ArticleLiterature Review

GABA System in Depression: Impact on Pathophysiology and Psychopharmacology

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Abstract

Background: The pathophysiology of major depressive disorder (MDD), one of the major causes of worldwide disability, is still largely unclear, despite the increasing data reporting evidence of multiple alterations of different systems. Recently, there was a renewed interest in the signalling of gamma aminobutyric acid (GABA) - the main inhibitory neurotransmitter. Objective: The aim of this study was to review and comment on the available literature about the involvement of GABA in MDD, as well as on novel GABAergic compounds possibly useful as antidepressants. Methods: We carried out a narrative review through Pubmed, Google Scholar and Scopus, by using specific keywords. Results: The results, derived from various research tools, strongly support the presence of a deficiency of the GABA system in MDD, which appears to be restored by common antidepressant treatments. More recent publications would indicate the complex interactions between GABA and all the other processes involved in MDD, such as monoamine neurotransmission, hypothalamus-pituitary adrenal axis functioning, neurotrophism, and immune response. Taken together, all these findings seem to further support the complexity of the pathophysiology of MDD, possibly reflecting the heterogeneity of the clinical pictures. Conclusion: Although further data are necessary to support the specificity of GABA deficiency in MDD, the available findings would suggest that novel GABAergic compounds might constitute innovative therapeutic strategies in MDD.

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... Dysregulation of the GABAergic system contributes to anxiety-like behaviors and emotional dysregulation observed in animal models following LPS exposure (Rezaei et al., 2024). Research has demonstrated that GABA dysfunction is closely linked to the pathophysiology of depression (Della Vecchia et al., 2022;Prévot & Sibille, 2021). For instance, the study by highlights that alterations in GABAergic signaling can lead to decreased inhibitory control over excitatory pathways, resulting in heightened neural excitability and increased susceptibility to mood disorders. ...
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In recent years, growing evidence suggests that lipopolysaccharide (LPS), a bacterial endotoxin found in the outer membrane of gram‑negative bacteria, can influence cognitive functions, particularly memory formation and retrieval. However, the underlying mechanisms through which LPS exerts its effects on memory remain incompletely understood. This review used various electronic databases, including PubMed, Scopus, and Web of Science, to identify relevant studies published between 2000 and 2024. Articles were selected based on their focus on LPS‑induced memory impairments, including experimental models, molecular pathways, and neurochemical alterations. LPS administration has been consistently shown to disrupt memory processes in both animals and humans, although the magnitude and duration of memory impairments might vary depending on factors such as dose, timing, and context of LPS exposure. Several potential mechanisms have been proposed to explain LPS‑induced memory deficits, including neuroinflammation, alterations in synaptic plasticity, disruption of neurotransmitter systems, and dysfunction of the blood‑brain barrier. Moreover, LPS has been found to activate immune signaling pathways, such as toll‑like receptors, interleukins, and microglia, which can further contribute to cognitive impairments. Such insights may pave the way for the development of targeted therapeutic interventions aimed at ameliorating memory deficits associated with conditions involving LPS exposure, including bacterial infections, sepsis, and neuroinflammatory disorders.
... This showed that the drug may have some central nervous system (CNS) depressant activity (Diniz et al. 2013). Most CNS depressants cause a decrease in the activity of the brain by increasing the activity of the major inhibitory neurotransmitter in the brain which is gamma-aminobutyric acid (GABA) and acting on its receptors (Della Vecchia et al. 2022). The actual mechanism by which alpha-onocerin caused this CNS depressant effect in the mice was, however, unknown. ...
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Background Gut microbiota plays a critical role in the onset and development of depression, but the underlying molecular mechanisms are unclear. This study was conducted to observe the characteristics of gut microbiota, lipid metabolism and neurotransmitters in Gut-Liver-Brain axis in depressed mice (DM), and identify some novel perceptions on relationships between gut microbiota and depression. Methods A mouse model of depression was built used chronic unpredictable mild stress (CUMS). Fecal samples (measuring gut microbiota compositions, microbial genes and lipid metabolites), liver samples (measuring lipid metabolites), and hippocampus (measuring neurotransmitters) were collected. Both univariate and multivariate statistical analyses were used to identify the differential gut microbiota, metabolic signatures and neurotransmitters in DM. Results There were significant differences on both microbial and metabolic signatures between DM and control mice (CM): 71 significantly changed operational taxonomic units (OTUs) (60.56% belonged to phylum Firmicutes) and 405 differential lipid metabolites (51.11% belonged to Glycerophospholipid (GP) metabolism) were identified. Functional analysis showed that depressive-like behaviors (DLB)-related differential microbial genes were mainly enriched in GP metabolism. Weighted correlation network analysis (WGCNA) showed that DLB-related differential metabolites mainly belonged to GPs. Meanwhile, seven differential neurotransmitters were identified. Comprehensive analysis found that Lachnospiraceae and gamma-aminobutyric acid (GABA) were significantly correlated with 94.20% and 53.14% differential GPs, respectively, and GABA was significantly correlated with three main DLB phenotypes. Conclusion Our results provided novel perceptions on the role of Gut-Liver-Brain axis in the onset of depression, and showed that GP metabolism might be the bridge between gut microbiota and depression. “Lachnospiraceae-GP metabolism-GABA” held the promise as a potential way between gut microbiota and brain functions in DM.
... Gamma-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the adult brain, having a critical function in maintaining its inhibitory/excitatory balance, producing brain oscillations, and allowing several cognitive processes, including memory [1,2]. The dysfunction of GABAergic activity has been linked to many psychiatric disorders, including anxiety-associated disorders [3] and depression [4], and its agonism is the target of the most common anxiolytics, benzodiazepines. ...
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... Chronic stress induced emotional disorders such as anxiety and depression involve imbalances between the excitatory glutamatergic system and the inhibitory GABAergic system in the PFC, GABA being the main inhibitory neurotransmitter in the mature mammalian CNS (Page and Coutellier, 2019) ( Figure 2). Moreover, the majority of data on GABAergic deficiencies in depression have been gathered and demonstrated by means of indirect/direct methods, such as assessments of GABA levels in cerebrospinal fluid (CSF), brain specimens obtained post-mortem, by brain imaging, or by other pharmacological studies (Della et al., 2021). There is currently little compelling evidence that any sigma receptor(s) interacts with GABA receptors directly in vivo. ...
