Kegg Pathway: Antipsychotics

Aliment Pharmacol Ther. 2008 Jul 11;
Christiansen C, Christensen S, Riis A, Thomsen RW, Johnsen SP, Tonnesen E, Sorensen HT

Background Peptic ulcer perforation is a serious surgical emergency with a substantial short-term mortality, but the influence of antipsychotic drug use on the prognosis remains unknown. Aim To examine the association between antipsychotic drug use and 30-day mortality following peptic ulcer perforation. Methods This cohort study comprised 2,033 patients with a first-time hospitalization with peptic ulcer perforation, in Northern Denmark, between 1991 and 2004. Data on preadmission use of Antipsychotics and other medications, psychiatric disease, other comorbidities, and mortality were obtained through population-based medical databases. We used Cox regression analyses to compute adjusted mortality rate ratios (MRRs). Results 116 (5.7%) patients with peptic ulcer perforation were current users of antipsychotic drugs at the time of hospital admission and 205 (10.1%) were former users. The overall 30-day mortality was 27%. Among current users of Antipsychotics 30-day mortality was 39%. The adjusted 30-day MRR for current users of antipsychotic drugs compared with non-users was 1.7 (95%CI 1.2-2.3). Former use was not a predictor of mortality. The increase in mortality was equal in users of conventional and atypical Antipsychotics. Conclusion Use of antipsychotic drugs is associated with substantially increased mortality following peptic ulcer perforation.

Drug Saf. 2008; 31(8): 685-94
Hägg S, Bate A, Stahl M, Spigset O

BACKGROUND: Concern has been raised about the occurrence of venous thromboembolism (VTE) during treatment with Antipsychotics. However, to date, clozapine is the only antipsychotic agent for which recurring evidence supports an association with VTE. Therefore, the aim of this study was to investigate the association between antipsychotic drugs, including clozapine and VTE. STUDY DESIGN AND METHODS: Data mining of the WHO database of adverse drug reactions (ADRs) using Bayesian statistics is in routine use for early alerting to possible ADRs. An information component measure was used to investigate the association between antipsychotic drugs and VTE reactions in the database. RESULTS: A total of 754 suspected cases of VTE related to treatment with Antipsychotics had been reported. After excluding cases related to clozapine, 379 cases remained. A robust association was found for the second-generation Antipsychotics group but not for the high-potency, first-generation Antipsychotics group or the low-potency first-generation Antipsychotics group. The individual compounds with statistically significant associations were olanzapine, sertindole and zuclopenthixol. A time-dependent analysis showed that the associations were positive for these drugs in 2002, 2001 and 2003, respectively. Case analyses were undertaken after excluding ten suspected duplicate reports. Of the remaining 369 cases, 91 cases were associated with olanzapine, 9 with zuclopenthixol and 6 with sertindole. CONCLUSIONS: VTE was more often reported with the antipsychotic drugs olanzapine, sertindole and zuclopenthixol than with other drugs in the WHO database. Further studies are warranted to explain this disproportional reporting. Since the associations found were based on incomplete clinical data, the results should be considered as preliminary and interpreted cautiously.

J Psychopharmacol. 2008 Jun; 22(4): 452-6
Franks M, Macritchie K, Mahmood T, Young A

