Catechol-O-methyltransferase (COMT) polymorphisms predict treatment response in electroconvulsive therapy.

Several lines of evidence suggest that catechol-O-methyltransferase (COMT) may be associated with treatment response in depression. We conducted a study on 119 patients with treatment-refractory depression admitted consecutively for electroconvulsive therapy (ECT). The COMT high/high genotype leads to a higher enzyme activity and thus lowers dopaminergic activity in the prefrontal cortex. In the present sample, those homozygous to high-active allele of COMT responded significantly more frequently to ECT.

Dopamine 2 receptor C957T and catechol-o-methyltransferase Val158Met polymorphisms are associated with treatment response in electroconvulsive therapy.

Alterations in dopamine levels and dopamine receptors in brain are suggested to be associated with treatment response in electroconvulsive therapy (ECT). Dopamine 2 receptor gene (DRD2) polymorphism C957T (rs6277) and cathechol-o-methyltransferase (COMT) polymorphism Val158Met (rs4680) interaction was studied in 118 patients suffering from major depressive disorder (MDD) treated with ECT and 383 healthy controls. It was found that the combination of COMT Met allele and DRD2 T allele predicted more severe depression in those already affected but did not predict the risk of depression when compared to normal population. The genotype modified the response to ECT. The patients with TT genotype of D2 receptor gene C957T polymorphism combined with COMT gene polymorphism Met/Met genotype did not achieve remission as often as those with CC genotype of DRD2 C957T combined with COMT Val/Val genotype. Thus the interaction of these polymorphisms may be associated with response to ECT.

Epidermal growth factor a61g polymorphism is associated with the age of onset of schizophrenia in male patients.

There is evidence to suggest that dysfunction of dopaminergic neurotransmission in the central nervous system (CNS) plays a role in the etiopathology of schizophrenia. Epidermal growth factor (EGF) gene polymorphism has an impact on EGF production in mononuclear cells, and EGF seems to affect the development of midbrain dopaminergic neurons. The few studies concerning EGF gene polymorphism and schizophrenia have yielded contradictory results. Our aim was to investigate whether EGF gene A61G polymorphism predisposes to schizophrenia, and this polymorphism was therefore studied in 149 schizophrenic patients and in 94 healthy controls using 5' nucleotidase assay (TaqMan). As far as EGF A61G polymorphism was concerned, we detected no significant differences in the allele and genotype frequencies between the patients and the controls. However, the G/G genotype was significantly associated with an earlier age of onset of schizophrenic psychosis in male subjects (P=0.005) as well as in the entire population, but not in female patients (P=0.008 and 0.46, respectively). The average age (+/-SD) of onset of schizophrenia was 20.1+/-3.9 years in male EGF A61G G/G homozygotes and 23.7+/-6.6 (P=0.02) years in other genotypes. In conclusion, EGF gene polymorphism was not associated with the risk of schizophrenia. However, the EGF G/G genotype, which has been suggested to involve abundant production of EGF, was associated with early onset of schizophrenia in male patients.

Association between 5-HT2A, TPH1 and GNB3 genotypes and response to typical neuroleptics: a serotonergic approach.

BACKGROUND: Schizophrenia is a common psychiatric disease affecting about 1% of population. One major problem in the treatment is finding the right the drug for the right patients. However, pharmacogenetic results in psychiatry can seldom be replicated. METHODS: We selected three candidate genes associated with serotonergic neurotransmission for the study: serotonin 2A (5-HT2A) receptor gene, tryptophan hydroxylase 1 (TPH1) gene, and G-protein beta-3 subunit (GNB3) gene. We recruited 94 schizophrenia patients representing extremes in treatment response to typical neuroleptics: 43 were good responders and 51 were poor responders. The control group consisted of 392 healthy blood donors. RESULTS: We do, in part, replicate the association between 5-HT2A T102C polymorphism and response to typical neuroleptics. In female patients, C/C genotype was significantly more common in non-responders than in responders [OR = 6.04 (95% Cl 1.67-21.93), p = 0.005] or in the control population [OR = 4.16 (95% CI 1.46-11.84), p = 0.005]. TPH1 A779C C/A genotype was inversely associated with good treatment response when compared with non-responders [OR = 0.59 (95% Cl 0.36-0.98), p = 0.030] or with the controls [OR = 0.44 (95% CI 0.23-0.86, p = 0.016], and GNB3 C825T C/T genotype showed a trend-like positive association among the male patients with a good response compared with non-responders [OR = 3.48 (95% Cl 0.92-13.25), p = 0.061], and a clearer association when compared with the controls [OR = 4.95 (95% CI 1.56-15.70), p = 0.004]. CONCLUSION: More findings on the consequences of functional polymorphisms for the role of serotonin in the development of brain and serotonergic neurotransmission are needed before more detailed hypotheses regarding susceptibility and outcome in schizophrenia can be formulated. The present results may highlight some of the biological mechanisms in different courses of schizophrenia between men and women.

