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Depression, a widespread and incapacitating mental health condition, significantly affects individuals' well-being and daily functioning, ranking as a leading cause of global disability. According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), experiencing a major depressive episode entails enduring symptoms for a minimum of two weeks, including depressed mood, loss of interest or pleasure, altered sleep or appetite, fatigue, and cognitive impairments, among others. ^[1]The worldwide prevalence of depressive disorders, encompassing major depressive disorder (MDD) and dysthymia, was approximately 3440.1 per 100,000 individuals in 2019, underscoring its pervasive impact.^[2]

Understanding the origins of depression remains complex due to its multifaceted nature involving genetic predispositions and environmental influences. Genetic studies involving large datasets have identified numerous gene variations associated with MDD, shedding light on its genetic underpinnings.^[3] Moreover, environmental stressors can trigger epigenetic modifications, altering gene expression patterns implicated in depression pathogenesis. Structural and functional brain imaging studies have revealed notable changes in regions such as the cingulate cortex, prefrontal cortex, hippocampus, and amygdala, indicating aberrant neural circuitry in depression.^[4] Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, diminished neurotrophic support, and neuroinflammation have also been implicated as contributing factors.^[5]

The pathophysiology of depression is complex and multifaceted, with various hypotheses proposed regarding altered neurotransmitter levels. Recent research underscores alterations in the sensorimotor and default mode networks as consistent features of depression. Notably, disruptions in these functional networks, mediated by neurotransmitters like glutamate and gamma-aminobutyric acid (GABA), are implicated in depression pathophysiology. Monoamines such as norepinephrine, dopamine, and serotonin further modulate mood and cognitive functions, suggesting intricate neurotransmitter dysregulation in depression. The monoamine hypothesis suggests that depletion of brain monoamine neurotransmitters, including norepinephrine, dopamine, and serotonin, contributes to depression, supported by the observation that many antidepressant therapies increase extracellular concentrations of these neurotransmitters. Another hypothesis implicates elevated glutamate levels in depression, based on preclinical evidence of antidepressant effects with N-methyl-D-aspartate (NMDA) receptor antagonists.^[6] However, evidence for elevated glutamate levels in depression is inconsistent, with studies reporting both increases and decreases in different brain regions. The GABAergic deficit hypothesis proposes that defects in GABAergic neural inhibition contribute to MDD, with reduced GABA levels observed in various brain regions of individuals with depression. This hypothesis is supported by findings of altered expression of GABA_A receptors and reduced levels of neuroactive steroids (NASs) in individuals with depression. Furthermore, impaired GABAergic signaling is implicated in postpartum depression and bipolar disorder.^{[7, 8]} To sum up, understanding these hypotheses and their implications for depression treatment is crucial for developing effective interventions. Investigating GABAergic compounds and NASs as potential therapies may offer novel treatment approaches with the aim of improving long-term outcomes for individuals with MDD.

Currently approved drugs for MDD encompass a spectrum of classes, each targeting different neurotransmitter systems. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are among the most commonly prescribed due to their relatively favorable side effect profiles compared to older antidepressants like tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). However, TCAs and MAOIs can still be effective but are often reserved for cases where SSRIs and SNRIs fail or are not tolerated.^{[9, 10]}

Despite their efficacy, TCAs carry a higher risk of adverse effects, including anticholinergic effects, orthostatic hypotension, and cardiotoxicity, and are associated with a higher risk of overdose-related fatalities compared to SSRIs and SNRIs. MAOIs, while effective, have potentially life-threatening interactions with certain foods and medications due to their mechanism of action inhibiting monoamine oxidase.^[10]

Monoaminergic antidepressants typically require several weeks of treatment before patients experience significant improvement in mood symptoms. However, response rates to these medications vary, with a significant proportion of patients failing to achieve remission. Moreover, even among those who initially respond, relapse rates can be high, especially if multiple treatment steps are required.

Research into novel antidepressants with alternative mechanisms of action is ongoing. Ketamine, for instance, acts as an NMDA receptor antagonist, leading to downstream effects on glutamatergic signaling pathways involved in synaptic plasticity and mood regulation.^[11] Its rapid onset of action, often within hours, makes it a promising option for treatment-resistant depression, although concerns remain regarding its long-term safety and potential for abuse. In addition to ketamine, there is growing interest in targeting the GABA neurotransmitter system for the development of new antidepressants.^[12] GABA is the primary inhibitory neurotransmitter in the brain and has been implicated in the pathophysiology of depression. Various compounds targeting GABA receptors or modulating GABAergic neurotransmission are currently under investigation, offering potential alternatives for patients who do not respond to traditional monoaminergic antidepressants.

In summary, depression arises from a complex interplay of genetic vulnerabilities, environmental stressors, and neurobiological alterations, involving structural, functional, and neurotransmitter dysregulations in the brain. Understanding these mechanisms is crucial for developing more effective interventions and treatments for depression.

References

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2. Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Psychiatry, 2022. 9(2): p. 137-150.

3. Levey, D.F., et al., Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals highlight new therapeutic directions. Nat Neurosci, 2021. 24(7): p. 954-963.

4. Sarawagi, A., N.D. Soni, and A.B. Patel, Glutamate and GABA Homeostasis and Neurometabolism in Major Depressive Disorder. Front Psychiatry, 2021. 12: p. 637863.

5. Li, Z., et al., Major Depressive Disorder: Advances in Neuroscience Research and Translational Applications. Neurosci Bull, 2021. 37(6): p. 863-880.

6. Wang, S., et al., Targeting NMDA Receptors in Emotional Disorders: Their Role in Neuroprotection. Brain Sci, 2022. 12(10).

7. Anderson, K.M., et al., Convergent molecular, cellular, and cortical neuroimaging signatures of major depressive disorder. Proc Natl Acad Sci U S A, 2020. 117(40): p. 25138-25149.

8. Li, J., et al., Cortical structural differences in major depressive disorder correlate with cell type-specific transcriptional signatures. Nat Commun, 2021. 12(1): p. 1647.

9. Mantas, I., et al., Update on GPCR-based targets for the development of novel antidepressants. Mol Psychiatry, 2022. 27(1): p. 534-558.

10. Protti, M., et al., New-generation, non-SSRI antidepressants: Drug-drug interactions and therapeutic drug monitoring. Part 2: NaSSAs, NRIs, SNDRIs, MASSAs, NDRIs, and others. Med Res Rev, 2020. 40(5): p. 1794-1832.

11. Matveychuk, D., et al., Ketamine as an antidepressant: overview of its mechanisms of action and potential predictive biomarkers. Ther Adv Psychopharmacol, 2020. 10: p. 2045125320916657.

12. Fogaça, M.V. and R.S. Duman, Cortical GABAergic Dysfunction in Stress and Depression: New Insights for Therapeutic Interventions. Front Cell Neurosci, 2019. 13: p. 87.