Keywords: major depressive disorder (MDD); tryptophan hydroxylase (TPH); serotonin transporter promoter region (5-HTTLPR); serotonin receptor 2A (HTR2A); serotonin receptor 2C (HTR2C); catechol-O-methyl transferase (COMT); dopamine D4 receptor (DRD4); dopamine transporter (DAT1)Major depressive disorder (MDD) is a severe psychiatric disorder with a lifetime prevalence of about 15%. 1 The importance of the genetic component is well accepted, 2 but the mode of inheritance is complex and non-Mendelian. A line of evidence suggests the involvement of serotonin and dopamine neurotransmitters in the pathophysiology of depression. In the present study, 102 unipolar MDD patients and 172 healthy controls were genotyped for polymorphisms in four serotonergic and three dopaminergic candidate genes [tryptophan hydroxylase (TPH), serotonin receptor 2A (HTR2A), serotonin receptor 2C (HTR2C), serotonin transporter promoter region (5-HTTLPR), dopamine receptor D4 (DRD4), dopamine transporter (DAT1) and catechol-O-methyl transferase (COMT)]. There were no statistical differences between MDD patients and healthy controls in the genotypic and allelic distribution of all polymorphisms investigated. Thus, our study does not support a major role for these polymorphisms in contributing to susceptibility to MDD, although it does not preclude minor effects.Pharmacological studies have suggested that MDD is associated with an impairment of brain neurotransmitters. The role of serotonin (5-HT), which is based mainly on the efficacy of selective and nonselective 5-HT reuptake inhibitors in the treatment of MDD, was reviewed by Maes and Meltzer. 3 Dopamine (DA), has also been implicated in the pathophysiology of mood disorders and hypoactivity of the mesolimbic DA pathway may be connected to depressive symptoms. 4 Thus, genes that control the brain 5-HT and DA pathways seem to be good candidates for mediating genetic susceptibility to MDD.Association of polymorphisms in seven genes from the serotonergic and dopaminergic pathways was studied in 102 unipolar patients and 172 healthy control subjects. The patient population was subdivided according to ethnic origin (63 Ashkenazi and 39 nonAshkenazi Jews) and compared to the corresponding group of mentally healthy controls. The distribution of genotypes and alleles in the different populations is shown in Table 1. Comparison of healthy individuals of Ashkenazi and non-Ashkenazi origin revealed that although frequencies of genotypes and alleles showed some differences, they did not reach statistical significance. Nevertheless, in order to avoid possible errors caused by population stratifications we compared the patients with their ethnic counterparts.When unipolar MDD patients were compared to healthy controls of the same ethnic origin (Table 1), the distribution of genotypes and alleles of the seven polymorphisms studied (TPH, HTR2A, HTR2C, 5-HTTLPR, DAT1, DRD4 and COMT) did not show statistically significant differences.Molecular genetic studies in mood disorders performed thus far, have focus...

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The beneficial effect of sulpiride augmentation of clozapine therapy for treatment-resistant schizophrenia patients is enhanced by its antisalivatory effect on clozapine-induced hypersalivation (CIH). Amisulpride, similar to sulpiride, is a substitute benzamide derivative with higher selective binding to the D2/D3 dopamine receptor. We hypothesized that add-on amisulpride would also be beneficial in controlling CIH. In a randomized, double-blind, placebo-controlled cross-over study, 20 clozapine-treated schizophrenia (DSM-IV criteria) inpatients with CIH were randomly initially assigned to add-on amisulpride (nine patients; 400 mg/day up-titrated from 100 mg/day over 1 week) or placebo (11 patients). Primary outcome was change in the five-point Nocturnal Hypersalivation Rating Scale (NHRS). Other measures included the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression scale (CGI) and Simpson-Angus Scale (SAS). Mean NHRS indices were considerably lower with amisulpride (1.79 +/- 1.25) than with placebo (2.63 +/- 1.33) [F(1,38) = 5.36, P < 0.05]. With amisulpride treatment, there was a significant improvement on the negative symptoms subscale of the PANSS [F(3,57) = 3.76, P < 0.05], but not on the SAS, CGI or other subscales of the PANSS (all F < 1). Short-term amisulpride augmentation has a strong ameliorating effect on CIH. A long-term, large-scale study with a broader dose range is warranted to evaluate the stability of this effect across time.

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Though the role of brain derived neurotrophic factor (BDNF) as a marker for major depressive disorder (MDD) and antidepressant efficacy has been widely studied, the role of BDNF in distinct groups of patients remains unclear. We evaluated the diagnostic value of BDNF as a marker of disease severity measured by HAM-D scores and antidepressants efficacy among MDD patients. Fifty-one patients who met DSM-IV criteria for MDD and were prescribed antidepressants and 38 controls participated in this study. BDNF in serum was measured at baseline, 1st, 2nd and 8th treatment weeks. Depression severity was evaluated using the Hamilton Rating Scale for Depression (HAM-D). BDNF polymorphism rs6265 (val66met) was genotyped. We found a positive correlation between blood BDNF levels and severity of depression only among untreated women with severe MDD (HAM-D>24). Serum BDNF levels were lower in untreated MDD patients compared to control group. Antidepressants increased serum BDNF levels and reduced between-group differences after two weeks of treatment. No correlations were observed between BDNF polymorphism, depression severity, duration of illness, age and BDNF serum levels. Further supporting the role of BDNF in the pathology and treatment of MDD, we suggest that it should not be used as a universal biomarker for diagnosis of MDD in the general population. However, it has diagnostic value for the assessment of disease progression and treatment efficacy in individual patients.