Association between the C957T polymorphism of the dopamine D2 receptor gene and schizophrenia.

The aim of this study was to investigate the relationship between the functional C957T single-nucleotide polymorphism of the dopamine D2 receptor (DRD2) gene and the risk for schizophrenia. We therefore conducted a case-control association study of 188 Finnish schizophrenia patients meeting the DSM-IV criteria and 384 healthy controls. The 5' nuclease assay (TaqMan) was used to determine genotypes. A greater proportion of patients with schizophrenia than healthy controls were C-allele carriers (odds ratio 1.5, 95% confidence interval (CI) 1.0-2.3, P=0.05). Our results are in agreement with an earlier association study suggesting that the C957T C-allele plays a role in the genetic vulnerability for schizophrenia and support the involvement of the DRD2 gene in schizophrenia pathogenesis.

Interaction between NOTCH4 and catechol-O-methyltransferase genotypes in schizophrenia patients with poor response to typical neuroleptics.

OBJECTIVE: In this study we attempted to show that the interaction between NOTCH4 and catechol-O-methyltransferase (COMT) polymorphism predicts the response to typical neuroleptics in schizophrenia. Our sample consisted of 94 Finnish patients with DSM-IV schizophrenia and 98 controls. METHODS: Several studies have connected COMT and NOTCH4 genes to schizophrenia. We have previously shown that COMT polymorphism is significantly associated with treatment response in schizophrenia. NOTCH4 SNP2 polymorphism has been associated with age of onset in schizophrenia, but there is also a trend that this polymorphism may predict response to typical neuroleptics. In the present sample, there is a strong gene-gene interaction between these genes (P = 0.003) and they have additive effect in treatment response. RESULTS: Patients carrying both NOTCH4 C/C genotype and COMT low/low genotype, had more than ten times higher risk of being a non-responder than responder to treatment with typical neuroleptics [OR = 10.25 (95% CI 2.21-47.53), P < 0.001]. This combination of genotypes is also more common in patients considered non-responders than in controls [OR = 3.00 (95% CI 1.33-6.76), P = 0.007]. CONCLUSION: Our results suggest that an interaction between COMT and NOTCH4 genotypes may predict the treatment response to typical neuroleptics in patients with schizophrenia.

Duloxetine Eli Lilly.

Duloxetine is a serotonin (5-HT) and norepinephrine (NE) uptake inhibitor in pre-registration for depression. In vivo studies demonstrate that duloxetine inhibits 5-HT and NE transporters and this may induce an antidepressant effect [159168]. In humans, duloxetine has a low affinity for most 5-HT subtypes and for muscarinic, histamine H1, alpha1-adrenergic, alpha2-adrenergic and dopamine D2 receptors [444103]. Thus, it is not surprising that the meta-analysis of four recent clinical studies suggests duloxetine is a potent and well-tolerated antidepressant [429723]. By December 2001, Lilly had filed an NDA for depression. The launch of duloxetine is planned for the second half of 2002 [434250], [436220]. In April 2002, filing for stress urinary incontinence was anticipated for later in 2002 [456894]. Analysts at Banc of America predicted in April 2002, that the drug will be launched in the first quarter of 2003. The company projects US $400 million in revenue in 2003 and anticipates duloxetine to reach peak sales of over US $1 billion [450920]. Analysts at Morgan Stanley, projected US $25 million in sales in the fourth quarter 2002, rising to US $900 million in 2006 [450937]. At the same time, Credit Suisse First Boston anticipated launch for late 2002, with US $220 million in duloxetine revenues in 2003 and US $457 million in 2004 [450936].

