The atypical
antipsychotic drugs are considered a first-line treatment for
mania in
bipolar disorder with many having a proven superiority to the classical mood stabilisers. This review addresses the pharmacological mechanisms underlying this therapeutic efficacy, as well as those mechanisms considered responsible for the adverse effects of
antipsychotic drugs, with a particular focus on the recently introduced
asenapine. The high efficacy in bipolar
mania of
haloperidol, a relatively selective
dopamine D2-like receptor antagonist, indicates that the one common receptor mechanism underlying
antipsychotic effects on
mania is antagonism at the D2 receptor.
Serotonin receptors are implicated in
antidepressant response, and relief of depressed mood in mixed states is likely to involve
drug effects at one, or more likely several interacting,
serotonin receptors.
Asenapine shows a unique breadth of action at these sites, with potential effects at clinical doses at 5HT1A, 1B, 2A, 2C, 6 and 7 receptors. Antagonism at alpha2
adrenoceptors may also be involved. Adverse effects include those classically associated with
dopamine D2 receptor blockade, the extrapyramidal side effects (EPS), and which are relatively diminished in the atypical (in comparison with the conventional)
antipsychotics. A variety of protective mechanisms against EPS associated with different drugs include low D2 affinity, D2 partial agonism, high 5-HT2A and 2C antagonism. Similar effects at the D2 and 5-HT2C receptors may underlie the low propensity for
hyperprolactinaemia of the atypicals, although the strong
prolactin-elevating effect of
risperidone reflects its relatively high blood/brain concentration ratio, a consequence of it being a substrate for the
p-glycoprotein pump.
Weight gain is a further concern of
antipsychotic treatment of
bipolar disorder which is particularly severe with
olanzapine.
Histamine H1, alpha1
adrenergic and particularly 5-HT2C receptors are implicated in this effect, although the lower propensity for
weight gain shown by
asenapine which, like
olanzapine, binds to these receptors, indicates that other protective receptor mechanisms, or subtle differences in the
5-HT2C receptor-mediated effects, may be important. Of other peripheral and central effects, the pharmacological basis of sedation (
H1 receptors) and
postural hypotension (alpha1
adrenoceptors) are rather better understood. The relative benefits of atypical
antipsychotics like
asenapine can be understood from their receptor pharmacology, and this understanding is key to the future development of improved treatment for
bipolar disorder.