Yuji Kitaichi

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.

Glucocorticoids and lithium reciprocally regulate the proliferation of adult dentate gyrus-derived neural precursor cells through GSK-3beta and beta-catenin/TCF pathway

Adult hippocampal neurogenesis is decreased in rodent models for stress-related disorders at least partly through an elevated level of glucocorticoids. On the other hand, the mood stabilizer lithium (Li) commonly used for their treatment increases it. This effect is thought to be one of the therapeutic actions of Li, but the molecular mechanism has been poorly understood. Here we established the culture system of adult rat dentate gyrus-derived neural precursor cells (ADPs) and examined the effects of dexamethasone (DEX), an agonist of glucocorticoids receptor, and Li on ADP proliferation. It is possible for ADP to be a type 2a cell, which corresponds to the second stage in a model of four differentiation stages in adult hippocampal neural precursor cells. DEX decreased ADP proliferation, but Li did not have any effect on it. However, Li recovered ADP proliferation decreased by DEX. The recovery effect of Li was abolished by quercetin, an inhibitor of β-catenin/TCF pathway. The intranuclear translocation of β-catenin and expression of cyclin D1 are reciprocally regulated by DEX and Li in a way similar to proliferation. In addition, DEX increased the phosphorylation of Tyr216, which renders glycogen synthase kinase-3β (GSK-3β) active on it. These results suggest that GSK-3β and β-catenin/TCF pathway might be important in the reciprocal effects between DEX and Li on ADP proliferation and are new targets of therapeutic agents for stress-related disorders.

The effect of dopamine on adult hippocampal neurogenesis

Cumulative studies indicated that adult hippocampal neurogenesis might be involved in the action mechanism of antidepressant drugs and/or the pathophysiology of depression. Dopamine (DA) is involved in the regulation of motivation, volition, interest/pleasure, and attention/concentration, all of which are likely to be impaired in depressed patients. Several previous reports suggest that depression may often be accompanied by a relative hypo-dopaminergic state, and some DA receptor agonists are beneficial effects in the treatment for refractory and bipolar depression. In the present study, to clarify the direct effect of DA on neural progenitor cells, we examined the effect of DA on the proliferation of adult rat dentate gyrus-derived neural precursor cells (ADPs). In addition, we examined the effect of DA receptor agonists on adult rat hippocampal neurogenesis in vivo. Results showed that DA promoted the increase of ADPs via D1-like receptor and D1-like receptor agonist promoted the survival of newborn cells in the adult hippocampus. On the contrary, D2-like receptor agonist did not affect both proliferation and survival. These results suggested that DA might play, at least in part, a role in adult hippocampal neurogenesis via D1-like receptor and the activation of D1-like receptor has a therapeutic potential for depression.

Monoamine oxidase inhibitors reduce conditioned fear stress-induced freezing behavior in rats

The present study examined the acute anxiolytic effects of monoamine oxidase inhibitors on freezing behavior, a putative index of anxiety induced by conditioned fear stress. The selective serotonin 1A receptor agonist tandospirone (0.1-10 mg/kg) inhibited freezing dose dependently. The irreversible, non-selective monoamine oxidase inhibitors tranylcypromine (3 and 15 mg/kg) and phenelzine (30 and 80 mg/kg) reduced freezing significantly. Clorgyline (10 mg/kg, irreversible selective monoamine oxidase A inhibitor), N-(2-aminoethyl)-5-(m-fluorophenyl)-4-thiazole carboxamide (Ro 41-1049) (30 mg/kg, reversible selective monoamine oxidase A inhibitor), selegiline (3 mg/kg, irreversible selective monoamine oxidase B inhibitor) and lazabemide (10 mg/kg, reversible selective monoamine oxidase B inhibitor) had no effect on freezing behavior. However, combined administration of clorgyline (10 mg/kg) and selegiline (3 mg/kg) reduced freezing significantly, as well as combined administration of clorgyline (10 mg/kg) and lazabemide (10 mg/kg), Ro 41-1049 (30 mg/kg) and selegiline (3 mg/kg), or Ro 41-1049 (30 mg/kg) and lazabemide (10 mg/kg). These effects of monoamine oxidase inhibitors on freezing were not due to non-specific motor effects. These results suggest that acute inhibition of both monoamine oxidase A and B reduced anxiety or fear, while inhibition of monoamine oxidase A or B alone failed to reduce anxiety or fear.

