Mammillary body and hypothalamic volumes in mood disorders.

We have previously reported an in vivo enlargement of the left hypothalamus in mood disorders using 7 T magnetic resonance imaging. The aim of this follow-up study was to find out whether the hypothalamic volume difference may be located in the mammillary bodies (MB) rather than being widespread across the hypothalamus. We developed and evaluated a detailed segmentation algorithm that allowed a reliable segmentation of the MBs, and applied it to 20 unmedicated (MDDu) and 20 medicated patients with major depressive disorder, 21 medicated patients with bipolar disorder, and 23 controls. 20 out of 23 healthy controls were matched to the MDDu. We tested for group differences in MB and hypothalamus without MB (HTh) volumes using analyses of covariance. Associations between both volumes of interest were analysed using bivariate and partial correlations. In contrast to postmortem findings, we found no statistically significant differences of the MB volumes between the study groups. Left HTh volumes differed significantly across the study groups after correction for intracranial volume (ICV) and for ICV and sex. Our result of an HTh enlargement in mood disorders was confirmed by a paired t-test between the matched pairs of MDDu and healthy controls using the native MB and HTh volumes. In the whole sample, MB volumes correlated significantly with the ipsilateral HTh volumes. Our results indicate a structural relationship between both volumes, and that our previous in vivo finding of a hypothalamus enlargement does not extend to the MB, but is limited to the HTh. The enlargement is more likely related to the dysregulation of the HPA axis than to cognitive dysfunctions accompanying mood disorders.

Therapeutic Effect and Mechanisms of Essential Oils in Mood Disorders: Interaction between the Nervous and Respiratory Systems.

Essential oils (EOs) are extracted from plants and contain active components with therapeutic effects. Evidence shows that various types of EOs have a wide range of health benefits. In our previous studies, the potential of lavender EO for prevention and even treatment of depression and anxiety symptoms was demonstrated. The favourable outcomes may be due to multiple mechanisms, including the regulation of monoamine level, the induction of neurotrophic factor expression, the regulation of the endocrine system and the promotion of neurogenesis. The molecules of EOs may reach the brain and exert an effect through two distinctive pathways, namely, the olfactory system and the respiratory system. After inhalation, the molecules of the EOs would either act directly on the olfactory mucosa or pass into the respiratory tract. These two delivery pathways suggest different underlying mechanisms of action. Different sets of responses would be triggered, such as increased neurogenesis, regulation of hormonal levels, activation of different brain regions, and alteration in blood biochemistry, which would ultimately affect both mood and emotion. In this review, we will discuss the clinical effects of EOs on mood regulation and emotional disturbances as well as the cellular and molecular mechanisms of action. Emphasis will be put on the interaction between the respiratory and central nervous system and the involved potential mechanisms. Further evidence is needed to support the use of EOs in the clinical treatment of mood disturbances. Exploration of the underlying mechanisms may provide insight into the future therapeutic use of EO components treatment of psychiatric and physical symptoms.

Cannabidiol as a Potential Treatment for Anxiety and Mood Disorders: Molecular Targets and Epigenetic Insights from Preclinical Research.

Cannabidiol (CBD) is the most abundant non-psychoactive component of cannabis; it displays a very low affinity for cannabinoid receptors, facilitates endocannabinoid signaling by inhibiting the hydrolysis of anandamide, and stimulates both transient receptor potential vanilloid 1 and 2 and serotonin type 1A receptors. Since CBD interacts with a wide variety of molecular targets in the brain, its therapeutic potential has been investigated in a number of neuropsychiatric diseases, including anxiety and mood disorders. Specifically, CBD has received growing attention due to its anxiolytic and antidepressant properties. As a consequence, and given its safety profile, CBD is considered a promising new agent in the treatment of anxiety and mood disorders. However, the exact molecular mechanism of action of CBD still remains unknown. In the present preclinical review, we provide a summary of animal-based studies that support the use of CBD as an anxiolytic- and antidepressant-like compound. Next, we describe neuropharmacological evidence that links the molecular pharmacology of CBD to its behavioral effects. Finally, by taking into consideration the effects of CBD on DNA methylation, histone modifications, and microRNAs, we elaborate on the putative role of epigenetic mechanisms in mediating CBD's therapeutic outcomes.

