Genetic polymorphisms in phase II metabolizing enzymes in alcoholic and idiopathic chronic pancreatitis: Indian scenario.

AIM: To study polymorphisms in glutathione-S-transferases (GST-T1, GST-M1, GST-P1) and uridine-5'-diphosphate-glucuronosyl-transferases (UGT1A7) genes and the risk of developing chronic pancreatitis (CP) associated with these polymorphisms. METHODS: This study included 49 alcoholic and 51 idiopathic chronic pancreatitis patients, 50 alcohol addicts and 50 healthy controls. Polymorphism(s) in GST-T1 and GST-M1 genes were assessed by multiplex polymerase chain reaction (PCR), while PCR-radiofrequency lesioning (RFLP) was employed to assess the same in GST-P1 and UGT1A7 genes. The differences in polymorphism frequency between groups and the risk of developing pancreatitis were assessed by the odds ratio. RESULTS: Strong association of the null genotype of GST-T1 with CP susceptibility was observed. Alcoholics with the Val allele of GST-P1 have higher chances of having pancreatitis. Idiopathic pancreatitis patients with higher age at the onset of pain were found to have the null genotype of GST-M1. CONCLUSION: Alcoholics with the null genotype of the GST-T1 gene and the Valine allele of the GST-P1 gene are at a higher risk of developing CP. Thus, genotyping of these genes may serve as an important screening tool for the identification of high-risk groups among alcoholics.

Dopamine transporter availability in alcohol and opioid dependent subjects - a 99mTc-TRODAT-1SPECT imaging and genetic association study.

Drug dependence associated with increased dopamine neurotransmission and neuroplastic changes is influenced by Dopamine transporters (DAT) which are modulated by genetic and epigenetic factors. This study assesses DAT availability in relation to the 40bp DAT1 VNTR (genetic) and DAT1 promoter methylation (epigenetic) changes in patients with alcohol dependence (AD) and opioid dependence (OD). A total of 60 subjects (n=20 each of AD, OD and controls) were recruited. SPECT/CT imaging using 99mTc-TRODAT-1 was performed for measuring striatal DAT availability and DNA screened to check DAT1promoter methylation and 40bp VNTR polymorphism. SPECT/CT imaging revealed significant decrease in DAT availability in the striatum and putamen and significant increase in DAT1 promoter methylation in AD compared to control and OD. The 40bp VNTR distribution was similar in all three groups with 10repeat and 9repeat alleles being the most common. The AD individuals with DAT1promoter methylation showed significantly lower TRODAT-1 uptake compared to the ones with no methylation. AD individuals homozygous for the 10repeat VNTR also showed reduced DAT availability. This is the first imaging study using 99mTc-TRODAT-1 from India documenting significantly reduced striatal DAT availability, increased DAT methylation and frequency of 10repeat individuals associated with decreased DAT availability in AD.

Association of serotonin and GABA pathway gene polymorphisms with alcohol dependence: A preliminary study.

BACKGROUND: Alcohol dependence (AD), characterized by profound disruptions in specific circuits of the brain is influenced by both environmental, which play a significant role in developing addiction and genetic factors, which make some individuals more susceptible to disruptions. Various polymorphisms in the neurotransmitter genes are reported to increase the risk of developing dependence. The present study aimed to identify association of serotonin and GABA polymorphisms with AD in Indian subjects. METHOD: The study group comprised of 141 AD cases recruited as per DSM IV TR criteria from the outpatient Department of Psychiatry and 110 volunteers from the general population. Clinical and family history was noted and 5 ml blood drawn for genetic studies. Polymorphisms 5-HTTLPR and STin2 of serotonin and rs2279020 and rs3219151 of the GABA pathway were analyzed and results correlated with age at first use quantity consumed, duration of use, dependence and age at onset of dependence. RESULTS: The marker frequencies were similar between cases and controls except for rs3219151. 5-HTTLPR was significantly associated with high AUDIT scores and alcohol intake (p < 0.0001), GABAA rs2279020 and rs3219151 with age at first use (p < 0.0001); rs2279020 with higher AUDIT score (p = 0.002) and rs3219151 with quantity (p = 0.0001). High frequency of GABRA6 rs3219151 TT genotype in AD and its association with lower age at first use, higher intake/day, and higher duration of dependence appears to confer risk. CONCLUSIONS: This preliminary study, though on a smaller sample size, suggests an association of 5-HTTLPR and GABAA receptor polymorphisms with AD in our population.

Case-control association analysis of dopamine receptor polymorphisms in alcohol dependence: a pilot study in Indian males.

