Prefrontal cortex activities during verbal fluency and emotional words tasks in major depressive, adjustment, and bipolar disorders with depressive states.

BACKGROUND: It can be difficult to differentiate psychiatric disorders from depressive states, with little knowledge on how to differentiate them. This study aimed to evaluate changes in brain activity during cognitive and emotional tasks in patients with depressive state to help with differential diagnoses. METHODS: Sixty-two patients with depressive states [17 with adjustment disorder (AD), 27 with major depressive disorder (MDD), and 18 with bipolar disorder (BD)] and 34 healthy controls (HC) were recruited. We used a verbal fluency task (VFT) and emotional word tasks with happy and threat words. Functional near-infrared spectroscopy measured the relative change in oxygenated hemoglobin in the frontotemporal areas. RESULTS: During the VFT, patients with AD or MDD showed significantly reduced activation in the bilateral frontotemporal region (all p < 0.01), whereas patients with BD demonstrated significantly reduced activation in the right frontotemporal areas compared to HC (p < 0.01). During the emotional words task with happy words, patients with MDD showed significantly increased activity in the frontopolar area compared to HC (p = 0.023). Binary logistic regression analysis showed that MDD or BD was significantly associated with brain activity during the happy word task. In distinguishing MDD or BD from HC, the happy words task performed equally well, with an area under the curve of 0.70. LIMITATIONS: All study patients were taking psychotropic drugs. CONCLUSIONS: Brain activation in response to a combination of cognitive or emotional stimuli could assist in distinguishing patients with depressive states from healthy controls.

Altered Connectivity of the Anterior Cingulate and the Posterior Superior Temporal Gyrus in a Longitudinal Study of Later-life Depression.

Patients with later-life depression (LLD) show abnormal gray matter (GM) volume, white matter (WM) integrity and functional connectivity in the anterior cingulate cortex (ACC) and posterior superior temporal gyrus (pSTG), but it remains unclear whether these abnormalities persist over time. We examined whether structural and functional abnormalities in these two regions are present within the same subjects during depressed vs. remitted phases. Sixteen patients with LLD and 30 healthy subjects were studied over a period of 1.5 years. Brain images obtained with a 3-Tesla magnetic resonance imaging (MRI) system were analyzed by voxel-based morphometry of the GM volume, and diffusion tensor imaging (DTI) and resting-state functional MRI were used to assess ACC-pSTG connectivity. Patients with LLD in the depressed and remitted phases showed significantly smaller GM volume in the left ACC and left pSTG than healthy subjects. Both patients with LLD in the depressed and remitted phases had significantly higher diffusivities in the WM tract of the left ACC-pSTG than healthy subjects. Remitted patients with LLD showed lower functional ACC-pSTG connectivity compared to healthy subjects. No difference was found in the two regions between depressed and remitted patients in GM volume, structural or functional connectivity. Functional ACC-pSTG connectivity was positively correlated with lower global function during remission. Our preliminary data show that structural and functional abnormalities of the ACC and pSTG occur during LLD remission. Our findings tentatively reveal the brain pathophysiology involved in LLD and may aid in developing neuroanatomical biomarkers for this condition.

Differences in frontotemporal dysfunction during social and non-social cognition tasks between patients with autism spectrum disorder and schizophrenia.

Although literature evidence suggests deficits in social and non-social cognition in patients with autistic spectrum disorder (ASD) and schizophrenia (SCZ), the difference in neural correlates of the impairments between the two disorders has not been elucidated. We examined brain function in response to a non-social cognition and a social cognition task using functional near-infrared spectroscopy (fNIRS) in 13 patients with ASD, 15 patients with SCZ, and 18 healthy subjects. We assessed the brain function of participants using a verbal fluency task and an emotional facial recognition task. The patients with ASD showed significantly reduced brain activation in the left frontotemporal area during both tasks compared to healthy subjects. The patients with ASD with larger score in 'attention to detail' in the autism spectrum quotient showed lower activation of the left frontotemporal area during the two tasks. The patients with SCZ showed significantly reduced activation, compared to healthy subjects, and greater activation, compared to patients with ASD, in the area during the verbal fluency task. The patients with SCZ with more severe symptoms had lower brain activation during the task in this area. Our results suggest that two distinct areas are involved in the distinctive brain pathophysiology relevant to cognitive processing in patients with ASD and SCZ.

