Dopamine Partial Agonists

This review examines the development of dopamine partial agonists as a new class of antipsychotic agents. Partial agonists have a lower intrinsic activity at receptors than full agonists, allowing them to act either as a functional agonist or a functional antagonist, depending on the surrounding levels of naturally occurring neurotransmitter (full agonist). In the absence of a full agonist, partial agonists show functional agonist activity, binding to the receptor to produce a response. In the presence of a full agonist, partial agonists show functional antagonist activity, as receptor binding reduces the response from that seen with the full agonist. A partial agonist at dopamine D₂ receptors therefore offers an attractive option for the treatment of schizophrenia. It should act as a functional antagonist in the mesolimbic dopamine pathway, where excessive dopamine activity is thought to cause positive symptoms, but show functional agonist activity in the mesocortical pathway, where reduced dopamine activity is thought to be associated with negative symptoms and cognitive impairment. In addition, it should avoid the complete blockade of the nigrostriatal or tuberoinfundibular pathways, associated with extrapyramidal symptoms (EPS) and elevated prolactin levels, respectively.

Clinical trials with aripiprazole — a new antipsychotic, which shows partial agonist activity at D₂ receptors and serotonin 5-HT_1A receptors, and antagonist activity 5-HT_2A receptors — have demonstrated the value of this treatment approach. Aripiprazole produced significant improvements in positive and negative symptoms in short- and long-term studies of patients with schizophrenia or schizoaffective disorder. Improvements occurred rapidly after the start of treatment, and were sustained throughout studies lasting up to 52 weeks. Significantly more patients responded to aripiprazole treatment than to haloperidol in the 52-week study, and aripiprazole-treated patients showed significantly greater improvements in negative and depressive symptoms than those receiving haloperidol. Aripiprazole treatment was well tolerated in both short- and long-term studies, showing a low liability for EPS and hyperprolactinemia, a lack of QTc prolongation, and minimal weight gain or sedation.

In conclusion, the findings from clinical studies of aripiprazole show that dopamine partial agonists offer a novel, effective and well-tolerated treatment approach for patients with schizophrenia.