BACKGROUND: Brain imaging studies and knock-out animal models have derived substantial abetment for dopamine receptor (DR) subtypes as potential candidates in susceptibility to addictive disorders, including alcohol dependence (AD). Various association studies that compared the frequencies of alleles of the dopamine D1, D2, D3 and D4 receptor genes between alcohol dependent and control subjects have produced suggestive results, though some of them are discordant in nature. In the absence of genetic data from Indian population, we evaluated genetic association of three polymorphisms namely rs4532 in DRD1, rs6280 in DRD3 and 120 bp duplication in 1.2 kb upstream region of DRD4 with AD. METHODS: A total of 90 cases (alcohol dependent males) and 122 age and ethnicity matched healthy male controls were recruited in the study by following DSM-IV criteria. Three polymorphisms, namely rs4532 in DRD1, rs6280 in DRD3 and 120 bp duplication in 1.2 kb upstream region of DRD4 were selected (based on minor allele frequency and available literature) for genotyping by PCR-RFLP/LP method. Allele and genotype frequencies of these genetic markers were compared using Pearson's χ2 test followed by risk assessment using odds ratio. Statistical analysis of clinical parameters such as AUDIT scores of case subjects was also performed. RESULTS: Statistically significant associations of polymorphisms in DRD1 and DRD4 with alcoholism were found. CONCLUSIONS: Our results underscore that genetic variations in dopamine receptors D1 and D4 may influence genetic predisposition to alcoholism. Unavailability of comparative data from Indian population and small sample size necessitate replication of results in an independent cohort.

Association study of the ß-arrestin 2 gene (ARRB2) with opioid and cocaine dependence in a European-American population.

The rewarding properties of drugs of abuse are mediated by the mu-opioid receptor (MOR). Genetic variations in MOR and MOR interacting proteins (MORIPs) involved in MOR signaling may increase the risk for drug dependence. The MORIP ß-arrestin plays an important role in the regulation of MOR trafficking, thereby highlighting it as a candidate gene for addiction phenotypes. In this case-control association study, DNA samples from cocaine-dependent (n=336) and opioid-dependent (n=335) patients and controls (n=656) were genotyped for seven single nucleotide polymorphisms (rs11868227, rs3786047, rs4522461, rs1045280, rs2271167, rs2036657, and rs4790694) across ARRB2, the gene encoding the ß-arrestin 2 protein. No significant differences were observed in genotype or allele frequency between drug-dependent and control individuals for any of the single nucleotide polymorphisms analyzed. Haplotype analysis was similarly negative. Further studies are needed to determine whether variations in ARRB2 (or other MORIPs) are relevant to cocaine or opioid dependence in different ethnic populations or whether they confer a risk that is specific to dependence on other drugs of abuse.

Post marketing surveillance of sublingual buprenorphine naloxone combination tablets.

BACKGROUND & OBJECTIVES: A combination of buprenorphine-naloxone (Addnok-N) tablets has been recently introduced in India as treatment for Opioid dependence. This study was undertaken to evaluate the possible adverse consequences following use of the buprenorphine-naloxone tablets through post marketing surveillance. METHODS: National Drug Dependence Treatment Centre (NDDTC), AIIMS, India, monitored all patients receiving buprenorphine-naloxone combination tablets from the centre over a period of two and half years. Evaluation included subjective and objective side effect checklist, physical examination, and laboratory investigation. RESULTS: Data was obtained from 1132 observations among 158 patients. Commonly reported medication effects, like muscle aches (44.0%), sleepiness (44.0%), relief from pain (41.3%), etc; are expected in opioid substitution treatment. Laboratory investigations were mostly normal except for liver enzyme abnormalities (52.2% of cases). Eight adverse events were reported in the study. No dangerous event or mortality was reported during the study.

Dopamine D2 receptor polymorphisms and susceptibility to alcohol dependence in Indian males: a preliminary study.

BACKGROUND: Dopamine is an important neurotransmitter involved in reward mechanism in the brain and thereby influences development and relapse of alcohol dependence. The dopamine D2 receptor (DRD2) gene on chromosome 11 (q22-q23) has been found to be associated with increased alcohol consumption through mechanisms involving incentive salience attributions and craving in alcoholic patients. Therefore, we investigated the association of three single nucleotide polymorphisms (SNP) in DRD2 gene with alcohol dependence in the north Indian subjects. METHODS: In a retrospective analysis, genetic association of three polymorphisms from DRD2 gene with alcohol dependence was investigated using a case-control approach. Alcohol dependence was determined by DSM-IV criteria and a total of 90 alcoholics and 60 healthy unrelated age-matched control subjects were recruited. Odds ratio and confidence interval was calculated to determine risk conferred by a predisposing allele/genotype/haplotype. Logistic regression analysis was carried out to correlate various clinical parameters with genotypes, and to study pair-wise interactions between SNPs. RESULTS: The study showed a significant association of -141C Ins allele and a trend of association of TaqI A1 allele of DRD2 with alcohol dependence. Haplotype with the predisposing -141C Ins and TaqI A1 alleles (-141C Ins-A-A1) seems to confer approximately 2.5 times more risk to develop alcohol dependence. CONCLUSIONS: The study provides preliminary insight into genetic risk to alcohol dependence in Indian males. Two polymorphisms namely, -141C Ins/Del and TaqI A in DRD2 gene may have clinical implications among Indian alcoholic subjects.

