The Role of Neurotrophic Factors in Pathophysiology of Major Depressive Disorder.

According to the neurotrophic hypothesis of major depressive disorder (MDD), impairment in growth factor signaling might be associated with the pathology of this illness. Current evidence demonstrates that impaired neuroplasticity induced by alterations of neurotrophic growth factors and related signaling pathways may be underlying to the pathophysiology of MDD. Brain-derived neurotrophic factor (BDNF) is the most studied neurotrophic factor involved in the neurobiology of MDD. Nevertheless, developing evidence has implicated other neurotrophic factors, including neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), nerve growth factor (NGF), vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF), glial cell-derived neurotrophic factor (GDNF), and fibroblast growth factor (FGF) in the MDD pathophysiology. Here, we summarize the current literature on the involvement of neurotrophic factors and related signaling pathways in the pathophysiology of MDD.

The role of CREB and BDNF in neurobiology and treatment of Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia worldwide. ß-amyloid peptide (Aß) is currently assumed to be the main cause of synaptic dysfunction and cognitive impairments in AD, but the molecular signaling pathways underlying its neurotoxic consequences have not yet been completely explored. Additional investigations regarding these pathways will contribute to development of new therapeutic targets. In context, developing evidence suggest that Aß decreases brain-derived neurotrophic factor (BDNF) mostly by lowering phosphorylated cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) protein. In fact, it has been observed that brain or serum levels of BDNF appear to be beneficial markers for cognitive condition. In addition, the participation of transcription mediated by CREB has been widely analyzed in the memory process and AD development. Designing pharmacologic or genetic therapeutic approaches based on the targeting of CREB-BDNF signaling could be a promising treatment potential for AD. In this review, we summarize data demonstrating the role of CREB-BDNF signaling pathway in cognitive status and mediation of Aß toxicity in AD. Finally, we also focus on the developing intervention methods for improvement of cognitive decline in AD based on targeting of CREB-BDNF pathway.

Evidence for additionally increased apoptosis in the peripheral blood mononuclear cells of major depressive patients with a high risk for suicide.

Several studies have suggested a pathophysiological role of blood cell apoptosis in major depressive disorder (MDD). The aim of this study was to evaluate mRNA expression levels of Bcl-2, Bax, and Fas in peripheral blood mononuclear cells (PBMCs) of MDD patients with a high risk for suicide relative to those without a high risk for suicide as well as healthy subjects. The mRNA expression of Bcl-2, Bax, and Fas as well as the Bcl-2/Bax ratio was examined in the PBMCs of 30 MDD patients with a high risk for suicide, 30 MDD patients without a high risk for suicide, and 30 healthy controls. The mRNA expression of target genes was measured using real-time quantitative Polymerase Chain Reaction (PCR). FAS mRNA expression was significantly increased, and Bcl-2 mRNA expression and the Bcl-2/Bax expression ratio were significantly decreased, in the PBMCs of MDD patients with or without a high risk for suicide attempts compared to healthy controls (p < .001). However, Bax mRNA expression was significantly increased only in MDD patients with a high risk for suicide. Moreover, MDD patients with a high risk for suicide had increased Bax and FAS mRNA expression and decreased Bcl-2 and Bcl-2/Bax ratio when compared to patients without risk for suicide (p < .001). Our findings may support the role of both internal and external apoptotic pathways in the interplay between the immune system and depressive symptoms, especially in patients with a high risk for suicide.

Unresolved Issues for Utilization of Atypical Antipsychotics in Schizophrenia: Antipsychotic Polypharmacy and Metabolic Syndrome.

