Suicide and depression in the quantitative analysis of glutamic acid decarboxylase-Immunoreactive neuropil.
ABSTRACT Alterations of GABAergic neurotransmission are assumed to play a crucial role in the pathophysiology of mood disorders. Glutamic acid decarboxylase (GAD) is the key enzyme of GABA synthesis.
Immunohistochemical staining of GAD 65/67 was performed in the orbitofrontal, anterior cingulate and dorsolateral prefrontal cortex (DLC), the entorhinal cortex (EC), the hippocampal formation, and the medial dorsal and lateral dorsal thalamic nuclei, with consecutive determination of GAD-immunoreactive (-ir) neuropil relative density. The study was performed on paraffin-embedded brains from 21 depressed patients (14 of whom had committed suicide) and 18 matched controls. The data were tested using Kruskal-Wallis, Mann-Whitney (U) and Spearman statistical procedures.
As shown by post-hoc U-tests, an increase in the relative density of GAD-ir neuropil was present in the hippocampal formation, specific for suicidal patients. The EC was the only area where non-suicidal patients also revealed an increase compared with controls. On the contrary, the DLC was the only area where a significant decrease existed, specific for non-suicidal patients. Numerous negative correlations were found between the investigated parameter and psychotropic medication.
A major limitation of this study is the relatively small case number. A further limitation is given by the lack of data on drug exposure across the whole life span. The possible impact of unipolar-bipolar dichotomy of mood disorders on the obtained results should also be considered.
The study, revealing predominantly an increased relative density of GAD-ir neuropil, suggests the diathesis of GABAergic system specific for depressed suicidal patients.
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ABSTRACT: Evidence suggesting that central nervous system γ-aminobutyric acid (GABA) concentrations are reduced in patients with major depressive disorder (MDD) has been present since at least 1980, and this idea has recently gained support from more recent magnetic resonance spectroscopy data. These observations have led to the assumption that MDD’s underlying etiology is tied to an overall reduction in GABA-mediated inhibitory neurotransmission. In this paper, we review the mechanisms that govern GABA and glutamate concentrations in the brain, and provide a comprehensive and critical evaluation of the clinical data supporting reduced GABA neurotransmission in MDD. This review includes an evaluation of magnetic resonance spectroscopy data, as well as data on the expression and function of the GABA-synthesizing enzyme glutamic acid decarboxylase, GABA neuron-specific cell markers, such as parvalbumin, calretinin and calbindin, and the GABAA and GABAB receptors in clinical MDD populations. We explore a potential role for glial pathology in MDD-related reductions in GABA concentrations, and evidence of a connection between neurosteroids, GABA neurotransmission, and hormone-related mood disorders. Additionally, we investigate the effects of GABAergic pharmacological agents on mood, and demonstrate that these compounds have complex effects that do not universally support the idea that reduced GABA neurotransmission is at the root of MDD. Finally, we discuss the connections between serotonergic and GABAergic neurotransmission, and show that two serotonin-focused antidepressants – the selective serotonin-reuptake inhibitor fluoxetine and the multimodal antidepressant vortioxetine – modulate GABA neurotransmission in opposing ways, despite both being effective MDD treatments. Altogether, this review demonstrates that there are large gaps in our understanding of the relationship between GABA physiology and MDD, which must be remedied with more data from well-controlled empirical studies. In conclusion, this review suggests that the simplistic notion that MDD is caused by reduced GABA neurotransmission must be discarded in favor of a more nuanced and complex model of the role of inhibitory neurotransmission in MDD.Drug Design, Development and Therapy 01/2015; 9:603-624. · 3.03 Impact Factor
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ABSTRACT: Objectives The development of more sophisticated models for understanding suicide among people with bipolar disorder (BD) requires diagnosis-specific data. The present study aimed to elucidate differences between people who die by suicide with and without BD, and to identify subgroups within those with BD. Methods Data on all suicide deaths in the city of Toronto from 1998 to 2010 were extracted from the Office of the Chief Coroner of Ontario, including demographics, clinical variables, recent stressors, and details of the suicide. Comparisons of person- and suicide-specific variables between suicide deaths among those with BD (n=170) and those without (n=2,716) were conducted, and a cluster analysis was performed among the BD suicide group only. ResultsThose in the BD suicide group were more likely than those in the non-BD suicide group to be female [odds ratio (OR)=1.75, 95% confidence interval (CI): 1.27-2.42; p=0.001], to have made a past suicide attempt (OR=2.01, 95% CI: 1.45-2.80; p<0.0001), and to have had recent contact with psychiatric or emergency services (OR=1.59, 95% CI: 1.00-2.52; p=0.049). Five clusters were identified within the BD group, with differences between clusters in age; sex; marital status; living circumstances; past suicide attempts; substance abuse; interpersonal, employment/financial, and legal/police stressors; and rates of death by fall/jump or self-poisoning. Conclusions The present findings identified differences between BD and non-BD suicide groups, providing support to the utilization of an illness-specific approach to better understanding suicide in BD. Subgroups of BD suicide deaths, if replicated, should also be incorporated into the design and analysis of future studies of suicide in BD.Bipolar Disorders 05/2014; 16(7). · 4.89 Impact Factor
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ABSTRACT: Suicide and bipolar disorder (BD) are challenging, complex, and intertwined areas of study in contemporary psychiatry. Indeed, BD is associated with the highest lifetime risk for suicide attempt and completion of all the psychiatric conditions. Given that several clinical risk factors for both suicide and BD have been well noted in the literature, exploring the neurobiological aspects of suicide in BD may provide insights into both preventive measures and future novel treatments. This review synthesizes findings regarding the neurobiological aspects of suicide and, when applicable, their link to BD. Neurochemical findings, genes/epigenetics, and potential molecular targets for current or future treatments are discussed. The role of endophenotypes and related proximal and distal risk factors underlying suicidal behavior are also explored. Lastly, we discuss the manner in which preclinical work on aggression and impulsivity may provide additional insights for the future development of novel treatments.Translational Neuroscience. 06/2013; 4(2).