Antipsychotics increase vesicular glutamate transporter 2 (VGLUT2) expression in thalamolimbic pathways

Recently the two vesicular-glutamate-transporters VGLUT1 and VGLUT2 have been cloned and characterized. VGLUT1 and VGLUT2 together label all glutamatergic neurons, but because of their distinct expression patterns in the brain they facilitate our ability to define between a VGLUT1-positive cortical and a VGLUT2-positive subcortical glutamatergic systems. We have previously demonstrated an increased cortical VGLUT1 expression as marker of antidepressant activity. Here, we assessed the effects of different psychotropic drugs on brain VGLUT2 mRNA and protein expression. The typical antipsychotic haloperidol, and the atypicals clozapine and risperidone increased VGLUT2 mRNA selectively in the central medial/medial parafascicular, paraventricular and intermediodorsal thalamic nuclei; VGLUT2 protein was accordingly amplified in paraventricular and ventral striatum and in prefrontal cortex. The antidepressants fluoxetine and desipramine and the sedative anxiolytic diazepam had no effect. These results highlight the implication of thalamo-limbic glutamatergic pathways in the action of antipsychotics. Increased VGLUT2 expression in these neurons might constitute a marker for antipsychotic activity and subcortical glutamate neurotransmission might be a possible novel target for future generation antipsychotics.     

Serotonin and emotional processing: does it help explain antidepressant drug action?

There is growing interest in the effects of antidepressant drug treatment on measures of emotional processing. Such actions may help us understand the role of monoamines in emotional dysfunction in depression and how antidepressant drug treatments work. Recent studies suggest that decreasing central serotonin function with tryptophan depletion can reinstate negative biases in recovered depressed patients, even at doses insufficient to induce changes in mood. Conversely, antidepressant drug administration increases the processing of positive emotional information in healthy volunteers and acutely depressed patients early in treatment. This increase in positive bias may provide a platform for subsequent cognitive restructuring and learning which contributes to the evolution of symptom change in depression. Functional neuroimaging studies suggest that these early antidepressant effects involve fronto-limbic and extra-striate circuitry suggestive of actions on both the initial appraisal and attentional processing of affective stimuli. This approach may therefore provide a framework for linking psychological and biological processes in emotional disorders and their treatment. Antidepressants may not directly modulate mood and anxiety but rather allow a different perspective for our ongoing evaluation of our self, the world and the future.     

Sequential changes in BDNF mRNA expression and synaptic levels of AMPA receptor subunits in rat hippocampus after chronic antidepressant treatment

Increased expression of brain-derived neurotrophic factor (BDNF) appears to be involved in the mechanism of action of antidepressant drugs. It has also been proposed that potentiation of the AMPA receptor (AMPAR) function may be useful in the treatment of depression. Here we looked for the time course of the effect of different doses of two antidepressants, desipramine (DMI) and paroxetine (PAR), which differentially affect monoamine reuptake, on BDNF mRNA expression in hippocampal subfields (CA1, CA3 and dentate gyrus) and levels of AMPAR subunits in total and membrane-enriched extracts from rat hippocampus. Acute antidepressant treatment changed neither BDNF mRNA expression nor AMPAR subunit levels. In chronic treatments, rats were treated daily with the antidepressants for 7–21 days. PAR produced a time- and dose-dependent increase of BDNF expression in the three hippocampal subfields examined. On the contrary, the effect of DMI on BDNF mRNA was neither dose- nor time-dependent. In rats receiving the same chronic antidepressant treatments, PAR produced a dose-dependent increase of GluR1 and GluR2/3 levels in the membrane fraction after a 3-week treatment, and not at earlier times. DMI increased the membrane levels of AMPAR subunits after a 3-week treatment with the lower dose tested. However, a higher dose, 15 mg/kg, did not produce any change in AMPAR subunits and reduced membrane levels of -tubulin and PSD-95, possibly indicating a disorganization of membrane scaffolding proteins. The results suggest that paroxetine, but not desipramine, enhances synaptic plasticity in the hippocampus by increasing BDNF mRNA expression, which determines a later AMPAR subunit trafficking to synaptic membranes.     

Forced swimming test in mice: a review of antidepressant activity

Rationale Among all animal models, the forced swimming test (FST) remains one of the most used tools for screening antidepressants.Objective This paper reviews some of the main aspects of the FST in mice. Most of the sensitivity and variability factors that were assessed on the FST are summarized.Mechanisms We have summarized data found in the literature of antidepressant effects on the FST in mice. From this data set, we have extrapolated information on baseline levels of strain, and sensitivity against antidepressants.Results We have shown that many parameters have to be considered in this test to gain good reliability. Moreover, there was a fundamental inter-strain difference of response in the FST.Conclusions The FST is a good screening tool with good reliability and predictive validity. Strain is one of the most important parameters to consider. Swiss and NMRI mice can be used to discriminate the mechanisms of action of drugs. CD-1 seems to be the most useful strain for screening purposes, but this needs to be confirmed with some spontaneous locomotor activity studies.Electronic Supplementary Material Supplementary material is available for this article at .     