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Highlights d Several antidepressants, including SSRIs and ketamine, directly bind to TRKB d TRKB dimerization at transmembrane region forms a binding pocket for fluoxetine d Antidepressant binding to TRKB facilitates BDNF action and plasticity d Point mutation in TRKB transmembrane region blocks the effects of antidepressants In Brief Direct binding of both typical and fast-acting antidepressants to the BDNF receptor TRKB accounts for cell biological and behavioral actions of antidepressants. This mechanism directly connects antidepressant action to neuronal plasticity and may explain the slow action of typical antidepressants. SUMMARY It is unclear how binding of antidepressant drugs to their targets gives rise to the clinical antidepressant effect. We discovered that the transmembrane domain of tyrosine kinase receptor 2 (TRKB), the brain-derived neurotrophic factor (BDNF) receptor that promotes neuronal plasticity and antidepressant responses, has a cholesterol-sensing function that mediates synaptic effects of cholesterol. We then found that both typical and fast-acting antidepressants directly bind to TRKB, thereby facilitating synaptic localization of TRKB and its activation by BDNF. Extensive computational approaches including atomistic molecular dynamics simulations revealed a binding site at the transmembrane region of TRKB dimers. Mutation of the TRKB an-tidepressant-binding motif impaired cellular, behavioral, and plasticity-promoting responses to antidepres-sants in vitro and in vivo. We suggest that binding to TRKB and allosteric facilitation of BDNF signaling is the common mechanism for antidepressant action, which may explain why typical antidepressants act slowly and how molecular effects of antidepressants are translated into clinical mood recovery.
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Neurodevelopmental disorders have a heritable component and are associated with region specific alterations in brain anatomy. However, it is unclear how genetic risks for neurodevelopmental disorders are translated into spatially patterned brain vulnerabilities. Here, we integrated cortical neuroimaging data from patients with neurodevelopmental disorders caused by genomic copy number variations (CNVs) and gene expression data from healthy subjects. For each of the six investigated disorders, we show that spatial patterns of cortical anatomy changes in youth are correlated with cortical spatial expression of CNV genes in neurotypical adults. By transforming normative bulk-tissue cortical expression data into cell-type expression maps, we link anatomical change maps in each analysed disorder to specific cell classes as well as the CNV-region genes they express. Our findings reveal organizing principles that regulate the mapping of genetic risks onto regional brain changes in neurogenetic disorders. Our findings will enable screening for candidate molecular mechanisms from readily available neuroimaging data.
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Background: Alterations in γ-aminobutyric acid (GABA) have been hypothesized to play a role in the pathogenesis of psychiatric illness. Our previous work has specifically linked anterior cingulate cortex (ACC) GABA deficits with anhedonia in youth with major depressive disorder (MDD). As anhedonia reflects alterations within the reward circuitry, we sought to extend this investigation and examine GABA levels in another key reward-related region, the striatum, in the same adolescent population. Methods: Thirty-six youth [20 with MDD and 16 healthy controls; (HC)], ages 12 to 21 years old, underwent J-edited proton magnetic resonance spectroscopy (1H MRS) whereby GABA levels were measured in striatal and ACC voxels. GABA levels were compared between groups and between voxel positions and were examined in relation to clinical symptomatology, such as depression severity, anhedonia, anxiety, and suicidality. Results: Depressed youth had unexpectedly higher GABA levels in the striatum compared to HC. In both depressed and healthy youth, GABA levels were higher in the striatum than in the ACC, while the differences in depressed youth were greater. Moreover, in depressed youth, higher striatal GABA above the mean of HCs was correlated with lower ACC GABA below the mean of HCs. Striatal GABA was not correlated with clinical symptomatology in this small sample. Conclusions: Together, these findings suggest that higher striatal GABA levels may serve some compensatory function as a result of lower ACC GABA in depressed adolescents. It is also possible that like lower ACC GABA, higher striatal GABA might simply be another pathological feature of adolescent depression.
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The human brain is comprised of a complex web of functional networks that link anatomically distinct regions. However, the biological mechanisms supporting network organization remain elusive, particularly across cortical and subcortical territories with vastly divergent cellular and molecular properties. Here, using human and primate brain transcriptional atlases, we demonstrate that spatial patterns of gene expression show strong correspondence with limbic and somato/motor cortico-striatal functional networks. Network-associated expression is consistent across independent human datasets and evolutionarily conserved in non-human primates. Genes preferentially expressed within the limbic network (encompassing nucleus accumbens, orbital/ventromedial prefrontal cortex, and temporal pole) relate to risk for psychiatric illness, chloride channel complexes, and markers of somatostatin neurons. Somato/motor associated genes are enriched for oligodendrocytes and markers of parvalbumin neurons. These analyses indicate that parallel cortico-striatal processing channels possess dissociable genetic signatures that recapitulate distributed functional networks, and nominate molecular mechanisms supporting cortico-striatal circuitry in health and disease.
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The functional integration of external and internal signals forms the basis of information processing and is essential for higher cognitive functions. This occurs in finely-tuned cortical microcircuits whose functions are balanced at the cellular level by excitatory glutamatergic pyramidal neurons and inhibitory γ-aminobutyric acid (GABA) interneurons. The balance of excitation and inhibition, from cellular processes to neural network activity, is characteristically disrupted in multiple neuropsychiatric disorders, including major depressive disorder (MDD), bipolar disorder (BPD), anxiety disorders, and schizophrenia (SCZ). Specifically, nearly three decades of research demonstrate a role for reduced inhibitory GABA level and function across disorders. In MDD, recent evidence from human postmortem and animal studies suggests a selective vulnerability of GABAergic interneurons that co-express the neuropeptide somatostatin (“SST cells/interneurons”). Advances in cell type-specific molecular genetics have now helped to elucidate several important roles for SST interneurons in cortical processing (regulation of pyramidal cell excitatory input) and behavioral control (mood and cognition). Here, we review evidence for altered inhibitory function arising from GABAergic deficits across disorders, and specifically in MDD. We then focus on properties of the cortical microcircuit, wherein SST-positive GABA interneuron deficits may disrupt functioning in several ways. Finally, we discuss the putative origins of SST cell deficits, as informed by recent research, and implications for therapeutic approaches. We conclude that deficits in SST interneurons represent a contributing cellular pathology, and therefore a promising target for normalizing altered inhibitory function in MDD and other disorders with reduced SST cell and GABA functions.
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The functional optimization of neural ensembles is central to human higher cognitive functions. When the functions through which neural activity is tuned fail to develop or break down, symptoms and cognitive impairments arise. This review will consider ways that disturbances in the balance of excitation and inhibition might develop and be expressed in cortical networks in association with schizophrenia. This presentation will be framed within a developmental perspective that begins with disturbances in glutamate synaptic development in utero. It will consider developmental correlates and consequences including compensatory mechanisms that increase intrinsic excitability or reduce inhibitory tone. It will also consider the possibility that these homeostatic increases in excitability have potential negative functional and structural consequences. These negative functional consequences of disinhibition may include reduced working memory-related cortical activity associated with the downslope of the “inverted-U” input-output curve, impaired spatial tuning of neural activity and impaired sparse coding of information, deficits in the temporal tuning of neural activity and its implication for neural codes, and conclude by considering the functional significance of noisy activity for neural network function. This presentation will draw on computational neuroscience and pharmacologic and genetic studies in animals and humans, particularly those involving NMDA glutamate receptor antagonists, to illustrate principles of network regulation that give rise to features of neural dysfunction associated with schizophrenia. While this presentation focuses on schizophrenia, the general principles outlined in this review may have broad implications for considering disturbances in the regulation of neural ensembles in psychiatric disorders.
