The monoamine theory

The monoamine theory of depression and drugs acting on monoamine neurotransmission has dominated the treatment of depression for over 30 years. Indeed, the monoamine reuptake inhibitors and the MAOIs were shown to have antidepressant activity by chance, and the discoveries of their modes of action were instrumental in developing the monoamine theory. In the days when the monoamine theory of depression was evolving, the focus was more on norepinephrine (NE) than 5HTor dopamine (DA). The theory developed from observations that reserpine depleted monoamines and caused depression, whereas the MAOIs and monoamine reuptake inhibitors enhanced monoamine function and thereby relieved depression. More recent studies indicate that it may be the inhibition of glial uptake 2 sites by normetanephrine (NMN) or other inhibitors of uptake 2 that results in an enhanced accumulation of NE in the synapse. The hypothesis proposed by Schildkraut and Mooney suggests that drugs or other agents that increase levels of NMN or otherwise inhibit the extraneuronal monoamine transporter, uptake 2, in the brain will accelerate the clinical effects of NE reuptake inhibitor antidepressant drugs.13 This hypothesis, as well as others discussed below, continue to drive pharmaceutical research for the Holy Grail, that is, a fast-acting antidepressant. However, Duman and others14 would contend that this approach may not be possible based on their neurogenesis hypothesis of antidepressant efficacy (see Section 6.03.3.1.1).19 To discover an antidepressant that has an effect within days rather than weeks has challenged researchers for decades to understand the reasons for the delay in onset of the antidepressant action. The focus has been mainly on the mechanism of action of SSRIs and one theory that inhibition of 5HT reuptake initially causes activation of the presynaptic 5HT1A receptors on the cell bodies in the dorsal and median raphe nucleus.15 This inhibits the firing of 5HT neurons, so reducing rather than increasing the release of 5HT from the terminals.16

According to the hypothesis first proposed by Blier et al. the primary mechanism of action of SSRIs is an increased activation of 5HT postsynaptic receptors in the forebrain, but this is not achieved until the raphe 5HT1A receptors become desensitized.16 The problem with putting this into practice clinically is that there are no selective 5HT1A receptor antagonists available for clinical use. Artigas et al. pioneered the use of pindolol as a 5HT1A receptor antagonist for proof of concept studies.15 However, evidence from at least half of the trials failed to show that the combination provided a faster onset of action. A few cases showed an improved response rate, but there was no benefit in treating resistant depression. Despite the limited clinical efficacy observed with this combination, pharmaceutical companies are still developing compounds with this combined approach to achieve fast onset of action.

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