Design, Synthesis, and Preclinical Evaluation of 3-Methyl-6-(5-thiophenyl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-ones as Selective GluN2B Negative Allosteric Modulators for the Treatment of Mood Disorders.

Selective inhibitors of the GluN2B subunit of N-methyl-d-aspartate receptors in the ionotropic glutamate receptor superfamily have been targeted for the treatment of mood disorders. We sought to identify structurally novel, brain penetrant, GluN2B-selective inhibitors suitable for evaluation in a clinical setting in patients with major depressive disorder. We identified a new class of negative allosteric modulators of GluN2B that contain a 1,3-dihydro-imidazo[4,5-b]pyridin-2-one core. This series of compounds had poor solubility properties and poor permeability, which was addressed utilizing two approaches. First, a series of structural modifications was conducted which included replacing hydrogen bond donor groups. Second, enabling formulation development was undertaken in which a stable nanosuspension was identified for lead compound 12. Compound 12 was found to have robust target engagement in rat with an ED70 of 1.4 mg/kg. The nanosuspension enabled sufficient margins in preclinical toleration studies to nominate 12 for progression into advanced good laboratory practice studies.

Calcium-Involved Action of Phytochemicals: Carotenoids and Monoterpenes in the Brain.

BACKGROUND: Neurodegenerative and mood disorders represent growing medical and social problems, many of which are provoked by oxidative stress, disruption in the metabolism of various neurotransmitters, and disturbances in calcium homeostasis. Biologically active plant compounds have been shown to exert a positive impact on the function of calcium in the central nervous system. METHODS: The present paper reviews studies of naturally occurring terpenes and derivatives and the calcium-based aspects of their mechanisms of action, as these are known to act upon a number of targets linked to neurological prophylaxis and therapy. RESULTS: Most of the studied phytochemicals possess anticancer, antioxidative, anti-inflammatory, and neuroprotective properties, and these have been used to reduce the risk of or treat neurological diseases. CONCLUSION: The neuroprotective actions of some phytochemicals may employ mechanisms based on regulation of calcium homeostasis and should be considered as therapeutic agents.

Virtual reality and music therapy as distraction interventions to alleviate anxiety and improve mood states in breast cancer patients during chemotherapy.

Psychological distress is a common consequence of breast cancer diagnosis and treatment and could further exacerbate therapy side effects. Interventions increasing treatment tolerance are crucial to improve both patients' quality of life and adherence to therapies. Virtual reality (VR) has emerged as an effective distraction tool for different medical procedures. Here, we assessed the efficacy of immersive and interactive VR in alleviating chemotherapy-related psychological distress in a cohort of Italian breast cancer patients, also comparing its effects with those of music therapy (MT). Thirty patients were included in the VR group, 30 in the MT group, and 34 in the control group, consisting of patients receiving standard care during chemotherapy. Our data suggest that both VR and MT are useful interventions for alleviating anxiety and for improving mood states in breast cancer patients during chemotherapy. Moreover, VR seems more effective than MT in relieving anxiety, depression, and fatigue.

Hypothalamus enlargement in mood disorders.

OBJECTIVE: The purpose of this study was to determine, in vivo, whether the hypothalamus volume is reduced in patients with mood disorders. METHODS: The cross-sectional study included 20 unmedicated (MDDu) and 20 medicated patients with major depressive disorder, 21 patients with bipolar disorder, and 23 controls. Twenty of the controls were matched to the MDDu. Seven Tesla, T1-weighted magnetic resonance images were acquired and processed using methods specifically developed for high-precision volumetry of the hypothalamus. RESULTS: An overall group difference was observed for the left hypothalamus volume corrected for intracranial volume. Planned contrasts identified that the left hypothalamus was approximately 5% larger in each patient group compared with the control group. A paired t-test with the 20 matched pairs of MDDu and controls and without correction for covariates confirmed the larger left hypothalamus volume in MDDu. CONCLUSIONS: Contrary to our expectations, the hypothalamus volume was increased in patients with uni- and bipolar affective disorders. The effect was left-sided and independent of medication status or statistical correction for covariates. Supported by emerging evidence that the stress response may be related to structural and functional asymmetry in the brain, our finding suggests a crucial role of the hypothalamus in mood disorders.

Direct Involvement of Androgen Receptor in Oxytocin Gene Expression: Possible Relevance for Mood Disorders.