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Major depressive disorder (MDD) is a prevalent neuropsychiatric disease that causes profound social and economic burdens. The impact of MDD is compounded by the limited therapeutic efficacy and delay of weeks to months of currently available medications. These issues highlight the need for more efficacious and faster-acting treatments to alleviate the burdens of MDD. Recent breakthroughs demonstrate that certain drugs, including ketamine and scopolamine, produce rapid and long-lasting antidepressant effects in MDD patients. Moreover, preclinical work has shown that the antidepressant actions of ketamine and scopolamine in rodent models are caused by an influx of extracellular glutamate, elevated BDNF, activation of the mammalian target of rapamycin complex 1 (mTORC1) cascade, and increased number and function of spine synapses in the prefrontal cortex (PFC). Here we review studies showing that both ketamine and scopolamine elicit rapid antidepressant effects through converging molecular and cellular mechanisms in the PFC. In addition, we discuss evidence that selective antagonists of NMDA and muscarinic acetylcholine (mACh) receptor subtypes (i.e., NR2B and M1-AChR) in the PFC produce comparable antidepressant responses. Furthermore, we discuss evidence that ketamine and scopolamine antagonize inhibitory interneurons in the PFC leading to disinhibition of pyramidal neurons and increased extracellular glutamate that promotes the rapid antidepressant responses to these agents. Collectively, these studies indicate that specific NMDA and mACh receptor subtypes on GABAergic interneurons are promising targets for novel rapid-acting antidepressant therapies.
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Depression with comorbid anxiety or cognitive symptoms can vary in terms of symptoms, pathophysiology and antidepressant efficacy, but the underlying neurobiological mechanisms remain to be elucidated. Previous studies from our group and others have shown that as a classic animal model of depression, adolescent social stress (ASS) could stably induce a variety of emotional and cognitive alterations in adult animals, and accompanied by transcriptional decrease in brain-derived neurotrophic factor (BDNF) total and promoter IV levels in the medial prefrontal cortex (mPFC). The present study further identified the GABAergic synaptic and molecular changes downstream of BDNF signaling impairment in the mPFC and roles in various behavioral phenotypes induced by ASS. We found that ASS induced a set of emotional and cognitive symptoms, including decreased social interest, impaired cognitive function, and increased anxiety-like behavior, as well as decreased GABAergic transmission in the mPFC. The specific deletion of BDNF promoter IV directly caused impairments in social interest, cognitive function, and inhibition of GABAergic transmission, but no changes in anxiety-like behavior. Acute microinjections of tropomyosin-related kinase B (TrkB) agonists into the mPFC and chronic antidepressant treatment ameliorated the changes in social behavior and cognition, as well as the reduction in GABAergic synaptic transmission in the mPFC, but not anxiety in previously stressed adult mice. These results suggest that the downstream GABAergic transmission of BDNF signaling in the mPFC involved in depression with comorbid cognitive dysfunction induced by ASS and can be used as a therapeutic target for the treatment of cognitive dysfunction in depression. This article is part of the special issue on Stress, Addiction and Plasticity.
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Objective: The neuroactive steroid metabolite of progesterone, allopregnanolone, is a positive allosteric modulator of γ-aminobutyric acid-A (GABAA) receptors and a putative treatment for mood disorders. This pilot study was performed to determine whether an oral allopregnanolone analog (ganaxolone) may be effective adjunctive therapy for persistent depression despite adequate antidepressant treatment in postmenopausal women. Method: Ten postmenopausal women (mean ± SD age: 62.8 ± 6.3 years; range, 53-69 years) with persistent depression despite adequate antidepressant treatment (current DSM-IV-TR major depressive episode per the Structured Clinical Interview for DSM-IV-TR, Montgomery-Asberg Depression Rating Scale [MADRS] score ≥ 16, and treated with an adequately dosed antidepressant for ≥ 6 weeks) were studied from December 2016 to April 2018. Open-label ganaxolone (225 mg twice daily, increased to 450 mg twice daily if tolerated) was administered for 8 weeks, followed by a 2-week taper. Results: Mean ± SEM total MADRS score (primary endpoint) decreased by 8 weeks (24.4 ± 1.6 to 12.8 ± 2.9, P = .015), and the decrease persisted over the 2-week taper (P = .019); of the 9 subjects who completed the full 8-week treatment period, 44% (4/9) experienced response (MADRS score decrease ≥ 50%) and remission (final MADRS score < 10), which persisted in 100% and 50% of subjects at 10 weeks, respectively. Secondary endpoints showed significant improvement, including Inventory of Depressive Symptomatology-Self-Report score (P = .003), MADRS reduced sleep subscale score (P < .001), total Symptoms of Depression Questionnaire (SDQ) score (P = .012), and scores on SDQ subscales for disruptions in sleep quality (P = .003) and changes in appetite and weight (P = .009) over 8 weeks. No significant effects were observed on quality of life or sexual function. All subjects experienced sleepiness and fatigue; 60% experienced dizziness. Conclusions: In this open-label, uncontrolled pilot study, adjunctive ganaxolone appears to exert antidepressant effects but produces sedation with twice-daily dosing. Ganaxolone may also improve sleep, which may be useful in patients with depression and insomnia. Trial registration: ClinicalTrials.gov identifier: NCT02900092.
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Background Both Major Depressive Disorder (MDD) and Primary Insomnia (PI) have been linked to deficiencies in cortical γ-aminobutyric acid (GABA) and glutamate (Glu) thus suggesting a shared neurobiological link between these two conditions. The extent to which comorbid insomnia contributes to GABAergic or glutamatergic deficiencies in MDD remains unclear. Methods We used single-voxel proton magnetic resonance spectroscopy (¹H MRS) at 4 Tesla to examine GABA+ and Glu relative to creatine (Cr) in the dorsal anterior cingulate cortex (dACC) and in the parieto-occipital cortex (POC) of 51 non-medicated adults with MDD, 24 adults with Primary Insomnia (PI), and 25 age- and sex-matched good sleeper controls (HC). Measures of depression severity and subjective and objective sleep quality were compared with ¹H MRS metabolite measures. Results MDD subjects exhibited a 15% decrease in Glu/Cr in the dACC compared to HC. Within the MDD group, there was a trend inverse correlation between dACC Glu/Cr and anhedonia ratings. We observed no significant association between measures of sleep quality with dACC Glu/Cr in those with MDD. Limitations The protocol and data interpretation would have been enhanced by the recruitment of MDD subjects with a broader range of affect severity and a more comprehensive assessment of clinical features. Conclusions These findings support the role of cortical glutamatergic mechanisms in the pathophysiology of MDD. Insomnia severity did not further contribute to the relative deficiency of glutamatergic measures in MDD.