Pramipexole for stage 2 treatment-resistant major depression: an open study.

OBJECTIVE To examine the effectiveness and safety of adjunctive pramipexole in the treatment of stage 2 treatment-resistant major depressive disorder. METHODS This study included patients with moderate or non-psychotic severe major depressive disorder according to DSM-IV-TR criteria despite at least two adequate treatment trials with antidepressants from different pharmacological classes. Pramipexole 0.25 to 2 mg daily was added to antidepressant therapy. Previous treatments were continued unchanged, but no new treatments were allowed. We conducted assessments at baseline and at weeks 2, 4, 6, and 8. We defined response as a 50% or greater reduction on the Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS Ten patients (4 men, 6 women) aged 43.7±11.4 years received pramipexole at mean dose of 1.3±0.6 mg/d. Mean MADRS scores improved significantly from baseline to endpoint (mean differences=11.4, 95% CI [4.1, 18.7], P=0.0064). At the endpoint, six of 10 (60%) were responders on MADRS (≥50% reduction). Two patients (20%) terminated early due to mild somatic and psychiatric adverse effects. CONCLUSION These preliminary data suggest that the addition of pramipexole to antidepressant treatment may be effective and well tolerated in patients with stage 2 treatment-resistant major depressive disorder.

The influence of childhood abuse, adult stressful life events and temperaments on depressive symptoms in the nonclinical general adult population.

BACKGROUND Previous studies have shown the interaction between heredity and childhood stress or life events on the pathogenesis of major depression. We hypothesized that childhood abuse, affective temperaments, and adult stressful life events interact and influence depressive symptoms in the general adult population and tested this hypothesis in this study. METHODS The 294 participants from the nonclinical general adult population were studied using the following self-administered questionnaire surveys: the Patient Health Questionnaire-9 (PHQ-9), Life Experiences Survey (LES), Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego auto-questionnaire (TEMPS-A), and Child Abuse and Trauma Scale (CATS). The data were analyzed with single and multiple regressions and structural equation modeling (Amos 20.0). RESULTS Childhood abuse indirectly predicted the severity of the depressive symptoms through affective temperaments measured by TEMPS-A in the structural equation modeling. Four temperaments - depressive, cyclothymic, irritable, and anxious - directly predicted the severity of depressive symptoms and the negative appraisal of life events during the past year. The negative appraisal of life events during the past year mildly, but significantly, predicted the severity of depressive symptoms. LIMITATIONS The subjects of this study were nonclinical. The findings might not be generalized to patients with mood disorders. CONCLUSIONS This study suggests that childhood abuse, especially neglect, indirectly increased depressive symptoms through increased affective temperaments, which, in turn, increase the negative appraisal of stressful life events. An important role of affective temperaments in the effect of childhood abuse and stressful life events on depressive symptoms was suggested.

Long-lasting change in 5-HT2A receptor-mediated behavior in rats after a single footshock

To investigate the long-term functional change in the 5-HT(2A) receptor after acute stress, we examined the effect of single footshock on head shake behavior induced by the 5-HT(2A) receptor agent (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) in rats. Head shakes were evoked in a dose-dependent manner by 0.1-10 mg/kg of DOI, and the maximal response was attenuated by a single footshock given 24 h before. This suggests that there is a decrease in the number of functionally effective 5-HT(2A) receptors. The single footshock-induced reduction in head shakes evoked by DOI was observed immediately and 24 h after footshock, and lasted until 1 and 2 weeks after footshock. Because there were no changes in the [3H]ketanserin binding of the frontal cortex 1 week after footshock, decreases in head shakes were not due to the down-regulation of 5-HT(2A) receptors evoked by footshock.

