4.1 Serotonergic drugs
Numerous drugs affect the serotonergic neurotransmission1,4,8,9,16. Table 116 provides a list of drugs commonly used (or misused) that have been associated with serotonin syndrome.
The involvement of antipsychotics in serotonin syndrome is discussed in the literature. Case reports suggest an association between specifically second‐generation antipsychotics and serotonin syndrome17. These drugs antagonize dopamine (D2) and serotonin (5‐HT2A) receptors, but many of them also act as partial agonists of 5‐HT1A receptors 18,19. The exact mechanism is not fully comprehended, but a common hypothesis in the literature is that the 5-HT2A receptor antagonism by these second‐generation antipsychotics may result in serotonin accumulation and cumulative activation of 5-HT1A receptors 1,2,4,6,10,17,20.
Paradoxically, there is also anecdotal evidence supporting the effectiveness of second‐generation antipsychotics – specifically olanzapine and chlorpromazine – in the treatment of serotonin syndrome. Safety and efficacy has not been thoroughly evaluated, and second‐generation antipsychotics are not considered part of the recommended treatment 1,2.
The drugs commonly associated with the development of serotonin syndrome differs by their mechanism of action with respect to serotonin. In table 21, these drugs are classified based on their pharmacological mechanism of action.
The inhibition of specific cytochrome P450 (CYP450) enzymes are a matter of potential great clinical importance as it can result in increased systemic exposure of some serotonergic drugs. For instance, concomitant use of an SSRI (e.g. sertraline) and tramadol – the most common cause of serotonin syndrome – may create a vicious cycle where the SSRI inhibits the metabolism of tramadol, which is a pro-drug that is activated by the CYP2D6 enzyme, causing increased serotonergic activity1,4.