4.5.3.2 Serotonin Reuptake Inhibitors
Reuptake through the presynaptic membrane is the major deactivation mechanism for
serotonin. It is prevented by the tricyclic antidepressants (see section 4.3.7), among
which the tertiary amines are more potent at serotonergic terminals than are the
secondary bases, whereas the reverse is true for catecholaminergic synapses.
Recently, a number of selective 5-HT reuptake inhibitors have enjoyed widespread
clinical success in the treatment of depression. Fluoxetine (4.112), sertraline (4.113),
fluvoxamine (4.114), and paroxetine (4.115) belong to this more recently developed
group of SSRIs (selective serotonin reuptake inhibitors). They are dimethylaminoethyl
or dimethylaminopropyl derivatives of ring systems usually carrying an electron-
attracting substituent (-CF 3 or -CN). All of these drugs are potent antidepressants, with
a lower cardiotoxicity than the classical tricyclic agents, which strongly suggests that
endogenous depression is a function of the availability of catecholamines as well as of
serotonin. This does not contradict the previous discussion of the involvement of adren-
ergic systems (section 4.3.7). In fact, both mechanisms probably contribute to antide-
pressant action. A number of compounds exploit this twofold mechanism. Venlafaxine
(4.116), for example, is an inhibitor of both serotonin reuptake and norepinephrine
reuptake. At low therapeutic doses, venlafaxine behaves like an SSRI; at higher doses
(e.g., more than 225 mg/day) it produces effects attributable to norepinephrine reuptake
inhibition. Therefore, when administered in doses greater than 300 mg/day, it may
confer a broader range of therapeutic effects than SSRIs alone.
When an SSRI agent is used with a MAO inhibitor, a dangerous pharmacodynamic
interaction may occur. The combination of increased stores of monoamine together
with reuptake inhibition leads to a phenomenon termed serotonin syndrome. This
syndrome, which arises from a marked increase in synaptic serotonin, is clinically
NEUROTRANSMITTERS AND THEIR RECEPTORS 253