In bipolar disorder the discontinuation of lithium prophylaxis is associated with early episode precipitation. Is this ;rebound' phenomenon peculiar to lithium? This naturalistic retrospective case note review investigated the frequency of immediate recurrence after discontinuation of any prophylactic treatment. Bipolar patients who stopped at least one medication after at least 6 months of remission were studied. A total of 310 case notes were examined in a systematic search. A total of 53 cases of discontinuation in 48 subjects were found. Discontinued medications included lithium, valproate, carbamazepine, typical and atypical Antipsychotics and antidepressants. Recurrence occurred within 3 months of medication withdrawal in 39 cases (74%). Over half of the discontinuation episodes involved lithium: recurrence occurred in 86% of these cases. In the groups stopping other prophylactic agents, a majority of subjects suffered recurrence: anticonvulsants (89%), Antipsychotics (64%) and antidepressants (58%). However, these groups were small and the clarity of the data was undermined by the simultaneous withdrawal of other agents. Manic and hypomanic episodes were the most common form of recurrences. Depressive episodes occurred proportionately most frequently following antidepressant withdrawal. More than half of recurrences required hospital admission. This study provides preliminary naturalistic evidence that early episode recurrence in bipolar disorder is not peculiar to lithium withdrawal but may occur following withdrawal of medication from all classes recommended in prophylaxis. These findings, if replicated, have important implications for clinical practice and for research.

J Psychopharmacol. 2008 Jul 17;
Liu YC, Huang CL, Wu PL, Chang YC, Huang CH, Lane HY

Abstract The elucidation of genotype-phenotype relationships in psychiatric research is at an early stage. V-akt murine thymoma viral oncogene homolog 1 (AKT1) is a serine/threonine kinase known as protein kinase B. Emerging studies have implicated the role of AKT1 in pathogenesis of schizophrenia; however, the findings have not been consistent. This study aims to examine the association of AKT1 polymorphisms with drug-free and post-treatment symptomatology and social function in patients with schizophrenia. One hundred and twenty newly hospitalised patients with acutely exacerbated schizophrenia who had never been treated by atypical Antipsychotics were recruited. They received optimal treatment of risperidone for up to 42 days in the inpatient research unit. Clinical manifestations were monitored by Positive and Negative Syndrome Scale (PANSS) and social function by Nurses' Observation Scale for Inpatients Evaluation (NOSIE). Patients were genotyped for eight AKT1 Single Nucleotide Polymorphism (SNPs), which have been previously investigated for association with schizophrenia. At drug-free status and after best possible treatment of risperidone, genotypes of each SNP did not influence performances in NOSIE, PANSS-total, -positive, -negative and -general psychopathology profiles. These results suggest that AKT1 does not play a significant role in clinical and functional manifestations in patients with schizophrenia who receive risperidone treatment. Future research should also focus on the relationships between genotypes of other susceptibility genes and phenotypes or functional outcomes of schizophrenia.

J Psychopharmacol. 2008 Jul 17;
Kleijer BC, van Marum RJ, Egberts AC, Jansen PA, Knol W, Heerdink ER

Abstract It has been shown that elderly patients with dementia treated with atypical and conventional Antipsychotics have a twofold increased risk of cerebrovascular adverse events (CVAEs). To investigate the temporal relationship between exposure to Antipsychotics and the risk of CVAE, a case-control analysis nested within a cohort of 26,157 community-dwelling patients (mean age 76 +/- 9.7) with at least one antipsychotic prescription was conducted. Data were used from Dutch community pharmacies and hospital discharge records. Five hundred and eighteen cases of hospital admission for CVAE were identified. For each case, four randomly selected controls matched by sex and age were sampled from the cohort. To evaluate the temporal relationship between antipsychotic use and the occurrence of CVAE, two measures were used: the first being a current, recent or past user, and the second for the current users, the duration of use up to the index date. In addition, the cumulative exposure was assessed. Current and recent exposure to Antipsychotics were associated with an increased risk of CVAE compared with non-users (odds ratio [OR] 1.7, CI 1.4-2.2). A strong temporal relationship was found; the OR for a history of use less than a week is 9.9 (5.7-17.2). The risk decreases in time and is comparable to non-users after 3 months of use (OR 1.0, CI 0.7-1.3). Cumulative exposure was not associated with an increase in risk. The risk of CVAE in elderly patients associated with Antipsychotics is elevated especially during the first weeks of treatment. This risk decreases over time and is back on base level after 3 months of treatment. Chronic use is not associated with CVAE.