Atypical antipsychotics (AAP) are the prevailing form of schizophrenia treatment today due to their low side effects and superior efficacy. Nevertheless, some issues still need to be addressed. First, there are still a large number of patients with treatment-resistant schizophrenia (TRS), which has led to a growing trend to resort to AAP polypharmacy with few side effects. Most clinical treatment guidelines recommend clozapine monotherapy in TRS, but around one third of schizophrenic patients fail to respond to clozapine. For these patients, with clozapine-resistant schizophrenia AAP polypharmacy is a common strategy with a continually growing evidence base. Second, AAP generally have great risks for developing metabolic syndrome, such as weight gain, abnormality in glucose, and lipid metabolism. These metabolic side effects have become huge stumbling blocks in today's schizophrenia treatment that aims to improve patients' quality of life as well as symptoms. The exact reasons why this particular syndrome occurs in patients treated with AAP is as yet unclear though factors such as interaction of AAP with neurotransmitter receptors, genetic pholymorphisms, type of AAPs, length of AAP use, and life style of schizophrenic patients that may contribute to its development. The present article aimed to review the evidence underlying these key issues and provide the most reasonable interpretations to expand the overall scope of antipsychotics usage.

The G allele in IL-10-1082 G/A may have a role in lowering the susceptibility to panic disorder in female patients.

BACKGROUND: Immune system activation is involved in the pathophysiology of panic disorder (PD). We investigated INF-γ+874 A/T, TNF-α-308 G/A, and IL-10-1082 G/A single nucleotide polymorphisms (SNPs) to determine their association with PD. METHOD: This study enroled 135 PD patients and 135 healthy controls. INF-γ+874 A/T (rs2430561), TNF-α-308 G/A (rs1800629), and IL-10-1082 G/A (rs1800896) were genotyped. RESULTS: There were no differences in genotypes or allele frequencies between the patient and control groups, regardless of accompanying agoraphobia. However, for female patients, the G allele frequency in IL-10 SNP was higher in the control group than in the patient group. Additionally, the female control group had a higher frequency of the A/G and G/G genotype in the IL-10 SNP than the female patient group. CONCLUSION: We suggest that the G allele in IL-10-1082 G/A might have a role in reducing the manifestations of PD in female patients. Further studies are needed to extend and confirm our findings.

Predicting the mortality from asbestos-related diseases based on the amount of asbestos used and the effects of slate buildings in Korea.

Asbestos has been used since ancient times, owing to its heat-resistant, rot-proof, and insulating qualities, and its usage rapidly increased after the industrial revolution. In Korea, all slates were previously manufactured in a mixture of about 90% cement and 10% chrysotile (white asbestos). This study used a Generalized Poisson regression (GPR) model after creating databases of the mortality from asbestos-related diseases and of the amount of asbestos used in Korea as a means to predict the future mortality of asbestos-related diseases and mesothelioma in Korea. Moreover, to predict the future mortality according to the effects of slate buildings, a comparative analysis based on the result of the GPR model was conducted after creating databases of the amount of asbestos used in Korea and of the amount of asbestos used in making slates. We predicted the mortality from asbestos-related diseases by year, from 2014 to 2036, according to the amount of asbestos used. As a result, it was predicted that a total of 1942 people (maximum, 3476) will die by 2036. Moreover, based on the comparative analysis according to the influence index, it was predicted that a maximum of 555 people will die from asbestos-related diseases by 2031 as a result of the effects of asbestos-containing slate buildings, and the mortality was predicted to peak in 2021, with 53 cases. Although mesothelioma and pulmonary asbestosis were considered as asbestos-related diseases, these are not the only two diseases caused by asbestos. However the results of this study are highly important and relevant, as, for the first time in Korea, the future mortality from asbestos-related diseases was predicted. These findings are expected to contribute greatly to the Korean government's policies related to the compensation for asbestos victims.

Alterations in plasma vascular endothelial growth factor levels in patients with schizophrenia before and after treatment.