Altered plasma protein glycosylation in a mouse model of depression and in patients with major depression.

BACKGROUND: Glycosylation is a common posttranslational modification in protein biosynthesis that is implicated in several disease states. It has been reported that specific protein glycan structures are useful as biomarkers for cancer and some neuropsychiatric diseases; however, the relationship between plasma protein glycosylation and major depressive disorder (MDD) has not been investigated to date. The aim of this study was to determine whether plasma protein glycan structures are altered in depression using a stress-based mouse model and samples from patients with MDD. METHODS: We used chronic ultra-mildly stressed mice that were untreated or treated with imipramine as mouse models of depression and remission, respectively. We also made comparisons between samples from depressed and remitted patients with MDD. Protein glycosylation was analyzed using a lectin microarray that included 45 lectins with binding affinities for various glycan structures. RESULTS: Sia-alpha2-6Gal/GalNAc was a commonly altered glycan structure in both depression model mice and patients with MDD. Moreover, the expression of ST6GALNAC2 was decreased in leukocytes from patients with MDD. LIMITATIONS: Our study samples were small and we did not identify specific alpha2-6Gal/GalNAc-sialylated proteins. CONCLUSIONS: The glycan structure Sia-alpha2-6GalNAc in plasma protein and ST6GALNAC2 expression in peripheral leukocytes may have utility as candidate biomarkers for the clinical diagnosis and monitoring of MDD.

Disconnectivity between Dorsal Raphe Nucleus and Posterior Cingulate Cortex in Later Life Depression.

The dorsal raphe nucleus (DRN) has been repeatedly implicated as having a significant relationship with depression, along with its serotoninergic innervation. However, functional connectivity of the DRN in depression is not well understood. The current study aimed to isolate functional connectivity of the DRN distinct in later life depression (LLD) compared to a healthy age-matched population. Resting state functional magnetic resonance imaging (rsfMRI) data from 95 participants (33 LLD and 62 healthy) were collected to examine functional connectivity from the DRN to the whole brain in voxel-wise fashion. The posterior cingulate cortex (PCC) bilaterally showed significantly smaller connectivity in the LLD group than the control group. The DRN to PCC connectivity did not show any association with the depressive status. The findings implicate that the LLD involves disruption of serotoninergic input to the PCC, which has been suggested to be a part of the reduced default mode network in depression.

Identification of commonly altered genes between in major depressive disorder and a mouse model of depression.

The heterogeneity of depression (due to factors such as varying age of onset) may explain why biological markers of major depressive disorder (MDD) remain uncertain. We aimed to identify gene expression markers of MDD in leukocytes using microarray analysis. We analyzed gene expression profiles of patients with MDD (age ≥50, age of depression onset <50) (N = 10, depressed state; N = 13, remitted state). Seven-hundred and ninety-seven genes (558 upregulated, 239 downregulated when compared to those of 30 healthy subjects) were identified as potential markers for MDD. These genes were then cross-matched to microarray data obtained from a mouse model of depression (676 genes, 148 upregulated, 528 downregulated). Of the six common genes identified between patients and mice, five genes (SLC35A3, HIST1H2AL, YEATS4, ERLIN2, and PLPP5) were confirmed to be downregulated in patients with MDD by quantitative real-time polymerase chain reaction. Of these genes, HIST1H2AL was significantly decreased in a second set of independent subjects (age ≥20, age of onset <50) (N = 18, subjects with MDD in a depressed state; N = 19, healthy control participants). Taken together, our findings suggest that HIST1H2AL may be a biological marker of MDD.

Distinct and Shared Endophenotypes of Neural Substrates in Bipolar and Major Depressive Disorders.

Little is known about disorder-specific biomarkers of bipolar disorder (BD) and major depressive disorder (MDD). Our aim was to determine a neural substrate that could be used to distinguish BD from MDD. Our study included a BD group (10 patients with BD, 10 first-degree relatives (FDRs) of individuals with BD), MDD group (17 patients with MDD, 17 FDRs of individuals with MDD), and 27 healthy individuals. Structural and functional brain abnormalities were evaluated by voxel-based morphometry and a trail making test (TMT), respectively. The BD group showed a significant main effect of diagnosis in the gray matter (GM) volume of the anterior cingulate cortex (ACC; p = 0.01) and left insula (p < 0.01). FDRs of individuals with BD showed significantly smaller left ACC GM volume than healthy subjects (p < 0.01), and patients with BD showed significantly smaller ACC (p < 0.01) and left insular GM volume (p < 0.01) than healthy subjects. The MDD group showed a tendency toward a main effect of diagnosis in the right and left insular GM volume. The BD group showed a significantly inverse correlation between the left insular GM volume and TMT-A scores (p < 0.05). Our results suggest that the ACC volume could be a distinct endophenotype of BD, while the insular volume could be a shared BD and MDD endophenotype. Moreover, the insula could be associated with cognitive decline and poor outcome in BD.

