturally appropriate beliefs, attributions and actions. The biomedical model of illness should be presented without dismissing patient beliefs or belittling local cultural explanations for illness. Clinical practice demands a negotiation of shared model of care and treatment plan between patient and physician perspectives. The diversity of patients, problems, beliefs and cultures mandates the need to educate, match, negotiate and integrate psychiatric and psychological frameworks and interventions. It calls for multifaceted and nuanced understanding of “insight” and explanatory models of illness.
[Show abstract][Hide abstract] ABSTRACT: Early detection of residual disease may benefit management strategies in patients undergoing transsphenoidal surgery for acromegaly. This requires establishing objective thresholds for early postoperative growth hormone (GH) assays, and incorporating these parameters into a scale for outcome prediction.
We analyzed a database containing the records of 86 patients who had undergone gross total transsphenoidal resection of GH-secreting pituitary adenomas. Early postoperative biochemical testing included a morning fasting basal GH assay on the first postoperative day (POD1) and a second GH assay following suppression with 100 g of oral glucose on the seventh postoperative day (POD7). Remission was defined as a normal IGF-1 with either a GH nadir <0.4 ng/ml following suppression with oral glucose or a basal fasting GH <1 ng/ml on follow-up dated >3 months after surgery. Receiver operator characteristic (ROC) curves identified optimal thresholds for all biochemical parameters. Logistic regression analysis assessed the statistical significance of factors associated with cure. A point system was developed, employing regression coefficients obtained from the multivariate statistical model to quantify the impact of each predictor on cure.
Remission was achieved in 34.6 % of patients and was associated with smaller, non-invasive tumors with lower preoperative, POD1 and POD7 GH levels. Optimal thresholds obtained from the ROC analysis suggested that lower POD1 and POD7 GH values provided good sensitivity and specificity for cure, despite modest predictive values. The model with the best ability to predict outcome included size, POD1 GH and POD7 GH levels, with a score of ≥95 demonstrating high specificity for prediction of remission.
Early postoperative GH assays are highly sensitivity and specific. The scoring system that we propose provided excellent predictive value and requires further validation in larger cohorts and in different populations. The model may help guide the intensity of follow-up and enable early identification of residual disease.
[Show abstract][Hide abstract] ABSTRACT: Background
There is a dearth of information about the predictors of disability in schizophrenia from low and middle-income countries. This study attempted to investigate the impact of socio-demographic and clinical variables on disability in a cohort of first episode schizophrenia.
Patients diagnosed to have DSM IV schizophrenia (n = 131) were assessed prospectively for psychopathology, functioning, insight and explanatory models of illness at baseline, 6, 12 and 60 months using standard instruments. Disability was assessed at 5 years. Multiple linear regression was employed to adjust for common confounders.
We could follow up 95 (72.5%) patients. Sixty-five of these patients (68.4%) achieved remission. Disability scores at 5 years were associated negatively with episodic nature of illness at baseline, functional assessments at 6 and 12 months and return to pre-morbid level function. Disability correlated positively with psychopathology at 6 and 12 months and time spent in psychotic episodes. It was also associated with psychopathology, remission, insight and patient perspectives at the 5th year cross-sectional evaluation. While employment status at recruitment was not associated with disability, it was associated with unemployment at follow up.
Disability at 5 years was associated with illness variables- episodic nature of illness at baseline, psychopathology and functioning, duration in psychotic episode and return to pre-morbid function. Patient perspectives about their illness (insight and patient explanatory models) were only associated cross-sectionally at 60 months but not earlier and are more suggestive of a coping response rather than being predictive of outcome. The relationship between unemployment and disability suggests that they are products of the same disease process.
[Show abstract][Hide abstract] ABSTRACT: The relative contributions of psychiatric morbidity and psychosocial stress to suicide, and the efficacy of mental health systems in reducing population suicide rates, are currently unclear. This study, therefore, aimed to investigate whether national suicide rates are associated with their corresponding mental health system indicators.
Relevant data were retrieved from the following sources: the World Health Organization, the United Nations Statistics Division and the Central Intelligence Agency World Fact book. Suicide rates of 191 countries were compared with their mental health system indicators using an ecological study design and multivariate non-parametric robust regression models.
Significant positive correlations between suicide rates and mental health system indicators (p<0.001) were documented. After adjusting for the effects of major macroeconomic indices using multivariate analyses, numbers of psychiatrists (p=0.006) and mental health beds (p<0.001) were significantly positively associated with population suicide rates.
Countries with better psychiatric services experience higher suicide rates. Although these associations should be interpreted with caution, as the issues are complex, we suggest that population-based public health strategies may have greater impact on national suicide rates than curative mental health services for individuals.