Vascular endothelial growth factor (VEGF), a potent angiogenetic factor, is a known neurotrophic factor. In this study, we examined plasma levels of VEGF in 50 patients with schizophrenia (SPR) and 50 healthy control subjects. We also explored any changes in plasma VEGF levels after 6-week treatment with antipsychotic agents in patients with schizophrenia. All subjects with schizophrenia were either medication-naïve or medication-free for at least 4 weeks before assessment. Plasma VEGF levels in all subjects were significantly correlated with smoking duration, which was considered to be a significant covariate. Pre-treatment plasma VEGF levels in patients with schizophrenia were significantly lower than those in healthy controls. Post-treatment VEGF levels were significantly increased in patients with schizophrenia. Plasma VEGF levels in patients with schizophrenia did not exhibit significant correlation with the total or subscale scores of the Positive and Negative Syndrome Scale (PANSS) either at baseline or at the end of the 6-week treatment. In conclusion, our findings reveal that plasma VEGF levels before treatment were lower in patients with schizophrenia and that their VEGF levels increased after treatment. Thus, VEGF may have a neuroprotective role in the improvement of schizophrenia or in the treatment effects of antipsychotics.

Bayesian Variable Selection under the Proportional Hazards Mixed-effects Model.

Over the past decade much statistical research has been carried out to develop models for correlated survival data; however, methods for model selection are still very limited. A stochastic search variable selection (SSVS) approach under the proportional hazards mixed-effects model (PHMM) is developed. The SSVS method has previously been applied to linear and generalized linear mixed models, and to the proportional hazards model with high dimensional data. Because the method has mainly been developed for hierarchical normal mixture distributions, it operates on the linear predictor under the Cox type models. The PHMM naturally incorporates the normal distribution via the random effects, which enables SSVS to efficiently search through the candidate variable space. The approach was evaluated through simulation, and applied to a multi-center lung cancer clinical trial data set, for which the variable selection problem was previously debated upon in the literature.

Network beyond IDO in psychiatric disorders: revisiting neurodegeneration hypothesis.

The involvement of immune system activation in the pathophysiology of certain psychiatric disorders is well documented. Inflammatory molecules such as pro-inflammatory cytokines could enhance the activity of the indoleamine 2,3-dioxygenase (IDO) enzyme which is the first rate-limiting enzyme of the tryptophan degradation pathway, the kynurenine pathway. The increased tryptophan degradation could induce serotonin depletion and depressive mood. On the other hand, the downstream metabolites from this pathway, such as 3-hydroxykynurenine, quinolinic acid and kynurenic acid, are neuroactive metabolites which can modulate several neurotransmissions, such as glutamatergic, GABAergic, dopaminergic and noradrenergic neurotransmissions, which in turn induce changes in neuronal-glial network and neuropsychiatric consequences. In this issue, we have revised the previous 'neurodegeneration hypothesis,' which explained the involvement of cytokines and IDO pathway interaction in depression, with a further extended view related to the network beyond IDO, the network between immune molecules, tryptophan metabolites and different neurotransmitters, in depression and other major psychiatric disorders such as schizophrenia, bipolar disorder and childhood psychiatric disorders.

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.

Plasma Levels of IL-23 and IL-17 before and after Antidepressant Treatment in Patients with Major Depressive Disorder.

OBJECTIVE: Cytokines are believed to have a role in the pathophysiology of major depression. The alteration in levels of pro-inflammatory cytokines [interleukin 1ß (IL-1ß), IL-2, IL-6, IL-12, interferon γ, and tumor necrosis factor α] in major depression supports the cytokine hypothesis of this illness. IL-23 and IL-17 are also pro-inflammatory cytokines, but few studies have focused on their role in major depression. This study investigated the potential role of the IL-23 and IL-17 axis in major depression. METHODS: Plasma IL-23 and IL-17 levels were measured in 26 major depressive disorder (MDD) patients before and after 6-week treatment with antidepressants; these levels were measured in 28 age- and sex-matched normal controls. Depression severity was assessed using the Hamilton Depression Rating Scale (HDRS). IL-23 and IL-17 plasma levels were estimated using quantitative enzyme-linked immunosorbent assay. RESULTS: Pre-treatment plasma levels of IL-23 and IL-17 in MDD patients were not significantly different from those of normal controls. In MDD patients, IL-23 and IL-17 levels after 6 weeks of antidepressant treatment were not different from the baseline levels. There was no significant correlation between changes in the cytokine levels and changes in the HDRS scores representing the severity of depression. CONCLUSION: The present study does not support a potential involvement of IL-23 and IL-17 axis in major depression. Replication and extension using a larger sample are required.

