자살 행동과 연관된 생물학적, 유전적 예측인자

김용구,Kim, Yong-Ku 대한생물정신의학회 2005 생물정신의학 Vol.12 No.1

Most suicides(about 90%) occur in the context of psychiatric disorders. Prediction of suicide risk in patients with mental illness is very important in preventing suicide attempts. However, current approaches to predict suicidality are based on clinical history and have low specificity and biological markers are not yet included. Many studies have explored the association between different biological parameters and suicidality. Studies of cerebro-spinal fluid(CSF) demonstrated that 5-HIAA and HVA levels were lower in patients with a history of suicide. Platelet serotonin transporter and the 5-HT2 serotonin receptor have also been studied in relation to violence and suicide. Depressive patients with greater suicidal tendency had significantly lower cholesterol concentrations but some researchers failed to find the correlation. DST non-supression is reported to predict suicidality in major depression. Several studies demonstrated a relationship between intron 7 polymorphism of tryptophan hydroxylase and suicidal behavior. Since suicide is not occurred in a single disease, the systematic and comprehensive study in large samples with various diagnoses is necessary to find the biological and genetic predictors of suicidal behavior.

정신분열병 환자에서 인지기능 및 정신병적 증상의 상관관계

김용구,이정애,이소연,이분희,한창수,Kim, Yong-Ku,Lee, Jung-Ae,Lee, So-Youn,Lee, Bun-Hee,Han, Chang-Su 대한생물정신의학회 2006 생물정신의학 Vol.13 No.3

Objectives : The purpose of this study was to investigate whether the cognitive functions would be correlated with psychotic symptoms and whether antipsychotic treatments would affect the cognitive functions after 8 weeks. Methods : The thirty-five schizophrenic patients were conducted in this study. The psychopathology was measured using PANSS. The memory function, executive function, and sustained attention were measured using Memory Assessment Scale(MAS), Wisconsin Card Sorting Test(WCST), and Vigilance(VIG) and Cognitrone(COG) in Vienna Test System. After 8 weeks of antipsychotic treatment, we retested the cognitive tests. Results : 1) The cognitive tests after the 8 week's treatment showed significant improvements in memory and executive function in the schizophrenic patients. On the other side, sustained attention did not show improvement. 2) The change of PANSS were correlated with perseverative response, perseverative error and total correct in WCST at baseline. WCST scores at baseline were correlated with negative symptoms, but not positive ones. Conclusion : These study suggests that 1) the impaired sustained attention could be a vulnerability marker in schizophrenia, 2) memory & executive function deficit could be reversible after treatment, and 3) medication might have a benefit in improving the cognitive functions in schizophrenia. Furthermore, the data supports that the better premorbid executive function was, the more favorable was the treatment response in schizophrenic patients. Finally, this study indicates that executive function might be an index of treatment improvement.

자살 : 유전자-환경 상호작용

김용구,Kim, Yong-Ku 대한생물정신의학회 2010 생물정신의학 Vol.17 No.2

Gene-environment interactions are important in pathogenesis of suicide or suicidal behavior. Twin and adoption studies and family studies show that genetic factors play a critical role in suicide or suicidal behavior. Given the strong association between serotonergic neurotransmission and suicide, recent molecular genetic studies have focused on polymorphisms of serotonin genes, especially on serotonin transporter and tryptophan hydroxylase genes. Some studies have revealed a significant interaction between s allele of the serotonin transporter gene and the risk of suicide attempt associated with childhood trauma. In addition, the polymorphism of brain-derived neurotrophic factor gene also may influence the effect of childhood trauma in relation to the risk of attempting suicide. Future studies should explore genetic and environmental factors in suicide or suicidal behavior and examine for gene and environment interaction.

