Serotonin transporter 5HTTLPR polymorphism and affective disorders: no evidence of association in a large European multicenter study.

The available data from preclinical and pharmacological studies on the role of the serotonin transporter (5-HTT) support the hypothesis that a dysfunction in brain serotonergic system activity contributes to the vulnerability to affective disorders (AD). 5-HTT is the major site of serotonin reuptake into the presynaptic neuron, and it has been shown that the polymorphic repeat polymorphism in the 5-HTT promotor region (5-HTTLPR) may affect gene-transcription activity. 5-HTT maps to chromosome 17 at position 17q11.

Genetic association between the phospholipase A2 gene and unipolar affective disorder: a multicentre case-control study.

The co-segregation in one pedigree of bipolar affective disorder with Darier's disease whose gene is on chromosome 12q23-q24.1, and findings from linkage and association studies with the neighbouring gene of phospholipase A2 (PLA2) indicate that PLA2 may be considered as a candidate gene for affective disorders. All relevant genetic association studies, however, were conducted on bipolar patients.

Lack of association between the 5HT2A receptor polymorphism (T102C) and unipolar affective disorder in a multicentric European study.

We report here a case-control association study with T102C polymorphism in the serotonin 2A receptor gene (HTR2A) in patients affected by unipolar affective disorder (UPAD) and in controls. A total of 284 subjects were genotyped (142 UPAD and 142 controls). All subjects were interviewed using standard diagnostic interviews and matched.

Dopamine receptor D2 and D3 gene variants are not associated with the antidepressant effect of total sleep deprivation in bipolar depression.

Total sleep deprivation (TSD) is an effective treatment for mood disorders that is thought to act through an enhancement in several neurotransmitter pathways including dopaminergic transmission. Genetic factors are likely to play a major role in determining individual differences in TSD response. The aim of this study is to investigate the influence of dopamine receptor D3 (DRD3) and dopamine receptor D2 (DRD2) variants on TSD antidepressant efficacy in bipolar disorder.

Multicentre Italian family-based association study on tyrosine hydroxylase, catechol-O-methyl transferase and Wolfram syndrome 1 polymorphisms in mood disorders.

Objective: The aim of the present study was to investigate tyrosine hydroxylase, catechol-O-methyl transferase and Wolfram syndrome 1 genes in mood disorders using a family-based association approach.

Methods: The sample included 134 nuclear mood disorder families, with subjects affected by bipolar disorder (n=103) or major depressive disorder (n=58). All subjects were genotyped using polymerase chain reaction techniques.

SSRIs antidepressant activity is influenced by G beta 3 variants.

The aim of the present study was to test a possible effect of the G-protein beta3-subunit (Gbeta3) C825T gene variant on the antidepressant activity of selective serotonin reuptake inhibitors (SSRIs) in a sample of major and bipolar depressives, with or without psychotic features. Four hundred and ninety inpatients were treated with fluvoxamine 300 mg/day (n=362) or paroxetine 40 mg/day (n=128) and either placebo or pindolol in a double-blind design for 6 weeks. The severity of depressive symptoms was weekly assessed with the Hamilton Rating Scale for Depression.

Influence of monoamine oxidase A and serotonin receptor 2A polymorphisms in SSRI antidepressant activity.

The aim of the present study was to test a possible effect of the monoamine oxidase A (MAOA) and serotonin receptor 2A (5-HT-2A) gene variants on the antidepressant activity of fluvoxamine and paroxetine in a sample of major (n = 248) and bipolar (n = 195) depressives, with or without psychotic features. A total of 443 in-patients were treated with 300 mg fluvoxamine (n = 307) or 20-40 mg paroxetine (n = 136) for 6 wk. The severity of depressive symptoms was assessed weekly with the Hamilton Rating Scale for Depression (HAMD).

Association study of MAO-A, COMT, 5-HT2A, DRD2, and DRD4 polymorphisms with illness time course in mood disorders.

