DRD2 and Antipsychotics Spotlight

What is the DRD2 gene?

DRD2 is the D2 subtype of the dopamine receptor, and is involved in the regulation of dopamine neurotransmission.^1,2  Most antipsychotics act primarily through modulation of the D2 receptor to reduce dopamine signaling.³   Affinity for this receptor has been shown to correspond to the risk for and degree of side effects to antipsychotic agents.³  Many studies have explored whether certain genetic variations, in particular the -141C insertion/deletion (-141C Ins/Del), can lead to altered treatment response and side effects with antipsychotic medications.  This deletion of the DNA base, cytosine (C), in the promoter region of DRD2 likely leads to reduced gene expression.⁴

Clinical studies have shown that a single base pair deletion in the promoter region of the DRD2 gene increases risk for poor response and adverse events with antipsychotic medications.  A meta-analysis of 6 studies examining the effect of the -141C variation in patients with schizophrenia or schizoaffective disorder (n=687) found that the Del variant is significantly associated with poorer response to antipsychotic medications (OR=0.65, p=0.03).⁴

Another study found that 61 patients with first-episode schizophrenia or schizoaffective disorder who had the -141C Del variant took a significantly longer amount of time to respond to treatment with risperidone or olanzapine (Figure 1). ⁵

A study that evaluated 208 hospitalized patients who were given haloperidol showed that individuals with the Del/Del genotype needed higher doses of antipsychotic drugs, had longer hospital stay, and had a minimum improvement of symptoms.  A total of 34 (54.8%) of Del/Del patients vs. 15 (45.5%) of Ins/Del patients vs. 25 (22.1%) of Ins/Ins patients required higher doses of antipsychotic.⁶   Similarly, another study showed that Del carriers were prescribed higher doses of olanzapine.  The same study examined weight gain with antipsychotics and found that patients who possess the Del variant displayed significantly more weight gain after 6 weeks of treatment with risperidone or olanzapine (Figure 2).⁷

^{Figure 1. Time to sustained antipsychotic medication response.}

^{Adapted from Lencz T, et al. DRD2 promoter region variation as a predictor of sustained response to antipsychotic medication in first-episode schizophrenia patients. Am J Psychiatry. 2006;163(3):529-31.}

^{Figure 2. Weight change from baseline over the course of the first six weeks of the trial}

^{Adapted from Lencz T, et al. DRD2 promoter region variation predicts antipsychotic-induced weight gain in first episode schizophrenia. 2010;20(9):569-72.}

Taken together, the data supports the role of the -141C DRD2 gene in the modulation of treatment response and side effect risk with antipsychotic agents.  While there is limited prospective data to suggest selection of optimal antipsychotic agents in patients who have this variation, it is hypothesized that medications with lower binding affinity to the D2 receptor have a reduced risk for a gene-drug interaction of this type.

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References

1. Felten A, Montag C, Kranczioch C, Markett, Walter NT, Reuter M. The DRD2 C957T polymorphism and the attentional blink–a genetic association study. Eur Neuropsychopharmacol. 2013;23(8):941-7.
2. Beaulieu JM and Gainetdinov RR, The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev. 2011;63(1):182-217.
3. Strange PG. Antipsychotic drugs: importance of dopamine receptors for mechanisms of therapeutic actions and side effects. Pharmacol Rev. 2001;53(1):119-33.
4. Zhang JP, Lencz T, Malhotra AK. D2 receptor genetic variation and clinical response to antipsychotic drug treatment: a meta-analysis. Am J Psychiatry. 2010;167(7):763-72.
5. Lencz T, Robinson DG, Xu K, Ekholm J, Sevy S, Gunduz-Bruce H, et al. DRD2 promoter region variation as a predictor of sustained response to antipsychotic medication in first-episode schizophrenia patients. Am J Psychiatry. 2006;163(3):529-31.
6. Syamsuddin S, Yusuf I, Tanra J, Idris I. The polymorphisms of DRD2 141-C Ins/Del receptor influenced the treatment responses of schizophrenia patients. Neuropsychiatry (London). 2019;9(5):2467-2470.
7. Lencz T, Robinson DG, Napolitano B, Sevy S, Kane JM, Goldman D, et al. DRD2 promoter region variation predicts antipsychotic-induced weight gain in first episode schizophrenia. 2010;20(9):569-72.