Changes in amygdala neural activity that occur with the extinction of context-dependent conditioned fear stress

The purpose of the present study was to characterize functional changes in the amygdala that accompany the extinction of context-dependent conditioned fear stress in a rat, an animal model of anxiety. Specifically, the effect of extinction of conditioned fear-induced cyclic AMP responsive element-binding protein (CREB) phosphorylation in the amygdala was investigated using immunohistochemistry. Experiments demonstrated that CREB phosphorylation in the basal nucleus of the amygdala decreased with the extinction of context-dependent conditioned fear-induced freezing behavior. These data suggest that the basal nucleus of the amygdala plays an essential role in the expression of context-dependent conditioned fear. Further, this is the first study to demonstrate that CREB phosphorylation in the basal nucleus of the amygdala changes in parallel with the extinction of context-dependent conditioned fear.

Valproate recovers the inhibitory effect of dexamethasone on the proliferation of the adult dentate gyrus-derived neural precursor cells via GSK-3β and β-catenin pathway.

Neurogenesis in the adult dentate gyrus (DG) is decreased in rodent models for mood disorders. Mood stabilizers including lithium (Li) and valproate (VPA) increase it. These increasing effects of Li and VPA on neurogenesis in adult DG are considered to be one of the therapeutic actions of Li and VPA, but their molecular mechanism remains unclear. We have already reported that Li recovers the inhibitory effects of dexamethasone (DEX), an agonist of glucocorticoid receptor, on the proliferation of adult rat DG-derived neural precursor cells (ADP) via GSK-3β and β-catenin pathway. Following it, here we investigated the mechanism underlying the recovery effects of VPA on DEX-induced decrease of ADP proliferation. VPA is an inhibitor of histone deacetylase (HDAC). However, Trichostatin A, a HDAC inhibitor, had no effect on ADP proliferation. In contrast, SB415286, a specific GSK-3β inhibitor, recovered DEX-induced decrease of ADP proliferation. In addition, quercetin (Que), a β-catenin pathway inhibitor, abolished such a recovery effect of VPA. Moreover, nuclear β-catenin and the expression of cyclin D1 were altered by DEX, VPA and Que like the proliferation. Moreover, VPA increased the phosphorylation of Ser(9), which is known as the inhibitory phosphorylation site of GSK-3β. These suggest that HDAC is not involved in the recovery effect of VPA on ADP proliferation and that VPA recovers the inhibitory effects of DEX via increasing the phosphorylation of Ser(9) on GSK-3β and following up-regulation of β-catenin pathway. Therefore, GSK-3β and β-catenin pathway might play a role in the increasing effects of VPA on neurogenesis on adult DG.

Mood stabilizers commonly restore staurosporine-induced increase of p53 expression and following decrease of Bcl-2 expression in SH-SY5Y cells.

Adult neurogenesis in dentate gyrus (DG) is involved in the action mechanism of mood stabilizers. However, it is poorly understood how mood stabilizers affect adult neurogenesis in DG. Neurogenesis consists of proliferation, survival (anti-apoptosis) and differentiation of neural precursor cells in adult DG. Using in vitro culture of adult rat DG-derived neural precursor cells (ADP), we have already shown that four mood stabilizers, such as lithium (Li), valproate (VPA), carbamazepine (CBZ) and lamotrigine (LTG), commonly decrease staurosporine (STS)-induced apoptosis of ADP. These suggest that the common anti-apoptotic effect of mood stabilizers could be involved in mood-stabilizing effects. Past studies have shown that Li and VPA increase the expression of Bcl-2, an anti-apoptotic gene. In addition, it has been shown that Li decreases the expression of p53, which plays a prominent role in apoptosis and regulates the expression of Bcl-2. Therefore, p53 and Bcl-2 can be considered to mediate the common anti-apoptotic effects of Li, VPA, CBZ and LTG. To elucidate the molecular mechanism underlying the common anti-apoptotic effects of mood stabilizers, we investigated the effects of Li, VPA, CBZ and LTG on STS-induced expression changes of p53, Bcl-2 and other p53-related molecules using SH-SY5Y cells as a model of neural precursor-like cells. STS increased the expression of p53 and decreased that of Bcl-2. These effects of STS on p53 and Bcl-2 are restored by all of Li, VPA, CBZ and LTG. In addition, p53 overexpression decreased the expression of Bcl-2. Taken together, these results suggest that p53 and Bcl-2 may be involved in a part of mood-stabilizing effects.