The aim of our study was to investigate a possible influence of monoamine oxydase A (MAO-A), catechol-O-methyltransferase (COMT), serotonin receptor 2A (5-HT2A), dopamine receptor D2 (DRD2), and dopamine receptor D4 (DRD4) gene variants on timing of recurrence in mood disorders. Gene variants were determined using PCR-based techniques in 550 inpatients affected by recurrent mood disorders (major depressives: n = 212; bipolars: n = 338), rapid cycling mood disorder (n = 81), and 663 controls. We investigated possible genetic influences by comparing illness time course of subjects subdivided according to genotype using multivariate analysis of variance (MANOVA).

Pharmacogenetics of lithium prophylaxis in mood disorders: analysis of COMT, MAO-A, and Gbeta3 variants.

We studied the possible association between the prophylactic efficacy of lithium in mood disorders and the following gene variants: catechol-O-methyltransferase (COMT) G158A, monoamine oxydase A (MAO-A) 30-bp repeat, G-protein beta 3-subunit (Gbeta3) C825T. A total of 201 subjects affected by bipolar (n = 160) and major depressive (n = 41) disorder were followed prospectively for an average of 59.8 months and were typed for their gene variants using PCR techniques.

Family-based association study of 5-HTTLPR, TPH, MAO-A, and DRD4 polymorphisms in mood disorders.

Variants of the functional polymorphism in the serotonin transporter (upstream regulatory region: 5-HTTLPR), the tryptophan hydroxylase (TPH), the monoamine oxidase A (MAO-A), and the dopamine receptor D4 (DRD4) genes have all been associated with mood disorders. The aim of this study was to test those hypotheses by using a family-based association approach. Both diagnoses and psychopathology were used for phenotype definitions.

Serotonin transporter gene associated with lithium prophylaxis in mood disorders.

The aim of this study was to investigate the possible association between the functional polymorphism in the upstream regulatory region of the serotonin transporter gene (5-HTTLPR) and the prophylactic efficacy of lithium in mood disorders. Two hundred and one subjects affected by bipolar (n = 167) and major depressive (n = 34) disorder were followed prospectively for an average of 58.2 months and were typed for their 5-HTTLPR variant using polymerase chain reaction techniques.

Pharmacogenetics in affective disorders.

Pharmacogenetics will be of substantial help in the field of affective disorders pharmacotherapy. The possible definition of a genetic liability profile for drug side-effects and efficacy will be of great help in treatments that need weeks to months to be effective. During the last few years, a number of groups have reported possible liability genes.

Excess of allele1 for alpha3 subunit GABA receptor gene (GABRA3) in bipolar patients: a multicentric association study.

The available data from preclinical and pharmacological studies on the role of gamma amino butyric acid (GABA) support the hypothesis that a dysfunction in brain GABAergic system activity contributes to the vulnerability to bipolar affective disorders (BPAD). Moreover, the localization of the alpha3 subunit GABA receptor GABRA3 gene on the Xq28, a region of interest in certain forms of bipolar illness, suggests that GABRA3 may be a candidate gene in BPAD. In the present study, we tested the genetic contribution of the GABRA3 dinucleotide polymorphism in a European multicentric case-control sample, matched for sex and ethnogeographical origin.

Serotonin transporter gene (5-HTTLPR) and major psychoses.

Serotoninergic neurotransmitter systems have been implicated in the pathogenesis of major psychoses. A functional polymorphism (5-HTTLPR) in the upstream regulatory region of the gene (SLC6A4) has been associated with a number of psychiatric disturbances, but conflicting replication followed. The aim of this study was to investigate the possibility that the 5-HTTLPR might be associated with major psychoses.

No association between dopamine D(2) and D(4) receptor gene variants and antidepressant activity of two selective serotonin reuptake inhibitors.

