Paroxetine versus Venlafaxine and Escitalopram in Korean Patients with Major Depressive Disorder: A Randomized, Rater-blinded, Six-week Study

Young Sup Woo,Roger S. McIntyre,Jung Bum Kim,Min Soo Lee,Jae-Min Kim,Hyeon Woo Yim,Tae-Youn Jun 대한정신약물학회 2017 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.15 No.4

Objective: The purpose of this study was to compare the efficacy and safety of escitalopram, paroxetine and venlafaxine in Korean patients with major depressive disorder (MDD). Methods: A total of 449 Korean MDD patients were recruited in a six-week, randomized, rater-blinded, active-controlled trial and were evenly randomized to paroxetine, venlafaxine, or escitalopram treatment. Results: When comparing the mean difference for the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating Scale (HDRS) total scores during six weeks, paroxetine (−6.4±0.4, and −5.4±0.4, respectively) was found to be significantly superior to escitalopram (−3.7±0.5 and −3.1±0.4, respectively). Venlafaxine had a significantly lower MADRS total score (−5.4±0.4) than escitalopram. When adjusting baseline variables, the response, according to the MADRS and HDRS scores, in the paroxetine group was greater than that for the escitalopram group (odds ratio [OR]=2.43, 95% confidence interval [CI]=1.42-4.16 for MADRS; and OR=2.32, 95% CI=1.35-3.97 for HDRS) and the venlafaxine group (OR=1.94, 95% CI=1.17-3.21 for MADRS; and OR=1.71, 95% CI=1.03-2.83 for HDRS). Despite that the overall tolerability was high and similar among the three groups, a total of 268 subjects (59.7%) prematurely discontinued treatment, representing the main limitation of the present study. Conclusion: Although a low study completion rate limits generalizability, our findings suggest that paroxetine might be superior to escitalopram in Korean MDD patients. Further studies should be conducted to draw a definite conclusion

Correlates of Metabolic Abnormalities in Bipolar I Disorder at Initiation of Acute Phase Treatment

Byungsu Kim,Sangeok Kim,Roger S. McIntyre,김성윤,주연호,Hui Joon Park 대한신경정신의학회 2009 PSYCHIATRY INVESTIGATION Vol.6 No.2

Objective: Treatment of bipolar patients is often complicated by metabolic abnormalities such as obesity, diabetes, and dyslipidemia. We therefore evaluated the prevalence of these abnormalities and their correlates, in bipolar I patients, at the time of commencement of pharmacological treatment for acute mood episodes. Methods: The study cohort consisted of 184 bipolar I patients hospitalized for treatment of acute mood episodes. Socio-demographic and clinical variables were noted and metabolic parameters, including body mass index, fasting plasma glucose, fasting total cholesterol, and current treatment(s) for diabetes and/or dyslipidemia were measured before initiating medication(s). ResultsaaFifty-six (30.4%) subjects met our criteria for obesity; 80 (43.5%) had hyperglycemia, with 8 (4.3%) receiving anti-diabetic medication; and 38 (20.7%) had hypercholesterolemia, with 2 (1.1%) receiving cholesterol-lowering agents. We found that male sex (χ2=5.359, p=0.021), depressed or mixed state versus manic state (χ2=4.302, p=0.038), and duration of illness (t=2.756, p=0.006) were significantly associated with obesity. Older age (t= 3.668, p<0.001), later age of disease onset (t=2.271, p=0.024), and lower level of educational attainment (β=-0.531, p=0.001) were associated with hyperglycemia. Conclusion: Our finding that metabolic abnormalities are prevalent when initiating acute pharmacological treatment in bipolar I patients indicates that these factors should be integrated into treatment plans at the onset of disease management.

Association of treatment response with obesity and other metabolic risk factors in adults with depressive disorders: Results from a National Depression Cohort study in Korea (the CRESCEND study)

Woo, Young Sup,McIntyre, Roger S.,Kim, Jung-Bum,Lee, Min-Soo,Kim, Jae-Min,Yim, Hyeon Woo,Jun, Tae-Youn Elsevier 2016 Journal of affective disorders Vol.203 No.-