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There has been much recent progress in understanding of the mechanism of ketamine's rapid and enduring antidepressant effects. Here we review recent insights from clinical and preclinical studies, with special emphasis of ketamine-induced changes in GABAergic synaptic transmission that are considered essential for its antidepressant therapeutic effects. Subanesthetic ketamine is now understood to exert its initial action by selectively blocking a subset of NMDA receptors on GABAergic interneurons, which results in disinhibition of glutamatergic target neurons, a surge in extracellular glutamate and correspondingly elevated glutamatergic synaptic transmission. This surge in glutamate appears to be corroborated by the rapid metabolism of ketamine into hydroxynorketamine, which acts at presynaptic sites to disinhibit the release of glutamate. Preclinical studies indicate that glutamate-induced activity triggers the release of BDNF, followed by transient activation of the mTOR pathway and increased expression of synaptic proteins, along with functional strengthening of glutamatergic synapses. This drug-on phase lasts for approximately 2 h and is followed by a period of days characterized by structural maturation of newly formed glutamatergic synapses and prominently enhanced GABAergic synaptic inhibition. Evidence from mouse models with constitutive antidepressant-like phenotypes suggests that this phase involves strengthened inhibition of dendrites by somatostatin-positive GABAergic interneurons and correspondingly reduced NMDA receptor-mediated Ca²⁺ entry into dendrites, which activates an intracellular signaling cascade that converges with the mTOR pathway onto increased activity of the eukaryotic elongation factor eEF2 and enhanced translation of dendritic mRNAs. Newly synthesized proteins such as BDNF may be important for the prolonged therapeutic effects of ketamine.
Article
Background: Previous magnetic resonance spectroscopic (MRS) studies have reported brain metabolic abnormalities in Major Depressive Disorder (MDD). Nevertheless, results have been inconsistent, focusing on fully developed major depression neglecting first episode patients (FED). Longitudinal studies have also been rare and with short follow-up periods. The aim of the current study was to investigate the differences between healthy controls and first episode patients at baseline, together with changes of metabolites after 1 year follow-up in the ventromedial prefrontal cortex. Methods: 1H-MRS images were obtained from 64 healthy controls and 31 FED patients using a 3T Philips Achieva scanner and processed with TARQUIN software at baseline and after 1 year. Examined metabolites included Glx (corresponding to Glu+Gln-peak), Glu, NAAG, myo-Ins, Cr, GSH and GABA. Clinical improvement was assessed by HDRS-17 scale. Differences in the concentrations of metabolites were evaluated by MANOVA/MANCOVA and GLM repeated measures for longitudinal changes. Results: FED patients had significantly decreased glutamate levels at baseline (p < 0.05) along with significantly elevated GABA (p < 0.01) compared to healthy controls. At the follow up, myo- Ins levels were significantly increased compared to baseline (p < 0.05) LIMITATIONS: The limited sample size, together with the unexpectedly high response rate after treatment (83%) might suggest decreased representativeness of the sample. Conclusions: Results indicate glutamatergic and GABAergic changes taking place within the ventromedial prefrontal region even at the early stage of depression prior to any medication treatment.
Article
Major depressive disorder has become a global public health problem of serious concern. Most of the clinical antidepressants are developed under the classic "monoamine hypothesis (strategy)". These drugs generally have such deficiencies including slow onset and limited efficiency, cognitive impairment and suicidal tendency. Therefore, it is the direction to break through the classic monoamine strategy framework for developing antidepressants that have fast-acting, lower side effects, and cognitive enhancement, to satisfy the major clinical needs. In 2019, the launch of fast-acting antidepressants such as S-ketamine(S-Ket) and brexanolone into market by FDA has opened up new prospects for non-monoamine strategy mainly based on the N-methyl-d-aspartate (NMDA) and γ-aminobutyric acid type A (GABAA) receptors. There are two main trends in the development of fast-onset antidepressants: the optimized multi-target monoamine strategy (modern monoamine strategy) and the non-monoamine strategy based on glutamate(Glu)-GABA balance modulation. Based to the research conducted by foreign peers and our lab, we propose a hypothesis of "monoamine (5-HT)- Glu/GABA long neural circuit", which holds the view that both monoaminergic mechanisms (such as 5-HT neurons located in raphe nucleus) and non-monoaminergic mechanisms (Glu/GABA neurons located in prefrontal cortex) are all part of the rapid-acting antidepressant mechanisms, and both of them form a long neural circuit mediating the fast synaptogenesis of the brain regions including prefrontal cortex. Based on this, it is proposed that fast launch and activation of this circuit may be an important mechanism for fast-onset of antidepressant, in which Glu/GABA (excitation/ inhibition, E/I) rebalance should be the critical rate-limiting step for the onset speed. Therefore, five potential strategies are proposed for fast-acting antidepressant based on this circuit: 1) Achieve the rapid E/I balance by relieving the inhibition of GABA interneurons on glutamatergic pyramidal neurons or directly activating pyramidal neurons; 2) Simultaneously modulate 5-HT neuronal activity and Glu/GABA balance by 5-HT transporter combining with some receptors such as 5-HT1A/1B (namely simultaneous enhancement of the 5-HT and Glu/GABA links); 3) Directly activate mammalian rapamycin target protein complex 1 (mTORC1) and rapidly enhance brain-derived neurotrophic factor (BDNF) -mTOR pathway; 4) Stimulate rapid release of BDNF in the brain; 5) Positive allosteric modulator of synaptic and extrasynaptic GABAA receptors. It is hoped that these ideas will provide possible strategies for the further development of a new generation of antidepressants and provide a useful reference for the further discovery of fast-onset antidepressant candidate targets.
Article
The pathophysiology and treatment of depression has been the focus of intense research and while there is much that remains unknown, modern neurobiological approaches are making progress. This work demonstrates that stress and depression are associated with atrophy of neurons and reduced synaptic connectivity in brain regions such as the hippocampus and prefrontal cortex that contribute to depressive behaviors, and conversely that antidepressant treatment can reverse these deficits. The role of neurotrophic factors, particularly brain derived neurotrophic factor (BDNF) have been of particular interest as these factors play a key role in activity dependent regulation of synaptic plasticity. Here we review the literature demonstrating that exposure to stress and depression decreases BDNF expression in the hippocampus and PFC and conversely that antidepressant treatment can up-regulate BDNF in the adult brain and reverse the effects of stress. We then focus on rapid acting antidepressants, particularly the NMDA receptor antagonist ketamine, which produces rapid synaptic and antidepressant behavioral actions that are dependent on activity dependent release of BDNF. This rapid release of BDNF differs from typical monoaminergic agents that require chronic administration to produce a slow induction of BDNF expression, consistent with the time lag for the therapeutic action of these agents. We review evidence that other classes of rapid acting agents also require BDNF release, demonstrating that this is a common, convergent downstream mechanism. Finally, we discuss evidence that the actions of ketamine are also dependent on another growth factor, vascular endothelial growth factor (VEGF) and its complex interplay with BDNF.
