Sang Woo Hahn

EFFECT OF SEROTONIN RECEPTOR 2A GENE POLYMORPHISM ON MIRTAZAPINE RESPONSE IN MAJOR DEPRESSION

The 5-HTR2A gene is a candidate gene for influencing the clinical response to treatment with antidepressants. The purpose of this study was to determine the relationship between the -1438A/G polymorphism of the 5-HTR2A gene and the response to mirtazapine in a Korean population with major depressive disorder. Mirtazapine was administered for eight weeks to the 101 patients who completed the study, during which we evaluated the clinical outcome using repeated-measures ANCOVA. A main effect of genotype or an effect of genotype-time interactions on the decrease in HAMD score during the eight-week follow-up was not found, which suggests that the 5-HTR2A -1438A/G polymorphism does not affect the clinical outcome to mirtazapine administration. However, significant effects of genotype and allele carriers on the decrease in the sleep score over the eight weeks were found (genotype: F = 4.093, p = 0.017; allele: F = 4.371, p = 0.037), whereas no effect of genotype-time interactions on the decrease in the HAMD score over the eight-week follow-up was found. These observations suggest that the -1438A/G polymorphism affects the sleep improvement but not the sleep pattern over time. A t-test-based evaluation of the effect of the 5-HTR2A -1438A/G polymorphism on the sleep improvement at each time period revealed significant differences in the sleep scores after two weeks of mirtazapine administration. The sleep scores were lower for carriers of the A+ allele than of the A — allele after two weeks of mirtazapine administration (p = 0.041), which means that the -1438GG genotype is associated with less improvement in sleep, and suggests that the effect of mirtazapine on improving the sleep quality differs with the 5-HTR2A -1438A/G polymorphism within two weeks of mirtazapine treatment. In conclusion, although the -1438A/G polymorphism affects the sleep improvement resulting from the administration of mirtazapine to Korean patients with major depressive disorder, our results do not support the hypothesis that this polymorphism of the 5-HTR2A gene is involved in the therapeutic response to mirtazapine.

Relationship between G-Protein Beta-3 Subunit C825T Polymorphism and Mirtazapine Responses in Korean Patients with Major Depression

Aims: This study aimed to determine the relationship between the C825T polymorphism in the G-protein β3 subunit (GNB3) gene and the response to mirtazapine in a Korean population with major depressive disorder (MDD). Method: Mirtazapine was administered for 8 weeks to the 101 MDD patients who completed this study. All subjects were examined using the Structured Clinical Interview for DSM-IV, and the severity of depression was assessed using the 21-item Hamilton Depression Rating (HAMD-21) scale. Results: There was a significant main effect of time on the decrease in the HAMD-21 score during the 8-week study period. However, a main effect of or an interaction of genotype with time on the decrease in the HAMD-21 score during the 8-week study period was not found. ANOVA revealed no significant effects of the GNB3 C825T polymorphism on the decrease in the HAMD-21 score at each time period. Conclusion: Although the C825T polymorphism of the GNB3 gene may affect the pathogenesis of MDD, our results do not support the hypothesis that this polymorphism is involved in the therapeutic response to mirtazapine in Korean patients with MDD.

High insulin-like growth factor-1 in patients with bipolar I disorder: A trait marker?

OBJECTIVES Neurotrophic factors exert substantial effects on the central nervous system. The present study investigates the roles of insulin-like growth factor-1 (IGF-1), β-nerve growth factor (β-NGF), and brain-derived neurotrophic factor (BDNF) in bipolar disorder. METHODS Baseline levels of culture-stimulated IGF-1, β-NGF, and BDNF were compared in 116 patients with bipolar I disorder and 123 healthy controls. Neurotrophic factors were also compared in patients before and after 6 weeks of pharmacotherapy. A multivariate logistic regression analysis was used to investigate the influence of the neurotrophic factors analyzed in quartile form, in relation to confounding variables, such as age, sex, and body mass index. RESULTS IGF-1 was significantly higher in patients (mean=514.57, SD=259.78) than in healthy controls (mean=316.82, SD=270.00, p<0.0001) at baseline. Furthermore, higher levels of IGF-1 substantially increased the risk for bipolar I disorder. IGF-1 level was not significantly changed at 6-weeks (mean=506.41, SD=313.66). No changes in BDNF or β-NGF-1 levels were found following the 6-week treatment period. IGF-1 and β-NGF were negatively correlated in healthy controls, but not in patients. Severity of manic symptoms was not associated with any of the neurotrophic factors. LIMITATIONS We did not measure cortisol, growth hormone, or IGF-1 receptors. This study is cross-sectional in design. CONCLUSIONS Elevated IGF-1 levels may be a trait marker for bipolar disorder. Further studies are needed to thoroughly investigate the role of IGF-1 in relation to other neuroendocrine factors and biological markers for bipolar disorder.