<P><B>Abstract</B></P> <P><B>Background</B></P> <P>Available studies indicate that obesity may exert a moderational effect on antidepressant treatment response. The aim of this study was to investigate the relationship between treatment response and metabolic abnormalities amongst patients with depressive disorders in a large naturalistic clinical setting.</P> <P><B>Methods</B></P> <P>A nationwide prospective study was conducted in 18 hospitals in South Korea; 541 depressive patients meeting DSM-IV criteria were recruited. After baseline evaluation, subjects received naturalistic clinician-determined antidepressant interventions. Assessment was performed at baseline and weeks 1, 2, 4, 8, 12, 24 and 52. Treatment response was defined as a ≥50% reduction from baseline on at least one evaluation point.</P> <P><B>Results</B></P> <P>In univariate comparison, the patients who showed insufficient response to antidepressant therapy were more likely to be male, unmarried, unemployed, and obese. After adjusting for baseline variables, male sex (OR=1.82) and obesity (OR=1.55) remained as were significant variables. Stratification of the subjects into one of three groups, i.e. male, pre-menopausal female and post-menopausal female, revealed that males with concurrent metabolic problems, (i.e. the presence of one or more of hypertension, hyperglycemia, or hypercholesterolemia) had significantly higher risk for insufficient response (OR=2.32) and, after adjusting for baseline variables, obesity predicted insufficient response in post-menopausal female (OR=2.41).</P> <P><B>Conclusions</B></P> <P>The presence of metabolic abnormalities in patients with depressive disorders was associated with decreased treatment response to antidepressants. These results underscore the neurobiological relationship between obesity and the central nervous system, and provide empiric evidence supporting stratification of treatment response in depression.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Male sex and obesity predicted poor treatment outcomes in patients treated with antidepressants. </LI> <LI> Male with concurrent metabolic problems had significantly higher risk for poor antidepressant treatment outcomes. </LI> <LI> Obesity predicted insufficient response in post-menopausal female patients with depressive disorders. </LI> </UL> </P>

Effects of Antipsychotic Drugs on the Epigenetic Modification of Brain-Derived Neurotrophic Factor Gene Expression in the Hippocampi of Chronic Restraint Stress Rats

Seo, Mi Kyoung,Kim, Young Hoon,McIntyre, Roger S.,Mansur, Rodrigo B.,Lee, Yena,Carmona, Nicole E.,Choi, Ah Jeong,Kim, Gyung-Mee,Lee, Jung Goo,Park, Sung Woo Hindawi 2018 Neural plasticity Vol.2018 No.-

<P>Recent studies have shown that antipsychotic drugs have epigenetic effects. However, the effects of antipsychotic drugs on histone modification remain unclear. Therefore, we investigated the effects of antipsychotic drugs on the epigenetic modification of the BDNF gene in the rat hippocampus. Rats were subjected to chronic restraint stress (6 h/d for 21 d) and then were administered with either olanzapine (2 mg/kg) or haloperidol (1 mg/kg). The levels of histone H3 acetylation and MeCP2 binding at BDNF promoter IV were assessed with chromatin immunoprecipitation assays. The mRNA levels of total BDNF with exon IV, HDAC5, DNMT1, and DNMT3a were assessed with a quantitative RT-PCR procedure. Chronic restraint stress resulted in the downregulation of total and exon IV BDNF mRNA levels and a decrease in histone H3 acetylation and an increase in MeCP2 binding at BDNF promoter IV. Furthermore, there were robust increases in the expression of HDAC5 and DNMTs. Olanzapine administration largely prevented these changes. The administration of haloperidol had no effect. These findings suggest that the antipsychotic drug olanzapine induced histone modification of BDNF gene expression in the hippocampus and that these epigenetic alterations may represent one of the mechanisms underlying the actions of antipsychotic drugs.</P>

Effects of olanzapine and haloperidol on mTORC1 signaling, dendritic outgrowth, and synaptic proteins in rat primary hippocampal neurons under toxic conditions

Park, Sung Woo,Seo, Mi Kyoung,McIntyre, Roger S.,Mansur, Rodrigo B.,Lee, Yena,Lee, Jae-Hon,Park, Seon-Cheol,Huh, Lyang,Lee, Jung Goo Elsevier 2018 Neuroscience Letters Vol.686 No.-

<P><B>Abstract</B></P> <P>Recent studies have demonstrated that antipsychotic drugs may activate mammalian target of rapamycin complex 1 (mTORC1) signaling in neurons. However, the relationship between mTORC1 signaling activation and currently prescribed antipsychotic drugs remains incompletely understood. The purpose of this study was to determine whether alterations in the level of mTORC1 signaling occur after rat primary hippocampal neurons are treated with olanzapine and haloperidol under toxic conditions. Additionally, we investigated whether these drugs affect dendritic outgrowth and synaptic protein expression through the mTORC1 signaling pathway. We measured changes in mTORC1-mediated and synaptic proteins by Western blotting assay under toxic conditions induced by B27 deprivation. Dendritic outgrowth was determined by a neurite assay. Olanzapine significantly increased the phosphorylated levels of mTORC1, its downstream effectors, and its upstream activators. The increased mTORC1 phosphorylation induced by olanzapine was significantly blocked by specific PI3K, MEK, or mTORC1 inhibitors. Olanzapine also increased dendritic outgrowth and synaptic proteins levels; all of these effects were blocked by rapamycin. However, haloperidol had none of these effects. We demonstrated that olanzapine, but not haloperidol, activated the mTORC1 signaling pathway and increased dendritic outgrowth and synaptic proteins by activating mTORC1 signaling in rat primary hippocampal neurons. These findings suggest that olanzapine affects neuroplasticity by activating mTORC1 signaling.</P> <P><B>Highlights</B></P> <P> <UL> <LI> B27 deprivation in hippocampal cultures decreases mTOR signaling activity. </LI> <LI> Olanzapine can actives the mTOR signaling pathway. </LI> <LI> Olanzapine increases synaptic plasticity through mTOR signaling. </LI> <LI> However, haloperidol has no such effects. </LI> </UL> </P>