Disrupted orbitomedial prefrontal limbic network in individuals with later-life depression.

BACKGROUND: Depression in old age is an increasing contributor to poor health and accompanying health care costs. Although there is an abundance of literature on later-life depression (LLD), the neural correlates have not been clarified. The aim of this study was to determine whether patients with LLD show abnormal gray matter volume (GMV) and white matter integrity by using multiple image analysis methods. METHODS: The study included 45 patients with LLD and 61 healthy participants who were matched for age, sex, years of education, and vascular risk factors. GMV was examined using voxel-based morphometry, while the white matter integrity was determined by tract-based spatial statistics and tract-specific analysis, which were obtained from high-resolution magnetic resonance images. RESULTS: Patients with LLD showed significantly less GMV in the orbitofrontal cortex, anterior cingulate, insula, amygdala, and temporal regions, as well as higher fractional anisotropy in the uncinate fasciculus, compared with healthy participants. Patients with LLD who had reduced orbitofrontal and insular GMV had more severe clinical variables. The reduced orbitofrontal GMV was associated with higher fractional anisotropy in the uncinate fasciculus. LIMITATION: The effects of medication should also be considered when interpreting the results of this study. CONCLUSION: Our results suggest that regional GMV is linked to white matter integrity of the uncinate fasciculus in the orbitomedial prefrontal limbic network, and the disruption of this network may be involved in the pathophysiology of LLD.

Precentral and inferior prefrontal hypoactivation during facial emotion recognition in patients with schizophrenia: A functional near-infrared spectroscopy study.

Although patients with schizophrenia demonstrate abnormal processing of emotional face recognition, the neural substrates underlying this process remain unclear. We previously showed abnormal fronto-temporal function during facial expression of emotions, and cognitive inhibition in patients with schizophrenia using functional near-infrared spectroscopy (fNIRS). The aim of the current study was to use fNIRS to identify which brain regions involved in recognizing emotional faces are impaired in patients with schizophrenia, and to determine the neural substrates underlying the response to emotional facial expressions per se, and to facial expressions with cognitive inhibition. We recruited 19 patients with schizophrenia and 19 healthy controls, statistically matched on age, sex, and premorbid IQ. Brain function was measured by fNIRS during emotional face assessment and face identification tasks. Patients with schizophrenia showed lower activation of the right precentral and inferior frontal areas during the emotional face task compared to controls. Further, patients with schizophrenia were slower and less accurate in completing tasks compared to healthy participants. Decreasing performance was associated with increasing severity of the disease. Our present and prior studies suggest that the impaired behavioral performance in schizophrenia is associated with different mechanisms for processing emotional facial expressions versus facial expressions combined with cognitive inhibition.

Blunted brain activation in patients with schizophrenia in response to emotional cognitive inhibition: a functional near-infrared spectroscopy study.

INTRODUCTION: Patients with schizophrenia (SZ) have deficits of facial emotion processing and cognitive inhibition, but the brain pathophysiology underlying these deficits and their interaction are not clearly understood. We tested brain activity during an emotional face go/no-go task that requires rapid executive control affected by emotional stimuli in patients with SZ using functional near-infrared spectroscopy (fNIRS). METHODS: Twenty-five patients with SZ and 28 healthy control subjects were studied. We evaluated behavioral performance and used fNIRS to measure oxygenated hemoglobin concentration changes in fronto-temporal areas during the emotional go/no-go task with emotional and non-emotional blocks. RESULTS: Patients with SZ made more errors and had longer reaction times in both test blocks compared with healthy subjects. Significantly greater activation in the inferior, superior, middle, and orbital frontal regions were observed in healthy subjects during the emotional go/no-go block compared to the non-emotional go/no-go block, but this difference was not observed in patients with SZ. Relative to healthy subjects, patients with SZ showed less activation in the superior and orbital frontal and middle temporal regions during the emotional go/no-go block. DISCUSSION: Our results suggest that fronto-temporal dysfunction in patients with SZ is due to an interaction between abnormal processing of emotional facial expressions with negative valence and cognitive inhibition, especially during the rapid selection of rule-based associations that override automatic emotional response tendencies. They indicate that fronto-temporal dysfunction is involved in the pathophysiology of emotional-cognitive deficits in patients with SZ.