快速起效抗抑郁药物的鼻腔给药:一种治疗重度抑郁症的新趋势（英文）

现有抗抑郁药物的起效时间较长,最新发现的相关受体与通路可以启发我们去寻找更多的快速起效抗抑郁药物,氯胺酮是其中最具潜力的药物之一。现已证明,通过鼻腔摄入途径,药物可以利用嗅觉神经通路直接被递送至脑部。设计良好的快速起效抗抑郁药物是抑郁症患者的迫切需求。作为一种具有潜力的递药策略,鼻腔给药可以提高药效,大幅缩短起效时间。本篇综述中,我们整理了一些利用不同机制和通路治疗抑郁症的新处方以及相关临床研究结果。快速起效抗抑郁药物与鼻腔给药相结合将引领抑郁症的治疗新趋势。     

Antidepressants reduce phosphoinositide-specific phospholipase C (PI-PLC) activity and the mRNA and protein expression of selective PLC beta 1 isozyme in rat brain

In order to examine whether antidepressants mediate their action by interacting with one of the key components of the phosphoinositide (PI) signaling pathway, i.e. PI-specific phospholipase C (PLC), and whether this represents a common mechanism of action of antidepressants, we determined the effects of antidepressants of various classes on PI-PLC activity and on the expression of PLC isozymes in rat brain. It was observed that chronic (21-day) but not acute (1-day) administration with desipramine (DMI), fluoxetine (FLX) and phenelzine (PHLZ), decreased PI-PLC activity in membrane and cytosol fractions of cortex and hippocampus. Similar changes were observed with alprazolam (ALP) and buspirone (BUS), who possess anxiolytic and antidepressant properties. On the other hand, an anxiogenic drug, metachlorophenylpiperazine (MCPP), increased PI-PLC activity in both membrane and cytosol fractions of cortex and hippocampus. The immunolabeling studies showed that all the antidepressants and anxiolytics that caused a decrease in PI-PLC activity also selectively decreased the protein levels of a specific isozyme of PLC, i.e. PLCβ₁, in membrane and cytosol fractions of cortex and hippocampus, whereas MCPP increased the levels of this particular isozyme. These changes were accompained with changes in the mRNA levels of PLCβ₁, as determined by quantitative RT-PCR. These antidepressants and anxiolytics did not cause significant changes in the expression of PLC δ₁ or γ₁ isozyme. Our results thus suggest that modulation of PI-PLC may be common to all classes of antidepressants, which in turn, may be associated with their mechanisms of action.     

Depression treatment use among stroke individuals with depression: A cross-sectional analysis of the Medical Expenditure Panel Survey

BackgroundDepression is the most prevalent psychiatric comorbidity among stroke individuals. Despite the effectiveness of antidepressants and psychotherapy, data on the use of these treatments among stroke survivors is limited.ObjectiveThe main objective of this study was to document prevalence of antidepressant use, types of antidepressants utilized, and adherence to antidepressants among stroke individuals.MethodsRetrospective, cross-sectional data obtained from the Medical Expenditure Panel Surveys (MEPS), for the years 2011, 2013 and 2015, was utilized for this study. Treatment for depression was categorized into three mutually exclusive categories: 1) antidepressants only, 2) antidepressants and psychotherapy (combination), and 3) No treatment. Adherence to antidepressants was measured using the Proportion of Days Covered (PDC) ratio. Adherence between antidepressant only and combination therapy group was compared using Student's t-test. A multinomial logistic regression analysis was used to further examine the association between patient characteristics and likelihood of receiving depression treatment.ResultsA total of 759 stroke individuals with comorbid depression were identified. Of these, 51.2% utilized only antidepressants, 12.6% utilized a combination treatment of antidepressants and psychotherapy and 31.7% did not receive treatment for depression. Selective Serotonin Reuptake Inhibitors (SSRI's) was the most commonly used antidepressants in the stroke population. Males (P = 0.04), age group of 40–64 years (P < 0.001), and African Americans (P = 0.02) constituted for the highest proportions of untreated stroke survivors. Among treated stroke individuals, adherence was higher for combination therapy users compared to those using antidepressants only (mean PDC = 65.8 ± 6.89 and 57.6 ± 3.74, respectively).ConclusionAlmost 70% of stroke individuals received some form of treatment for depression and several patient-related factors (gender, age, race, marital status, and comorbidity burden) were associated with the utilization of depression treatment. Future researchers need to investigate the factors responsible for lack of depression treatment in stroke individuals and policy makers should aim for a more patient centered care.     

抗抑郁药用于疼痛治疗的研究进展

慢性痛或神经痛是一种临床综合征,常伴有抑郁障碍,严重影响患者生活质量.对于神经痛,常规镇痛药物、甚至麻醉性镇痛药经常无效,而抗抑郁药、抗精神病药和抗癫痫药物等则有效.本文综述了抗抑郁药用于镇痛的作用机制和不同类型的抗抑郁药在疼痛治疗中的应用,旨在为疼痛的临床治疗提供参考.