Alpha-adrenoceptor modulation hypothesis of antipsychotic atypicality

Although all currently used antipsychotic drugs act as dopamine (DA) D2 receptor antagonists, clozapine, the prototype for atypical antipsychotics, shows superior efficacy, especially regarding negative and cognitive symptoms, in spite of a significantly reduced central D2 receptor occupancy compared with typical (conventional) antipsychotic drugs. Clozapine, as well as several other atypicals, displays significant affinities also for several other neurotransmitter receptors, including other dopaminergic receptors, alpha-adrenergic receptors and different serotonergic and cholinergic receptors, which in several ways may contribute to the clinical effectiveness of the drugs. Preclinical and clinical results suggest a dysregulated mesocorticolimbic DA system in schizophrenia, with an impaired prefrontal DA projection, which may relate to negative and cognitive symptoms, concomitant with an overactive or overreactive striatal DA projection, with bearing on psychotic (positive) symptomatology. Available data suggest that blockage of alpha1-adrenoceptors by antipsychotics may contribute to suppress positive symptoms, especially in acute schizophrenia, whereas alpha2-adrenoceptor blockage, a prominent effect of clozapine and, to some extent, risperidone but not other antipsychotics, may rather be involved in relief of negative and cognitive symptoms. Whereas alpha1-adrenoceptor blockage may act by suppressing, at the presynaptic level, striatal hyperdopaminergia, alpha2-adrenoceptor blockage may act by augmenting and improving prefrontal dopaminergic functioning. Thus, the prominent alpha1- and alpha2-adrenoceptor blocking effects of clozapine may generally serve to stabilize dysregulated central dopaminergic systems in schizophrenia, allowing for improved efficacy in spite of a reduced central D2 receptor occupancy compared with typical antipsychotic drugs.