Ziprasidone was the fifth atypical
antipsychotic approved by Food and Drug Administration (FDA) for use in bipolar
mania and mixed episodes. This atypical
antipsychotic has a unique profile, as it acts primarily through serotonergic and dopaminergic receptor antagonism, but also exerts effects as an inhibitor of
norepinephrine reuptake. Moreover, one of the advantages of
ziprasidone is its safety profile as it is not associated with clinically significant metabolic side effects and little or no effect on
prolactin level or
anticholinergic side effects. Most of the studies evaluating
ziprasidone's efficacy and safety are short-term double-blind, placebo-controlled studies in acute
mania and mixed episodes. In two of them,
ziprasidone was associated to significant improvement in the primary measures assessed. However, an add-on study,
lithium plus
ziprasidone showed similar results than
lithium monotherapy, although there was a significant advantage for the combination within the first week. In a more recent trial,
ziprasidone was compared with placebo and
haloperidol as monotherapies, again beating placebo. In that trial,
ziprasidone appeared to be safer and better tolerated, although less likely efficacious than
haloperidol. Particularly, subjects treated with
ziprasidone were less likely to switch to depression. Despite the well-studied efficacy of
ziprasidone in the first weeks of treatment, there are no controlled trials that evaluate the role and efficacy of
ziprasidone in long-term treatment of
bipolar disorder (BD). Overall, in the open-label extension studies, there was a global improvement at all visits compared with baseline scores. Furthermore,
ziprasidone appears to offer some
antidepressant effect in patients with major depressive episode and resistant to treatment, as demonstrated in add-on open-label studies with
ziprasidone plus
selective serotonin reuptake inhibitor (SSRI).