Meera Vaswani

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.

Urinary excretion of minerals, oxalate, and uric acid in north Indian children

Abstract. Urinary excretion of calcium, magnesium, phosphate, uric acid, oxalate, and creatinine was measured in 208 children (aged 8 – 15 years, 124 boys, 84 girls), living in a residential school near New Delhi. Levels were reduced compared with those reported from developed countries. The 95th percentile value of 24-h creatinine excretion was 33.4 mg/kg, calcium 2.2 mg/kg, magnesium 2.9 mg/kg, phosphate 9.4 mg/kg, uric acid 4.4 mg/kg, and oxalate 1.5 mg/kg. The 95th percentile value of the urine calcium/creatinine ratio was 0.15 and oxalate/creatinine 0.06. The dietary intake of proteins, calcium, and other nutrients in these children was less than recommended and explained the reduced urinary excretion observed. Physicians need to be aware of the regional patterns of normal urinary excretion of these constituents.

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

BackgroundDopamine 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.MethodsIn 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.ResultsThe 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 ≈ 2.5 times more risk to develop alcohol dependence.ConclusionsThe 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 alcoholdependent 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 Students t-test or Mann Whitneys 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.

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.

Emerging trend of drug abuse pattern in India: The role of urine testing

BackgroundThere is worldwide consensus that misuse of narcotics and psychoactive substances is on the rise, and India is no exception to this. Poly drug use is now a well-established pattern of drug misuse. To complement the effects of preferred drugs, users select a substitute from a range of drugs. In India, street heroin (commonly known as brown sugar) is mainly used by chasing or smoking. The abused drug and its abuse pattern form an important part of medical history without which a proper treatment schedule cannot be planned. AimsIn view of the changing pattern of drug abuse, the study was planned to examine the emerging trend of drug addiction from a laboratory perspective. ResultsOf 1509 urine samples received over a 1-year period, a significant change in drug abuse pattern was evident when present data was compared with previous data from our center (P < 0.001). Age wise distribution of drug abuse pattern showed that >95% of addicts fell in the age group of 14–45 years. A significant correlation (P < 0.01) between screening and confirmatory test was seen. One third of urine samples indicated discrepancy in self-reported drug abuse history and laboratory confirmation. ConclusionLaboratory findings have supported clinical reports where addiction to compounds other than heroin has been reported to be on the rise. There is need to restrict usage of these drugs especially in the younger age groups.

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.

An Association Study on the Glutamate Pathway GRIN2A Gene Polymorphisms with Heroin Dependence

Background: Heroin dependence (HD) is a complex disorder characterized by disruption in particular circuits of the brain and influenced by environmental and genetic factors. Glutamate pathway plays a role in normal brain functions including learning, memory, and cognition. Disturbances in Glutamate pathways are implicated in many psychiatric disorders, including heroin dependence, and polymorphisms present in these pathway genes are reported to increase the risk of developing heroin dependence. Aim: To identify association of single nucleotide polymorphisms (SNPs) of Glutamate pathway genes with heroin dependence and correlate with heroin use parameters. Method: A total of 103 HD patients were recruited as per DSM IV criteria from the Department of Psychiatry, and 100 healthy volunteers from the general population. Genomic DNA from peripheral blood samples was processed for PCR followed by restriction digestion to screen for presence of GRIN2A polymorphisms in the glutamate pathway. GRIN2A SNPs i.e. rs11866328, rs1071502, rs1375067, rs1530669, rs12325652, rs16966381, rs1104068, rs16966448, rs9927871 and rs1366076 were selected based on the Hap Map project and Tagger program (r2 ≥ 0.8). Genotype and allele frequencies were estimated and the difference between patient and control groups were assessed by chi-square test of significance and the results correlated with duration, age at onset of heroin use, the quantity of heroin consumed and WHO ASSIST score. Statistical analysis was done using Haploview v4.1 and SPSSv21.0. Results: Haplotype analyses revealed three SNPs (rs1071502-rs1366076-rs1104068) with alleles A-T-A to confer risk while the haplotypes A-T-G had a protective effect on HD. Another haplotype (rs1530669-rs9927871) was also found significantly associated with heroin dependence (p=0.039). Conclusion: The study reports for the first time, a possible association of GRIN2A SNPs with age at onset of heroin use, duration and quantity of use, and also suggests an important role in severity of heroin dependence.

Alcohol Dehydrogenase: An Indicator of Hepatic Damage or a Marker in Alcohol Dependence

Aims Due to paucity of Indian data on ADH, the study was planned to examine its usefulness as a biological marker for alcohol dependence, and as an indicator of alcoholic liver dysfunction Methods Seventy alcohol dependent patients and 50 normal healthy control subjects were included. A single point estimation of serum levels of Alcohol Dehydrogenase, Aspartate Amino Tranferase, Alanine Amino Tranferase, and Gamma Glutamyl Transferase was performed. On the basis of severity of liver dysfunction, the study group was divided in 2 subgroups.F Results Alcohol Dehydrogenase levels were higher in patients of alcohol dependence as compared with controls but did not reach the significance levels. Using Gamma Glutamyl Transferase and Aspartate Amino Tranferase as reference standard, levels of Alcohol Dehydrogenase were significantly higher in patients of alcohol dependence with sever liver dysfunction as compared with those without severe liver dysfunction. Stepwise discriminant analysis indicated that Aspartate Amino Tranferase and Gamma Glutamyl Transferase best identified patients of alcohol dependence from normal controls with good diagnostic accuracy. Serum levels of Alcohol Dehydrogenase showed good sensitivity but poor specificity and low kappa value. Conclusion The study provides evidence for use of serum ADH level as a useful indicator of alcoholic liver dysfunction, but does not support the hypothesis for it being a useful marker for alcohol dependence.