NOTCH4 gene promoter polymorphism is associated with the age of onset in schizophrenia.

OBJECTIVES: The NOTCH4 gene has a promoter polymor-phism at position -25, which leads to the three genotypes TT, CT and CC. These have been suggested to present a novel independent genetic risk factor for schizophrenia. We conducted a prospective case-control study to explore the impact of NOTCH4 T-25C polymorphism on the factors associated with schizophrenia. METHOD: NOTCH4 gene promoter T-25C polymorphism was determined by polymerase chain reaction among 94 patients with schizophrenia and 94 healthy age-matched and sex-matched blood donors. RESULTS: The T allele was highly associated with an earlier age of onset in male patients of schizophrenia (Kaplan-Meier log-rank test P<0.0001). Moreover, the male patients carrying the T allele were born significantly more often in June-November compared with other months of the year [odds ratio=3.92 (95% confidence interval=1.025-15.018), P=0.046]. No association was determined, however, between the NOTCH4 gene polymorphism under study and schizophrenia. CONCLUSION: The NOTCH4 T-25C polymorphism has an important effect on the age of onset in schizophrenia and thus may be related to an early pathogenesis of schizophrenia in young patients. Alternatively, these findings may represent a significant genetic marker for managing subgroups and etiological clues in schizophrenia.

Association of EGF polymorphism with schizophrenia in Finnish men.

Some recent data suggest that epidermal growth factor (EGF) protein levels are altered in the brain of schizophrenic patients. In addition, a novel polymorphism of the EGF gene is associated with enhanced production of EGF in vitro. We conducted a retrospective study to explore the impact of EGF polymorphism on factors associated with schizophrenia. The sample consisted of 94 patients with schizophrenia who had either responded to treatment with conventional neuroleptics or who were considered non-responders. The control sample consisted of 98 blood donors. In our sample, the G allele was associated with schizophrenia in male patients (OR = 3.594 (95% CI 1.347-9.591), p = 0.008). The G allele was also associated with a later age at onset in male patients with schizophrenia. However, no association was found between treatment response and EGF polymorphism.

Neuregulin genotype and medication response in Finnish patients with schizophrenia.

Neuregulin 1 is involved both in neurodevelopment and neurotransmitter mechanisms in the brain. There is evidence of an association between neuregulin 1 genotype and schizophrenia. We compared neuregulin 1 genotypes in patients with schizophrenia (n=94) and control subjects (n=395) of Finnish origin by using one SNP (SNP8NRG221533) as a genetic marker. We also analyzed NRG1 genotype with regard to age at onset and between responders and non-responders to conventional antipsychotics. The NRG1 genotype or allele frequencies showed similar distributions between patient and control groups. Age at onset was not associated with NRG1 genotype. The TT genotype was overrepresented in the non-responders group compared with the responders (p=0.013). Further studies are needed to ascertain the significance of neuregulin genotype in medication response to schizophrenia.

Interaction between angiotensin-converting enzyme and catechol-O-methyltransferase genotypes in schizophrenics with poor response to conventional neuroleptics.

Angiotensin-converting enzyme (ACE) modulates dopamine turnover in the brain and catechol-O-methyltransferase (COMT) enzyme is an important agent in the metabolic inactivation of dopamine and norepinephrine. Functional polymorphism in the COMT and ACE genes causes variation in enzyme activities. We investigated the relationship of COMT and ACE gene polymorphism with response to conventional neuroleptic treatment in schizophrenia. In this study population we had earlier detected that COMT genotype is associated with unsatisfactory drug response. A total of 94 schizophrenic patients were evaluated either as responders (n=43) or non-responders (n=51). The responders had experienced a fair and steady response to conventional neuroleptics. The non-responders had failed to achieve an acceptable response to conventional neuroleptics. We also used a control population of 94 age- and gender-matched blood donors. Genotyping of the COMT and ACE genes was performed by polymerase chain reaction. The risk of having both low activity COMT and high activity ACE genotypes was over 10 times higher (odds ratio=10.89, 95%CI 1.14-103.98, P=0.04) in the non-responders compared to responders. ACE genotype alone did not differ between any groups. This finding may suggest a possible interaction with low activity COMT and high activity ACE genotype in association with poor response to conventional neuroleptics.

Dopamine receptor D2 -141C Insertion/Deletion polymorphism in a Finnish population with schizophrenia.