J Psychopharmacol. 2008 Jul 17;
Harrison-Read PE

Abstract Datasets of antimanic potency ratings and receptor-binding affinities [inhibition constants (Ki)] at dopamine D2 and serotonin 5-HT2A brain receptors were accessed from published literature for a large series (n = 24) of typical neuroleptic drugs, many of which are now obsolete and unobtainable. There was a strong positive association between antimanic potency and affinity for D2 receptors, in support of a 'dopamine-blockade hypothesis' of antimanic drug action. Taking the series of neuroleptics as a whole, there was no association between antimanic potency and affinity for 5-HT2A receptors. Despite this, within a subsample of typical neuroleptics with low affinity for D2 receptors resembling new generation atypical Antipsychotics, a positive association between antimanic potency and affinity for 5-HT2A receptors emerged. This suggests that blockade of brain 5-HT2A receptors plays at least a subsidiary role in the antimanic effects of some typical neuroleptics. Other considerations also suggest that combining drugs to achieve high affinity for and blockade of both dopamine D2 receptors and serotonin 5-HT2A receptors, possibly with additional direct or indirect stimulation of postsynaptic 5-HT1A receptors, might maximize antimanic efficacy.

J Psychopharmacol. 2008 Jul 17;
Medved V, Kuzman MR, Jovanovic N, Grubisin J, Kuzman T

Abstract The objective of this study was to determine the occurrence of metabolic abnormalities among previously unmedicated female patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition schizophrenia spectrum disorders and their associations with olanzapine and risperidone treatment. We analysed 94 female patients who were treated with olanzapine or risperidone in the period of 3 months. Analysed variables included fasting glucose, total cholesterol, low-density lipoprotein (LDL), high-density lipoproteins and triglycerides in blood, blood pressure (BP), waist and hip circumferences and body mass index (BMI). At baseline, 14 patients (15%) fulfilled criteria for metabolic syndrome. After 3 months of treatment, 25 patients (27%) fulfilled criteria for metabolic syndrome, and their baseline BMI was the only predictor for its development. Treatment with both Antipsychotics was associated with significant increase in waist circumference. Positive family history of diabetes mellitus contributed to a significant greater increase in abdominal obesity, significant higher baseline levels and a borderline significant increase in fasting glucose among olanzapine-treated patients. Olanzapine admission was associated with a significant increase in LDL and risperidone with a significant increase in triglycerides. Metabolic abnormalities seem to be more prevalent in unmedicated female patients with schizophrenia spectrum disorders than expected based on results in general population (adjusted for age and sex). Olanzapine treatment might induce significant alterations in metabolic profiles, especially among patients with positive family history of diabetes, mostly by inducing abdominal obesity. The association of risperidone application and increase in triglyceride level still needs to be determined.

Ann Clin Psychiatry. 2008 Jul-Sep; 20(3): 139-44
Brar JS, Parepally H, Chalasani L, Gopalani A, Appel N, Chengappa KN

Background. Tardive dyskinesia is a serious adverse event, which is associated mainly with the use of the first-generation antipsychotic agents. Convergent data from clinical trials suggest that second-generation antipsychotic agents are less likely to cause tardive dyskinesia. However, the data with regard to the effect of switching from first- to second-generation antipsychotic agents on pre-existing dyskinetic symptoms during routine clinical care is sparse. Methods. Sixty-three patients with DSM-IV schizophrenia or schizoaffective disorder (n = 61) or bipolar I disorder (n = 2) consecutively admitted to a state hospital, who were treated either with olanzapine (n = 35) or conventional antipsychotic agents (n = 28) by physician choice, were enrolled in the study. The severity and frequency of tardive dyskinetic symptoms using the Abnormal Involuntary Movement Scale were assessed in the two medication groups at baseline, 8 weeks, and 6 months. Results. There were statistically significant reductions in the prevalence and severity of dyskinetic symptoms at 8 weeks and 6 months for the group treated with olanzapine but not for those treated with conventional agents. Conclusions. These preliminary data suggest that olanzapine may be a treatment option for subjects with tardive dyskinesia. However, the question whether olanzapine treats, ameliorates, or masks preexisting tardive dyskinesia was difficult to answer, as no dosage reduction or withdrawal was undertaken.