International Journal of Law and Psychiatry 07/2013; · 1.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: PURPOSE: To determine whether motion preservation following oblique cervical corpectomy (OCC) for cervical spondylotic myelopathy (CSM) persists with serial follow-up. METHODS: We included 28 patients with preoperative and at least two serial follow-up neutral and dynamic cervical spine radiographs who underwent OCC for CSM. Patients with an ossified posterior longitudinal ligament (OPLL) were excluded. Changes in sagittal curvature, segmental and whole spine range of motion (ROM) were measured. Nathan's system graded anterior osteophyte formation. Neurological function was measured by Nurick's grade and modified Japanese Orthopedic Association (JOA) scores. RESULTS: The majority (23 patients) had a single or 2-level corpectomy. The average duration of follow-up was 45 months. The Nurick's grade and the JOA scores showed statistically significant improvements after surgery (p < 0.001). 17 % of patients with preoperative lordotic spines had a loss of lordosis at last follow-up, but with no clinical worsening. 77 % of the whole spine ROM and 62 % of segmental ROM was preserved at last follow-up. The whole spine and segmental ROM decreased by 11.2° and 10.9°, respectively (p ≤ 0.001). Patients with a greater range of segmental movement preoperatively had a statistically greater range of movement at follow-up. The analysis of serial radiographs indicated that the range of movement of the whole spine and the range of movement at the segmental spine levels significantly reduced during the follow-up period. Nathan's grade showed increase in osteophytosis in more than two-thirds of the patients (p ≤ 0.01). The whole spine range of movement at follow-up significantly correlated with Nathan's grade. CONCLUSIONS: Although the OCC preserves segmental and whole spine ROM, serial measurements show a progressive decrease in ROM albeit without clinical worsening. The reduction in this ROM is probably related to degenerative ossification of spinal ligaments.
European Spine Journal 03/2013; · 2.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: AIM: We examinted the attitude, knowledge and perceived barriers to evidence-based practice of radiology (EBPR) among residents in radiology. STUDY DESIGN AND SETTING: We used the McColl questionnaire (1) and the BARRIERS scale (2) to assess the issues among radiology trainees attending an annual refresher course. Ninety six residents from 32 medical colleges from Southern India attended the course. RESULTS: Eighty (83.3%) residents, 55 male and 25 female of age range 24-34 years, consented and returned the questionnaire. The majority of the participants had a positive attitude towards EBPR. However, 45% were unaware of sources for evidence based literature although many had access to Medline (45%) and the internet (80%). The majority (70%) were aware of the common technical terms (e.g. odds ratio, absolute and relative risk) but other complex details (e.g. meta-analysis, clinical effectiveness, confidence interval, publication bias and number needed to treat) were poorly understood. Though majority of residents (59%) were currently following guidelines and protocols laid by colleagues within their departments, 70% of residents were interested in learning the skills of EBPR and were willing to appraise primary literature or systematic reviews by themselves. Insufficient time on the job to implement new ideas (70.1%); relevant literature is not being complied in one place (68.9%); not being able to understand statistical methods (68.5%) were considered to be the major barriers to EBPR. Training in critical appraisal significantly influence usage of bibliographic databases (p<0.0001). Attitude of collegues (p=0.006) influenced attitude of the trainees towards EBPR. Those with higher knowledge scores (p=0.02) and a greater awareness of sources for seeking evidence based literature (p=0.05) held stronger beliefs that EBPR significantly improved patient care. CONCLUSIONS: The large knowledge gap related to EBPR suggests the need to incorporate structured training into the core-curriculum of training programmes in radiology.
European journal of radiology 02/2013; · 2.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND
Clozapine is the treatment of choice for treatment-resistant schizophrenia (TRS). Its use is, however, often associated with variable clinical outcomes. It acts as an antagonist of dopamine receptors, with a high affinity for dopamine receptor 4 (DRD4). Polymorphisms in the DRD4 gene have been suggested to contribute to variable drug responses seen.
The aim of this study was to determine whether a 120 base-pair duplication polymorphism in the DRD4 gene affects response to clozapine.
Patients diagnosed to have TRS, on stable doses of clozapine were the subjects of the study. Genomic DNA was isolated from peripheral venous blood from the patients, and genotyped for the polymorphism. Serum clozapine levels were also measured. Participants’ socio-demographic and clinical profiles were recorded. Standard assessment schedules were used to assess premorbid adjustments, response to traumatic events, cognitive status and disability. Clozapine response was defined a priori; allelic and genotypic frequencies were determined and correlated with the clinical responses.