We examined the occurrence of the -141C Ins/Del polymorphism in 93 Finnish patients with schizophrenia. In comparison with previous studies with Japanese and Caucasian populations, the incidence of this polymorphism was unexpectedly low. The findings suggest that the frequency of the -141C Ins/Del polymorphism is lower in Northern Europe compared to other Caucasian and Japanese populations.

P2RX7 polymorphisms Gln460Arg and His155Tyr are not associated with major depressive disorder or remission after SSRI or ECT.

Purinergic receptor P2X, ligand-gated ion channel, 7 (P2RX7) gene polymorphism, has been suggested to be associated with major depressive disorder (MDD). The association between P2RX7 gene polymorphism and remission after serotonin selective reuptake inhibitors (SSRI) or electroconvulsive therapy (ECT) has not previously been studied. The aims of the present study were to test for an association between P2RX7 polymorphisms Gln460Arg (rs2230912) and His155Tyr (rs208294) and MDD in two patient populations compared to controls. The first patient sample consisted of 119 subjects with treatment-resistant major depressive disorder, who were treated with ECT and the second of 99 depressive outpatients treated with SSRI. Genotype frequencies were also compared between remitters (Montgomery and Åsberg Depression Rating Scale (MADRS)<8) and non-remitters (defined as MADRS≥8) to SSRI or ECT treatment. There were no differences in allele or genotype frequencies of either rs2230912 or rs208294 between patient groups and controls. Neither rs2230912 nor rs208294 was associated with MDD or remission after SSRI or ECT. The results suggest that P2RX7 gene polymorphisms Gln460Arg (rs2230912) and His155Tyr (rs208294) are not associated with MDD or remission after SSRI or ECT.

Vascular endothelial growth factor (VEGF) polymorphism is associated with treatment resistant depression.

Antidepressive medication and electroconvulsive therapy (ECT) increase hippocampal neurogenesis by promoting expression of trophic factors, including brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF). The aims were to test for an association between the VEGF 2578 C/A polymorphism and major depressive disorder (MDD) in two patient populations compared to controls, and the association between this polymorphism and response to serotonin selective reuptake inhibitors (SSRI) and to ECT. The first patient sample consisted of 119 subjects with treatment resistant major depressive disorder who were treated with ECT and the second of 98 depressive patients treated with SSRI. Treatment response was assessed by the Montgomery and Asberg Depression Rating Scale (MADRS). Patients scoring <8 in post-treatment MADRS were considered remitters. There was a trend that CC genotype of VEGF 2578C/A polymorphism was more common in ECT-treated and SSRI-treated patients than in controls (31.1%, 25.5% and 18.7% respectively; p=0.056). The VEGF 2578 C/A polymorphism was associated with treatment resistant MDD. CC genotype was more common in ECT patients than in controls (31.1% and 18.7% respectively; p=0.015). The VEGF 2578 C/A polymorphism was not associated with treatment response to SSRI or to ECT. The finding suggests an association between VEGF 2578 C/A polymorphism and treatment resistant depression which is reported for the first time. Further studies with larger samples will be required to confirm the results.

TPH1 218A/C polymorphism is associated with major depressive disorder and its treatment response.

The association between the tryptophan hydroxylase 1 (TPH1) 218A/C polymorphism and (1) severity of major depressive disorder (MDD) and (2) response to treatment was studied. There were three study populations, the first consisting of 119 treatment-resistant MDD inpatients treated with electro-convulsive therapy (ECT), and the second of 98 MDD open care patients treated with selective serotonin reuptake inhibitors (SSRI). In addition, there was a control population of 395 healthy blood donors. The first aim of the study was to compare the genotypes of the patient with those of the healthy controls and between patient populations. The second aim was to compare the genotypes of MDD patients achieving remission with basic SSRI treatment (MADRS<8) with the genotypes of non-responders to ECT (defined as MADRS>15). TPH1 218A/C polymorphism was associated with the risk of MDD. CC genotype was significantly more common in patients (including both ECT and SSRI treated patients) than in controls (38.2% and 26.8% respectively; p=0.008), and its frequency was significantly higher in more severe forms of depression, i.e. in ECT treated patients compared with SSRI treated patients (42.0% and 33.7%, p=0.026). CC genotype was also associated with lower probability of achieving remission. It was significantly more frequent among ECT non-responders than among SSRI remitters (53.1% and 23.3%, p=0.049). In this Finnish population TPH1 218A/C polymorphism was associated with the risk of MDD and treatment response; CC genotype was associated with the increased risk of MDD and lower probability of responding treatment. Further studies with larger samples will be required to confirm the results.