The possible association of the dopamine receptor D(2) (Ser 311Cys) and D(4) exon 3 (48 base pair repeat) gene variants with the antidepressant activity of selective serotonin reuptake inhibitors (SSRIs) was investigated in a sample of 364 inpatients affected by a major depressive episode treated with fluvoxamine, 300 mg/day (n=266), or paroxetine, 20-40 mg/day (n=98). The severity of depressive symptoms was assessed weekly with the Hamilton Rating Scale for Depression. Dopamine receptor D(2) (DRD2) and dopamine receptor D(4) (DRD4) allelic variants were determined in each subject by polymerase chain reaction.

Influence of 5-HTTLPR and TPH variants on illness time course in mood disorders.

The aim of our study was to investigate gene variants in the long-term outcome of mood disorders. We retrospectively studied a sample of inpatients affected by recurrent and rapid cycling mood disorders. The serotonin transporter gene-linked functional polymorphic region (5-HTTLPR) and the A218C tryptophan hydroxylase (TPH) gene variant were determined using a PCR-based technique.

Influence of tryptophan hydroxylase and serotonin transporter genes on fluvoxamine antidepressant activity.

The aim of the present study was to test a possible effect of the A218C tryptophan hydroxylase (TPH) gene variant on the antidepressant activity of fluvoxamine in a sample of major and bipolar depressives, with or without psychotic features. Two hundred and seventeen inpatients were treated with fluvoxamine 300 mg and either placebo or pindolol in a double blind design for 6 weeks. The severity of depressive symptoms was weekly assessed with the Hamilton Rating Scale for Depression.

Variability of 5-HT2C receptor cys23ser polymorphism among European populations and vulnerability to affective disorder.

Substantial evidence supports a role for dysfunction of brain serotonergic (5-HT) systems in the pathogenesis of major affective disorder, both unipolar (recurrent major depression) and bipolar.(1) Modification of serotonergic neurotransmission is pivotally implicated in the mechanism of action of antidepressant drugs(2) and also in the action of mood stabilizing agents, particularly lithium carbonate.(3) Accordingly, genes that code for the multiple subtypes of serotonin receptors that have been cloned and are expressed in brain,(4) are strong candidates for a role in the genetic etiology of affective illness.

Tryptophan hydroxylase gene and major psychoses.

Disturbances of the serotoninergic neurotransmitter system have been implicated in the pathogenesis of mood disorders. The tryptophan hydroxylase (TPH) gene, which codes for the rate-limiting enzyme of serotonin biosynthesis, has been recently reported to be associated with bipolar disorder. In this study, we investigated TPH A218C gene variants in a sample of subjects affected by major psychoses.

DRD4 exon 3 variants associated with delusional symptomatology in major psychoses: a study on 2,011 affected subjects.

We previously reported an association of DRD4 exon3 long allele variants with delusional symptomatology independently from diagnoses. The aim of this investigation was to study DRD4 in major psychoses and to test the association in a larger sample. We studied 2,011 inpatients affected by bipolar disorder (n = 811), major depressive disorder (n = 635), schizophrenia (n = 419), delusional disorder (n = 104), psychotic disorder not otherwise specified (n = 42), and 601 healthy controls.

Dopamine receptor D3 gene and response to lithium prophylaxis in mood disorders.

Lithium has established itself as an effective prophylactic agent in mood disorders, but not all patients respond to lithium therapy. It is probable that genetic factors play a substantial role in determining the differences in response to lithium. The aim of this study was to investigate the association between the dopamine receptor D3 (DRD3) gene and prophylactic efficacy of lithium in mood disorders.

Serotonin-2C and serotonin-1A receptor genes are not associated with psychotic symptomatology of mood disorders.

The serotonergic system is involved in both pathophysiology and treatment of mood disorders. In the present study we investigated the possible influence of the polymorphisms of the serotonin-1A and 2C receptor genes on the symptomatology of mood disorders. Eighty-four inpatients affected by mood disorders (72 bipolar and 12 major depressive disorder) were assessed by the Operational Criteria Checklist for Psychotic Illness to score their lifetime psychotic symptomatology.