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.

Increased plasma VEGF levels in major depressive or manic episodes in patients with mood disorders.

BACKGROUND: The neurotrophic hypothesis suggests that mood disorders are associated with dysfunction of neuronal networks under the influence of neurotrophic factors. Vascular endothelial growth factor (VEGF) is a neurotrophic factor as well as an angiogenic cytokine. METHODS: We examined plasma VEGF levels in 35 unipolar patients who were diagnosed with current major depressive disorder (MDD), 35 bipolar patients who were diagnosed with bipolar I disorder, manic episode (BM), and 60 healthy controls. The severity of depressive or manic symptoms was measured using the Hamilton Depression Rating Scale (HDRS) or the Young Mania rating scale (YMRS), respectively. RESULTS: Plasma VEGF levels were 163.28±135.33 pg/mL in MDD patients, 199.82±182.59 pg/mL in BM patients, and 110.05±109.57 pg/mL in healthy controls. Both MDD and BM patients had significantly higher VEGF levels than healthy controls when controlling for BMI as a covariate (p=0.010). Patients' VEGF levels were not correlated with either HDRS or YMRS scores. LIMITATIONS: We assessed plasma VEGF levels at one time point, and we did not determine the source of VEGF in our samples. CONCLUSIONS: Plasma VEGF levels were elevated in patients with acute episodes of major depressive disorder and bipolar disorder. Such an alteration of VEGF in acute episode, mood disorders may be associated with a neuroprotective role for VEGF.

Role of cytokines in atypical depression.

BACKGROUND: Atypical depression (AD) is considered a biologically and psychologically distinct subtype of depression. AD, contrary to melancholic depression (MD), may have different alteration in cytokine activity. AIMS: We aimed to investigate the differences of cytokine activity between AD patients and MD patients. Among psychiatric patients visited to the Psychiatry Department, Korea University Medical Center, 105 patients with major depression who met the Diagnostic and Statistical Manual (DSM-IV) criteria based on clinical interviews using a Structured Clinical Interview for DSM-IV were recruited. Among 105 patients, 35 patients had atypical feature. We measured in vitro cytokines (interleukins) IL-2, IL-4, IL-6 and tumor necrosis factor-α (TNF-α). RESULTS: Decreased IL-4 and increased IL-2 was observed in AD patients. IL-6 and TNF-α level of AD patients showed no difference from the controls. CONCLUSIONS: Contrary to MD, AD has reversed vegetative symptoms, i.e. hypersomnia and hyperphagia. It is assumed that the phenotype difference between AD and MD might be related to Th1 cytokines (IL-2) and Th2 cytokines (IL-4) and not related to monocytic cytokines (IL-6, and TNF-α).

Cytokine changes and tryptophan metabolites in medication-naïve and medication-free schizophrenic patients.