Article
The mechanisms underlying the pathophysiology and treatment of depression and stress-related disorders remain unclear, but studies in depressed patients and rodent models are beginning to yield promising insights. These studies demonstrate that depression and chronic stress exposure cause atrophy of neurons in cortical and limbic brain regions implicated in depression, and brain imaging studies demonstrate altered connectivity and network function in the brains of depressed patients. Studies of the neurobiological basis of the these alterations have focused on both the principle, excitatory glutamate neurons, as well as inhibitory GABA interneurons. They demonstrate structural, functional, and neurochemical deficits in both major neuronal types that could lead to degradation of signal integrity in cortical and hippocampal regions. The molecular mechanisms underlying these changes have not been identified but are thought to be related to stress induced excitotoxic effects in combination with elevated adrenal glucocorticoids and inflammatory cytokines as well as other environmental factors. Transcriptomic studies are beginning to demonstrate important sex differences and, together with genomic studies, are starting to reveal mechanistic domains of overlap and uniqueness with regards to risk and pathophysiological mechanisms with schizophrenia and bipolar disorder. These studies also implicate GABA and glutamate dysfunction as well as immunologic mechanisms. While current antidepressants have significant time lag and efficacy limitations, new rapid-acting agents that target the glutamate and GABA systems address these issues and offer superior therapeutic interventions for this widespread and debilitating disorder.
Article
Background: Altered neurotransmission of γ-aminobutyric acid (GABA) has been implicated in the pathogenesis of depression. Whether SAGE-217, an oral, positive allosteric modulator of GABA type A receptors, is effective and safe for the treatment of major depressive disorder is unknown. Methods: In this double-blind, phase 2 trial, we enrolled patients with major depression and randomly assigned them in a 1:1 ratio to receive 30 mg of SAGE-217 or placebo once daily. The primary end point was the change from baseline to day 15 in the score on the 17-item Hamilton Depression Rating Scale (HAM-D; scores range from 0 to 52, with higher scores indicating more severe depression). Secondary efficacy end points, which were assessed on days 2 through 8 and on days 15, 21, 28, 35, and 42, included changes from baseline in scores on additional depression and anxiety scales, a reduction from baseline of more than 50% in the HAM-D score, a HAM-D score of 7 or lower, and a Clinical Global Impression of Improvement score of 1 (very much improved) or 2 (much improved) (on a scale of 1 to 7, with a score of 7 indicating that symptoms are very much worse). Results: A total of 89 patients underwent randomization: 45 patients were assigned to the SAGE-217 group, and 44 to the placebo group. The mean baseline HAM-D score was 25.2 in the SAGE-217 group and 25.7 in the placebo group. The least-squares mean (±SE) change in the HAM-D score from baseline to day 15 was -17.4±1.3 points in the SAGE-217 group and -10.3±1.3 points in the placebo group (least-squares mean difference in change, -7.0 points; 95% confidence interval, -10.2 to -3.9; P<0.001). The differences in secondary end points were generally in the same direction as those of the primary end point. There were no serious adverse events. The most common adverse events in the SAGE-217 group were headache, dizziness, nausea, and somnolence. Conclusions: Administration of SAGE-217 daily for 14 days resulted in a reduction in depressive symptoms at day 15. Adverse events were more common in the SAGE-217 group than in the placebo group. Further trials are needed to determine the durability and safety of SAGE-217 in major depressive disorder and to compare SAGE-217 with available treatments. (Funded by Sage Therapeutics; ClinicalTrials.gov number, NCT03000530.).
Article
Objective: To review the safety and efficacy of brexanolone for the treatment of moderate to severe postpartum depression (PPD). Data Sources: A literature search through PubMed was conducted (January 2012 to July 2019) using the keyword brexanolone for clinical trials published in the English language. Study Selection and Data Extraction: Articles were selected if they were related to the Food and Drug Administration (FDA) approval of brexanolone or provided novel clinical information regarding this drug entity. Data Synthesis: The findings of the review show that brexanolone administered via IV infusion is both an effective and a fairly safe option for the treatment of PPD. Relevance to Patient Care and Clinical Practice: There are several antidepressants currently used to treat PPD; however, this is the first with FDA approval for this indication. The rapid onset of action of brexanolone may offer a quicker relief of these symptoms and may possibly lead to improved quality of life for both the mother and the child. Conclusion and Relevance: The recent FDA approval of brexanolone may offer an effective treatment of moderate to severe PPD and has been shown to rapidly decrease depression symptoms.
Article
Major depressive disorder (MDD) is a prevalent and heterogeneous disorder. Although there are many treatment options for MDD, patients with treatment-resistant depression (TRD) remain prevalent, wherein delayed time to response results in inferior chances of achieving remission. Recently, therapeutics have been developed that depart from the traditional monoamine hypothesis of depression and focus instead on the glutamatergic, GABAergic, opioidergic, and inflammatory systems. The literature suggests that the foregoing systems are implicated in the pathophysiology of MDD and preclinical trials have informed the development of pharmaceuticals using these systems as therapeutic targets. Pharmaceuticals that target the glutamatergic system include ketamine, esketamine, and rapastinel; brexanolone and SAGE-217 target the GABAergic system; minocycline targets the inflammatory system; and the combinatory agent buprenorphine + samidorphan targets the opioidergic system. The aforementioned agents have shown efficacy in treating MDD in clinical trials. Of particular clinical relevance are those agents targeting the glutamatergic and GABAergic systems as they exhibit rapid response relative to conventional antidepressants. Rapid response pharmaceuticals have the potential to transform the treatment of MDD, demonstrating reduction in depressive symptoms within 24 hours, as opposed to weeks noted with conventional antidepressants. Novel therapeutics have the potential to improve both patient mood symptomatology and economical productivity, reducing the debased human capital costs associated with MDD. Furthermore, a selection of therapeutic targets provides diverse treatment options which may be beneficial to the patient considering the heterogeneity of MDD.
Article
In 2003 Rubenstein and Merzenich hypothesized that some forms of Autism (ASD) might be caused by a reduction in signal-to-noise in key neural circuits, which could be the result of changes in excitatory-inhibitory (E-I) balance. Here, we have clarified the concept of E-I balance, and updated the original hypothesis in light of the field’s increasingly sophisticated understanding of neuronal circuits. We discuss how specific developmental mechanisms, which reduce inhibition, affect cortical and hippocampal functions. After describing how mutations of some ASD genes disrupt inhibition in mice, we close by suggesting that E-I balance represents an organizing framework for understanding findings related to pathophysiology and for identifying appropriate treatments.
