Antidepressant - Mechanisms of Action

Mechanisms of Action

The therapeutic effects of antidepressants are believed to be caused by their effects on neurotransmitters and neurotransmission. The Monoamine Hypothesis is a biological theory stating that depression is caused by the underactivity in the brain of monoamines, such as dopamine, serotonin, and norepinephrine. In the 1950s the monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants were accidentally discovered to be effective in the treatment of depression. These findings and other supporting evidence led Joseph Schildkraut to publish his paper called "The Catecholamine Hypothesis of Affective Disorders" in 1965. Schildkraut associated low levels of neurotransmitters with depression. Research into other mental impairments such as schizophrenia also found that too little activity of certain neurotransmitters were connected to these disorders. The hypothesis has been a major focus of research in the fields pathophysiology and pharmacotherapy for over 25 years.

Monoamine oxidase inhibitors (MAOIs) block the degradation of the monoamine neurotransmitters serotonin, norepinephrine, and dopamine by inhibiting the enzyme monoamine oxidase, leading to increased concentrations of these neurotransmitters in the brain and an increase in neurotransmission.

Tricyclic antidepressants (TCAs) prevent the reuptake of various neurotransmitters, including serotonin, norepinephrine, and to a much less extent, dopamine. Nowadays the most common antidepressants are selective serotonin reuptake inhibitors (SSRIs), which prevent the reuptake of serotonin (thereby increasing the level of active serotonin in synapses of the brain). Other novel antidepressants affect norepinephrine reuptake, or different receptors on the nerve cell.

While MAOIs, TCAs and SSRIs increase serotonin levels, others prevent serotonin from binding to 5-HT_2A receptors, suggesting it is too simplistic to say serotonin is a happy hormone. 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-HT_2A receptors evolved as a saturation signal (people who use 5-HT_2A 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-HT_2A 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-HT_2A 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-HT_2A receptors or by overstimulating them until they decrease via tolerance.

The stimulation or blocking of different receptors on a cell affects its genetic expression. Recent findings have shown that neurogenesis, and thus, changes in brain morphogenesis, mediate the effects of antidepressant drugs.

Another hypothesis is that antidepressants may have some longer-term effects due to the promotion of neurogenesis in the hippocampus, an effect found in mice. Other animal research suggests that antidepressants can affect the expression of genes in brain cells, by influencing "clock genes".

Other research suggests that delayed onset of clinical effects from antidepressants indicates involvement of adaptive changes in antidepressant effects. Rodent studies have consistently shown upregulation of the 3, 5-cyclic adenosine monophosphate (cAMP) system induced by different types of chronic but not acute antidepressant treatment, including serotonin and norepinephrine uptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, lithium and electroconvulsions. cAMP is synthesized from adenosine 5-triphosphate (ATP) by adenylyl cyclase and metabolized by cyclic nucleotide phosphodiesterases (PDEs). Data also suggest that antidepressants can modulate neural plasticity in long-term administration.

One theory regarding the cause of depression is that it is characterized by an overactive hypothalamic-pituitary-adrenal axis (HPA axis) that resembles the neuro-endocrine (cortisol) response to stress. These HPA axis abnormalities participate in the development of depressive symptoms, and antidepressants serve to regulate HPA axis function.

Aimee Hunter and her team discovered that the brain has been somewhat conditioned to produce effects resulting from antidepressants, proven by the use of a placebo. Even when the placebo was distributed to those who have never ingested any antidepressants in their lives have shown a brain response like that of previous users. This shows that by just "remembering" what the drugs look like will induce the antidepressant response.