The Neurogenic Theory of Depression: A Case Against the Monoamine Theory of Depression

Written by Justin Belko

A critical examination of SSRIs and atypical antidepressants may help us better understand the nature of depression.

History of the Monoamine Theory

The monoamine theory asserts that depression is due to a neurotransmitter deficiency of serotonin and norepinephrine, a theory that dates back to the 1950s [1]. The theory stems primarily from studies on two drugs, reserpine and iproniazid that occurred around the same time.

Reserpine, the primary alkaloid of Indian Snakeroot, was largely used for its sedative and anti-hypertensive properties. In 1954, M.D Edward Freis found a correlation between chronic reserpine use and depression, which promoted further investigation into reserpine’s safety [2]. Further investigation concluded that reserpine inhibited the uptake of monoamines, norepinephrine and dopamine, prompting it to be considered depressogenic.

Around the same time, the novel tuberculosis drug Iproniazid was found to have antidepressant effects but was discontinued in the 60s when it was found to be hepatoxic [3]. Despite both drugs only being popular for a short time, they left the false notion that depression is rooted in a monoamine deficit upon the medical community.

Interestingly, numerous studies over the last ten years have found that there is actually no relationship between reserpine’s usage and depression, suggesting that studies from the 1950s may have mistaken correlation for causation [1, 4]. While iproniazid undoubtedly raises monoamine levels, its antidepressant properties are likely the downstream effects of elevated monoamines, which promote neurogenesis and neurostructural changes.

Indian Snakeroot

An Alternative Take On The Nature of Depression

As contradictions to the monoamine theory accumulate, one might look to alternative explanations for the biological nature of depression. One such theory is the Neurogenic Theory of depression. The theory asserts that depression can be attributed to fluctuations in neurogenesis and neuroplasticity [5-12]. More specifically that chronic stress often associated with negative affective disorders such as depression decreases neuroplasticity in the hippocampus and prefrontal cortex (mPFC), which in turn, can further contribute to one’s depression if no intervention is taken. Unsurprisingly, individuals suffering from chronic depression were observed to have a reduction in grey matter in the mPFC and hippocampus [14-15].

The mechanisms by which chronic stress hinders neurogenesis are likely via cortisol release and by decreasing neurotrophic factors, most notably brain-derived neurotrophic factor (BDNF) [5-7, 9, 13-15]. BDNF is significant in the fact that it plays a role as a neuroprotectant, ensuring the brain maintains its plasticity.

It’s important to note that the Monoamine theory isn't completely incorrect. Given neurogenesis is multimodal and depends on numerous variables, monoamine serotonin plays a positive role in neurogenesis [16]. That being said, the monoamine theory is incorrect in its assertion that monoamine deficit alone causes depression.

Contradictions in the Use of SSRIs for Depression

One of the largest contradictions to the Monoamine theory can be seen when observing the mechanisms behind SSRIs and the delay between when a patient begins use of the medication and the onset of therapeutic effects. If a deficit in serotonin was the sole cause of depression, then shortly after the first or second dose the SSRI should alleviate depressive symptoms, because the brain is reuptaking less serotonin leaving more in the synapse. However, this is not the case, as SSRIs generally take 2-6 weeks before therapeutic effects can be observed [17-19]. Rather than a serotonin increase directly alleviating depression, it is instead downstream neurogenesis and other structural changes taking place over the course of multiple weeks that alleviate depression.

Atypical Antidepressants as Instigators of Neurogenesis

Ketamine, Esketamine, Agmatine Sulfate, Memantine, and MXE all share similar mechanisms of action by which they alleviate depressive symptoms in an acute fashion, unlike SSRIs [20-25]. It seems that all of these drugs modulate neurotransmitter levels and receptors of the glutamate system. The glutamate system consists of NMDA and AMPA receptors, both of which are affected when taking the aforementioned drugs [26-27]. This modulation of glutamate neurotransmitters and receptors promotes neurogenesis and other structural changes, resulting in the alleviation of depression and anxiety [21, 28].

LSD and psilocybin are both commonly known classical serotonergic psychedelics and are growing in popularity for their acute antidepressant effects. As psychedelics have made their resurgence in American culture, so has their relevance in Western medicine. Serotonergic psychedelics like LSD, psilocybin, and ayahuasca were found to have lasting antidepressant and anxiolytic effects and are sparking great interest in the world of medical research [29-35]. The mechanisms by which this occurs are thought to be through neurogenesis and other structural changes that occur upon administration [35-36].

Depression Treatments Going Forward

So what is the takeaway?  One can hope as research progresses and the monoamine theory is cast aside, people suffering from depression will be readily allowed alternatives to current approach of SSRI treatment. A deeper understanding of neurogenesis, neuroplasticity, and the mechanisms by which atypical antidepressants operate will allow sensible research studies to take place surrounding these compounds, a trend that's slowly becoming apparent in the United States and abroad.

References

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