Cytokine imbalances especially between T helper type (Th) 1 and Th2 and tryptophan breakdown were reported to be involved in the pathophysiology of schizophrenia. The hyperactive inflammatory response system could induce enhanced tryptophan breakdown. This study aimed to investigate the relationship between cytokine changes, tryptophan breakdown parameter changes and clinical parameters in patients with schizophrenia in comparison with normal controls. In the plasma of schizophrenic patients, Th1-specific interferon-gamma was significantly higher (F = 7.485, p = 0.007) and Th2-specific interleukin (IL)-4 was significantly lower (F = 126.327, p < 0.0001). The Th1-related cytokine IL-2 was lower (F = 5.409, p = 0.021) but tumor necrosis factor-alpha (TNF-alpha) and Th2-related IL-6 were higher (F = 95.004, p < 0.0001 and F = 408.176, p < 0.0001, respectively) in the plasma of schizophrenic patients. After 6 weeks of treatment, IL-6 and TNF-alpha were significantly reduced (t = -3.762, p < 0.0001 and z = -2.668, p = 0.008). At the time of admission, plasma tryptophan concentrations were lower (F = 6.339, p = 0.012) in schizophrenic patients and were negatively correlated with the total positive symptoms score (r(2) = -0.343, p = 0.004). After 6 weeks of medication, both plasma tryptophan and kynurenine concentrations were increased (t = -2.937, p = 0.005 and t = -3.214, p = 0.002, respectively). The findings of this study indicate a hyperactive pro-inflammatory response inducing a change in tryptophan metabolism that might be related to the development of positive symptoms in schizophrenia.

Monocytic, Th1 and th2 cytokine alterations in the pathophysiology of schizophrenia.

A growing body of evidence suggests that changes in the serum levels and cellular production of various cytokines are associated with the immunological abnormalities of schizophrenia. Several studies have examined alterations in T helper type 1 (Th1) and T helper type 2 (Th2) cytokines in schizophrenia. We explored monocytic, Th1 and Th2 cytokines in 43 schizophrenia patients and 50 normal controls. The mitogen-induced production of tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), IL-4, gamma-interferon (IFN-gamma) and IL-2 was measured with enzyme-linked immunosorbent assays before and after antipsychotic treatment. IL-6 and TNF-alpha production by schizophrenic patients was significantly higher than by normal controls, while IL-2, IL-4 and IFN-gamma production was significantly lower in schizophrenic patients. After 6 weeks of antipsychotic treatment, IL-6 and TNF-alpha production was significantly decreased, while IL-4, IFN-gamma and IL-2 productions were not significantly changed. Our results suggest that increased monocytic cytokines and decreased Th1 and Th2 cytokines may be associated with the immunopathogenesis of acute psychotic schizophrenia, and that antipsychotics may play an important role in immune response by decreasing elevated monocytic cytokines.

Increased plasma brain-derived neurotrophic factor levels in chronic smokers following unaided smoking cessation.

Recent animal studies have suggested an association between nicotine and alterations in brain-derived neurotrophic factor (BDNF) expression levels. However, the role of BDNF in humans with nicotine dependence has not yet been investigated. In this study, we explored the differences in the plasma BDNF levels of chronic smokers and healthy nonsmokers, and we investigated the changes in plasma BDNF levels in chronic smokers following unaided smoking cessation. Forty voluntary participants (20 smokers and 20 nonsmokers) were enrolled in this study. We measured the plasma BDNF levels at baseline (both groups) and at the end of the two-month study period (smoker group only) using an enzyme-linked immunosorbent assay. A total of 12 smokers (60.0%) completed the two-month study. ANCOVA with age and body mass index as covariates showed that the baseline plasma BDNF levels in smokers were significantly lower than those in nonsmokers (F=4.626, p=0.038). The plasma BDNF levels in the smokers significantly increased from baseline after the two-month smoking cessation period (Z=-3.059, p=0.002). These findings suggest that BDNF may play a role in the pathophysiology of smoking behavior.

Imbalance between pro-inflammatory and anti-inflammatory cytokines in bipolar disorder.