남자 정신분열증 환자에서 혈청 Interlenkin-2 농도의 증가

김용구,김사준,이민수,Kim, Yong-Ku,Kim, Sa-Jun,Lee, Min-Soo 대한생물정신의학회 1996 생물정신의학 Vol.3 No.1

We have previously reported that Korean schizophrenic patients hove low production of IL-2 in vitro suggestive of autoimmunity to the pathogenesis of the disorder. In an attempt to further explore this issue, we measured in vivo serum levels of interleukins(IL-$1{\beta}$, IL-2, and IL-6) using a quantitative "sandwich" enzyme immunoassay(ELISA) in 26 male schizophrenic patients and in 26 age-matched normal controls. Patients met DSM-IV criteria for schizophrenia and were drug free for at least six months. The severity of symptoms was assessed by SANS and SAPS. We found a significant increase of IL-2 level(p<0.05) in schizophrenic patients as compared with normal controls. There were significant positive correlations between IL-2, IL-6 levels and negative symptom scores. There were no correlations between age, age at onset, duration of illness and interleukin levels. Our results may support the hypothesis of viral-autoimmune dysfunction in schizophrenia. IL-2 or IL-6 may be associated with specific clinical feature in schizophrenic syndrome, especially negative symptom. 정신분열증에서 interleukin의 변화는 그 질환에서의 면역학적 가설의 부가적인 증거로 제시되어 왔다. 본 연구에서는 quantitative "sandwich" ELISA 법을 이용하여 26명의 정신분열증 환자를 대상으로 연령을 상응시킨 정상대조군과 비교해 IL-$1{\beta}$, IL-2, IL-6 농도의 차이가 있는지 알아보았다. 또한 정신분열증 환자에서 IL농도와 양성증상 및 음성증상, 연령, 유병기간 등의 임상변인과의 상관관계를 조사하여 다음과 같은 결론을 얻었다. 1) 정신분열증군이 정상대조군보다 IL-2 농도의 유의한 중가를 나타내었으며, IL-$1{\beta}$와 IL-6는 유의한 차이가 없었다. 2) 정신분열증군에서 IL-2, IL-6와 음성증상간의 유의한 상관관계가 있었다. 본 연구는 정신분열증의 연역학적 가설을 지지하고 있으며, IL은 정신분열증의 음성증상에 관련된다고 생각된다. 앞으로 국내에서도 이러한 환자들의 임상적 특징, 진단, 치료에 관심을 갖아야 할 것으로 사료된다.

주요우울증에서 스트레스, 염증반응, 신경조직발생

김용구,Kim, Yong-Ku 대한생물정신의학회 2011 생물정신의학 Vol.18 No.4

Stress, a risk factor of major depression induces cytokine mediated inflammation and decreased neurogenesis. In patients with major depression, significant increases of pro-inflammatory cytokines have been consistently reported. The pro-inflammatory cytokines can stimulate the hypothalamic-pituitary-adrenal (HPA) axis to release glucocorticoids. In the brain, microglia and play a role of immune activation in response to stress. Increased pro-inflammatory cytokine play a role in restricting neurogenesis in the brain. Although neurogenesis may not be essential for the development of depression, it may be required for clinically effective antidepressant treatment. Hence, stimulation of neurogenesis is regarded as a promising strategy for new antidepressant targets. This review introduces changes in neurotransmitter, cytokine and neurogenesis in major depression and explores the possible relationship between pro-inflammatory cytokines and neurogenesis related to stress in major depression.

치료저항성 우울증의 연구에서 패러다임의 전환

김용구,Kim, Yong-Ku 대한생물정신의학회 2016 생물정신의학 Vol.23 No.2

Treatment-resistant depression (TRD) is a major public health problem. It is estimated that about 30% of patients with major depressive disorder do not show substantial clinical improvement to somatic or psychosocial treatment. Most of studies for TRD have focused on the subjects already known as TRD. Patients with unipolar depressive episodes that do not respond satisfactorily to numerous sequential treatment regimens were included in the TRD studies. Such post hoc experimental design can be regarded only as consequences of having TRD, rather than as causal risk factors for it. Although informative, data derived from such studies often do not allow a distinction to be made between cause and effect. So, we should shift paradigm toward examining the risk for developing TRD in untreated depressed patients. To deal with this problem, untreated depressed patients should be enrolled in the study to identify biological markers for treatment resistance. The peripheral or central biological markers should be explored before starting treatment. Subsequent systematic administration of treatments with appropriate monitoring in the subjects can determine the risk for developing treatment resistance in untreated individuals. Such information could give a cue to improve the initial diagnosis and provide more effective treatment for TRD.