Ann Clin Psychiatry. 2008 Jul-Sep; 20(3): 131-7
Fiedorowicz JG, Palagummi NM, Forman-Hoffman VL, Miller del D, Haynes WG

Background. Bipolar disorder is associated with excess cardiovascular mortality. We hypothesized outpatients with bipolar disorder would exhibit excess cardiovascular risk factors, particularly among prevalent users of the second-generation Antipsychotics associated with weight gain and valproic acid derivatives. Methods. This chart review of 217 patients with bipolar disorder examined cardiovascular risk factors of the metabolic syndrome. We also evaluated if certain medications were cross-sectionally associated with metabolic syndrome. Results. Fifty-six patients were not weighed and many did not have available lipid profiles. Over three-quarters of those with available data (n = 161) were overweight or obese (body mass index >/= 25) and nearly half were obese (body mass index >/= 30). A prevalence exceeding general population estimates was also observed for hypertriglyceridemia, elevated blood pressure/hypertension, and elevated fasting glucose/diabetes. Among those with all requisite data (n = 60), over 50% met criteria for National Cholesterol Education Program-defined metabolic syndrome, nearly double the expected prevalence. A trend toward greater prevalence of metabolic syndrome among prevalent users of the second-generation Antipsychotics associated with weight gain was observed. Conclusions. Obesity and the metabolic syndrome were common in patients with bipolar disorder. These patients may be under-evaluated for cardiovascular risk and warrant screening and early intervention.

BMJ. 2008; 337: a796
Quail P

Assist Inferm Ric. 2008 Apr-Jun; 27(2): 91-8

Ann Pharmacother. 2008 Jul 15;
Stevens DL

OBJECTIVE: To review the published reports of neuroleptic malignant syndrome (NMS) associated with the use of selective serotonin-reuptake inhibitors (SSRIs) and second-generation Antipsychotics. DATA SOURCES: Information was selected from a MEDLINE search of English language literature (1950-May 2008). Manual search of all published cases indexed in MEDLINE (English language only) of NMS associated with second-generation Antipsychotics was also performed. STUDY SELECTION AND DATA EXTRACTION: Pertinent information from all reports obtained was included, with specific emphasis on patient age, sex, second-generation antipsychotic involved, SSRI or other antidepressant involved, time of onset of NMS symptoms in relation to medication changes, treatment administered, and outcome of the reaction. DATA SYNTHESIS: NMS has been reported with every second-generation antipsychotic agent. It is unclear whether concomitant therapy with other agents may increase the risk of NMS development via pharmacodynamic or pharmacokinetic mechanisms or both. The suggested pharmacodynamic mechanism for increased risk of NMS with concomitant use of SSRIs is the effect of serotonin on dopamine release. Serotonin further inhibits dopamine release and thereby may worsen a hypodopaminergic state induced by Antipsychotics. Pharmacokinetic factors may also play a role in some NMS cases involving an SSRI by increasing antipsychotic concentrations. An examination of case reports seems to indicate that at least in some cases, a temporal relationship exists with the addition of an SSRI to existing antipsychotic therapy. CONCLUSIONS: The use of SSRIs may be associated with an increased risk of NMS development in those receiving second-generation Antipsychotics. Clinicians should closely monitor patients for the potential development of NMS.