BACKGROUND: The role of cytokines in bipolar disorder is still controversial. Although a few studies have found alterations of cytokines in bipolar disorder, their findings were inconsistent. The aim of this study was to determine whether the cytokines are involved in the pathophysiology of bipolar disorder. METHODS: A total of 37 manic patients with bipolar disorder and 74 control subjects were recruited. The mitogen-induced production of tumor necrosis factor (TNF)-alpha, interleukin-6 (IL-6), IL-4, interferon (IFN)-gamma, and IL-2 was measured using quantitative sandwich ELISA at the time of admission and 6 weeks after mood stabilizer treatment. RESULTS: IL-6 and TNF-alpha production of bipolar manic patients was significantly higher than those of normal controls, while IL-4 values of the patients were significantly lower than normal controls. IL-6/IL-4, TNF-alpha/IL-4, IL-2/IL-4, and IFN-gamma/IL-4 ratios were significantly higher in bipolar manic patients than in normal controls. After 6 weeks of treatment, the levels of IL-6 significantly decreased compared with baseline. LIMITATIONS: The effect of various types of mood stabilizers on cytokine production should be considered. CONCLUSIONS: These findings suggest that the increased activity of pro-inflammatory cytokines and an imbalance between pro-inflammatory and anti-inflammatory cytokines may play a role in the pathophysiology of bipolar disorder.

Cytokine imbalance in the pathophysiology of major depressive disorder.

OBJECTIVE: A substantial body of evidence indicates that dysregulation of the immune system is associated with Major Depressive Disorder (MDD). Because most cytokines have pleiotropic effects, we measured various subsets of cytokines to examine the association between immune response and MDD. METHODS: Forty-eight hospitalized MDD patients and 63 normal controls were recruited. We measured in vitro monocytic (IL-6 and tumor necrosis factor (TNF)-alpha), Th1 (interferon (IFN)-gamma and interleukin (IL)-2), Th2 (IL-4), and Treg (transforming growth factor (TGF)-beta1) cytokine production as well as IL-2/IL-4 and IFN-gamma/IL-4 ratios for both groups. Depressive symptoms were assessed by Hamilton Depression Rating Scale. Patients were evaluated before and after 6 weeks of antidepressant treatment. RESULTS: At admission, IL-6, TNF-alpha, TGF-beta1 production, and IFN-gamma/IL-4 ratio were significantly higher, whereas IFN-gamma, IL-2, and IL-4 were significantly lower in MDD patients. After treatment, IL-6 and TGF-beta1 production were significantly lower than before treatment. CONCLUSION: We suggest that activation of monocytic proinflammatory cytokines, and inhibition of both Th1 and Th2 cytokines may be associated with immunological dysregulation in MDD. TGF-beta1 may be associated with the regulation of monocytic cytokines as well as Th1 and Th2 cytokines in MDD.

Th1, Th2, and Th3 cytokine alterations in major depression.

BACKGROUND: Many studies have shown that the balance between Th1 cytokines and Th2 cytokines plays a role in modulation of cellular responses in the brain during psychological stress and psychiatric disorders. The Th3 cytokine, transforming growth factor beta-1 (TGF-beta1), has been shown to regulate the balance between Th-1 and Th-2 cytokines. However, the role of TGF-beta1 in the psychoimmunology of depression has never been explored. METHODS: A total of 40 depressed patients and 80 normal controls were recruited. The plasma levels of IFN-gamma, IL-4, and TGF-beta1 were studied at the time of admission and 8 weeks after antidepressant treatment. RESULTS: The proportion of patients who showed immunoreactivity to IFN-gamma and IL-4 in the plasma, and the plasma IFN-gamma/IL-4 ratio, were significantly higher in depressed patients than in controls. The IFN-gamma/TGF-beta1 ratio was also higher in depressed patients, and TGF-beta1 levels showed a significant negative correlation with the HDRS depression scale. After treatment, TGF-beta1 level increased significantly, and the IFN-gamma/IL-4 ratio decreased significantly, in the patient group. However, Th1 changes in male and female showed different trend such as Th1 arm was decreased after the treatment in all male, whereas it was increased in premenopausal age women. LIMITATIONS: Replication and extension using a larger sample size are required. CONCLUSIONS: The Th1 and Th2 cytokine imbalance was observed in subpopulation of depressed patients. TGF-beta1 seemed to play a role in the pathophysiology of depression in this population. Moreover, antidepressant treatment was found to affect the Th1/Th2 balance through the action of TGF-beta1.