Article
Background: Panic disorder is characterised by recurrent unexpected panic attacks consisting of a wave of intense fear that reaches a peak within a few minutes. Panic disorder is a common disorder, with an estimated lifetime prevalence of 1% to 5% in the general population and a 7% to 10% prevalence in primary care settings. Its aetiology is not fully understood and is probably heterogeneous.Panic disorder is treated with psychological and pharmacological interventions, often used in combination. Although benzodiazepines are frequently used in the treatment of panic disorder, guidelines recommend antidepressants, mainly selective serotonin reuptake inhibitors (SSRIs), as first-line treatment for panic disorder, particularly due to their lower incidence of dependence and withdrawal reaction when compared to benzodiazepines. Despite these recommendations, benzodiazepines are widely used in the treatment of panic disorder, probably because of their rapid onset of action. Objectives: To assess the efficacy and acceptability of benzodiazepines versus placebo in the treatment of panic disorder with or without agoraphobia in adults. Search methods: We searched the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR Studies and References), the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1950-), Embase (1974-), and PsycINFO (1967-) up to 29 May 2018. We handsearched reference lists of relevant papers and previous systematic reviews. We contacted experts in the field for supplemental data. Selection criteria: All double-blind (blinding of patients and personnel) controlled trials randomising adults with panic disorder with or without agoraphobia to benzodiazepine or placebo. Data collection and analysis: Two review authors independently checked the eligibility of studies and extracted data using a standardised form. Data were then entered data into Review Manager 5 using a double-check procedure. Information extracted included study characteristics, participant characteristics, intervention details, settings, and outcome measures in terms of efficacy, acceptability, and tolerability. Main results: We included 24 studies in the review with a total of 4233 participants, of which 2124 were randomised to benzodiazepines and 1475 to placebo. The remaining 634 participants were randomised to other active treatments in three-arm trials. We assessed the overall methodological quality of the included studies as poor. We rated all studies as at unclear risk of bias in at least three domains. In addition, we judged 20 of the 24 included studies as having a high risk of bias in at least one domain.Two primary outcomes of efficacy and acceptability showed a possible advantage of benzodiazepines over placebo. The estimated risk ratio (RR) for a response to treatment was 1.65 (95% confidence interval (CI) 1.39 to 1.96) in favour of benzodiazepines, which corresponds to an estimated number needed to treat for an additional beneficial outcome (NNTB) of 4 (95% CI 3 to 7). The dropout rate was lower among participants treated with benzodiazepines (RR 0.50, 95% CI 0.39 to 0.64); the estimated NNTB was 6 (95% CI 5 to 9). We rated the quality of the evidence as low for both primary outcomes. The possible advantage of benzodiazepine was also seen for remission (RR 1.61, 95% CI 1.38 to 1.88) and the endpoint data for social functioning (standardised mean difference (SMD) -0.53, 95% CI -0.65 to -0.42), both with low-quality evidence. We assessed the evidence for the other secondary outcomes as of very low quality. With the exception of the analyses of the change score data for depression (SMD -0.22, 95% CI -0.48 to 0.04) and social functioning (SMD -0.32, 95% CI -0.88 to 0.24), all secondary outcome analyses showed an effect in favour of benzodiazepines compared to placebo. However, the number of dropouts due to adverse effects was higher with benzodiazepines than with placebo (RR 1.58, 95% CI 1.16 to 2.15; low-quality evidence). Furthermore, our analyses of adverse events showed that a higher proportion of participants experienced at least one adverse effect when treated with benzodiazepines (RR 1.18, 95% CI 1.02 to 1.37; low-quality evidence). Authors' conclusions: Low-quality evidence shows a possible superiority of benzodiazepine over placebo in the short-term treatment of panic disorders. The validity of the included studies is questionable due to possible unmasking of allocated treatments, high dropout rates, and probable publication bias. Moreover, the included studies were only short-term studies and did not examine the long-term efficacy nor the risks of dependency and withdrawal symptoms. Due to these limitations, our results regarding the efficacy of benzodiazepines versus placebo provide only limited guidance for clinical practice. Furthermore, the clinician's choice is not between benzodiazepines and placebo, but between benzodiazepines and other agents, notably SSRIs, both in terms of efficacy and adverse effects. The choice of treatment should therefore be guided by the patient's preference and should balance benefits and harms from treatment in a long-term perspective.
Article
Vascular endothelial cell damage is related to many vascular diseases, including cardiovascular disease (CVD). Reactive oxygen species (ROS) play a vital role in the pathogenesis of many cardiovascular diseases. Herein, H2O2-induced human umbilical vein endothelial cell (HUVEC) injury model was used to explore the mechanisms involved in the pathogenesis of ROS-induced oxidative stress and cell dysfunction. Gamma-aminobutyric acid (GABA), a naturally occurring four-carbon non-protein amino acid, has antioxidant activity and anti-inflammatory action. In the present study, we demonstrated that GABA could scavenge free radicals including DPPH and ABTS, reverse H2O2-induced suppression on HUVEC proliferation, HUVEC apoptosis and ROS formation via p65 signaling. Interestingly, GABA treatment alone did not cause significant changes in p65 phosphorylation, suggesting that GABA will not cause imbalance in NF-κB signaling and ROS formation without oxidative stress. Moreover, GABA also modulated Keap1-Nrf2 and Notch signaling pathways upon H2O2 stimulation, suggesting that GABA may exert its effect via multi mechanisms. In conclusion, the present study demonstrated that GABA inhibits H2O2-induced oxidative stress in HUVECs via inhibiting ROS-induced NF-κB and Caspase 3 pathway activation. GABA may, therefore, have potential as a pharmacological agent in the prevention or treatment of oxidative injury-related cardiovascular disease.
Article
Mood disorders represent the largest cause of disability worldwide. The monoaminergic deficiency hypothesis, which has dominated the conceptual framework for researching the pathophysiology of mood disorders and the development of novel treatment strategies, cannot fully explain the underlying neurobiology of mood disorders. Mounting evidence collected over the past two decades suggests the amino acid neurotransmitter systems (glutamate and GABA) serve central roles in the pathophysiology of mood disorders. Here, we review progress in the development of compounds that act on these systems as well as their purported mechanisms of action. We include glutamate-targeting drugs, such as racemic ketamine, esketamine, lanicemine (AZD6765), traxoprodil (CP-101,606), EVT-101, rislenemdaz (CERC-301/MK-0657), AVP-786, AXS-05, rapastinel (formerly GLYX-13), apimostinel (NRX-1074/AGN-241660), AV-101, NRX-101, basimglurant (RO4917523), decoglurant (RG-1578/RO4995819), tulrampator (CX-1632/S-47445), and riluzole; and GABA-targeting agents, such as brexanolone (SAGE-547), ganaxolone, and SAGE-217.