Does Age at Onset of First Major Depressive Episode Indicate the Subtype of Major Depressive Disorder?: The Clinical Research Center for Depression Study

Purpose The purpose of this study was to evaluate the effects of age at onset of the first major depressive episode on the clinical features of individuals with major depressive disorder (MDD) in a large cohort of Korean depressed patients. Materials and Methods We recruited 419 MDD patients of age over 18 years from the Clinical Research Center for Depression study in South Korea. At the start of the study, the onset age of the first major depressive episode was self-reported by the subjects. The subjects were divided into four age-at-onset subgroups: childhood and adolescent onset (ages <18), early adult onset (ages 18-44), middle adult onset (ages 45-59), and late onset (ages 60+). Using analysis of covariance (ANCOVA) and ordinal logistic regression analysis with adjusting the effect of age, the relationships between clinical features and age at onset of MDD were evaluated. Results There was an apparent, but inconsistent correlation between clinical features and age at onset. Earlier onset MDD was significantly associated with higher proportion of female gender [adjusted odds ratio (AOR)=0.570, p=0.022], more previous suicide attempts (AOR=0.635, p=0.038), greater number of previous depressive episodes (F=3.475, p=0.016) and higher scores on the brief psychiatric rating scale (F=3.254, p=0.022), its negative symptom subscale (F=6.082, p<0.0001), and the alcohol use disorder identification test (F=7.061, p<0.0001). Conclusion Early age at onset may increase the likelihood of distinguishable MDD subtype, and age at onset of the first major depressive episode is a promising clinical indicator for the clinical presentation, course, and outcome of MDD.

TNF-alpha −308G>A polymorphism is associated with suicide attempts in major depressive disorder

BACKGROUND Despite the substantial role of the cytokine network in depression and suicide, few studies have investigated the role of genetic polymorphisms of pro- and anti-inflammatory cytokines in suicide in major depressive disorder (MDD). The aim of this study was to investigate whether tumor necrosis factor-alpha (TNF-alpha) -308G>A, interferon-gamma (IFN-gamma) +874A>T, and interleukin-10 (IL-10) -1082A>G are associated with increased risk for suicide attempts in MDD. METHODS Among patients with MDD, 204 patients who had attempted suicide and 97 control patients who had not attempted suicide were recruited. A chi-square test was used to identify a possible risk genotype or allele type for suicide. A subsequent multivariate logistic regression analysis was conducted to investigate the influence of a risk genotype or allele type adjusted for other environmental factors. The lethality of the suicide attempt was also tested between genotype and allele types among suicidal patients with MDD. RESULTS The GG genotype of the TNF-alpha -308G>A polymorphism was found to significantly increase risk for suicide attempt (adjusted OR=2.630, 95% CI=1.206 to 5.734). IFN-gamma +874A>T and IL-10 -1082A>G were not associated with risk for suicide. Lethality of the suicide attempt was not associated with any of the three cytokine genotypes or allele types. LIMITATIONS Limitations include a relatively small sample size and a cross-sectional design. CONCLUSIONS TNF-alpha -308G>A polymorphism is an independent risk factor for suicide attempts in MDD. Future studies should clarify the neural mechanisms by which the GG genotype of TNF-alpha -308G>A influences suicide in MDD.

Association between norepinephrine transporter gene (SLC6A2) polymorphisms and suicide in patients with major depressive disorder

BACKGROUND Although several studies have investigated possible associations between norepinephrine neurotransmitter transporter gene (SLC6A2) polymorphisms and depression, few studies have examined associations between SLC6A2 polymorphisms and suicide. METHODS Three single-nucleotide polymorphisms (rs2242446, rs28386840, and rs5569) were measured in 550 patients: 201 with major depressive disorder (MDD) and suicide attempt/s, 160 with MDD without suicide attempts, and 189 healthy controls. Analysis of single-nucleotide polymorphisms (SNPs) and haplotype was conducted for the three groups. Subsequently, multivariate logistic regression analysis adjusting for age and gender was conducted to identify independent influences of each SNP. A possible association between suicide lethality and SLC6A2 polymorphisms was also investigated. RESULTS In the genotype and allele frequency analysis, there were significant differences in rs28386840 between suicidal MDD patients and healthy controls. In the haplotype analysis, TAA (rs2242446-rs28386840-rs5569, from left to right) was associated with suicide attempts in MDD, although the significance (p=0.043) disappeared after Bonferroni correction. There were no relationships between lethality scores and SLC6A2 polymorphisms in suicidal MDD. LIMITATIONS Modest sample size and a single type of neurotransmitter analyzed (norepinephrine) are the primary limitations. CONCLUSION Our results suggest that SLC6A2 polymorphisms were associated with suicide risk in patients with MDD. Future studies are warranted to elucidate possible mechanisms by which SLC6A2 polymorphisms influence suicide risk.

