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Background: Antipsychotic drugs are widely used for the treatment of psychosis, especially schizophrenia. Their long-term use can result at times in serious side-effects such as Tardive Dyskinesia (TD). Since over 80% of schizophrenia sufferers (lifetime prevalence 1%) receive long-term antipsychotic drug treatment, the extent of the problem is potentially large. Increasing age is the most consistently demonstrated risk factor for TD., Aims: To assess effect of different clinical factors and demographic variables in India and Israel and sib pair concordance of Tardive Dyskinesia (TD) in India., Settings and Design: The study was conducted simultaneously among Indian and Israeli subjects: ascertainment was family-based in India and hospital-based in Israel., Methods and Material: In India the instruments used were: Diagnostic Interview for Genetic Studies (DIGS), Positive and Negative Syndrome Scale (PANSS), Abnormal Involuntary Movement Scale (AIMS), and Simpson Angus Scale (SAS). The last three instruments were also used in Israel., Statistical Analysis: Regression analysis and Pearson's correlation., Results and Conclusions: TD symptoms were present in 40.4% of 151 Israeli subjects and 28.7% of 334 Indian subjects. While age at onset and total scores on PANSS were significant predictors of TD in both the samples, lower scores on the Global Assessment of Functioning Scale (GAF), diagnostic sub-group and male gender were significant predictors among Indians. There was no concordance of TD symptoms among 33 affected sib-pairs from India.

Rationale: Tardive dyskinesia (TD) is a longterm adverse effect of dopamine receptor blockers. The dopamine D3 receptor gene (DRD3) ser9gly polymorphism has been previously associated with susceptibility to TD. Serotonin receptor antagonism has been proposed as a common mechanism contributing to the low extra-pyramidal effects profile of atypical antipsychotic drugs., Objectives: To examine the association of a functional polymorphism in the 5-HT2C receptor gene (HT2CR) with TD and the joint contribution of HT2CR and DRD3 to susceptibility., Methods: Case control association analysis of allele and genotype frequencies among schizophrenia patients with (n=55) and without TD (n=60), matched for antipsychotic drug exposure and other relevant variables, and normal control subjects (n=97). Parametric analyses of the contribution of 5-HT2Cser and DRD3gly alleles to dyskinesia scores., Results: We found a significant excess of 5-HT2Cser alleles in schizophrenia patients with TD (27.2%) compared to patients without TD (14.6%) and normal controls (14.2%; chi2=6.4, df 2, P=0.03) which was due to the female patients (chi2=8.6, df 2, P=0.01). Among the female TD patients there was an excess of cys-ser and ser-ser genotypes (chi2= 11.9, df 4, P=0.02). Analysis of covariance (ANCOVA), controlling for age at first antipsychotic treatment, revealed a significant effect of 5-HT2C genotype on orofacial dyskinesia (OFD) scores (F=3.47, df 2, P=.03). In a stepwise multiple regression analysis, 5-HT2C and DRD3 genotype (5-HT2Cser and DRD3gly allele carriage) respectively contributed 4.2% and 4.7% to the variance in OFD scores., Conclusions: These findings support a small but significant contribution of the HT2CR and DRD3 to susceptibility to TD, which is additive in nature.

In spite of substantial advances in the treatment of major depression by pharmacotherapy and other means, a significant number of depressed patients require hospitalization. In the context of the Jerusalem Collaborative Depression Project, possible precipitants of psychiatric hospitalization were sought in a cohort of patients (n = 107) who were admitted to hospitals in the Jerusalem area during a 14-month period because of a depressive episode. The patients fulfilled DSM III-R criteria for major depression, single or recurrent; bipolar 1 disorder, depressed or mixed; bipolar 2, depressed. The cohort encompassed more than two thirds of potential subjects admitted during this period with the ICD-9 equivalents of the specified diagnoses (as reported to the Israel Ministry of Health National Psychiatric Case Register) and were similar to the entire potential population in terms of their diagnostic breakdown. The patients underwent extensive socio-demographic and clinical evaluation that included detailed documentation of treatment received prior to hospitalization. Notwithstanding the absence of a comparison group of depressed patients who were not hospitalized, a number of potential precipitants were identified. These included older age (55.2% > 60 years, 20.6% > 70 years), immigration to Israel during the preceding 5 years (34.7%), concomitant physical illness (60%) which was associated with moderate to severe disability in 41% and poor quality of antidepressant pharmacotherapy prior to hospitalisation (only 24.3% received an adequate trial of antidepressant medication). Further evaluation of these and other potential factors could facilitate targeting of patient groups at particular risk for hospitalization and reduce the need for it.

Despite the demonstrated anti-depressant efficacy of the selective serotonin reuptake inhibitors (SSRIs), increased suicidal ideation and/or agitation have been reported in a small proportion of individuals receiving fluoxetine or other SSRIs. Part II of this review examines fluoxetine's acute effects on serotonergic functioning. Although acute fluoxetine administration produces a short-term compensatory decrease in the firing of 5-HT neurons, the neurobiological data reviewed suggests that this decrease probably does not lead to an over-compensatory net decrease in 5-HT functioning. The implications of fluoxetine's complex effects on the 5-HT systems are discussed with respect to clinical practices and future research.

The general enhancement of central serotonin (5-HT) neurotransmission following long-term administration of serotonin-selective reuptake inhibitors (SSRIs) appears to play an important role in these drugs' anti-depressant efficacy. Because suicide and/or aggression appear linked to diminished levels of brain 5-HT and its metabolites, it has been suggested that SSRIs may be particularly effective in reducing suicidality. Case reports of increased or new suicidal ideation following administration of fluoxetine and other SSRIs, however, raise questions about how these potential side effects may relate to the SSRI's acute effects on 5-HT transmission. Part I of this review examines fluoxetine's effects on suicidality and related behaviors and reviews the relationship of suicidality to serotonergic dysregulation.