Oxytocin (OXT), synthesized in the hypothalamic paraventricular nucleus (PVN) and then released into different brain areas, may play a crucial role in various behaviors and neuropsychiatric disorders, including depression. Testosterone has been proposed by clinical studies to have the opposite effect of oxytocin in these disorders. We began by studying, in the postmortem hypothalamus of fifteen patients with mood disorders and fifteen matched controls, the expression of OXT in the PVN by means of immunocytochemistry (ICC) and the co-localization of OXT and androgen receptor (AR) by means of double labeling ICC. Subsequently, the regulatory effect of AR on OXT gene expression was studied in vitro. We found a higher expression of PVN OXT in the mood disorder patients than in the control subjects, and observed a clear co-localization of AR in OXT-expressing neurons, both in the cytoplasm and in the nucleus. In addition, a significant decrease in OXT-mRNA levels was observed after pre-incubation of the SK-N-SH cells with testosterone. A further potential androgen-responsive element in the human OXT gene promotor was revealed by electrophoretic mobility shift assays and co-transfections in neuroblastoma cells. Finally, in vitro studies demonstrated that AR mediated the down-regulation of OXT gene expression. These results suggest that the fact that OXT and testosterone appear to have opposite effects in neuropsychiatric disorders might be based upon a direct inhibition of AR on OXT transcription, which may provide a novel target for therapeutic strategies in depression.

The neuroprotective effect of lithium against high dose methylphenidate: Possible role of BDNF.

Methylphenidate (MPH) is a neural stimulant with unclear neurochemical and behavioral effects. Lithium is a neuroprotective agent in use clinically for the management of manic-depressive and other neurodegenerative disorders. This study investigated the protective effect of lithium on MPH-induced oxidative stress, anxiety, depression and cognition impairment. Forty-eight adult male rats were divided randomly and equally into 6 groups. Treatment groups were received MPH (10mg/kg) and various doses of lithium (75, 150 and 300mg/kg) simultaneously and also lithium (150mg/kg) alone for 21 days. Elevated Plus Maze and Forced Swim Test were used to determine the level of anxiety and depression in animals. Morris Water Maze was used to evaluate spatial learning and memory. The hippocampi of rats were isolated and the level and activity of oxidative, anti-oxidant and inflammatory factors were measured. Also brain derived neurotropic factor expression level was measured by RT-PCR and western blotting. MPH (10mg/kg) caused behaviors indicative of anxiety and depression-like phenotypes in EPM and FST and cognition impairment in MWM. While lithium in all mentioned doses inhibited these effects. Treatment with MPH significantly increased lipid peroxidation, mitochondrial GSH content and IL-1ß and TNF-α levels in isolated hippocampal cells. Moreover superoxide dismutase and glutathione peroxidase activities and BDNF expression remarkably decreased. Various doses of lithium attenuated these effects and significantly mitigated MPH-induced oxidative damage, inflammation and increased BDNF expression level. Lithium has the potential to act as a neuroprotective agent against MPH induced toxicity in rat brain and this might be mediated by BDNF expression in hippocampus of rats.

Social Welfare Centers Protect Outpatients with Mood Disorders from Risk of Hospital Admission.

BACKGROUND: South Korea faces difficulties in the management of mental disorders, and those difficulties are expected to gradually worsen. Therefore, we analyzed the relationship between social welfare centers and hospital admission after outpatient treatment for mood disorders. METHODS: We used data from the National Health Insurance Service National Sample Cohort 2002-2013, which included all medical claims filed for the 50,160 patients who were newly diagnosed with a mood disorder among the 1,025,340 individuals in a nationally representative sample. We performed a logistic regression analysis using generalized estimating equation (GEE) models to examine the relationship between social welfare centers and hospital admission after outpatient treatment for mood disorders (ICD-10: F3). RESULTS: There was a 3.9% admission rate among a total of 99,533 person-years. Outpatients who lived in regions with more social welfare centers were less likely to be admitted to a hospital (per increase of five social welfare centers per 100,000 people; OR: 0.958; 95% CI: 0.919-0.999). Social welfare centers had an especially strong protective effect on patients with relatively mild mood disorders and those who were vulnerable to medical expenditures. CONCLUSIONS: Considering the protective role of social welfare centers in managing patients with mood disorders, health-policy makers need to consider strategies for activating mental healthcare.