Chapter
Approximately one third of depressed patients fail to respond to currently available antidepressant therapies. Therefore, new conceptual frameworks are needed to identify pathophysiologic pathways and neurobiological targets for the development of novel treatment strategies. In this regard, recent evidence suggests that inflammation may contribute to symptoms relevant to a number of psychiatric disorders and particularly depression. Numerous studies (including meta-analyses) have found elevated peripheral and central inflammatory cytokines and acute phase proteins in depression. Chronic exposure to increased inflammation is thought to drive changes in neurotransmitters and neurocircuits that lead to depressive symptoms and that may also interfere with or circumvent the efficacy of antidepressants. Indeed, patients with high inflammation have been shown to exhibit poor response to conventional antidepressant therapies. Recent developments in our ability to understand and measure the effects of inflammation on the brain in patients have opened new doors for the testing of novel treatment strategies that target the immune system or its consequences on neurotransmitter systems. Such recent developments in the field of behavioral immunology and their translational implications for the treatment of depression are discussed herein.
Article
Background: Post-partum depression is associated with substantial morbidity, and improved pharmacological treatment options are urgently needed. We assessed brexanolone injection (formerly SAGE-547 injection), a positive allosteric modulator of γ-aminobutyric-acid type A (GABAA) receptors, for the treatment of moderate to severe post-partum depression. Methods: We did two double-blind, randomised, placebo-controlled, phase 3 trials, at 30 clinical research centres and specialised psychiatric units in the USA. Eligible women were aged 18-45 years, 6 months post partum or less at screening, with post-partum depression and a qualifying 17-item Hamilton Rating Scale for Depression (HAM-D) score (≥26 for study 1; 20-25 for study 2). Women with renal failure requiring dialysis, anaemia, known allergy to allopregnanolone or to progesterone, or medical history of schizophrenia, bipolar disorder, or schizoaffective disorder were excluded. Patients were randomly assigned (1:1:1) to receive a single intravenous injection of either brexanolone 90 μg/kg per h (BRX90), brexanolone 60 μg/kg per h (BRX60), or matching placebo for 60 h in study 1, or (1:1) BRX90 or matching placebo for 60 h in study 2. Patients, the study team, site staff, and the principal investigator were masked to treatment allocation. The primary efficacy endpoint was the change from baseline in the 17-item HAM-D total score at 60 h, assessed in all patients who started infusion of study drug or placebo, had a valid HAM-D baseline assessment, and had at least one post-baseline HAM-D assessment. The safety population included all randomised patients who started infusion of study drug or placebo. Patients were followed up until day 30. The trials have been completed and are registered with ClinicalTrials.gov, numbers NCT02942004 (study 1) and NCT02942017 (study 2). Findings: Participants were enrolled between Aug 1, 2016, and Oct 19, 2017, in study 1, and between July 25, 2016, and Oct 11, 2017, in study 2. We screened 375 women simultaneously across both studies, of whom 138 were randomly assigned to receive either BRX90 (n=45), BRX60 (n=47), or placebo (n=46) in study 1, and 108 were randomly assigned to receive BRX90 (n=54) or placebo (n=54) in study 2. In study 1, at 60 h, the least-squares (LS) mean reduction in HAM-D total score from baseline was 19·5 points (SE 1·2) in the BRX60 group and 17·7 points (1·2) in the BRX90 group compared with 14·0 points (1·1) in the placebo group (difference -5·5 [95% CI -8·8 to -2·2], p=0·0013 for the BRX60 group; -3·7 [95% CI -6·9 to -0·5], p=0·0252 for the BRX90 group). In study 2, at 60 h, the LS mean reduction in HAM-D total score from baseline was 14·6 points (SE 0·8) in the BRX90 group compared with 12·1 points (SE 0·8) for the placebo group (difference -2·5 [95% CI -4·5 to -0·5], p=0·0160). In study 1, 19 patients in the BRX60 group and 22 patients in the BRX90 group had adverse events compared with 22 patients in the placebo group. In study 2, 25 patients in the BRX90 group had adverse events compared with 24 patients in the placebo group. The most common treatment-emergent adverse events in the brexanolone groups were headache (n=7 BRX60 group and n=6 BRX90 group vs n=7 placebo group for study 1; n=9 BRX90 group vs n=6 placebo group for study 2), dizziness (n=6 BRX60 group and n=6 BRX90 group vs n=1 placebo group for study 1; n=5 BRX90 group vs n=4 placebo group for study 2), and somnolence (n=7 BRX60 group and n=2 BRX90 group vs n=3 placebo group for study 1; n=4 BRX90 group vs n=2 placebo group for study 2). In study 1, one patient in the BRX60 group had two serious adverse events (suicidal ideation and intentional overdose attempt during follow-up). In study 2, one patient in the BRX90 group had two serious adverse events (altered state of consciousness and syncope), which were considered to be treatment related. Interpretation: Administration of brexanolone injection for post-partum depression resulted in significant and clinically meaningful reductions in HAM-D total score at 60 h compared with placebo, with rapid onset of action and durable treatment response during the study period. Our results suggest that brexanolone injection is a novel therapeutic drug for post-partum depression that has the potential to improve treatment options for women with this disorder. Funding: Sage Therapeutics, Inc.
Article
Dysfunction of gamma-aminobutyric acid (GABA) and/or glutamate neurotransmitter systems have increasingly been implicated in the aetiology of Major Depressive Disorder (MDD). It has been proposed that alterations in GABA and/or glutamate result in an imbalance of inhibition and excitation. In a review of the current literature, we identified studies using Magnetic Resonance Spectroscopy (MRS) to examine the neurotransmitters GABA, glutamate, and the composite glutamate/glutamine measure Glx in patients diagnosed with MDD and healthy controls. Results showed patients with MDD had significantly lower GABA levels compared to controls (-0.35 [-0.61,-0.10], p = 0.007). No significant difference was found between levels of glutamate. Sub-analyses were performed, including only studies where the Anterior Cingulate Cortex (ACC) was the region of interest. GABA and Glx levels were lower in the ACC of MDD patients (-0.56 [-0.93,-0.18] p = 0.004, and 0.40 [-0.81,0.01] p = 0.05). This review indicates widespread cortical reduction of GABA in MDD, with a trend towards a localised reduction of Glx in the ACC. However, given both GABA and glutamate appear decreased a simple interpretation in terms of an imbalance of overall excitation-inhibition is not feasible.
Article
People that committed suicide were reported to have enhanced levels of gene transcripts for synaptic proteins in their prefrontal cortex (PFC). Given the close association of suicide with major depressive disorder (MDD), we here assessed whether these changes are related to suicide or rather to depression per se. We used quantitative PCR to determine mRNA levels of 32 genes encoding for proteins directly involved in glutamatergic or GABAergic synaptic transmission in postmortem samples of the anterior cingulate cortex (ACC) and the dorsolateral PFC (DLPFC). Seventy-two brain samples from 3 groups of subjects were derived from the Stanley Medical Research Institute (SMRI): i) patients with MDD who committed suicide (MDD-S), ii) MDD patients who died of non-suicidal causes (MDD-NS) and iii) age-matched, non-psychiatric control subjects. In the ACC, a significantly enhanced expression of genes related to glutamatergic or GABAergic synaptic transmission was found only in MDD-S patients, whereas in MDD-NS patients, decreased levels for these transcripts were found. Moreover, in the DLPFC, expression of these genes was decreased in MDD-S, relative to MDD-NS patients, whereas both groups showed increased expression compared to control subjects. In conclusion, our findings indicate that MDD is associated with increases in GABA and glutamate related genes in the DLPFC (irrespective of suicide), while in the ACC, the increase in GABA and glutamate related genes may relate to suicide, rather than to MDD per se.
