Han Yong Jung

The role of pro-inflammatory cytokines in the neuroinflammation and neurogenesis of schizophrenia

Schizophrenia is a serious mental illness with chronic symptoms and significant impairment in psychosocial functioning. Although novel antipsychotics have been developed, the negative and cognitive symptoms of schizophrenia are still unresponsive to pharmacotherapy. The high level of social impairment and a chronic deteriorating course suggest that schizophrenia likely has neurodegenerative characteristics. Inflammatory markers such as pro-inflammatory cytokines are well-known etiological factors for psychiatric disorders, including schizophrenia. Inflammation in the central nervous system is closely related to neurodegeneration. In addition to pro-inflammatory cytokines, microglia also play an important role in the inflammatory process in the CNS. Uncontrolled activity of pro-inflammatory cytokines and microglia can induce schizophrenia in tandem with genetic vulnerability and glutamatergic neurotransmitters. Several studies have investigated the possible effects of antipsychotics on inflammation and neurogenesis. Additionally, anti-inflammatory adjuvant therapy has been under investigation as a treatment option for schizophrenia. Further studies should consider the confounding effects of systemic factors such as metabolic syndrome and smoking. In addition, the unique mechanisms by which pro-inflammatory cytokines are involved in the etiopathology of schizophrenia should be investigated. In this article, we aimed to review (1) major findings regarding neuroinflammation and pro-inflammatory cytokine alterations in schizophrenia, (2) interactions between neuroinflammation and neurogenesis as possible neural substrates for schizophrenia, and (3) novel pharmacological approaches.

Association between the Catechol O-Methyltransferase Val108/158Met Polymorphism and Alexithymia

It has been suggested that the characteristics of alexithymia result from deficits in frontal lobe functioning, and the prefrontal cortex is particularly dependent on the catechol O-methyltransferase (COMT) pathway. We investigated the relationship between COMT Val108/158Met, serotonin transporter coding sequence (5-HT transporter gene-linked polymorphic region; 5-HTTLPR) polymorphisms, and alexithymia.The study sample comprised 109 students at the Korea University. All participants were tested using the 20-item Toronto Alexithymia Scale (TAS-20). They were genotyped for COMT Val108/158Met and 5-HTTLPR polymorphisms. Genotyping was analyzed using polymerase chain reaction. Subjects with Val/Val genotype had significantly higher TAS-20 scores than those with Met/Met or Met/Val genotypes. However, there was no significant relationship between the 5-HTTLPR genotype and TAS-20 scores. This indicates a possible association between the COMT Val108/158Met gene polymorphism and alexithymia.

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

OBJECTIVESnNeurotrophic 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.nnnMETHODSnBaseline 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.nnnRESULTSnIGF-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.nnnLIMITATIONSnWe did not measure cortisol, growth hormone, or IGF-1 receptors. This study is cross-sectional in design.nnnCONCLUSIONSnElevated 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.

Comparison of efficacy and safety of milnacipran and fluoxetine in Korean patients with major depression.

ABSTRACT Object: To compare efficacy and safety of milnacipran and fluoxetine in a population of Korean patients with major depression. Research design and methods: The design was a multi-centre, randomised, comparative clinical study. Patients with major depression (DSM‐IV diagnostic criteria) scoring over 17 points on the 17-item Hamilton Depression Scale (HAM‐D) and over 21 points on the Montgomery-Asberg Depression Rating Scale (MADRS) were recruited and randomised to receive milnacipran (50u2009mg/day increasing after 1 week to 100u2009mg/day) or fluoxetine (20u2009mg/day) for 6 weeks. All previous medication was stopped at least 7 days before entry into the study. Patients were evaluated (HAM‐D, MADRS and clinical global impression scale, CGI) at baseline and after 1, 2, 4 and 6 weeks of treatment. All adverse events which developed during the study period were recorded. Results: 70 patients (milnacipran 39; fluoxetine 31) were included in the study. Total score on both HAM‐D, MADRS and CGI decreased significantly in both groups after 1 week and continued to decrease throughout the study. There was no significant difference between the two groups for any measurement at any time point. Both antidepressants were well tolerated. In the milnacipran group, 13 patients reported 28 adverse reactions, and in the fluoxetine group 11 patients reported 18 adverse reactions. Two patients discontinued due to adverse events in the milnacipran group and three in the fluoxetine group. There were no clinically significant modifications in vital signs, routine blood laboratory tests, biochemistry or ECG throughout the study. Nausea and headache were the most frequently reported adverse events with milnacipran while digestive disturbances, diarrhoea and insomnia were more common with fluoxetine. Conclusion: Milnacipran, like fluoxetine, was found to be effective and well tolerated for the treatment of major depression in this population of depressed Korean patients. Principal limitations of the study were its open design, its small sample size and its relatively short duration.

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

BACKGROUNDnDespite 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.nnnMETHODSnAmong 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.nnnRESULTSnThe 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.nnnLIMITATIONSnLimitations include a relatively small sample size and a cross-sectional design.nnnCONCLUSIONSnTNF-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.