Different and shared brain volume abnormalities in late- and early-onset schizophrenia.

The differences in clinical characteristics between late- (LOS) and early-onset schizophrenia (EOS) are well documented. However, very little is known about the neural mechanisms underlying these differences. Here, we compared morphometric abnormalities between patients with EOS and those with LOS. A total of 22 patients with LOS, 24 patients with EOS and 41 healthy control subjects were included in this magnetic resonance imaging study. Brain images were analyzed using DARTEL preprocessing for voxel-based morphometry in SPM8. We tested a main effect of diagnosis in the whole-brain analysis and compared the results among the three groups. We also carried out correlation analyses between regional volumes and clinical variables. Patients with LOS showed larger gray matter (GM) volume of the left precuneus compared with healthy subjects and patients with EOS. Patients with LOS and EOS showed decreased GM volumes in the right insula, left superior temporal gyrus and left orbitofrontal gyrus compared with healthy subjects. A longer duration of illness was associated with reduced GM volume in the temporal pole in patients with EOS. Our findings may help improve our understanding of schizophrenia pathophysiology and shed light on the different and shared neurobiological underpinnings of LOS and EOS.

[Clinical examination of 3 patients with delayed neuropsychiatric encephalopathy induced by carbon monoxide poisoning, who recovered from severe neurocognitive impairment by repetitive hyperbaric oxygen therapy].

We performed hyperbaric oxygen (HBO) therapy for 3 patients with delayed neuropsychiatric encephalopathy induced by carbon monoxide (CO) poisoning. All patients were male and around 50 years old, and they had not received HBO therapy within 24 h after CO poisoning, even though they showed severe consciousness disturbance. In these patients, delayed neuropsychiatric encephalopathy appeared about 25 days after acute CO poisoning, and HBO therapy was initiated within 8 days after disease onset. Although the condition of 2 of the patients worsened initially, they showed significant improvement of neurocognitive impairment after 30 sessions of HBO therapy. The clinical courses of these patients suggest that the effect of HBO therapy can be evaluated after 30 sessions. To evaluate the validity of the indices of the clinical effect of HBO therapy, we performed brain magnetic resonance imaging, single photon emission computed tomography, electroencephalography (EEG), and neurocognitive tests (HDS-R, and Wechsler Adult Intelligence Scale-Revised or III). Our results showed that changes in EEG signals and neurocognitive tests were closely correlated with the patients' clinical courses.

Prefrontal activation in response to emotional words in patients with bipolar disorder and major depressive disorder.

Abnormal emotional processing is involved in the pathophysiology of bipolar disorder (BD) and major depressive disorder (MDD). However, whether the neural mechanism underlying this deficit is a trait characteristic of BD and MDD is unclear. The aim of this study was to elucidate the similarities and differences in processing of emotional stimuli between patients with BD and MDD in remission, using functional near-infrared spectroscopy (fNIRS). Thirty-two patients (16 with BD and 16 with MDD) and 20 healthy control subjects matched for age, sex, handedness, and years of education were included. An emotional Stroop task, including happy, sad, and threat words, was used. The relative oxygenated and deoxygenated hemoglobin concentration ([oxy-Hb] and [deoxy-Hb]) changes in the frontal region were measured using 52-channels of NIRS. During the threat task, compared to healthy control subjects, patients with BD showed significantly increased [oxy-Hb] in the left inferior frontal region whereas patients with MDD showed significantly increased [oxy-Hb] in the left middle frontal region. During the happy task, compared to healthy control subjects, patients with BD showed significantly decreased [oxy-Hb] in the middle frontal region in both hemispheres. Moreover, patients with BD exhibited decreased [oxy-Hb] and increased [deoxy-Hb] in the superior frontal and middle frontal regions compared to MDD in response to the happy stimulus. No significant differences in [oxy-Hb] or [deoxy-Hb] were seen between the groups during the sad task. These results suggest that abnormal neural responses to emotional stimuli in patients with mood disorders in remission may be a trait characteristic, that negative emotional stimuli are associated with similar prefrontal responses, and that positive emotional stimuli are associated with different prefrontal responses in patients with BD and MDD. These findings indicate that different neural circuits play a role in emotional processing in BD and MDD; this may aid the elucidation of the pathophysiology of these two disorders.

