Depression: Current and future hypotheses

The major dominating depression hypothesis in biological science over the past half century has been the monoamine hypothesis (1965>). This hypothesis posits that depression is caused by deficiency of monoamine neurotransmitters (serotonin, dopamine and noradrenaline), which was later refined mostly to serotonin (at least in the mainstream). This hypothesis is based primarily upon the observation that serotonergic agents are effective in treating depression. This is the oldest depression hypothesis, and the one which most clinical antidepressants are still based upon. Through the media it has become ingrained into the consciousness of mass culture (for review see [1]), and speaks of a simple reductionist view of mood which parallels a reductionist pharmacological understanding of disease. In its raw form (e.g. serotonin deficiency as the underlying cause of depression) this hypothesis has been shaken in science. Below I will quickly go through some of the main evidence arguing for and against this hypothesis.

The monoamines in depression

An obvious place to start to unravel the role of monoamines in mood is to modify their levels in healthy controls and depressed patients. Studies through the late 1900s showed that inducing monoamine deficiency in healthy, depressed or recovered depression patients only produced depressive symptoms in recovered patients who had been treated by drugs acting upon the respective monoamine system [2]. However more recent ATD (acute tryptophan depletion) experiments in healthy individuals have revealed a more subtle role of serotonin in mood memory bias [3-6]. There are also cases of genetic monoamine deficiency in humans; genetic deficiency of sepiapterin reductase leads to a combined deficit of serotonin and dopamine, causing dopamine-responsive parkinsonism and serotonin-responsive eating disorder, cognition, and ultradian sleep-wake rhythm (melatonin deficiency), but no depression [7]. Perhaps the best support for gross monoamine deficiency in depression are in vivo reports of increased MAO-A activity [8-10] and inconsistent reports of lowered serum tryptophan [11].

In reality dysfunction of neurotransmitter systems in depression could occur at multiple levels beyond their basic metabolism (synthesis, reuptake and catabolism). For instance the serotonin system comprises of a family of 5-HT (1-7) receptors further divided into subtypes which are heterogeneously distributed in the body and activated by serotonin (5-HT). All these receptors have differing effects on the postsynaptic neuron, but most of which are metabotropic, so serve to modulate specific intracellular pathways. The serotonin system also comprises of presynaptic autoreceptors which homeostatically regulate serotonin release. The past decade of research into synaptic plasticity has taught us that receptors are not fixed in the nervous system, in fact many are extremely dynamic and their expression is controlled by a variety of environmental factors/stimuli. Overall, in vivo brain imaging studies looking directly for monoamine dysfunction in depression have so far failed to consistently support monoamine hypotheses [12], and some post-mortem receptor-level studies have shown decreased 5-HT1A binding [13], and increased 5-HT2 expression [14,15]. These studies above both justify and limit the role of serotonin in depression, especially when considered in context of the plethora of other abnormalities found in depression, some of which are discussed below.

New paradigms for understanding depression

The serotonin hypothesis of depression is endlessly challenged by observations made on the therapeutic and physiological activity of antidepressant agents. For instance current serotonergic antidepressants (e.g. SSRI & SNRI) typically take weeks to bring about clinical symptom improvement despite fairly instant blockade of serotonin uptake, a fact which may partly be attributable to the homeostatic activity of 5-HT autoreceptors [16]. Serotonergic antidepressants also only tend to work in 50% of patients, and many treatments which have no primary effect on monoamine systems have strong antidepressant effects (e.g. glutamatergic agents, neuropeptide modulators, neurotrophic modulators and NOS antagonists). 5-HT1A is often regarded as the major antidepressant target of serotonergic medications, however one of the most effective treatments for TRD (treatment-resistant depression) is ECT (electro-convulsive therapy) which seems to have no effect on 5-HT1A activity [17], but instead promotes neurotrophic and glutamatergic modifications [18,19]. In fact neurotrophic pathways have been shown to be required for the antidepressant activity of serotonergic drugs [20], and glutamatergic drugs such as NMDA antagonists have over the past 10 years displayed remarkably rapid and robust antidepressant activity in animals and humans [19,21]. A single IV dose of ketamine (NMDA antagonist) can send TRD patients into remission within hours, an effect which is sustained for over a week; unfortunately these drugs are typically too dangerous for clinical use. This leads us to the current understanding of how serotonergic antidepressants may at least partially work: by indirectly modulating downstream intracellular targets which promote structural changes. Serotonergic antidepressants have been shown to modulate the glutamate system, nNOS (neuronal nitric oxide synthase), and neurotrophic and inflammatory cascades amongst other systems. 

Indeed it has become clear that there is far more to depression than serotonin dysfunction and even simple gross chemical imbalances. In the brain, at the molecular level depression is associated with changes to many receptor systems, intracellular signalling pathways, and redox [19,22]; at the neuroanatomical-level depression is associated with glia loss [23], altered neuronal morphology, and atrophy to structures such as the hippocampus and PFC [22]. Even throughout the body depression is associated with biological changes such as inflammation and metabolic disturbances. For instance recent research has linked body-wide inflammation to mood disorders [11]; IFN-α treatment causes inflammation-induced depression in humans which correlates with CSF KA and quinolinic acid (NMDA agonist) concentrations rather than serotonin depletion [24]. This new depression pathway is supported by a recent study which found increased microglial quinolinic acid in sub-regions of the anterior cingulate cortex in severe depression [25]. Recent studies have also consistently found massive changes in NMDA receptor subunit expression in depression [26-30], for instance 115% increase in GluN2A in the amygdala [30] and 50% reduction of GluN2A and B in the PFC [26]. These results are striking given the prevalence and importance of the NMDAR to basic cognition.

In summary, the monoamine hypothesis has been an extremely important step in the evolution of our understanding of mood disorders, although our complacence and attachment to it has perhaps closed many minds.  However some new depression hypotheses have emerged over the past decade, all of which broaden and deepen our understanding of mood disorders.  These include the neurotrophic hypothesis (circa 2000>) [18,31], the inflammatory hypothesis (circa 2005>) [11,32], and most recently glutamate/NMDA hypotheses of depression (circa 2005>) [19,21,33].

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