Changes in density of calcium-binding-protein-immunoreactive GABAergic neurons in prefrontal cortex in schizophrenia and bipolar disorder.

There is evidence that GABAergic neurotransmission is altered in mental disorders such as schizophrenia (SCZ) and bipolar disorder (BPD). The calcium-binding proteins (CBPs) calbindin (CB), calretinin (CR), and parvalbumin (PV) are used as markers of specific subpopulations of cortical GABAergic interneurons. We examined the postmortem prefrontal cortical region (Brodmann's area 9) of patients with SCZ and BPD, and of age-matched control subjects, excluding suicide cases. The laminar density of neurons immunoreactive (IR) for three CBPs, namely CB, CR, and PV, was quantified. The densities of CB-IR neurons in layer 2 and PV-IR neurons in layer 4 in the SCZ subjects decreased compared with those in the control subjects. When CBP-IR neurons were classified according to their size, a reduction in the density of medium CB-IR neurons in layer 2 in SCZ subjects and an increase in the density of large CR-IR neurons in layer 2 in BPD subjects were observed. These results suggest that alterations in specific GABAergic neurons are present in mental disorders, and that such alterations may reflect the vulnerability toward the disorders.

HPA axis dysfunction in unmedicated major depressive disorder and its normalization by pharmacotherapy correlates with alteration of neural activity in prefrontal cortex and limbic/paralimbic regions.

Dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) axis is one of the most prominent neurobiological findings in major depressive disorder (MDD). The relationship of regional brain metabolism to HPA axis dysfunction in depressed patients, however, is still unclear. In this study, to examine the clinical pharmacotherapeutic effects on HPA axis function and brain metabolism in MDD patients, we performed the combined dexamethasone (DEX)/corticotropin-releasing hormone (CRH) test on 24 antidepressant-free patients with MDD a few days after positron emission tomography (PET) with a radiotracer, [(18)F]-fluorodeoxyglucose (FDG). Moreover, 10 patients who responded to pharmacotherapy were re-tested. 75% of unmedicated MDD patients exhibited a heightened cortisol response to the DEX/CRH test, and thus were defined as non-suppressors. Non-suppressors showed a marked hypometabolism in the medial prefrontal cortex as compared with suppressors. After successful pharmacotherapy, enhanced cortisol responsiveness normalized. Prior to treatment of the unmedicated MDD, a significant hypometabolism in various frontal regions and a significant hypermetabolism in the right hippocampus and parahippocampal gyrus were observed compared with controls. Metabolic activity in treatment responders showed a normalizing pattern in almost all the areas that had been characterized by metabolic abnormality at baseline except for the medial prefrontal cortex. These results indicate that depressed patients remitted with antidepressant treatment were accompanied by resolution of HPA dysregulation and alteration of regional glucose metabolism in the prefrontal cortical, limbic and paralimbic regions.

[Clinical availability of biological markers for diagnosis of schizophrenia: reactivity of frontal lobe function assessed with near-infrared spectroscopy].

Biological markers of psychiatric disorders can be employed both for research and clinical purposes, are classified into state, trait, and morbid markers, and are expected to be useful in diagnosis, treatment, and prediction of psychiatric disorders in clinical settings. Near-infrared spectroscopy that can measure reactivity of cerebral cortex function is one of biological markers for clinical purposes, and has revealed characteristic patterns of frontal lobe function in psychiatric disorders. Availability of biological makers for diagnosis of psychiatric disorders was examined by reviewing effect sizes of various biological markers in schizophrenia, showing that more elaborated markers for higher brain functions are promising: cognition (1.0-1.4), neurophysiology (0.8-1.0), functional brain imaging (0.6-0.8), and structural brain imaging (0.5-0.6).

Assessment of the dexamethasone/CRH test as a state-dependent marker for hypothalamic-pituitary-adrenal (HPA) axis abnormalities in major depressive episode: a Multicenter Study.

There is compelling evidence for the involvement of hypothalamic-pituitary-adrenal (HPA) axis abnormalities in depression. Growing evidence has suggested that the combined dexamethasone (DEX)/corticotropin-releasing hormone (CRH) test is highly sensitive to detect HPA axis abnormalities. We organized a multicenter study to assess the DEX/CRH test as a state-dependent marker for major depressive episode in the Japanese population. We conducted the DEX/CRH test in 61 inpatients with major depressive episode (Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV)) and 57 healthy subjects. In all, 35 patients were repeatedly assessed with the DEX/CRH test on admission and before discharge. The possible relationships between clinical variables and the DEX/CRH test were also examined. Significantly enhanced pituitary-adrenocortical responses to the DEX/CRH test were observed in patients on admission compared with controls. Such abnormalities in patients were significantly reduced after treatment, particularly in those who underwent electroconvulsive therapy (ECT) in addition to pharmacotherapy. Age and female gender were associated with enhanced hormonal responses to the DEX/CRH test. Severity of depression correlated with DEX/CRH test results, although this was explained, at least in part, by a positive correlation between age and severity in our patients. Medication per se was unrelated to DEX/CRH test results. These results suggest that the DEX/CRH test is a sensitive state-dependent marker to monitor HPA axis abnormalities in major depressive episode during treatment. Restoration from HPA axis abnormalities occurred with clinical responses to treatment, particularly in depressed patients who underwent ECT.

[Establishing biological markers for diagnosis and treatment of depression: possible availability of PET, NIRS, and DST].

Current diagnosis of depression depends on its clinical symptoms and signs, not on the results of any laboratory examinations. Establishing biological markers for diagnosis and treatment of depression is one of the most important problems to be solved in psychiatry practice. Near infrared spectroscopy(NIRS) is one of the recently developed methodologies, and can measure cerebral blood volumes simultaneously in multiple points with high time resolution. Multi-channel NIRS machines for clinical use have recently been developed by two medical companies in Japan. Authors presented the preliminary NIRS data showing that depression is characterized by decrease in cerebral blood volume activation during a word fluency task, and discussed their possible availability for diagnosis of depression.

Fluvoxamine modulates pain sensation and affective processing of pain in human brain.

To better understand the antinociceptive effect of fluvoxamine, we measured regional cerebral blood flow during laser-evoked pain and hot sensations using H(2)15O positron emission tomography and also subjective pain and hot sensations before and after fluvoxamine or placebo administration for 7 days to 12 healthy volunteers. The subjectively rated pain score was significantly reduced by fluvoxamine administration. Painful stimuli activated multiple brain regions. After fluvoxamine administration the ipsilateral anterior cingulate cortex (ACC), contralateral insular cortex (IC), and contralateral secondary somatosensory cortex (SII) activations were reduced. The bilateral IC activation was also reduced in the placebo group. These results suggest that fluvoxamine specifically reduced activation of the ACC and SII, which are areas concerned with the affective and integrative components of pain.