[Functional biomarkers of mood disorders: differential diagnosis and clinical classification with gene expression in peripheral leukocytes].

In order to identify the possible biomarkers of mood disorders, we measured the mRNA levels for a variety of genes in peripheral leukocytes of mood disorder patients in a depressive, as well as in a remissive state, comparing with healthy controls. We selected and measured the levels of genes of interest, which are listed as follows: glucocorticoid receptor, neurotrophic factors, cell adhesion molecules, SR protein splicing factors, transcription factors, epigenetic factors (histone deacetylase, sirtuin, DNA methyltransferase), since these molecules are suggested to be associated with the neural function, synaptic plasticity, and behaviors in animal models, as well as with the pathophysiology and pathogenesis of mood disorders. We found the three different types of biological markers: 1) state markers those revealed alterations of gene expression only in a depressive state of major depressive patients and/or bipolar depressive patients, 2) trait markers those showed altered gene expression both in a depressive and a remissive state of major depressive patients and/or bipolar depressive patients, and 3) markers of the treatment resistance those revealed different alterations of gene expression between treatment resistant and treatment responsive patients in a depressive state. The use of state and trait markers in combination would allow us to put a differential diagnosis between major depressive and bipolar depressive states, as well as between mood disorders and neurotic depressive states. Furthermore, candidate biomarkers of treatment resistance could be used to consider forward of applying the electric convulsive therapy even in an early stage of a depressive state.

Neural correlates of plasma acylated ghrelin level in individuals with major depressive disorder.

Anhedonic symptoms, which include loss of pleasure, appetite and motivation, are key symptoms of major depressive disorder (MDD) and are thought to depend on a neural circuit of the mesolimbic system. The neuropeptide ghrelin plays a crucial role in appetite and reward. Little is known, however, about the role of ghrelin in MDD. We examined the association between morphometric change and plasma ghrelin levels in patients with MDD. Twenty-four patients with MDD and 24 healthy control subjects were studied. Plasma concentration of acylated ghrelin was measured after a period of fasting. Using voxel-based morphometry, we found a main effect of ghrelin on the volume of several brain regions. We then compared these regional volumes in patients with MDD versus healthy subjects. We also compared brain volumes between the two groups, controlling for ghrelin level. There was no significant difference in plasma acylated ghrelin level between patients with MDD and healthy subjects. In the MDD group, ghrelin levels positively correlated with the severity of reduced appetite. Ghrelin levels negatively correlated with gray matter volume of the ventral tegmental area (VTA) in the total sample. The patients with MDD showed significantly smaller VTA gray matter volume compared to healthy subjects. Controlling for the plasma acylated ghrelin level, patients with MDD showed significantly smaller gray matter volume of right substantia nigra compared to healthy subjects. Our findings suggest that plasma acylated ghrelin is associated with neural abnormalities of the pleasure/reward system and may be involved in the pathophysiology of MDD.

Reduced expression of glyoxalase-1 mRNA in mood disorder patients.

Glyoxalase-1 (Glo1) is an antioxidant enzyme which detoxifies alpha-ketoaldehydes to prevent the accumulation of pro-oxidant compounds, such as methylglyoxal, in all cell types. Glo1 has been suggested to be involved in anxiety disorders, autism, and Alzheimer's disease. Mood disorders have a high rate of comorbidity with anxiety disorders although, to date, little is known of the involvement of Glo1 in the pathophysiology of these conditions. In the present study, we examined the expression levels of Glo1 mRNA in peripheral white blood cells of mood disorder patients to understand the role of Glo1 in mood disorders. Quantitative real-time polymerase chain reaction experiments revealed that reduced expression of Glo1 mRNA was observed in major depressive and bipolar disorder patients in a current depressive state, as compared with healthy control subjects. In contrast, the expression of Glo1 mRNA in major depressive and bipolar patients, in a remissive state, showed no significant alteration when compared with healthy control subjects. These results suggest that the aberrant expression of Glo1 might be involved in the pathophysiology of mood disorders.

