The place of partial agonism in psychiatry: Recent developments

Institute of Psychiatry, De Crespigny Park, London, UK.
Journal of Psychopharmacology (Impact Factor: 3.59). 08/2005; 19(4):408-13. DOI: 10.1177/0269881105053308
Source: PubMed


Drugs used to treat psychiatric disorders, although effective, are often restricted by adverse events. The use of partial agonists for treating hypertension was found to limit some of the side-effects in some patients. This led to the investigation of partial agonists as a treatment modality in psychiatric disorders. Partial agonists have a lower intrinsic efficacy than full agonists leading to reduced maximum response. They can act as antagonists by competing for receptor binding with full agonists. The level of activity depends on the level of endogenous receptor activity. Buprenorphine, a partial agonist at the mu-opioid receptor, is used to treat patients with addiction and decreases the symptoms of withdrawal and risks of overdose and intoxication. The anxiolytic buspirone shows partial agonism at 5-HT(1A) receptors, and this seems to provide anxioselective effects, without inducing extrapyramidal side-effects, convulsions, tolerance or withdrawal reactions. In schizophrenia, partial dopamine agonism results in antagonistic effects at sites activated by high concentrations of dopamine and agonistic effects at sites activated by low concentrations of dopamine. This stabilizes the dopamine system to effect antipsychotic action without inducing adverse motor or hormonal events. Aripiprazole is the first 'dopamine system stabilizer', and the data are promising, with efficacy at least equivalent to that with current atypical antipsychotics but fewer of the troublesome side-effects. Partial agonists seem to provide a way to fine-tune the treatment of psychiatric disorders by maximizing the treatment effect while minimizing undesirable adverse events.

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    • "Fluoxetine is a potent and highly selective inhibitor of the transporter for serotonin reuptake at the presynaptic membrane, causing increases in serotonin concentrations at postsynaptic receptor sites (Wong et al., 1995). Buspirone exerts anxiolytic effects by acting as a partial agonist at serotonin 5-HT1A receptors (Ohlsen and Pilowsky, 2005), and it also interacts to a lesser degree with other receptors, such as the dopamine D2 receptor (Dhavalshankh et al., 2007). The antipsychotic drug risperidone belongs to the benzisoxazole chemical class (Kumar et al., 2008; Courchesne et al., 2007) and has been reported to act therapeutically by blocking serotonin and dopamine receptors (Grant, 2007); thus, it is useful for studying increases in serotonin neurotransmission . "
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    Comparative Biochemistry and Physiology Part C Toxicology & Pharmacology 08/2015; 179. DOI:10.1016/j.cbpc.2015.08.009 · 2.30 Impact Factor
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    • "Apart from this antipsychotic activity, other therapeutic uses for aripiprazole have been considered, including the treatment of mood disorders (Aitchison et al., 2009; Chernoloz et al., 2009; Keck et al., 2003; Simon and Nemeroff, 2005). Another possibility is administering it as a substitutive therapy for substance use disorders (Brunetti et al., 2012; Moreira and Dalley, 2015; O'Brien, 2008; Ohlsen and Pilowsky 2005). Accordingly, this antipsychotic attenuates the stimulant, rewarding and reinforcing effects of drugs of abuse in animal models (Feltenstein et al., 2007; Leite et al., 2008; Sorensen et al., 2008; Viana et al., 2013; Wee et al., 2007). "
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    European journal of pharmacology 08/2015; 765. DOI:10.1016/j.ejphar.2015.08.053 · 2.53 Impact Factor
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    • "Partial agonists have been widely used to treat psychiatric disorders such as schizophrenia (Ohlsen and Pilowsky, 2005), which act by counteracting excessive dopaminergic activation whilst ensuring sufficient dopamine transmission to avoid adverse motor and other side effects. Examples include preclamol and terguride (Carlsson, 1988) and, more recently, aripiprazole (Ohlsen and Pilowsky, 2005; Tamminga, 2002), which acts as a partial agonist at dopamine D 2 /D 3 receptors and 5-hydroxytryptamine (serotonin) 5-HT 1A receptors, and curiously as a serotonin 5-HT 2A receptor antagonist as well (Burris et al., 2002; Hirose et al., 2004; Shapiro et al., 2003; Stark et al., 2007). Nevertheless, therapeutic doses of this compound fully occupy D 2 receptors with only minor binding at serotonin receptors (Natesan et al., 2006). "
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