The pharmacology of antidepressants is not entirely clear. The earliest and probably most popular scientific theory of antidepressant action is the monoamine hypothesis (which can be traced back to the 1950s), which states that depression is due to an imbalance (most often a deficiency) of the monoamine neurotransmitters (namely serotonin, norepinephrine and dopamine). It was originally proposed based on the observation that certain hydrazine anti-tuberculosis agents produce antidepressant effects, which was later linked to their inhibitory effects on monoamine oxidase, the enzyme that catalyses the breakdown of the monoamine neurotransmitters. All antidepressants that have entered the market before 2011 had the monoamine hypothesis as their initial theoretical basis, with the possible exception of agomelatine, which acts on a dual melatonergic-serotonergic pathway. Despite the success of the monoamine hypothesis it has a number of limitations: for one, all monoaminergic antidepressants have a delayed onset of action of at least a week; and secondly, there are a sizeable portion (>40%) of depressed patients that do not adequately respond to monoaminergic antidepressants. Further evidence to the contrary of the monoamine hypothesis are the recent findings that a single intravenous infusion with ketamine, an antagonist of the NMDA receptor — a type of glutamate receptor — produces rapid (within 2 hours), robust and sustained (lasting for up to 2 weeks) antidepressant effects. Monoamine precursor depletion also fails to alter mood. To overcome these flaws with the monoamine hypothesis a number of alternative hypotheses have been proposed, including the glutamate, neurogenic, epigenetic, cortisol hypersecretion and inflammatory hypotheses. Another hypothesis that has been proposed which would explain the delay is the hypothesis that monoamines don't directly influence mood, but influence emotional perception biases.
Monoamine hypothesis
In 1965, Joseph Schildkraut published a review article stating that several researchers had found an association between depression and deficiency of the catecholamine family of monoamine neurotransmitters, which they had begun calling the "catecholamine hypothesis", also known as the monoamine hypothesis. By 1985, the monoamine hypothesis was mostly dismissed until it was revived with the introduction of SSRIs through the successful direct-to-consumer advertising, often revolving around the claim that SSRIs correct a chemical imbalance caused by a lack of serotonin within the brain. Serotonin levels in the human brain is measured indirectly by sampling cerebrospinal fluid for its main metabolite, 5-hydroxyindole-acetic acid, or by measuring the serotonin precursor, tryptophan. In one placebo controlled study funded by the National Institute of Health, tryptophan depletion was achieved, but they did not observe the anticipated depressive response. Similar studies aimed at increasing serotonin levels did not relieve symptoms of depression. At this time, decreased serotonin levels in the brain and symptoms of depression have not been linked Although there is evidence that antidepressants inhibit the reuptake of serotonin, norepinephrine, and to a lesser extent dopamine, the significance of this phenomenon in the amelioration of psychiatric symptoms is not known. Given the low overall response rates of antidepressants, and the poorly understood causes of depression, it is premature to assume a putative mechanism of action of antidepressants. While MAOIs, TCAs and SSRIs increase serotonin levels, others prevent serotonin from binding to 5-HT2Areceptors, suggesting it is too simplistic to say serotonin is a "happy neurotransmitter". In fact, when the former antidepressants build up in the bloodstream and the serotonin level is increased, it is common for the patient to feel worse for the first weeks of treatment. One explanation of this is that 5-HT2A receptors evolved as a saturation signal (people who use 5-HT2A antagonists often gain weight), telling the animal to stop searching for food, a mate, etc., and to start looking for predators. In a threatening situation it is beneficial for the animal not to feel hungry even if it needs to eat. Stimulation of 5-HT2A receptors will achieve that. But if the threat is long lasting the animal needs to start eating and mating again - the fact that it survived shows that the threat was not so dangerous as the animal felt. So the number of 5-HT2A receptors decreases through a process known as downregulation and the animal goes back to its normal behavior. This suggests that there are two ways to relieve anxiety in humans with serotonergic drugs: by blocking stimulation of 5-HT2A receptors or by overstimulating them until they decrease via tolerance.
Hypothalamic-pituitary-adrenal axis One manifestation of depression is an altered hypothalamic-pituitary-adrenal axis (HPA axis) that resembles the neuro-endocrine (cortisol) response to stress, that of increased cortisol production and a subsequent impaired negative feedback mechanism. It is not known whether this HPA axis dysregulation is reactive or causative for depression. A 2003 briefing suggests that the mode of action of antidepressants may be in regulating HPA axis function. A 2011 study combines aspects of the HPA axis theory and the neurogenic theory (see below). The researchers showed that mice under unpredictable chronic mild stress (a well-known animal model of depression) have impaired hippocampal neurogenesis and greatly reduced ability of the hippocampus to regulate the HPA axis, causing anhedonia as measured by the Cookie Test. Administration of fluoxetine (an SSRI) without removing the stressor causes increased hippocampal neurogenesis, normalization of the HPA axis, and improvement of anhedonia. If X-ray irradiation is used on the hippocampus before drug treatment to prevent neurogenesis, no improvement of anhedonia occurs. However, if an irradiated mouse is given a corticotropin-releasing factor 1 antagonist – a drug that directly targets the HPA axis – anhedonia is improved. Combined with the fact that irradiation without stressing does not impair hippocampal control of the HPA axis, the authors conclude that fluoxetine works by improving hippocampal neurogenesis, which then helps restore the HPA axis, in turn leading to improvements in depression symptoms such as anhedonia.
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