Chemical approaches to therapeutically target the metabolism and signaling of the endocannabinoid 2-AG and eicosanoids.

The endocannabinoid system, most popularly known as the target of the psychoactive component of marijuana, Δ(9)-tetrahydrocannabinol (THC), is a signaling network that modulates a diverse range of physiological processes including nociception, behavior, cognitive function, appetite, metabolism, motor control, memory formation, and inflammation. While THC and its derivatives have garnered notoriety in the eyes of the public, the endocannabinoid system consists of two endogenous signaling lipids, 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (anandamide), which activate cannabinoid receptors CB1 and CB2 in the nervous system and peripheral tissues. This review will focus on the recent efforts to chemically manipulate 2-AG signaling through the development of inhibitors of the 2-AG-synthesizing enzyme diacylglycerol lipase (DAGL) or the 2-AG-degrading enzyme monoacylglycerol lipase (MAGL), and assessing the therapeutic potential of DAGL and MAGL inhibitors in pain, inflammation, degenerative diseases, tissue injury, and cancer.

Reversal of monoarthritis-induced affective disorders by diclofenac in rats.

BACKGROUND: Nonsteroidal anti-inflammatory drugs are effective for arthritic pain, but it is unknown whether they also benefit anxiety and depression that frequently coexist with pain. Using the monoarthritis model, the authors evaluated the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in structures implicated in both sensorial and emotional pain spheres, and it was verified whether analgesia can reverse monoarthritis-mediated affective responses. METHODS: Monoarthritis was induced in male rats by complete Freund's adjuvant injection. Allodynia (ankle-bend test), mechanical hyperalgesia (paw-pinch test), anxiety- and depression-like behaviors (elevated zero maze and forced swimming tests, respectively), and ERK1/2 phosphorylation (Western blot) in the spinal cord, paragigantocellularis nucleus, locus coeruleus, and prefrontal cortex were evaluated at 4, 14, and 28 days postinoculation (n = 6 per group). Changes in these parameters were evaluated after induction of analgesia by topical diclofenac (n = 5 to 6 per group). RESULTS: Despite the pain hypersensitivity and inflammation throughout the testing period, chronic monoarthritis (28 days) also resulted in depressive- (control [mean ± SEM]: 38.3 ± 3.7 vs. monoarthritis: 51.3 ± 2.0; P < 0.05) and anxiogenic-like behaviors (control: 36.8 ± 3.7 vs. monoarthritis: 13.2 ± 2.9; P < 0.001). These changes coincided with increased ERK1/2 activation in the spinal cord, paragigantocellularis, locus coeruleus, and prefrontal cortex (control vs. monoarthritis: 1.0 ± 0.0 vs. 5.1 ± 20.8, P < 0.001; 0.9 ± 0.0 vs. 1.9 ± 0.4, P < 0.05; 1.0 ± 0.3 vs. 2.9 ± 0.6, P < 0.01; and 1.0 ± 0.0 vs. 1.8 ± 0.1, P < 0.05, respectively). Diclofenac decreased the pain threshold of the inflamed paw and reversed the anxio-depressive state, restoring ERK1/2 activation levels in the regions analyzed. CONCLUSION: Chronic monoarthritis induces affective disorders associated with ERK1/2 phosphorylation in paragigantocellularis, locus coeruleus, and prefrontal cortex which are reversed by diclofenac analgesia. (Anesthesiology 2014; 120:1476-90).

Volumetric analysis of the hypothalamus, amygdala and hippocampus in non-suicidal and suicidal mood disorder patients--a post-mortem study.

In recent years, the hypothalamus, amygdala and hippocampus have attracted increased interest with regard to the effects of stress on neurobiological systems in individuals with depression and suicidal behaviour. A large body of evidence indicates that these subcortical regions are involved in the pathogenetic mechanisms of mood disorders and suicide. The current neuroimaging techniques inadequately resolve the structural components of small and complex brain structures. In previous studies, our group was able to demonstrate a structural and neuronal pathology in mood disorders. However, the impact of suicide remains unclear. In the current study we used volumetric measurements of serial postmortem sections with combined Nissl-myelin staining to investigate the hypothalamus, amygdala and hippocampus in suicide victims with mood disorders (n = 11), non-suicidal mood disorder patients (n = 9) and control subjects (n = 23). Comparisons between the groups by using an ANCOVA showed a significant overall difference for the hypothalamus (p = 0.001) with reduced volumes in non-suicidal patients compared to suicide victims (p = 0.018) and controls (p = 0.006). To our surprise, the volumes between the suicide victims and controls did not differ significantly. For the amygdala and hippocampus no volume changes between the groups could be detected (all p values were n. s.). In conclusion our data suggest a structural hypothalamic pathology in non-suicidal mood disorder patients. The detected differences between suicidal and non-suicidal patients suggest that suicidal performances might be related to the degree of structural deficits.