Support Cancer Ther. 2005 Apr 1; 2(3): 176-80
Shaiova L

The World Health Organization recommends a step-by-step approach to the management of chronic cancer pain, called the analgesic ladder. Traditionally, morphine has been the prototypical opioid for chronic cancer pain because there is no ceiling effect or upper limit and it is a naturally occurring pure mu-opioid agonist. Occasionally, there are dose-limiting side effects and/or lack of efficacy. Opioid rotation is important because it improves analgesia and the side effect profile. Two principal reasons for failure of strong opioids are the presence of incident pain and/or neuropathic pain. Incident pain usually occurs in a patient with osseous metastases or another movement-related pain syndrome. Other reasons to rotate opioids are side effects such as intractable nausea and vomiting, sedation, dysphoria, delirium, and constipation, which are unresponsive to simple measures such as retitration, antiemetic agents, antipsychotic agents, psychostimulants, and laxatives. There are recent data that demonstrate that the accumulation of active metabolites in patients receiving common opioids such as morphine and hydromorphone are partly responsible for adverse effects. This premise has prompted clinicians and researchers to consider opioid rotation as a valid tool for cancer pain management to increase the probability of acceptable adverse effects with adequate analgesia. Methadone is an opioid agonist with a lack of known active metabolites, which are known to produce side effects with other opioids. Methadone has excellent bioavailability, making it a desirable analgesic agent for refractory types of cancer pain.

Curr Psychiatry Rep. 2008 Aug; 10(4): 359-69
Glazer WM, Byerly MJ

The occurrence of treatment nonadherence among patients with schizophrenia is clinically significant. However, studies show that clinicians do not make systematic efforts to identify and monitor it over time. This paper reviews the various tactics for identifying and monitoring adherence behavior. A comprehensive review of published studies comparing typical and atypical Antipsychotics in terms of medication adherence yields mixed results at best. Changing forces in the delivery of health care in the United States will promote efforts to improve the recognition of nonadherence in patients with schizophrenia and develop strategies and tactics to decrease the current rates of nonadherence. Such tactics are described in this paper, and emerging best practices are identified. Ultimately, if nonadherence rates are to decrease, it will be necessary to align the incentives of the treater and the treated.

Curr Psychiatry Rep. 2008 Aug; 10(4): 352-8
Webber MA, Marder SR

Despite the expansion of available antipsychotic drugs over the past 50 years, functional outcomes for individuals with schizophrenia have not markedly improved. These agents are efficacious for psychosis but do not adequately address other core domains of schizophrenia psychopathology, namely negative symptoms and cognitive impairment, which have a greater impact on functional outcomes, including vocational or academic performance and interpersonal relationships. In addition, treatment-refractory psychosis still precludes functional improvement in many patients. Schizophrenia is a clinical syndrome consisting of these domains, which likely have some disparities in their respective pathophysiologies. This suggests that drug development should look to other molecular targets besides the D2 receptor, which characterizes the mechanism of available medications for schizophrenia. In this report, we review novel pharmacologic approaches that aim to specifically address each individual domain of schizophrenia. The goal of this future pharmacotherapy strategy is to advance outcomes beyond psychosis remission and toward functional recovery.

J Clin Psychopharmacol. 2008 Aug; 28(4): 401-5
Janowsky DS, Barnhill LJ, Khalid AS, Davis JM

Severe intellectual and developmental disabilities are frequently associated with aggression toward self and others, destruction of property, and disruption. Antipsychotic medications are a mainstay of treatment of such behaviors. National and state guidelines suggest stopping these medications or decreasing their dosages when possible if patients have maintained stability. The current study evaluated the likelihood of future antipsychotic drug withdrawal-induced relapses in those individuals where such a relapse had occurred previously. Subjects were 57 institutionalized adults with severe or profound intellectual disability. Between 1990 and 2000, each had experienced an initial activation of maladaptive aggressive behaviors after an attempt at antipsychotic drug withdrawal and/or termination. Quarterly behavioral reports were evaluated to determine whether subsequent antipsychotic drug withdrawal attempts were also associated with future relapses. Initial relapse was followed by subsequent antipsychotic drug withdrawal attempts in 49 of the 57 individuals. Between 1990 and 2005, 28.6% of these 49 subjects had experienced 1, 38.7% had 2, 20.4% had 3, and 8.2% had 4 additional relapses. Two (4.1%) had not relapsed. Eight individuals remained on antipsychotic agents without a subsequent withdrawal attempt. By the end of 2005, only 4 (7%) of the 57 individuals had become antipsychotic drug free, 22.8% were receiving first-generation antipsychotic agents alone, 45.6% were receiving second-generation antipsychotic agents alone, and 24.6% were receiving a combination of first- and second-generation antipsychotic agents. Thus, if relapse occurs after an antipsychotic drug withdrawal attempt, subsequent attempts at withdrawal are also very likely to lead to further relapses.