Article
The central nervous system (CNS) is unique in being the only organ system lacking lymphatic vessels to assist in the removal of interstitial metabolic waste products. Recent work has led to the discovery of the glymphatic system, a glial-dependent perivascular network that subserves a pseudolymphatic function in the brain. Within the glymphatic pathway, cerebrospinal fluid (CSF) enters the brain via periarterial spaces, passes into the interstitium via perivascular astrocytic aquaporin-4, and then drives the perivenous drainage of interstitial fluid (ISF) and its solute. Here, we review the role of the glymphatic pathway in CNS physiology, the factors known to regulate glymphatic flow, and the pathologic processes in which a breakdown of glymphatic CSF-ISF exchange has been implicated in disease initiation and progression. Important areas of future research, including manipulation of glymphatic activity aiming to improve waste clearance and therapeutic agent delivery, are also discussed. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease Volume 13 is January 24, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Article
Evidence for the potential utility of GABAB antagonists has been assembled from a variety of sources, including clinical experience with the GABAB agonist baclofen, murine genetic GABAB knock-outs, rodent studies of GABAB receptor expression and function following treatment with antidepressant therapies, animal models of depression, and some functional and post mortem data from human subjects. Definitive testing of GABAB antagonists in depression, however, still awaits the development of potent, selective and brain-penetrant compounds for human testing.
Article
Women are about twice as likely as are men to develop depression during their lifetime. This Series paper summarises evidence regarding the epidemiology on gender differences in prevalence, incidence, and course of depression, and factors possibly explaining the gender gap. Gender-related subtypes of depression are suggested to exist, of which the developmental subtype has the strongest potential to contribute to the gender gap. Limited evidence exists for risk factors to be specifically linked to depression. Future research could profit from a transdiagnostic perspective, permitting the differentiation of specific susceptibilities from those predicting general psychopathologies within and across the internalising and externalising spectra. An integration of the Research Domain Criteria framework will allow examination of gender differences in core psychological functions, within the context of developmental transitions and environmental settings. Monitoring of changing socioeconomic and cultural trends in factors contributing to the gender gap will be important, as well as the influence of these trends on changes in symptom expression across psychopathologies in men and women.
Article
Cortical networks are composed of glutamatergic excitatory projection neurons and local GABAergic inhibitory interneurons that gate signal flow and sculpt network dynamics. Although they represent a minority of the total neocortical neuronal population, GABAergic interneurons are highly heterogeneous, forming functional classes based on their morphological, electrophysiological, and molecular features, as well as connectivity and in vivo patterns of activity. Here we review our current understanding of neocortical interneuron diversity and the properties that distinguish cell types. We then discuss how the involvement of multiple cell types, each with a specific set of cellular properties, plays a crucial role in diversifying and increasing the computational power of a relatively small number of simple circuit motifs forming cortical networks. We illustrate how recent advances in the field have shed light onto the mechanisms by which GABAergic inhibition contributes to network operations.
Article
The inhibitory gamma-aminobutyric acid (GABA) system is involved in the etiology of most psychiatric disorders, including schizophrenia, autism spectrum disorder (ASD) and major depressive disorder (MDD). It is therefore not surprising that proton magnetic resonance spectroscopy ((1) H-MRS) is increasingly used to investigate in vivo brain GABA levels. However, integration of the evidence for altered in vivo GABA levels across psychiatric disorders is lacking. We therefore systematically searched the clinical (1) H-MRS literature and performed a meta-analysis. A total of 40 studies (N = 1,591) in seven different psychiatric disorders were included in the meta-analysis: MDD (N = 437), schizophrenia (N = 517), ASD (N = 150), bipolar disorder (N = 129), panic disorder (N = 81), posttraumatic stress disorder (PTSD) (N = 104), and attention deficit/hyperactivity disorder (ADHD) (N = 173). Brain GABA levels were lower in ASD (standardized mean difference [SMD] = -0.74, P = 0.001) and in depressed MDD patients (SMD = -0.52, P = 0.005), but not in remitted MDD patients (SMD = -0.24, P = 0.310) compared with controls. In schizophrenia this finding did not reach statistical significance (SMD = -0.23, P = 0.089). No significant differences in GABA levels were found in bipolar disorder, panic disorder, PTSD, and ADHD compared with controls. In conclusion, this meta-analysis provided evidence for lower brain GABA levels in ASD and in depressed (but not remitted) MDD patients compared with healthy controls. Findings in schizophrenia were more equivocal. Even though future (1) H-MRS studies could greatly benefit from a longitudinal design and consensus on the preferred analytical approach, it is apparent that (1) H-MRS studies have great potential in advancing our understanding of the role of the GABA system in the pathogenesis of psychiatric disorders. Hum Brain Mapp, 2016. © 2016 Wiley Periodicals, Inc.
Article
Background: Multiple neuropsychiatric disorders, e.g., depression, are linked to imbalances in excitatory and inhibitory neurotransmission and prefrontal cortical dysfunction, and are concomitant with chronic stress. Methods: We used electrophysiologic (n = 5-6 animals, 21-25 cells/group), neuroanatomic (n = 6-8/group), and behavioral (n = 12/group) techniques to test the hypothesis that chronic stress increases inhibition of medial prefrontal cortex (mPFC) glutamatergic output neurons. Results: Using patch clamp recordings from infralimbic mPFC pyramidal neurons, we found that chronic stress selectively increases the frequency of miniature inhibitory postsynaptic currents with no effect on amplitude, which suggests that chronic stress increases presynaptic gamma-aminobutyric acid release. Elevated gamma-aminobutyric acid release under chronic stress is accompanied by increased inhibitory appositions and terminals onto glutamatergic cells, as assessed by both immunohistochemistry and electron microscopy. Furthermore, chronic stress decreases glucocorticoid receptor immunoreactivity specifically in a subset of inhibitory neurons, which suggests that increased inhibitory tone in the mPFC after chronic stress may be caused by loss of a glucocorticoid receptor-mediated brake on interneuron activity. These neuroanatomic and functional changes are associated with impairment of a prefrontal-mediated behavior. During chronic stress, rats initially make significantly more errors in the delayed spatial win-shift task, an mPFC-mediated behavior, which suggests a diminished impact of the mPFC on decision making. Conclusions: Taken together, the data suggest that chronic stress increases synaptic inhibition onto prefrontal glutamatergic output neurons, limiting the influence of the prefrontal cortex in control of stress reactivity and behavior. Thus, these data provide a mechanistic link among chronic stress, prefrontal cortical hypofunction, and behavioral dysfunction.