Reduced regional gray matter volume in patients with chronic obstructive pulmonary disease: a voxel-based morphometry study.

BACKGROUND AND PURPOSE: Decreased oxygen supply may cause neuronal damage in the brains of patients with COPD, which is manifested by clinical symptoms such as neuropsychological deficits and mood disorders. The aim of the present study was to investigate brain gray matter change in COPD. MATERIALS AND METHODS: Using voxel-based morphometry based on the high-resolution 3D T1-weighted MR images of GM volume, we investigated 25 stable patients with COPD and 25 matching healthy volunteers. A battery of neuropsychological tests was also performed. RESULTS: Patients with COPD (versus controls) showed reduced GM volume in the frontal cortex (bilateral gyrus rectus, bilateral orbital and inferior triangular gyri, and left medial superior gyrus), right anterior insula, cingulate cortex (left anterior and middle gyri, right middle gyrus), right thalamus/pulvinar, right caudate, right putamen, right parahippocampus, and left amygdala. In COPD, in some of these regions, regional GM volume had positive correlations with arterial blood po(2), while in some regions, regional GM volume had negative correlations with disease duration. Patients with COPD (versus controls) had poorer performance in the Mini-Mental State Examination, Visual Reproduction, and Figure Memory tests. Moreover, the GM volume in the inferior triangular frontal cortex in patients with COPD was significantly correlated with the Picture Memory score. CONCLUSIONS: Our findings suggest GM reductions in a number of brain regions in COPD, which were associated with disease severity and may underlie the pathophysiologic and psychological changes in patients with COPD.

A systematic review of resting-state functional-MRI studies in major depression.

BACKGROUND: To evaluate the literature pertaining to the use of resting-state functional magnetic resonance imaging (fMRI) in Major Depression (MD). METHODS: A search for papers published in English was conducted using MedLine, Embase, PsycINFO, OvidSP, and ScienceDirect with the following words: resting state, depression, MRI, affective, and default-mode. RESULTS: The findings from 16 resting-state fMRI studies on MD are tabulated. Some common findings are discussed in further detail. CONCLUSION: The use of resting-state fMRI in MD research has yielded a number of significant findings that provide the basis for understanding the pathophysiology of depressive symptoms. Of particular note and deserving of further research are the roles of the cortico-limbic mood regulating circuit (MRC) and the interaction between task-positive and task-negative networks in MD. There is increasing interest in the use of resting-state fMRI in the study of psychiatric conditions, and continued improvement in technique and methodology will prove valuable in future research.

Structural studies of the hypothalamus and its nuclei in mood disorders.

A large body of evidence indicates that the hypothalamus is involved in pathogenetic mechanisms of mood disorders. It has been suggested that functional abnormalities of the hypothalamus are associated with structural hypothalamic changes. Structural neuroimaging allows in vivo investigation of the hypothalamus that may shed light on the underlying pathogenetic mechanisms of unipolar and bipolar disorder. Clearly, the detection of subtle structural cerebral changes depends on the limitations of the neuroimaging technique used. Making a comprehensive database search, we reviewed the literature on hypothalamic macrostructure in affective disorders, addressing the specific question of what structural magnetic resonance imaging might be expected to show. Studies with convincing methodology, although rare, suggest a global volume decrease in the hypothalamus in affective disorders, a decrease which is not shown by the two specific nuclei investigated, the paraventricular and supraoptic nuclei. We discuss the implications of these findings and provide directions for future research.

Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders.