We have analyzed 95 patients in the age group of 20 – 60 (mean age – 35.43; males-69; females-26) of which 13 are of wild type, 40 are homozygous and 42 are heterozygous for the 120-base-pair duplication polymorphism in DRD4. No genotypic association was found between the polymorphism and serum clozapine levels or response to treatment with clozapine in patients with TRS. Similarly, there was no significant association between the polymorphism and disability or common adverse effects of the drug.
Our results show that DRD4 – 120 base pair duplication polymorphism is not significantly associated with clozapine treatment response, psychopathology, cognitive status and disability.
Third Asian Congress on Psychiatry, Bali, Indonesia; 02/2013
[Show abstract][Hide abstract] ABSTRACT: PURPOSE: This study aims to determine the incidence, predictors, early post-operative course of diabetes insipidus (DI) in paediatric craniopharyngiomas(CP) and compare the findings with adults. METHODS: Retrospective analysis of clinical, biochemical, radiological and operative data for 102 consecutive CP surgeries (45 paediatric and 57 adult cases) was done. Bivariate and multivariate analyses were done to determine the predictors of DI. The incidence of the triphasic response and electrolyte abnormalities in the first post-operative week was compared between children and adults. RESULTS: Children had larger tumours and higher incidence of cystic tumours and hydrocephalus. Preoperative DI was close to 15 % in both the age groups. Radical/subtotal excision was achieved in 58 % of children and 53 % of adults. The incidence of post-operative DI was 80 % and 63 % in children and adults, respectively. Children had significantly higher incidence of permanent DI (55.6 %). Radical excision in children (p = 0.000); previous tumour surgery (p = 0.014) and new onset hypopituitarism (p = 0.019) in adults were associated with permanent DI. The triphasic response (23 %), wide intra-day serum sodium fluctuations and hyponatraemia were more common in children. CONCLUSIONS: Post-operative DI is a frequent and significant cause of morbidity in children undergoing surgery for CP. Children have a higher incidence of permanent DI. Radical excision is a predictor of permanent DI in children, whereas previous tumour excision and new onset hypopituitarism were predictors of permanent DI among adults. The management of post-operative DI is more difficult in children and the treating physician needs to be alert to detect the triphasic response.
Child s Nervous System 02/2013; · 1.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The development of the Diagnostic and Statistical Manual-5 (DSM-5) has been an exhaustive and elaborate exercise involving the review of DSM-IV categories, identifying new evidence and ideas, field testing, and revising issues in order that it is based on the best available evidence. This report of the Task Force of the Indian Psychiatric Society examines the current draft of the DSM-5 and discusses the implications from an Indian perspective. It highlights the issues related to the use of universal categories applied across diverse cultures. It reiterates the evidence for mental disorders commonly seen in India. It emphasizes the need for caution when clinical categories useful to specialists are employed in the contexts of primary care and in community settings. While the DSM-5 is essentially for the membership of the American Psychiatric Association, its impact will be felt far beyond the boundaries of psychiatry and that of the United States of America. However, its atheoretical approach, despite its pretensions, pushes a purely biomedical agenda to the exclusion of other approaches to mental health and illness. Nevertheless, the DSM-5 should serve a gate-keeping function, which intends to set minimum standards. It is work in progress and will continue to evolve with the generation of new evidence. For the DSM-5 to be relevant and useful across the cultures and countries, it needs to be broad-based and consider social and cultural contexts, issues, and phenomena. The convergence and compatibility with International Classification of Diseases-11 is a worthy goal. While the phenomenal effort of the DSM-5 revision is commendable, psychiatry should continue to strive for a more holistic understanding of mental health, illness, and disease.
Indian Journal of Psychiatry 01/2013; 55(1):12-30.
[Show abstract][Hide abstract] ABSTRACT: The universal models employed by psychiatry de-emphasise the role of context and culture. Despite highlighting the impact of culture on psychiatric diagnosis and management in the Diagnostic and Statistical Manual of Mental Disorders-5, most of the changes suggested remain in the introduction and appendices of the manual. Nevertheless, clinical and biological heterogeneity within phenomenological categories mandates the need to individualise care. However, social and cultural context, patient beliefs about causation, impact, treatment and outcome expectations are never systematically elicited, as they were not essential to diagnosis and classification. Patient experience and narratives are trivialised and the biomedical model is considered universal and transcendental. The need to elicit patient perspectives, evaluate local reality, assess culture, educate patients about possible interventions, and negotiate a shared plan of management between patient and clinician is cardinal for success. The biopsychosocial model, which operates within a paternalistic physician-patient relationship, needs to move towards a shared approach, within a more equal patient-clinician partnership.