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.