The GABAergic Hypothesis of Depression/Anxiety

The GABAergic Deficit Hypothesis of Major Depressive Disorder – free full-text /PMC3412149/ – Mol Psychiatry. – Apr 2011

This is a very technical article on a newer theory about what “causes” depression and anxiety.

My increasing desperation during bouts of increasing anxiety lately has motivated me to search for alternate routes of treating it (since I cannot have benzodiazepines due to taking opioids). It feels like my depression and anxiety always come together, so any new idea about treating depression gives me hope it could also alleviate my anxiety.

Here we summarize clinical and preclinical evidence supporting a central and causal role of GABAergic deficits in the etiology of depressive disorders. Increasing evidence points to an association between major depressive disorders (MDDs) and diverse types of GABAergic deficits.

Studies of depressed patients indicate that MDDs [Major Depressive Disorders] are accompanied by reduced brain concentration of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) as well as alterations in the subunit composition of the principal receptors (GABAA receptors) mediating GABAergic inhibition.

In addition, there is abundant evidence that GABA plays a prominent role in the brain control of stress, the most important vulnerability factor in mood disorders

Furthermore, preclinical evidence suggests that currently used antidepressant drugs designed to alter monoaminergic transmission as well as non-pharmacologic therapies may ultimately act to counteract GABAergic deficits.

In particular, GABAergic transmission plays an important role in the control of hippocampal neurogenesis and neural maturation, which are now established as cellular substrates of most if not all antidepressant therapies.

Lastly, comparatively modest deficits in GABAergic transmission in GABAA-receptor-deficient mice are sufficient to cause behavioral, cognitive, neuroanatomical, and neuroendocrine phenotypes as well as antidepressant drug response characteristics expected of an animal model of MDD.

The GABAergic hypothesis of MDD suggests that alterations in GABAergic transmission represent fundamentally important aspects of the etiological sequelae of major depressive disorders that are reversed by monoaminergic antidepressant drug action.

Brain imaging studies suggest a role for altered GABAergic transmission in anxiety and depressive disorders

GABA deficits in depression

The strongest evidence that GABAergic deficits may contribute to depressive disorders is based on reduced GABA levels in plasma and cerebrospinal fluid or resected cortical tissue of depressed patients.

GABAAR deficits in anxiety disorders

Reduced abundance of GABAAR binding sites suggests a role for GABAergic deficits in anxiety disorders.

Similar analyses have revealed GABAAR deficits in the temporal lobe of patients with generalized anxiety disorder and medial prefrontal cortex of patients suffering from posttraumatic stress disorder

Collectively, the data suggest that different anxiety disorders involve GABAAR deficits in different brain regions.

Conclusions, limitations, and outlook

The collective evidence summarized here indicates that reduced concentrations of GABA and altered expression of GABAARs are common abnormalities observed in MDDs.

GABAergic transmission is vital for the control of stress and impaired by chronic stress, the most important vulnerability factor of MDD.

Despite remarkable recent progress we are left with a number of significant gaps in understanding. GABAergic deficits are not unique to MDD but similarly implicated in a number of other neuropsychiatric disorders, especially schizophrenia.

The question arises whether and how GABAergic deficits can help to differentiate between these different disorders. Moreover, the mechanisms that lead to initial GABAergic deficits remain poorly understood and they are so far not explained by mutations or functional polymorphisms in genes intimately involved in GABAergic transmission.

We have listed a number of reasons that explain why currently available GABA potentiating drugs are ineffective as antidepressants, yet it remains to be established whether next generation GABAergic drugs that are more selective for GABAARs expressed in corticolimbic circuits affected in depression exhibit more convincing efficacy as antidepressants.

Furthermore, a number of aspects of major depressive disorders are not known to involve GABAergic deficits. For example, there is increasing preclinical evidence that resilience to stress and stress-induced neuropsychiatric disorders including depression are subject to epigenetic mechanisms, yet there is little evidence for epigenetic regulation of GABAergic transmission.

Transcriptional and immunohistochemical alterations in brain of depressed patients suggest links between depressive disorders and inflammation, apoptosis and oligodendrocyte dysfunction, but none of these have been linked to GABAergic deficits.

Many, many more details in the full article: The GABAergic Deficit Hypothesis of Major Depressive Disorder – free full-text /PMC3412149/

2 thoughts on “The GABAergic Hypothesis of Depression/Anxiety

  1. Kathy C


    “Research Reveals a Surprising Solution for Anxiety”

    We don’t have to think about all of that sciencey stuff. The content marketers at this site have the “cure.” No doubt that compassion may alleviate something or serve as a distraction, but like mindfulness, it is just more misreported and distorted science. It is really troubling the length these marketers and self promoting, wanna be web influencers will go to. They don’t ever even stop and consider how this kind of thing could be harmful.

    Another peddler of Woo and magical thinking.

    Liked by 1 person

    1. canarensis

      I couldn’t resist (trying to) read the article on compassion…made it most of the way thru before I realized that in another few seconds my palm was going to be welded to my face forevermore.
      Sheeeesh. I guess at least they weren’t selling an aromatherapy product called “compassion”…tho that part may have shown up farther on.

      Thank you (I think ;-) for reminding me of the depths of woowoo they can hit –tho living in Oregon, I rarely get a chance to forget. Unfortunately.
      Best to ya.



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