from 14 days to 9 years (no evidence of any patient having periods of discontin- uation), although 5 cases occurred within 4 months of initiating treatment. No one was on high-dose clozapine (9600 mg/d), but concurrent medications were frequently present and 1 patient was receiving elec- troconvulsive therapy. Several types of co- litis were reported, including 2 cases each of necrotizing and pseudomembranous, and one each of microscopic, acute, and eosin- ophilic. One of the 7 patients died as a re- sult of colitis, and 3 required major bowel surgery. In 3 cases, clozapine was restarted, with 2 patients experiencing a recurrence of colitis and no follow-up was reported in the third case. The growing body of case reports suggests a need for more detailed research into both frequency of serious intestinal sequelae and mechanism of any possible causative link with clozapine treatment. In particular, whether colitis may be a distinct pathological process from the risk of clozapine causing bowel obstruction or pseudo-obstruction. 2,3 In the interim, it re- mains imperative that intestinal symptoms in patients receiving clozapine be taken seriously and addressed early. AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. Keith Richard Linsley, FRCPsych Tees Esk and Wear Valleys NHS Foundation Trust Durham, UK keith.linsley@tewv.nhs.uk Octavia Williams, MBBS, MRCPsych NHS Foundation Trust Durham, UK REFERENCES 1. NICE Core Interventions in the Treatment and Management of Schizophrenia in Primary and Secondary Care (Update): CG82 2009. 2. Palmer SE, McLean RM, Ellis PM, et al. Life-threatening clozapine-induced gastrointestinal hypomobility: An analysis of 102 cases. J Clin Psych. 2008;69(5): 759Y768. 3. Hibbard KR, Propst A, Frank DE, et al. Fatalities associated with clozapine-related constipation and bowel obstruction: A literature review and two case reports. Psychosomatics. 2009;50(4):416Y419. 4. Leong QM, Wong KS, Koh DC. Necrotising colitis related to clozapine? A rare but life threatening side effect. World J Emerg Surg. 2007;2(21):1749Y7922. 5. Shammi CM, Remington G. Clozapine-induced necrotising colitis. J Clin Psychopharmacol. 1997;17(3): 230Y232. 6. Sim K, Yong TW, Liew E, et al. Clozapine-associated pseudomembranous colitis. J Clin Psychopharmacol. 2006;26(1):89. 7. Hawe R, Bolton JM. Response to clozapine-induced microscopic colitis. A case report and review of the literature (letter). J Clin Psychopharmacol. 2008;28(4):454Y455. 8. Ginsberg DL. Clozapine-induced eosinophilic colitis. Prim Psychiatry . 2005;12(8):27Y28. 9. Karmacharya R, Mino M, Pirl WF. Clozapine-induced eosinophilic colitis (letter). Am J Psychiatry . 2005;162: 1386Y1387. 10. Ginsberg DL. Clozapine-Induced Pseudomembranous Colitis. 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The evi- dence that they all block dopamine D2 receptors and that sustained exposure to dopamine D2 receptor agonists induces psychosis-like symptoms have led to the classical dopamine hypothesis of schizo- phrenia. 1 The theory postulates that hal- lucinations and delusions arise from the hyperstimulation of dopamine D2 receptors caused by an excess of subcortical dopa- mine. Second-generation antipsychotics, such as risperidone and quetiapine, act as antagonists at both dopaminergic (in par- ticular D2) and serotonergic receptors and show some improvement on 50% to 80% of patients. 2 However, treatment response is largely unpredictable and discontinuation rates are high. 2 Limited evidence from twin and family studies suggest that response to antipsychotic medication is a heritable complex trait influenced by a number of genes and environmental factors. 2 The ge- netic variants mostly reported are dopa- mine receptors, in particular, D2 and D3 2 ; in general, alleles associated with lower ex- pression are also associated with poorer response. The D2 receptor is the major target of antipsychotic blockade and is pres- ent in high density in the basal ganglia. 3 The A9G rs1800497 single nucleotide poly- morphism (SNP) (aka Taq1A) in DRD2 encodes a cytosine-to-thiamine amino acid change. The A allele has been associated with reduced receptor density in the stria- tum and related structures in vitro and in vivo but with higher D2 density in patients with schizophrenia after antipsychotic use. 3 Catechol-O-methyltransferase (COMT) cata- lyzes the degradation of dopamine in the postsynaptic neuron. 4 It regulates dopami- nergic function in the prefrontal cortex, 4 which in turn influences striatal function, 5 and may thus influence treatment response to dopamine antagonists. It may also directly regulate striatal tonic dopamine release. 6 Its gene contains an A9G SNP (rs4680) that causes a valine-to-methionine change that results in a 2- to 3-fold reduction in enzy- matic metabolic activity and stability. 4 The dopamine D4 receptor is highly expressed in the prefrontal cortex 7 and, like D2, is a target of antipsychotic drugs. The DRD4 gene contains a T9C SNP in the promoter region (rs1800955, aka C-521T) that influ- ences expression: the T allele has been as- sociated with about 40% lower transcription levels, 7 although this finding has not been consistently demonstrated. 8 Given the importance of dopaminergic transmission blockade by antipsychotics in the early response (up to 4 weeks) of first onset psychosis patients, 9 and that treat- ment response is influenced by genetic variability, 2 we hypothesized that com- monly occurring variation in genes rele- vant to the dopaminergic system (COMT [rs4680], DRD4 [rs1800955], and DRD2 [rs1800497]) would have an impact on symptom improvement. Based on current evidence, we predicted that the COMT A, the DRD2 A, and the DRD4 C alleles would be associated with greater improve- ment in symptoms (compared with their opposite alleles). We further hypothesized that the effect of these genetic variants would be greatest for positive symptoms, given that these are thought to arise from a hyperdopaminergic state in the basal ganglia 1 and that they typically subside within 4 weeks of effective antipsychotic Letters to the Editors Journal of Clinical Psychopharmacology & Volume 32, Number 4, August 2012 566 www.psychopharmacology.com * 2012 Lippincott Williams & Wilkins Copyright © 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.