Monoamine hypothesis problem

However, the amine theory of depression and mania is overly simplistic. It fails to explain why the pharmacologic effects of any of the antidepressant and anti-mania drugs on neurotransmission occur immediately, whereas the time course for a therapeutic response occurs over several weeks. Furthermore, the potency of the antidepressant drugs in blocking neurotransmitter uptake often does not correlate with clinically observed antidepressant effects. This suggests that decreased uptake of the neurotransmitter is only an initial not be directly responsible for the antidepressant effects. It has been proposed that presynaptic inhibitory receptor densities in the brain decrease over a 2 to 4 week period with antidepressant drug use. This down-regulation of inhibitory receptors permits greater synthesis and release of neurotransmitters into the synaptic cleft and enhanced signaling in the postsynaptic neurons, presumably leading to a therapeutic response. effect of the drugs, which may not be directly responsible for the antidepressant effects. It has been proposed that presynaptic inhibitory receptor densities in the brain decrease over a 2 to 4 week period with antidepressant drug use. This down-regulation of inhibitory receptors permits greater synthesis and release of neurotransmitters into the synaptic cleft and enhanced signaling in the postsynaptic neurons, presumably leading to a therapeutic response.Difficulties with this hypothesis include the facts that (1) postmortem studies of patients do not reveal decreases in the brain levels of NE or 5-HT; (2) although antidepressant drugs may cause changes in brain amine activity within hours, clinical response requires weeks; (3) most antidepressants ultimately cause a downregulation of amine receptors; (4) bupropion has minimal effects on brain NE or 5-HT; (5) Brain-derived neurotrophic factor (BDNF) is depressed in the brains of depressed patients.