미래의 항우울제:어떠한 것들이 개발되고 있는가?

김용구,Kim, Yong-Ku 대한생물정신의학회 2004 생물정신의학 Vol.11 No.1

The current understanding of the mechanisms of pharmacotherapy for depression is characterized by an emphasis on increasing synaptic availability of serotonin, noradrenaline, and possibly dopamine, while minimizing side effects. The acute effects of current available effective antidepressants include blocking selective serotonin or noradrenaline reuptake, alpha2 autoreceptors or monoamine oxidase. Although efficacious, current treatments often produce partial or limited symptomatic improvement rather than remission. While current pharmacotherapies target monoaminergic systems, distinct neurobiological underpinnings and other systems are likely involved in the pathogenesis of depression. Recently, several promising hypotheses of depression and antidepressant action have been formulated. These hypotheses are largely based on dsyregulation of neural plasticity, CREB, BDNF, corticotropin-releasing factor, glucocorticoid, hypothalamic-pituitary adrenal axis and cytokines. Based on these new theories and hypotheses of depression, a number of new and novel agents, including corticotropin-releasing factor antagonists, antiglucocorticoids, and substance P antagonists show a considerable promise for refining treatment options for depression. In this article, the current available pharmacotherapies, current understanding of neurobiology and pathogenesis of depression and new and promising directions in pharmacological research on depression will be discussed.

자살을 시도한 정신과 환자에서 낮은 혈청 콜레스테롤 농도와 심각한 자살 수행과의 연관성

김용구,이헌정,김지연,최소현,이민수,Kim, Yong Ku,Lee, Heon Jeong,Kim, Ji Yeon,Choi, So Hyun,Lee, Min Soo 대한생물정신의학회 1999 생물정신의학 Vol.6 No.2

자살 시도군 231명, 환자 대조군 231명, 정상대조군 231명을 대상으로 혈청 콜레스테롤 농도를 측정하여 다음의 결과를 얻었다. 1) 자살 시도군이 환자대조군 혹은 정상대조군보다 혈청 콜레스테롤 농도의 유의한 저하를 보였다. 2) 진단별로는 우울증과 인격장애에서 자살 시도군이 환자대조군보다 콜레스테롤 농도의 유의한 저하를 보였으나, 정신분열병과 양극성 정동장애 조증형에선 차이가 없었다. 3) 자살 시도군의 남녀별로 비교시, 남자가 여자보다 콜레스테롤 농도의 유의한 저하를 보였으며, 진단별로는 우울증에서만 유의한 차이를 보였다. 4) 자살 시도군에서 낮은 콜레스테롤 농도는 심각한 자살 수행과 연관성이 있었다. 5) 자살 시도군에서 치료전에 비해 치료후 혈청 콜레스테롤 농도의 유의한 증가를 보였다. 본 연구의 결과는 자살 시도의 예측인자로서 혈청 콜레스테롤이 이용될 수 있음을 시사한다. 향후 콜레스테롤 농도에 미치는 변인들을 통제한 전향적 방법을 통해 원인적 측면에서 혈청 콜레스테롤 농도와 세로토닌, 인터루킨-2, 멜라토닌 간의 연관성에 관한 연구가 이루어져야 하겠다. An association of low total cholesterol in blood with psychiatric diseases and suicidal behavior has been suggested. As part of an attempt to further explore this relationship, we examine first, whether serum cholesterol levels in psychiatric patients with suicidal attempt would be lower than in non-suicidal psychiatric inpatients or normal controls, second, whether such significant difference of cholesterol levels would be present when the diagnostic groups are analyzed separately, third, whether low cholesterol level would be associated with a history of serious suicidal attempts, and finally, whether low cholesterol level in suicide attempters is a state or a trait marker. We determined the serum cholesterol levels in 231 patients admitted to an emergency room following an suicidal attempt, in the same numbers of age-, sex- and diagnosis- matched non-suicidal psychiatric controls, and in the same numbers of age-, sex matched normal controls. The seriousness of an attempt was divided into 5 grades according to the degree of the resulting medical injury. Total cholesterol levels in suicide attempters were significantly lower compared with both psychiatric and normal controls, when sex, age, and nutritional status (i.e., body mass index) were controlled for. This significant relationship was observed in major depressive disorders and personality disorders, but not in schizophrenia and bipolar type I disorders. The severity of suicide by a lowering of blood cholesterol was related to the magnitude of the cholesterol reduction. After treatment of their psychiatric ailments, the cholesterol levels in suicide attempters were significantly increased. This result suggests that low cholesterol level in psychiatric patients might be a potential biological marker of suicide risk. It is hypothesized that low cholesterol levels is associated with the suicide by modifying the serotonin metabolism, the production of interleukin-2 and melatonin metabolism in psychiatric patients.

