Early pharmacotherapeutic agents used for schizophrenia targeted neuronal pathways related to psychosis. One of the first pharmacologic agents used in the treatment of patients with schizophrenia was the antihypertensive agent reserpine. The antipsychotic effects of this drug result from reduction of synaptic dopamine release.
For those who believe that focusing on these variations in neuropharmacologic binding effects is of minor importance, recall that the first effective antiobsessive, the tricyclic antidepressant chlomipramine, differs from imipramine by only 1 chloride atom substitution.31 It was hard to believe that chlomipramine would be effective for obsessive-compulsive disorder (OCD) when imipramine was not, but that is, in fact, what happened.
Iloperidone is an antipsychotic that was approved in May 2009 for the acute treatment of schizophrenia in adults. The mechanism of action, which involves antagonism of serotonin-2A (5HT-2A) and dopamine 2 receptors with a high 5HT-2A/D2 ratio, is similar to other atypical antipsychotics. Its efficacy appears to be similar to haloperidol, risperidone, and ziprasidone. It also has a very low EPS and akathisia profile, for reasons that are not well understood. It has strong alpha-adrenergic antagonism effects, and therefore requires a cautious dosing and titration schedule to reduce the potential for orthostatic hypotension and dizziness. The lack of affinity of iloperidone for other receptors (e.g., histamine, muscarinic) results in a low antihistaminic and anticholinergic side effect profile.37
Asenapine, approved for acute and maintenance treatment of schizophrenia, has a unique human receptor signature with binding affinities and antagonistic properties that are substantially different from other available schizophrenia treatments. Asenapine, which is administered sublingually, is a potent antagonist at several serotonin receptors38 and also has high affinity for alpha-adrenergic and dopaminergic receptors, which suggests potential for both antipsychotic and cognitive-enhancing properties.39 Clinical trial data demonstrate strong efficacy for positive symptoms, and there is some evidence of beneficial effects on negative and cognitive symptoms.
Expanding the Treatment Paradigm in Patients With Schizophrenia: Beyond Psychotic Symptoms
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