Alexithymia and low cooperativeness are associated with suicide attempts in male military personnel with adjustment disorder: A case–control study

Subpopulations of patients with adjustment disorder are at increased risk for suicide. The current study investigated whether personality traits, including alexithymia, temperament, and character, are associated with an increased risk of suicide in individuals with adjustment disorder. Age- and sex-matched patients meeting the diagnostic and statistical manual of mental disorders (DSM-IV) criteria for adjustment disorder with (n=92) and without (n=92) a history of suicide attempts were recruited for the present study. Ninety-two healthy individuals who did not meet diagnostic criteria for Axis I or II diagnoses were used as controls. The Toronto alexithymia scale-20 (TAS-20) and the temperament and character inventory (TCI) were used to assess personality traits. Significantly higher total and subscale scores on the TAS-20, including on the difficulty-identifying-feelings (DIF) and difficulty-describing-feelings (DDF) subscales, and lower scores on the TCI cooperativeness subscale were noted in adjustment-disorder patients with previous suicide attempts. In the multivariate regression analysis, high DDF and DIF and low cooperativeness increased the risk of suicide attempts in adjustment-disorder patients. A subsequent path analysis revealed that high DDF had a direct effect on suicide attempts, whereas high DIF had an indirect effect on suicide attempts via low cooperativeness.

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

BACKGROUNDnAlthough 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.nnnMETHODSnThree 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.nnnRESULTSnIn 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.nnnLIMITATIONSnModest sample size and a single type of neurotransmitter analyzed (norepinephrine) are the primary limitations.nnnCONCLUSIONnOur 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.

Temperament and character of young male conscripts with adjustment disorder: a case-control study.

Abstract Personality is an important clinical factor for successful adjustment in stressful situations. The aim of this study was to examine possible differences in temperament and character dimensions between patients with adjustment disorder with depressed mood and healthy controls. Among the young male conscripts, 86 subjects with adjustment disorder with depressed mood and 86 healthy controls were included. The mean scores in the 7 dimensions and 25 subscales of the Temperament and Character Inventory were compared between the patients with adjustment disorder with depressed mood and the control group by an independent t-test. The patients with adjustment disorder with depressed mood had significantly higher scores on harm-avoidance and lower scores on self-directedness, cooperativeness, and self-transcendence than did the controls. There were no differences in novelty seeking, reward dependence, and persistence in temperament between the two groups. The results of this study suggest that the personality traits of the subjects with adjustment disorder with depressed mood would make them vulnerable to stressful situations and less skilled in coping with conscription.

Decreased medial frontal gyrus in patients with adjustment disorder

BACKGROUNDSnAdjustment disorder is a frequent mental illness that occurs under various stressful situations. Whereas adjustment disorder has distinct clinical manifestations and diagnostic entity, few studies have investigated its underlying neural substrate. This study aimed to identify brain structural abnormalities among patients with adjustment disorder.nnnMETHODSnTwenty-five patients with adjustment disorder and 25 healthy controls participated in the study. Structural magnetic resonance imaging was performed, and a voxel-based morphometry was applied. Family-wise error-corrected p values for statistical analysis of comparative gray matters between patients with adjustment disorder and healthy controls were used.nnnRESULTSnPatients with adjustment disorder had decreased gray matter volume in the right medial frontal gyrus as compared to healthy controls. There were no brain regions that were decreased in the healthy controls as compared to patients with adjustment disorder.nnnLIMITATIONSnThis study was a cross-sectional design.nnnCONCLUSIONSnOur results suggest that adjustment disorder arises from characteristic neural abnormalities, contrary to previous notions suggesting that adjustment disorder is a non-specific and/or residual diagnostic term. Moreover, future studies should examine the underlying neural substrates responsible for successful adaptation to unfamiliar and stressful situations.

Incidence and course of depression in patients with Alzheimer’s disease

Objective Depressive symptoms are common in Alzheimers disease (AD) and they might influence the course and prognosis of AD. Depression could appear anytime in the course of the disease, and could either last considerably long or disappear easily. This study is intended to investigate the occurrence of depression in the course of AD and the risk factors of incidence. Methods This study targeted 1,272 AD patients without depressive symptoms at the start of this study in Korea. A total of 775 subjects completed the study, and the occurrence of depression was assessed after 12 months. Demographic information of subjects was collected and cognitive functions, overall functions, and depression severity were assessed at the start of this study and after 12 months. Results Among the 775 subjects, 103 subjects (13.29%) developed depression 12 months later. The MMSE-KC scores showed significant changes in both groups that developed depression and did not. In the univariate analysis, significant differences in the incidence of depression were found in terms of gender, the administration of the antidepressant at the baseline, the SGDS-K score, and the GDS score. The multiple logistic regression analysis showed that the increase in the incidence of depression was associated with a female, in the increase in SGDS-K score and the GDS score. Conclusion The incidence of depression in the subjects who completed the 12-month follow-up observation was 13.29%. Moreover, in the multivariate analysis, a female gender and the severity of dementia, including the overall functions, seemed associated with the occurrence of depression.