TPH2 polymorphisms may modify clinical picture in treatment-resistant depression.

The association of two tryptophan hydroxylase 2 (TPH2) polymorphisms and treatment response in electroconvulsive therapy (ECT) and the risk of depression was studied. The patient sample consisted of 119 subjects with treatment-resistant major depressive disorder who were treated with ECT. Treatment response was assessed by the Montgomery and Asberg Depression Rating Scale (MADRS) scores. Patients who had <8 scores in post-treatment MADRS were considered remitters; scores >15 indicated non-response. The polymorphisms studied (rs1386494 and rs1843809) were not associated with treatment response to ECT. However, TPH2 rs1386494 A/A genotype carrying patients had significantly higher MADRS scores before ECT than A/G+G/G genotype carriers (p<0.001). A/A genotype carriers also had a greater decline in MADRS scores than A/G+G/G genotype carriers during the course of ECT treatment (p=0.03). This polymorphism may be associated with the severity of treatment-resistant depression. ECT may able to counteract a putative genetically driven worse depressive phenotype.

ACE polymorphism and response to electroconvulsive therapy in major depression.

The angiotensin I-converting enzyme gene (ACE) has been repeatedly suggested as a major gene affecting affective disorders and their treatment, but the study results have been ambiguous so far. The primary purpose of this study was to compare the effects of the ACE genotype distributions and treatment response to electroconvulsive therapy (ECT) in patients with major depressive disorder (MDD). The association in ACE genotypes and the age at onset of depression was also analyzed and these gene distributions were also compared between patients and healthy controls. The study included 119 treatment-resistant MDD patients who were referred to ECT treatment, and 392 voluntary blood donors as controls. All participants were tested for their ACE genotype, and all study patients were evaluated both before and after treatment. The Montgomery-Asberg Depression Scale (MADRS) was used as a primary efficacy evaluating method. The ACE genotype was not associated in treatment results for MDD. However, younger onset age of primary depression was associated with the I/D genotype in the whole patient group. The finding was partly gender dependent; in male patients the I allele carried a higher risk of earlier depression onset age, while in female patients the higher risk was seen only in the heterozygous I/D allele carriers. Distributions of these genotypes or alleles did not differ between patients and controls. The studied ACE genotype was not associated with ECT results but may be associated with age of onset of the illness in patients with MDD.

RGS4 polymorphism and response to electroconvulsive therapy in major depressive disorder.

We studied the association between RGS4 (rs951436) polymorphism and treatment response in electroconvulsive therapy (ECT) as well as risk of treatment-resistant depression. The study sample consisted of 119 patients with major depressive disorder (MDD) and 384 healthy control subjects. RGS4 polymorphism was not associated with treatment response in ECT or risk of MDD. According to the present data, the impact of RGS4 genotype is not decisive in major depressive disorder. The results provide preliminary data on the impact of RGS4 polymorphism in treatment response in ECT.

Brain-derived neurotrophic factor (BDNF) polymorphisms G196A and C270T are not associated with response to electroconvulsive therapy in major depressive disorder.

The aim of the present study was to examine an association of brain-derived neurotrophic factor (BDNF) polymorphisms G196A and C270T and the response to electroconvulsive therapy (ECT) in major depressive disorder (MDD). The study group consisted of 119 patients consecutively admitted for ECT in the Department of Psychiatry, Tampere University Hospital. All patients fulfilled the diagnostic criteria of DSM-IV for MDD. ECT was administered three times a week with a brief pulse constant current device. The Montgomery and Asberg Depression Rating Scale (MADRS) was used as an outcome measure of depression. Genotyping was performed using fluorescent allele-specific TaqMan probes. No association between either G196A or C270T and the response to ECT was found in the whole population. There were no significant differences in responses between men and women or between psychotic and non-psychotic patients. However, within subgroups such as in psychotic and in late-onset depression CC genotype of C270T may predict good response. BDNF may not be associated with response to ECT in general, but some association in subgroups may exist.