Time to demote monoamine hypotheses of depression to a historical footnote

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James Wallace

Major depressive disorder (MDD) is a chronic mental illness and the leading cause of disability worldwide, with more than 264 million people affected globally (World Health Organization, 2019).

However, the pathogenesis of this debilitating disorder remains elusive mired by suboptimal diagnostic biomarkers, delayed therapeutic response to first-line antidepressant treatments and low remission rates (Lui et al., 2011, Krishanan & Nestler, 2008). 

This has cast a long shadow over the efficacy of these antidepressants (i.e. specifically, serotonin reuptake inhibitor (SSRI)), and the underlying hypothesis, a collection of divergent theories birthed 55 years ago and known as “the monoamine hypotheses”. 

These hypotheses, initially separate before morphing over time, postulated that the pathogenesis of MDD results from a deficiency of two monoamine neurotransmitters: noradrenaline (NE; see Schildkraut, 1965) and serotonin (5-HT; see Coppen, 1967), in the synaptic cleft and that the combined inhibition and synthesis of these monoamines is an effective treatment (Lui et al., 2011).

Almost a decade after the original hypothesis, deficiency of the dopamine neurotransmitters was added to the hypothesis, specific to schizophrenia (Tissot, 1975), and bipolar disorder (see Ashok et al., 2017).

Each of these neurotransmitters transmits messages between nerve cells throughout the body: NE mobilises energy resources to increase arousal and alertness; 5-HT regulates mood; while dopamine is associated with the reward system and pleasure in the brain (Pinel & Barnes, 2018).

The monoamine hypothesis gained traction from the notion, advanced by Schildkraut, that chemical compounds which deplete catecholamines cause depression, while those which enhance concentrations are effective antidepressants (Mulinari, 2012). Initial clinical evidence was two-fold.

First, reserpine (i.e. an antipsychotic alkaline used to treat hypertensive vascular disease) was found to deplete monoamines; second, the mechanism of action of monoamine oxidase inhibitors (MAOI) and tricyclic antidepressants (TCA) prevented monoamine neurotransmitters reduction in the synaptic space and induced synthesis which activated postsynaptic receptors (Hillhouse & Porter, 2015). 

This rationale supported SSRI development in the mid-1980s (Mulinari, 2012), as the pendulum swung in favour of the serotonin over the NE-related hypothesis.

SSRI’s mechanism of action prevents normal serotonin regulation, increases the synthesis of serotonin neurotransmitters which enhance postsynaptic receptor activation to augment mood regulation (Pinel & Barnes, 2018).

Fluoxetine was the first developed SSUI; its mechanism of action is to block the “re-uptake” of serotonin neurotransmitters (Rossi et al., 2004), which prompts reattachment to receptors which produce the additional mood-enhancing signals which are circulated throughout the body (Pinel & Barnes, 2018). 

The development of SSRIs further supported the monoamine hypothesis and helped popularise the term “chemical imbalance” to explain the cause of depression and MDD.

However, over subsequent decades scientists have been unable to demonstrate unequivocal efficacy of the hypothesis or SSRIs.

In a clear logical fallacy, the claimed efficacy of SSRIs has been cited as indirect support for the serotonin hypothesis, while contradictory evidence accumulated (Lacasse & Leo, 2005).

For example, Mendels et al. (1975) administered high doses of serotonin-inducing amino acids, levodopa and L tryptophan, into 15 hospitalised depressed patients in a double-blind placebo-controlled study, which failed induce clinical improvement.

Two decades later, Heninger et al. (1996) attempted to induce depression in patients off medication and healthy controls through depletion of noradrenaline and serotonin levels. The study failed to support either hypothesis.

Neither serotonin or catecholamine (i.e. noradrenaline) depletion produced an increase in clinical depression in healthy controls or depressed patients off medication, which Heninger et al. (1996) concluded forced a major revision of the current monoamine theories of depression.

A related study by Salomon et al. (1997) showed monoamine depletion in healthy subjects did not induce depressive symptoms. 

The authors suggested their findings showed the efficacy of antidepressant drugs was not due to a common mechanism related to the monoamine system (Salomon et al., 1997).

Further, a study by Berman et al., (2002) found the simultaneous functional disruption of serotonin and catecholamine (i.e. both dopamine and noradrenaline) did not exacerbate symptoms in unmedicated depressed subjects.

The authors concluded its findings lent support to the notion that monoamines regulate mood in actively depressed patients via indirect mechanisms.

Lacasse and Leo (2005) compiled a litany of evidence which contradicted the serotonin theory, which included clinical trials which showed: no statistic difference in efficacy between SSRIs and tricyclic antidepressants; St. John’s Wort and placebos outperformed SSRIs, and exercise as effective as SSRIs.

In a separate review by Krishanan and Nestler (2008), it was concluded there is some evidence that monoamine-based agents are potent antidepressants but alterations in monoamine function contributed only marginally to MDD genetic vulnerability. 

Taken together, the torrent of studies with findings inconsistent with the original hypothesis demonstrated beyond doubt that monoamine deficiency is too simplistic to explain the pathogenesis of MDD (Lui et al., 2011).

This inescapable conclusion motivated the postulation several new hypotheses over subsequent decades, including the monoaminergic receptor hypothesis and, more recently, the neuroplasticity hypothesis (Racagni & Popoli, 2008), which differ markedly from the original hypotheses (Lui et al., 2011).

One study by Andrews et al., (2015) even attempted a direct challenge to the prevailing monoamine hypothesis in a study which paradoxically hypothesised depression results from elevated, rather than deficient, serotonin concentrations.

Further, that elevation of serotonin (i.e. via SSRIs) disturbed energy homeostasis and worsened symptoms (Andrews et al., 2015). 

Elsewhere, the monoaminergic receptor hypothesis, first postulated in the 1980s, that depression is associated with monoamine receptor lesions.

It was hypothesised that the effective desensitisation of monoamine autoreceptor (such as 5-HT), rather than its enhanced synthesis and inhibited reuptake is the key mechanism of antidepressant efficacy (Lui et al., 2011). However, this hypothesis has been superseded by contemporary neuroscience research. 

The neuroplasticity hypothesis purports that depression results from stress-induced neuronal damage which impairs brain function (Lui et al., 2011), which, inter alia, is mediated by gene-environment interactions, endocrine, immunological and metabolic mediators (Krishanan & Nestler, 2008).

Substantial gaps in the knowledge and effective treatment for MDD remain. However, the original and modified monoamine hypothesis failed to account for the aetiology of this complex disorder which has demoted the hypothesis to a historical footnote among ever-growing sections of the scientific community.

This essay was submitted as part of my MSc in Psychology at Leeds Beckett University in January 2020. Students are reminded copying this essay is plagiarism. 

Suggested citation

Wallace, J. (2020). Time to demote monoamine hypotheses of depression to a historical footnote. Retrieved from: www.james-wallace.uk

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