J Clin Psychopharmacol. 2008 Aug; 28(4): 384-91
Bolton JM, Metge C, Lix L, Prior H, Sareen J, Leslie WD

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs), benzodiazepines, and Antipsychotics have each been associated with an increased risk of fracture in older individuals. The aim of this study was to better define the magnitude of fracture risk with psychotropic medications and to determine whether a dose-effect relationship exists. METHODS: Population-based administrative databases were used to examine psychotropic medication exposure and fractures in persons aged 50 years and older in Manitoba between 1996 and 2004. Persons with osteoporotic fractures (vertebral, wrist, or hip [n = 15,792]) were compared with controls (3 controls for each case matched for age, sex, ethnicity, and comorbidity [n = 47,289]). Medications examined included antidepressants (SSRIs vs other monoamines), Antipsychotics, lithium, and benzodiazepines. RESULTS: Selective serotonin reuptake inhibitors were associated with the highest adjusted odds of osteoporotic fractures (odds ratio [OR] = 1.45; 95% confidence interval [CI], 1.32-1.59). Other monoamine antidepressants (OR = 1.15; 95% CI, 1.07-1.24) and benzodiazepines (OR = 1.10; 95% CI, 1.04-1.16) were also associated with greater fracture risk, although the relationship was weaker. Lithium was associated with lower fracture risk (OR = 0.63; 95% CI, 0.43-0.93), whereas the relationship with Antipsychotics was not significant in the models that adjusted for diagnoses. A dose-effect relationship was seen with SSRIs and benzodiazepines. CONCLUSIONS: This study provides novel insight into the relationship between fractures and psychotropic medications in the elderly. Selective serotonin reuptake inhibitors seem to have a greater risk than other psychotropic classes, and higher doses may further increase that risk. Lithium seems to be protective against fractures.

Int J Psychiatry Med. 2008; 38(1): 61-70
Castilla-Puentes R

OBJECTIVE: The purpose of this study was to delineate the prevalence, demographic characteristics, comorbidity, hospitalization, and medication use of a large cohort of patients with and without multiple episodes per year. We hypothesized that children and adolescents with multiple episodes per year would have a higher comorbidity and require more hospitalizations and pharmacological treatment than their counterparts without multiple episodes. METHODS: Analysis was conducted on a cohort of 8,129 children and adolescents patients (< or = 18 y.o.) with bipolar disorders (BD), from the Integrated Healthcare Information Services (IHCIS) identified from June 30, 2000 to July 1, 2003. Demographics variables, type of hospitalization, and psychotropic medication used in the year of follow-up were compared between children and adolescents with multiple and those without multiple episodes per year. RESULTS: Included were 58 patients with multiple episodes (defined as: > or = 4 or more reports of inpatient treatment for any affective disorders per year) and 8,071 without multiple episodes. Children and adolescents with multiple episodes versus those without multiple episodes were differentiated as follows: more comorbid attention deficit disorder (ADD) (80.9% versus 29.4%) (chi2 = 70.61, df = 1, p < 0.0001); higher rate of hospital admission for depression (12.1% vs. 1.8%, chi2 = 27.86, df = 1, p < 0.0001); for other psychiatric conditions (48.3% vs. 11.2, chi2 = 74.47, df = 1, p < 0.0001) and for medical conditions (22.4% vs. 3.9%, chi2 = 46.26, df = 1, p < 0.0001). Patients with multiple episodes per year were more likely than those without multiple episodes to be given mood stabilizers (91.4% vs. 60.3%, chi2 = 22.02, df = 1, p < 0.0001), antidepressants (79.3% vs. 59.2%, chi2 = 8.82, df = 1, p = .0003), and Antipsychotics (89.7% vs. 45.8%, chi2 = 42.91, df = 1, p < 0.0001). The use of stimulants did not differ between the two groups (24.1% vs. 23.0%), chi2 = 0.02, df = 1, p = 0.96). CONCLUSIONS: Our findings support previous studies demonstrating that children and adolescents with multiple episodes per year present a higher comorbidity and require more hospitalizations and pharmacological treatment than those without multiple episodes. The diagnosis and treatment of children and adolescents with BD will have to take into account the high comorbidity of ADD mainly in children and adolescents with multiple episodes. Future prospective studies will help to better characterize the impact of multiple episodes in the course of pediatric BD and facilitate appropriate treatment strategies.