Suicidal thoughts/acts and clinical correlates in patients with depressive disorders in Asians: Results from the REAP-AD study

Objective Using data from the Research on Asian Psychotropic Prescription Patterns for Antidepressants (REAP-AD) study, we aimed to present the rates and clinical correlates of suicidal thoughts/acts in patients recruited from a total of 40 centres in 10 Asian countries/areas: China, Hong Kong, India, Indonesia, Japan, Korea, Malaysia, Singapore, Taiwan, and Thailand. Methods Data from 1122 patients with depressive disorders in the REAP-AD study were used. The ICD-10 was employed to diagnose depressive episodes and recurrent depressive disorder. The presence or absence of suicidal thoughts/acts and profile of other depressive symptoms was established using the National Institute for Health and Clinical Excellence guidelines for depression. Country/area differences in rates of suicidal thoughts/acts were evaluated with the χ2 test. In addition, depressive symptom profiles, other clinical characteristics, and patterns of psychotropic drug prescription in depressed patients with and without suicidal thoughts/acts were compared using analysis of covariance for continuous variables and logistic regression analysis for discrete variables to adjust the effects of covariates. Results The rates of suicidal thoughts/acts in 10 countries/areas varied from 12.8% in Japan to 36.3% in China. Patients with suicidal thoughts/acts presented more persistent sadness (adjusted odds ratio [aOR]=2.64, p<0.001), loss of interest (aOR=2.33, p<0.001), fatigue (aOR=1.58, p<0.001), insomnia (aOR=1.74, p<0.001), poor concentration (aOR=1.88, p<0.001), low self-confidence (aOR=1.78, p<0.001), poor appetite (aOR=2.27, p<0.001), guilt/self-blame (aOR=3.03, p<0.001), and use of mood stabilisers (aOR=1.79, p<0.001) than those without suicidal thoughts/acts. Conclusion Suicidal thoughts/acts can indicate greater severity of depression, and are associated with a poorer response to antidepressants and increased burden of illness. Hence, suicidal thoughts/acts can provide a clinical index reflecting the clinical status of depressive disorders in Asians.

No Association between Serotonin Receptor 2C-759C/T Polymorphism and Weight Change or Treatment Response to Mirtazapine in Korean Depressive Patients

Objective Activation of one or more serotonin (5-HT) receptors may play a role in mediating the antidepressant effects of serotonergic antidepressants. The serotonin 2C (5HT 2C) receptor is known to be associated with antidepressant action and weight gain. We sought to determine whether the 5-HTR 2C receptor -759C/T polymorphism was associated with weight gain and treatment response to mirtazapine in major depressive disorder (MDD) patients. Methods The 5-HT 2C receptor -759C/T polymorphism was analyzed in 323 MDD patients. All patients were evaluated using the 21-item Hamilton Depression Rating Scale at the beginning of the study and at 1, 2, 4, and 8 weeks of mirtazapine treatment. Results There was no significant difference in the 5-HT 2C receptor -759C/T genotype distribution between responder and non-responder groups. The 5-HT 2C receptor -759C/T polymorphism was not associated with weight change over time after mirtazapine administration. Conclusion The 5-HT 2C receptor -759C/T polymorphism does not appear to be a predictor of treatment response to mirtazapine. This polymorphism was not associated with weight change after 8 weeks of mirtazapine treatment. Further investigation on other polymorphisms of the 5-HT 2C gene is required to determine whether the 5-HT 2C gene influences treatment response and weight change after mirtazapine administration in patients with major depressive disorder.

Association between brain-derived neurotrophic factor V66M and treatment responses to escitalopram in patients with major depressive disorder

Brain‐derived neurotrophic factor (BDNF) is a candidate molecule for influencing the clinical response to antidepressant treatment. Among polymorphisms on the BDNF gene, V66M (rs6265) has been reported to be associated with response to antidepressant treatment. The aims of this study were to determine the relationship between the V66M polymorphism and the response to escitalopram in patients with major depressive disorder (MDD).

Clinical characteristics and psychotropic prescribing patterns associated with impaired concentration in asians with depressive disorders: The REAP-AD study

The Research on Asian Psychotropic Prescription Patterns for Antidepressants (REAP-AD) study aimed to survey and review antidepressant prescribing patterns in different clinical settings in Asian countries/areas. The REAP-AD study collected comprehensive data for psychiatric patients prescribed antidepressants in 10 Asian countries/areas during the period from March to June 2013. Depressive disorders have been an important issue closely associated with ill-health and disability in the realm of mental health. Impaired concentration was found to be a consistent symptom in depressive disorders regardless of clinical course, and a predictor of poor treatment outcome. In this work we aimed to identify clinical characteristics independently associated with impaired concentration in patients with depressive disorders, using data from the REAP-AD study. A total of 336 depressive disorder patients with impaired concentration and 786 depressive disorder patients without impaired concentration were recruited from 40 centers in 10 Asian countries/areas. A binary logistic regression model was fitted to identify the independent correlates of impaired concentration in patients with depressive disorders. After adjusting the effects of covariates, the binary logistic model showed that impaired concentration was independently associated with higher rates of loss of interest (P < 0.0001), fatigue (P < 0.0001), low self-confidence (P < 0.0001) and appetite disturbance (P < 0.0001) and with a lower rate of adjunctive antipsychotic prescription (P = 0.007). Our findings suggest that impaired concentration and its associated depressive symptom profiles constitute a unitary depressive symptom cluster that is also an intervening variable for poor social function.