정신분열증 환자에서 혈장 HVA 및 5-HIAA 농도와 정신병리와의 상관성

김용구,박성근,김인,이민수,Kim, Yong-Ku,Park, Sung-Geun,Kim, Leen,Lee, Min-Soo 대한생물정신의학회 1997 생물정신의학 Vol.4 No.1

The recent hypothesis about the pathophysiology of schizophrenia has been centered mainly on two theories, i.e. dopamine hypothesis and serotonin hypothesis. We investigate the correlations between plasma monoamine metabolite concentrations and clinical symptoms in schizophrenic patients. The first purpose of our study was to examine whether the plasma levels of HVA(homovanillic acid) and 5-HIAA(hydroxyindoleacetic acid) are significantly different in schizophrenics, compared to normal controls. And, with the intention of clarifying the interaction between dopaminergic system and serotoninergic system, the ratio of HVA/5-HIAA also was measured. The second purpose was whether the basal(pre-treatment) levels of these metabolites show the correlation with clinical symptoms. Finally, third purpose was whether basal HVA and 5-HIAA levels can be held as a predictor of treatment response. We used Scale for the Assessment of Positive Symptoms(SAPS) and Scale for the Assessment of Negative Symptoms(SANS) as the clinical symptom rating scales. Our results were as followed, 1) only the level of basal plasma HVA was significantly differ in schizophrenics. 5-HIAA and HVA/5-HIAA were not. 2) basal HVA showed significant correlation with SAPS score, especially delusion subscale. 3) the higher was the basal HVA level, the more improvement in clinical symptoms was observed. The basal 5-HIAA level and the HVA/5-HIAA ratio did not show any significant findings. These results support the dopamine hypothesis of schizophrenia, but fail to examine on the possible involvement of serotonin in schizophrenia.

우울증의 새로운 신경생물학

김용구,Kim, Yong Ku 대한생물정신의학회 2001 생물정신의학 Vol.8 No.1

Recent basic and clinical studies demonstrate a major role for neural plasticity in the etiology and treatment of depression and stress-related illness. The neural plasticity is reflected both in the birth of new cell in the adult brain(neurogenesis) and the death of genetically healthy cells(apoptosis) in the response to the individual's interaction with the environment. The neural plasticity includes adaptations of intracellular signal transduction pathway and gene expression, as well as alterations in neuronal morphology and cell survival. At the cellular level, repeated stress causes shortening and debranching of dendrite in the CA3 region of hippocampus and suppress neurogenesis of dentate gyrus granule neurons. At the molecular level, both form of structural remodeling appear to be mediated by glucocorticoid hormone working in concert with glutamate and N-methyl-D-aspartate(NMDA) receptor, along with transmitters such as serotonin and GABA-benzodiazepine system. In addition, the decreased expression and reduced level of brain-derived neurotrophic factor(BDNF) could contribute the atrophy and decreased function of stress-vulnerable hippocampal neurons. It is also suggested that atrophy and death of neurons in the hippocampus, as well as prefrontal cortex and possibly other regions, could contribute to the pathophysiology of depression. Antidepressant treatment could oppose these adverse cellular effects, which may be regarded as a loss of neural plasticity, by blocking or reversing the atrophy of hippocampal neurons and by increasing cell survival and function via up-regulation of cyclic adenosine monophosphate response element-binding proteins(CREB) and BDNF. In this article, the molecular and cellular mechanisms that underlie stress, depression, and action of antidepressant are precisely discussed.