Eur Arch Psychiatry Clin Neurosci. 2008 Jul 11;
Möller HJ

In recent years, so-called "effectiveness studies" have gained increasing importance in the context of evidence-based medicine. These studies supposedly follow less restrictive methodological standards than phase III studies in terms of patient selection, co-medication and other design issues, and their results should therefore be better generalisable than those of phase III studies. Effectiveness studies, like other types of phase IV studies, can therefore contribute to the knowledge about Antipsychotics or other psychopharmaceuticals and supply relevant information in addition to that gained from phase III trials. However, the less restrictive design and inherent methodological problems of phase IV studies mean that their results cannot falsify the results of phase III studies. The greater complexity of phase IV studies, for example the greater variance caused by the different kinds of confounders, means that their results have to be interpreted with great care and especially with a high degree of awareness of problematic design issues, such as insensitive primary outcome criteria, biased randomisation, unblinded treatment conditions, inclusion of chronic refractory patients, etc. Some recently published effectiveness studies on antipsychotic treatment of schizophrenia will be discussed under these methodological aspects. The main conclusions of these trials will be questioned on the basis of their severe methodological pitfalls.

Pharmacogenet Genomics. 2008 Aug; 18(8): 721-727
Gu B, Wang L, Zhang AP, Ma G, Zhao XZ, Li HF, Feng GY, He L, Xing QH

OBJECTIVES: Certain components of the serotonin system have been known for some time to be risk factors for schizophrenia. Few studies have, however, focused on the association between the therapeutic responses to atypical Antipsychotics, such as risperidone, and polymorphisms of the 5-HT3 receptor, the only ionotropic ligand-gated serotonin receptor, even though there have been some genetic clues linking HTR3A and schizophrenia. We therefore postulated that such a polymorphism might be an explanatory factor in the diversity of response to risperidone treatment. METHODS: The study recruited 107 drug-naive Chinese schizophrenia patients who were given 8 weeks of risperidone monotherapy and it explored three of four single nucleotide polymorphisms spanning HTR3A for possible association with therapeutic improvement, using the Positive and Negative Symptom Scale. RESULTS: Significant correlation between the baseline score and therapeutic improvement was observed in each subscale (P<0.001). Statistical analysis revealed association between genotypes of g.14396A>G polymorphism (rs1176713) and score reductions of negative and general subscales after adjusting for the influence of the baseline scores of each subscale [P (F, d.f.)=0.026 (3.763, 2), 0.023 (3.937, 2) respectively]. One haplotype, C-A-G, contributed to an effective response in general symptoms (chi=7.3, P=0.007, odds ratio=3.371). CONCLUSION: The results of this study are the first to suggest that the polymorphism of HTR3A may be a useful predictor of therapeutic response to risperidone treatment in Chinese schizophrenic patients, although these conclusions should be treated with caution because of the intricacy of the variety of the therapeutic effects to risperidone.