Cognitive Deficits as a Mediator of Poor Occupational Function in Remitted Major Depressive Disorder Patients

우영섭,Joshua D. Rosenblat,Ron Kakar,박원명,Roger S. McIntyre 대한정신약물학회 2016 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.14 No.1

Cognitive deficits in major depressive disorder (MDD) patients have been described in numerous studies. However, few reports have aimed to describe cognitive deficits in the remitted state of MDD and the mediational effect of cognitive deficits on occupational outcome. The aim of the current review is to synthesize the literature on the mediating and moderating effects of specific domains of cognition on occupational impairment among people with remitted MDD. In addition, predictors of cognitive deficits found to be vocationally important will be examined. Upon examination of the extant literature, attention, executive function and verbal memory are areas of consistent impairment in remitted MDD patients. Cognitive domains shown to have considerable impact on vocational functioning include deficits in memory, attention, learning and executive function. Factors that adversely affect cognitive function related to occupational accommodation include higher age, late age at onset, residual depressive symptoms, history of melancholic/psychotic depression, and physical/psychiatric comorbidity, whereas higher levels of education showed a protective effect against cognitive deficit. Cognitive deficits are a principal mediator of occupational impairment in remitted MDD patients. Therapeutic interventions specifically targeting cognitive deficits in MDD are needed, even in the remitted state, to improve functional recovery, especially in patients who have a higher risk of cognitive deficit.

The association between insulin resistance and depression in the Korean general population

Lee, Jae-Hon,Park, Sung Keun,Ryoo, Jae-Hong,Oh, Chang-Mo,Mansur, Rodrigo B.,Alfonsi, Jeffrey E.,Cha, Danielle S.,Lee, Yena,McIntyre, Roger S.,Jung, Ju Young Elsevier 2017 Journal of affective disorders Vol.208 No.-

<P><B>Abstract</B></P> <P><B>Background</B></P> <P>Previous studies showed that the insulin resistance (IR) could be related to depression. However, this association is still equivocal in the general population. Herein, we aimed to investigate the association between IR and depressive symptoms in a large sample in South Korea.</P> <P><B>Methods</B></P> <P>A cross-sectional study was carried out for 165,443 Korean men and women who received a health checkup including various clinical parameters and the Center for Epidemiologic Studies Depression scales (CES-D). Subjects were stratified into subgroups by CES-D score, sex, age, and presence of diabetes. The odd ratios (ORs) for homeostasis model assessment of insulin resistance (HOMA-IR) were compared between groups using multivariable logistic regression analyses.</P> <P><B>Results</B></P> <P>After adjusting covariates (e.g. smoking, family income, marriage state, unemployment status, average alcohol use, BMI, physical activity, systolic blood pressure, diabetes), increased IR was weakly associated with greater depressive symptoms (adjusted OR=1.01 [95% CI 1.0001–1.03]). Subgroup analysis revealed this association was statistically significant in females (adjusted OR=1.03, [95% CI 1.001–1.06]), non-diabetic group (adjusted OR=1.04, [95% CI 1.02–1.06]), and young participants under the age of thirty (adjusted OR=1.17, [95% CI 1.07–1.27]). But we couldn’t find significant association in diabetic and middle to elderly participants.</P> <P><B>Conclusions</B></P> <P>This study demonstrates that there is a relationship between IR and depressive symptoms in the Korean general population. Results from this epidemiological study revealed that young adults and non-diabetic individuals with increased IR may be related with depressive symptoms.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Increased insulin resistance was associated with depressive symptoms in the Korean general population (N=165,443). </LI> <LI> The subgroup analysis revealed the association was statistically significant in female, non-diabetic and young groups. </LI> <LI> Increased insulin resistance in non-diabetic participants was more strongly associated with depressive symptoms. </LI> <LI> These findings suggest that early management of insulin resistance may prevent progression toward depressive symptoms. </LI> </UL> </P>