Half a century after the first formulation of the monoamine hypothesis, compelling evidence implies that long-term changes in an array of brain areas and circuits mediating complex cognitive-emotional behaviors represent the biological underpinnings of mood/anxiety disorders. A large number of clinical studies suggest that pathophysiology is associated with dysfunction of the predominant glutamatergic system, malfunction in the mechanisms regulating clearance and metabolism of glutamate, and cytoarchitectural/morphological maladaptive changes in a number of brain areas mediating cognitive-emotional behaviors. Concurrently, a wealth of data from animal models have shown that different types of environmental stress enhance glutamate release/transmission in limbic/cortical areas and exert powerful structural effects, inducing dendritic remodeling, reduction of synapses and possibly volumetric reductions resembling those observed in depressed patients. Because a vast majority of neurons and synapses in these areas and circuits use glutamate as neurotransmitter, it would be limiting to maintain that glutamate is in some way 'involved' in mood/anxiety disorders; rather it should be recognized that the glutamatergic system is a primary mediator of psychiatric pathology and, potentially, also a final common pathway for the therapeutic action of antidepressant agents. A paradigm shift from a monoamine hypothesis of depression to a neuroplasticity hypothesis focused on glutamate may represent a substantial advancement in the working hypothesis that drives research for new drugs and therapies. Importantly, despite the availability of multiple classes of drugs with monoamine-based mechanisms of action, there remains a large percentage of patients who fail to achieve a sustained remission of depressive symptoms. The unmet need for improved pharmacotherapies for treatment-resistant depression means there is a large space for the development of new compounds with novel mechanisms of action such as glutamate transmission and related pathways. This article is part of a Special Issue entitled 'Anxiety and Depression'.

The role of asymmetric frontal cortical activity in emotion-related phenomena: a review and update.

Conceptual and empirical approaches to the study of the role of asymmetric frontal cortical activity in emotional processes are reviewed. Although early research suggested that greater left than right frontal cortical activity was associated with positive affect, more recent research, primarily on anger, suggests that greater left than right frontal cortical activity is associated with approach motivation, which can be positive (e.g., enthusiasm) or negative in valence (e.g., anger). In addition to reviewing this research on anger, research on guilt, bipolar disorder, and various types of positive affect is reviewed with relation to their association with asymmetric frontal cortical activity. The reviewed research not only contributes to a more complete understanding of the emotive functions of asymmetric frontal cortical activity, but it also points to the importance of considering motivational direction as separate from affective valence in psychological models of emotional space.

Tratorno delirante celotípico / The delussive jealousy disorder

El trastorno delirante celotípico es un cuadro conocido y recogido en las clasificaciones CIE-10 y DSM-IV. No obstante existen numerosas lagunas de algunos aspectos destacados del cuadro. Se describe un caso clínico y se discuten las cuestionas más polémicas a la luz de una revisión. Particular interés tiene la terapia de los cuadros delirantes,el tratamiento eficaz, los fármacos más útiles o la duración del tratamiento

The delusive jealousy disorder is today a diagnostic perfectly known and typified in the systems CIE-10 and DSM-IV. However, there still are important lacks of knowledge about other importants aspects of the this pathology. In this paper, we report a case and we discuss about the more polemics questions, consecuence of our revision. Is very important the therapy of the delusional disorder, the effective treatment, the more useful drugs or the duration of treatment

Hypothalamic nitric oxide synthase in affective disorder: focus on the suprachiasmatic nucleus.

Depression is frequently associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which leads to repeated episodes of hypercortisolemia. Hypothalamic paraventricular neurons are believed to trigger these processes by aberrant generation and/or release of corticotropin releasing hormone, oxytocin, vasopressin, and nitric oxide (NO). Recent findings from two independent laboratories have demonstrated that the suprachiasmatic nucleus, which in part controls the cellular activity of paraventricular neurons (PVN), is also involved in affective disorder. The aim of the present study was to elucidate by stereological analysis, whether suprachiasmatic nucleus (SCN) nitric oxide synthase and neurophysin generating neurons are affected in neuropsychiatric disorders. We show that compared to controls the number of nitric oxide synthase immunoreactive neurons is greatly reduced both in depression and in schizophrenia. In subjects with affective disorder there was a correlation between the number of NOS-expressing cells and duration of treatment with antidepressants. The number of neurophysin-expressing SCN neurons was also fewer in cases with mood disorder. It is concluded that SCN-derived NO may be a relevant pathophysiological factor in neuropsychiatric disorders.