Association of ADH1B and ALDH2 gene polymorphisms with alcohol dependence: a pilot study from India.

Functional polymorphism in the genes encoding alcohol dehydrogenase (ADH) 1B and aldehyde dehydrogenase (ALDH) 2 are considered most important among several genetic determinants of alcohol dependence, a complex disorder. There is no report on the widely studied Arg47His and Glu487Lys polymorphisms from Indian alcohol-dependent populations. In this paper, we report, for the first time, allelic and genotypic frequencies of Arg47His and Glu487Lys single nucleotide polymorphisms (SNPs) in North Indian alcohol-dependent subjects. A total of 174 alcohol-dependent males, recruited using DSM IV criteria (American Psychiatric Association, 1994), were genotyped using the polymerase chain reaction-restriction fragment length polymorphism method. The results obtained from genetic analysis were correlated with clinical parameters using Student's t-test or Mann Whitney's U test. The highlight of the study findings was the uniquely high frequency of the ALDH2*2/*2 genotype (among alcohol-dependent subjects) being a risk-conferring factor for alcohol dependence.

HIV infection and high-risk behaviors in opioid dependent patients: the Indian context.

Various risk behaviors promote the spread of HIV in drug addicts. Reflecting the substantial regional and geographic differences in the impact of HIV, its prevalence rates vary from country to country. In view of increasing reports of injection drug-uses (IDUs) from different parts of India, the study was aimed to examine and investigate the difference in prevalence rates of seropositivity between IDUs and non-IDUs in patients of drug dependence and to compare the pattern of risk behaviors due to sexual and drug use practice in IDUs and non-IDUs. A high HIV seroprevalence of 8.3% between IDUs and 1.8% in non-IDUs was found. The study findings suggest a trend towards drug-related risks being higher than sex-related risks in IDUs.

Selective serotonin re-uptake inhibitors in anorexia nervosa.

Anorexia nervosa (AN), one of the major eating disorders, is a primarily psychiatric illness affecting a number of adolescents and young adults. AN usually runs a chronic course and is associated with significant morbidity and mortality. Drug therapy has modest success in its treatment. Various pharmacotherapeutic agents are being tested, with variable success. Selective serotonin re-uptake inhibitors are the one class of drug that has been found to be effective in AN, especially in preventing relapse. This article provides an overview of the current literature on the role of selective serotonin re-uptake inhibitors in the treatment of AN.

Role of selective serotonin reuptake inhibitors in psychiatric disorders: a comprehensive review.

The selective serotonin reuptake inhibitors (SSRIs) have emerged as a major therapeutic advance in psychopharmacology. As a result, the discovery of these agents marks a milestone in neuropsychopharmacology and rational drug design, and has launched a new era in psychotropic drug development. Prior to the SSRIs, all psychotropic medications were the result of chance observation. In an attempt to develop a SSRI, researchers discovered a number of nontricyclic agents with amine-uptake inhibitory properties, acting on both noradrenergic and serotonergic neurons with considerable differences in potency. A given drug may affect one or more sites over its clinically relevant dosing range and may produce multiple and different clinical effects. The enhanced safety profile includes a reduced likelihood of pharmacodynamically mediated adverse drug-drug interactions by avoiding affects on sites that are not essential to the intended outcome. SSRIs were developed for inhibition of the neuronal uptake pump for serotonin (5-HT), a property shared with the TCAs, but without affecting the other various neuroreceptors or fast sodium channels. The therapeutic mechanism of action of SSRIs involves alteration in the 5-HT system. The plethora of biological substrates, receptors and pathways for 5-HT are candidates to mediate not only the therapeutic actions of SSRIs, but also their side effects. A hypothesis to explain these immediate side effects is that 5-HT is increased at specific 5-HT receptor subtypes in discrete regions of the body where the relevant physiologic processes are regulated. Marked differences exist between the SSRIs with regard to effects on specific cytochrome P450 (CYP) enzymes, and thus the likelihood of clinically important pharmacokinetic drug-drug interactions. Although no clear relationship exists between the clinical efficacy, plasma concentration of SSRIs, nor any threshold that defines toxic concentrations, but therapeutic drug monitoring (TDM) may be useful in special populations, such as in elderly patients, poor metabolizers (PM) of sparteine (CYP2D6) or mephenytoin (CYP2C19), and patients with liver and kidney impairment. Several meta-analyses have reviewed the comparative efficacy of TCAs and SSRIs, and concluded that both TCAs and SSRIs have similar efficacy in the treatment of depression. SSRIs have demonstrated better efficacy and tolerability in the treatment of obsessive compulsive disorder (OCD). They have also been found to be effective in the treatment for social anxiety disorder both in reducing total levels of social anxiety and in improving overall clinical condition. The benefit of SSRIs in anorexia nervosa (AN) is apparently short-term unless medication is given in the context of nutritional or behavioral therapy. No single antidepressant can ever be recommended for every patient, but in a vast majority of patients, SSRIs should be considered as one of the first-line drugs in the treatment of depression.