Glial Purinergic Signals and Psychiatric Disorders

Emotion-related neural networks are regulated in part by the activity of glial cells, and glial dysfunction can be directly related to emotional diseases such as depression. Here, we discuss three different therapeutic strategies involving astrocytes that are effective for treating depression. First, the antidepressant, fluoxetine, acts on astrocytes and increases exocytosis of ATP. This has therapeutic effects via brain-derived neurotrophic factor-dependent mechanisms. Second, electroconvulsive therapy is a well-known treatment for drug-resistant depression. Electroconvulsive therapy releases ATP from astrocytes to induce leukemia inhibitory factors and fibroblast growth factor 2, which leads to antidepressive actions. Finally, sleep deprivation therapy is well-known to cause antidepressive effects. Sleep deprivation also increases release of ATP, whose metabolite, adenosine, has antidepressive effects. These independent treatments share the same mechanism, i.e., ATP release from astrocytes, indicating an essential role of glial purinergic signals in the pathogenesis of depression.

Antidepressive Effect of Antipsychotics in the Treatment of Schizophrenia: Meta-Regression Analysis of Randomized Placebo-Controlled Trials

Background Antipsychotics improve the positive symptoms of schizophrenia. However, little is known about the extent of antidepressive effects of antipsychotics and their correlation with effects on other symptom domains in schizophrenia. The aim was to investigate whether antidepressive effects of antipsychotics have a significant correlation with the effects on specific symptom domains of schizophrenia. Methods Electronic databases were searched to identify eligible studies that reported antidepressive effects of antipsychotics for the treatment of adult patients with schizophrenia in double-blind, randomized placebo-controlled trials (RCTs). Mean change from baseline in depressive symptoms was meta-analyzed, and the correlation with the effects on other symptom domains was examined through meta-regression analysis. Results Thirty-five RCTs (13 890 patients) were included in this meta-analysis. Overall, antipsychotics showed greater efficacy than placebo in reducing depressive symptoms, with small to medium effect sizes (standardized mean difference = −0.27, 95% confidence interval −0.32 to −0.22, P < .001). All the antipsychotics, except for chlorpromazine, haloperidol, and ziprasidone, were associated with significantly greater decreases in depressive symptoms compared with placebo (standardized mean difference = −0.19 to −0.40). A higher antidepressive effect was significantly correlated with a higher improvement in Positive and Negative Syndrome Scale/Brief Psychiatric Rating Scale total, positive, and negative, and Positive and Negative Syndrome Scale-general psychopathology symptoms (β = .618, P < .001; β = .476, P < .001; β = .689, P < .001; β = .603, P < .001, respectively). Conclusions Second-generation antipsychotics (except for ziprasidone) were associated with small to medium effects sizes on improvement in depressive symptoms among adult patients with schizophrenia. The antidepressive effect of antipsychotics was significantly correlated with improvement in other symptom domains, with the highest correlation observed for improvement in negative symptoms. PROSPERO registration number CRD42019133015

Behavioral appraisal by implementing a short sequence of stress resolves adaptively changed stress gains

Chronic stress produces adaptive changes in the brain via the cumulative action of glucocorticoids, which causes psychiatric illnesses such as depression. Here we show that a behavioral method implementing weak stress does not strengthen but resolves existing stress gains. Chronic stress produces persistent depressive behaviors in mice, and repeated daily treatment with 5-min restraint produces antidepressive effects. Repeated treatment with low-dose glucocorticoids mimics the anti-depressive effects of weak stress. Repeated weak stress or low-dose glucocorticoid treatment distinctively activates the prelimbic cortex (PL), and reverses the stress-induced altered gene expression profiles. Chemogenetic inhibition of PL outputs projecting to the nucleus accumbens, basolateral amygdala, or bed nucleus of the stria terminalis (BNST) dissipates antidepressive effects of weak stress, but only the PL-to-BNST circuit produces changes in dysregulated glucocorticoid release. Our results suggest that behavioral appraisal by implementing weak stress can resolve adaptively altered stress gains and rectify stress-induced depressive behaviors.

Attenuation of antidepressive effects of transcranial magnetic stimulation in patients whose medication includes drugs for psychosis

Objective: To assess whether concomitant antipsychotic treatment has an influence on the antidepressive effects of repetitive transcranial magnetic stimulation (rTMS). Methods: We analyzed severity of depression before and after treatment with rTMS in a sample of 299 depressed in- and outpatients in retrospect in relation to treatment with drugs for psychosis. The sample consisted of real-life patients in a tertiary hospital. We ran group contrasts between the group taking and the group not taking drugs for psychosis, testing for differences in Hamilton Depression Rating Scale (HDRS). Effect sizes for HDRS group contrasts were reported as Cohen’s d and number needed to treat (NNT) calculated from d. To control for group differences we repeated the Student t-tests for the change in the HDRS using analysis of covariance including confounding variables. Results: Depressed patients taking drugs for psychosis showed significantly less amelioration of depressive symptoms after rTMS treatment as measured by absolute and relative change in HDRS with small effect size or NNT of 4.5 to 8.4, respectively. Controlling significant group contrasts revealed that the effect of taking drugs for psychosis does not depend on age, number of applied TMS pulses, type or severity of depression at baseline, comorbidities or differences in the intake of additional medication. Conclusion: Drugs for psychosis attenuate antidepressive effects of rTMS independently of confounding factors. The effect is statistically significant and of potentially great clinical importance. The exact mechanism remains to be elucidated and further studies are warranted.