Partial agonists in schizophrenia

The editorial by Bolonna & Kerwin (2005) is both timely and important. The authors succinctly present the case for the use of partial agonists of dopamine receptors, concluding that ‘the reviewed evidence suggests a promising future for dopamine receptor partial agonists’. While this is arguably true on the basis of the evidence presented, theoretical and empirical concerns regarding the use of these medications remain. The introduction of aripiprazole on an individual patient level may prove problematic (DeQuardo, 2004; Ramaswamy et al, 2004). Although effective switching strategies from atypical agents to aripiprazole have been described, a number of reports of worsening psychosis following the introduction of aripiprazole (DeQuardo, 2004; Ramaswamy et al, 2004) have been published. While these cases may be accounted for by unrelated illness relapse, other theoretical explanations should be considered. Up-regulation of dopamine receptors is well recognised during treatment with neuroleptics, and results in supersensitivity to dopamine at the sites of receptor blockage. This has led to the concept of a neuroleptic-induced supersensitivity psychosis (Steiner et al, 1990) wherein up-regulation effectively outstrips receptor blockade with emergent psychosis resistant to treatment. Supersensitivity could explain cases of psychosis developing with aripiprazole. Cessation of an antagonist with subsequent introduction of a partial agonist could result in a net excess of neurotransmission due to over-stimulation of a supersensitive system (despite the partial agonist demonstrating sub-maximal stimulation in normal systems). The high receptor affinity of partial agonists may make such symptoms difficult to treat, as few drugs are likely to be able to displace these agents from receptor complexes. Drugs that can displace partial agonists run the risk of negating the therapeutic effects of stabilisation of the dopaminergic system in schizophrenia, perhaps most importantly at times of relapse when patients are likely to receive ‘as required’ doses of potent D2 antagonists. While empirical evidence largely supports the primary efficacy of these agents (DeLeon et al, 2004), clinical experience of partial agonists is in its infancy. Goodquality data from naturalistic studies are required to establish the effectiveness of these drugs, but in the meantime we call for post-marketing surveillance to quantify the scale of the problem of cross-titration.