Characterization of the vulnerability to repeated stress in Fischer 344 rats: possible involvement of microRNA-mediated down-regulation of the glucocorticoid receptor.

In the present study, we established and characterized an animal model of vulnerability to repeated stress. We found that control Sprague-Dawley (SD) rats showed a gradual decrease in the HPA axis response following 14 days of repeated restraint stress, whereas Fischer 344 (F344) rats did not show such HPA axis habituation. Similar habituation was observed in the expression of c-fos mRNA, corticotropin-releasing hormone hnRNA, and phospho-CREB and phospho-ERK proteins in the hypothalamic paraventricular nucleus (PVN) of SD rats, but not in the F344 rats. In addition, repeatedly restrained F344 rats exhibited decreased cell proliferation in the dentate gyrus of the hippocampus and increased anxiety-related behaviours, while repeatedly restrained SD rats exhibited a selective enhancement of hippocampal cell proliferation in the ventral area. Moreover, we found a lower expression of glucocorticoid receptor (GR) protein, but not mRNA, in the PVN of F344 rats compared to SD rats. We also identified that microRNA (miR)-18a inhibited translation of GR mRNA in cultured neuronal cells and that increased expression of miR-18a in the PVN was observed in F344 rats compared with SD rats. These strain differences in GR protein levels were not found in the hippocampus and prefrontal cortex, and the expression of miR-18a was much lower in these brain regions than in the PVN. Our results suggest that F344 rats could be a useful animal model for studying vulnerability to repeated stress, and that miR-18a-mediated down-regulation of GR translation may be an important factor to be considered in susceptibility to stress-related disorders.

State-dependent changes in the expression levels of NCAM-140 and L1 in the peripheral blood cells of bipolar disorders, but not in the major depressive disorders.

Recent postmortem brain and imaging studies provide evidence for disturbances of structural and synaptic plasticity in patients with mood disorders. Several lines of evidence suggest that the cell adhesion molecules (CAMs), neural cell adhesion molecules (NCAM) and L1, play important roles in both structural and synaptic plasticity. Although postmortem brain studies have indicated altered expression levels of NCAM and L1, it is still unclear whether these changes are state- or trait-dependent. In this study, the mRNA levels for various CAMs, including NCAM and L1, were measured using quantitative real-time PCR in peripheral blood cells of major depressive disorder patients, bipolar disorder patients and normal healthy subjects. Reduced expression levels of NCAM-140 mRNA were observed in bipolar disorder patients in a current depressive state. In contrast, L1 mRNA levels were increased in bipolar disorder patients in a current depressive state. NCAM-140 and L1 mRNA levels were not changed in bipolar disorder patients in a remissive state, or in major depressive disorder patients. In addition, there were no significant changes in the expression levels of intercellular adhesion molecule -1, vascular cell adhesion molecule -1, E-cadherin, or integrin alphaD among healthy controls, major depressive or bipolar disorder patients. Our results suggest that the reciprocal alteration in the expression of NCAM-140 and L1 mRNAs could be state-dependent and associated with the pathophysiology of bipolar disorder.

Altered expression of neurotrophic factors in patients with major depression.

There is an abundance of evidence suggesting the involvement of altered levels of expression of neurotrophic factors in the pathophysiology of neuropsychiatric disorders. Although postmortem brain studies have indicated the alterations in the expression levels of neurotrophic factors in mood disorder patients, it is unclear whether these changes are state- or trait-dependent. In this study, we examined the expression levels of the members of the glial cell line-derived neurotrophic factor (GDNF) family (GDNF, artemin (ARTN), neurturin, and persephin), brain-derived neurotrophic factor, nerve growth factor, neurotrophin-3 (NT-3), and neurotrophin-4 mRNAs by using quantitative real-time PCR method in peripheral blood cells of patients with major depressive and bipolar disorders in both a current depressive and a remissive states. Reduced expression levels of GDNF, ARTN, and NT-3 mRNAs were found in patients with major depressive disorder in a current depressive state, but not in a remissive state. Altered expressions of these mRNAs were not found in patients with bipolar disorder. Our results suggest that the changes in the expression levels of GDNF, ARTN, and NT-3 mRNAs might be state-dependent and associated with the pathophysiology of major depression.