Dr KASIKRISHNARAJA DPM DNB Asst proff of psychiatry

Classifications Based on Acute Pharmacological Actions There are at least eight separate pharmacological mechanisms of action and more than two dozen antidepressants TCAs SSRIs SNRIs

SARIs NDRIs NRIs NaSSA SSNRI DRI Mood stabilizers MAOIs RIMAs

The topography of serotonin receptor subtypes in different serotonin pathways may thus help to explain how side effects are mediated. Thus, acute stimulation of serotonin 2A and 2C receptors in the projection from raphe to limbic cortex may cause the acute mental agitation,anxiety, or induction of panic attacks that can be observed with early dosing of an SSRI . Acute stimulation of the 2A receptors in the basal ganglia may lead to changes in motor movements due to serotonin's inhibition of dopamine neurotransmission there. Thus, akathisia (restlessness), psychomotor retardation, or even mild parkinsonism and dystonic movements can result. Stimulation of serotonin 2A receptors in the brainstem sleep centers may cause rapid muscle movements called myoclonus during the night; it may also disrupt slow-wave sleep and cause nocturnal awakenings. Stimulation of serotonin 2A receptors in the spinal cord may inhibit the spinal reflexes of orgasm and ejaculation and cause sexual dysfunction. Stimulation of serotonin 2A receptors in mesocortical pleasure centers may reduce dopamine activity there and cause apathy (e.g., apathetic recoveries discussed in or decreased libido.

Stimulation of serotonin 3 receptors in the hypothalamus or brainstem may cause nausea or vomiting, respectively. Stimulation of serotonin 3 and 4 receptors in the gastrointestinal tract may cause increased bowel motility,gastrointestinal cramps and diarrhea

At least four clinically important noradrenergic receptor subtypes in various parts of the brainand body may be responsible for mediating these undesirable actions. This includes alpha 1 postsynaptic receptors, alpha 2 presynaptic receptors, alpha 2 postsynaptic receptors, and beta 1 postsynaptic noradrenergic receptors. Side effects of selective NRIs seem to involve not only specific noradrenergic receptor subtypes, but also the action of nor-epinephrine at its receptors in specific areas of the body, including brain, spinal cord, heart, gastrointestinal tract, and urinary bladder.

Thus, acute stimulation of beta 1 receptors in the cerebellum or peripheral sympathetic nervous system may cause motor activation or tremor. Acute stimulation of noradrenergic receptors in the limbic system maycause agitation. Acute stimulation of noradrenergic receptors in the brainstem cardiovascular centers and descending into the spinal cord may alter blood pressure.

Stimulation of beta 1 noradrenergic receptors in the heart may cause changes in heart rate. Stimulation of noradrenergic receptors in the sympathetic nervous system may also cause a net reduction of parasympathetic cholinergic tone,since these systems often have reciprocal roles in peripheral organs and tissues. Thus, a "pseudo-anticholinergic" syndrome of dry mouth, constipation, and urinary retention may be caused by selective NRIs, even though they have no direct actions on cholinergic receptors

In addition to reboxetine, which is currently marketed, other selective NRIs are in clinical testing at present for depression or attention deficit disorder. These include atomoxetine.

Bupropion Other prodopaminergic agents are available as antidepressants in some countries,for example, amineptine in France and Brazil. Brasofensine, a dopamine reuptake blocker, is in clinical testing. Another vaguely prodopaminergic agent is modafanil,recently approved for the treatment of narcolepsy but not depression.

There is another chemical class of antidepressants known as phenylpiperazines,which are more selective than the tricyclic antidepressants and whose most powerful pharmacological action is to block serotonin 2A receptors. This includes the agents nefazodone and trazodone. Nefazodone is the prototypical member of the SARI class of antidepressants. It is a powerful serotonin 2A antagonist with secondary actions as a serotonin and norepinephrine reuptake inhibitor

norepinephrine turns off its own release by interacting with presynaptic alpha 2 autoreceptors on noreadrenergic neurons. norepinephrine also turns off serotonin release by interacting with presynaptic alpha 2heteroreceptors on serotonergic neurons. If an alpha 2 antagonist is administered, norepinephrine can no longer turn off its own release, and noradrenergic neurons are thus disinhibited . That is, the alpha 2 antagonist "cuts the brake cable" of the noradrenergic neuron, and norepinephrine release is thereby increased.

Alpha 2 antagonists act at serotonergic neurons to "cut the brake cable" of noradrenergic inhibition ie norepinephrine brake on serotonin. Serotonin release is therefore increased. A second mechanism to increase serotonin release after administration of an alpha2 antagonist may be even more important. Recall that norepinephrine neurons fromthe locus coeruleus innervate the cell bodies of serotonergic neurons in the midbrain raphe

Two other alpha 2 antagonists are marketed as antidepressants in some countries (but not the United States), namely, mianserin (worldwide except in the United States) and setiptilene (Japan)