Neurobiological mechanisms associated with antipsychotic drug-induced dystonia.

Dystonia is by far the most intrusive and invalidating extrapyramidal side effect of potent classical antipsychotic drugs. Antipsychotic drug-induced dystonia is classified in both acute and tardive forms. The incidence of drug-induced dystonia is associated with the affinity to inhibitory dopamine D2 receptors. Particularly acute dystonia can be treated with anticholinergic drugs, but the tardive form may also respond to such antimuscarinic treatment, which contrasts their effects in tardive dyskinesia. Combining knowledge of the pathophysiology of primary focal dystonia with the anatomical and pharmacological organization of the extrapyramidal system may shed some light on the mechanism of antipsychotic drug-induced dystonia. A suitable hypothesis is derived from the understanding that focal dystonia may be due to a faulty processing of somatosensory input, so leading to inappropriate execution of well-trained motor programmes. Neuroplastic alterations of the sensitivity of extrapyramidal medium-sized spiny projection neurons to stimulation, which are induced by the training of specific complex movements, lead to the sophisticated execution of these motor plans. The sudden and non-selective disinhibition of indirect pathway medium-sized spiny projection neurons by blocking dopamine D2 receptors may distort this process. Shutting down the widespread influence of tonically active giant cholinergic interneurons on all medium-sized spiny projection neurons by blocking muscarinic receptors may result in a reduction of the influence of extrapyramidal cortical-striatal-thalamic-cortical regulation. Furthermore, striatal cholinergic interneurons have an important role to play in integrating cerebellar input with the output of cerebral cortex, and are also targeted by dopaminergic nigrostriatal fibres affecting dopamine D2 receptors.

Factors associated with expression of extrapyramidal symptoms in users of atypical antipsychotics.

PURPOSE: The aim of this study was to investigate factors associated with the occurrence of extrapyramidal symptoms (EPS) in users of second-generation antipsychotics (SGA). METHODS: Observational cross-sectional study based on a random sample of subjects from three outpatient clinics. Inclusion criteria were age between 18 and 65 years, of both genders, with a diagnosis of schizophrenia and under the use of a single SGA agent. Subjects who had received i.m. long-acting antipsychotics in the past were excluded. The families of eligible patients were contacted by phone and, if willing to participate in the study, a household visit was scheduled. Informed consent was obtained from all study subjects and their next of kin. The risk of EPS associated with sociodemographic, clinical features and medications used was analyzed by logistic regression. RESULTS: The study population consisted of 213 subjects. EPS were observed in 38.0% of subjects. The more commonly used SGA were olanzapine (76, 35.7%), risperidone (74, 34.3%), quetiapine (26, 12.2%), and ziprasidone (23, 10.8%). Among the drugs used as adjunctive therapy for schizophrenia, benzodiazepines were the most prevalent (31.5%), followed by carbamazepine (24.4%) and antidepressants (20.2%). Multivariate analysis showed that the risk of EPS was associated with the use of carbamazepine (odds ratio 3.677, 95% CI 1.627-8.310). We found no evidence that the type of SGA modified the risk of EPS. CONCLUSION: The occurrence of EPS in SGA users is a common finding, with no difference of antipsychotics studied in relation to the risk of extrapyramidal manifestations. The adjunctive use of carbamazepine may predispose the user of SGA to the occurrence of EPS.

Extrapyramidal Reactions Associated with Serotonergic Antidepressants.

OBJECTIVE: Extrapyramidal reactions (EPRs) associated with serotonergic antidepressant treatments have been reported since 1958. These reactions can be distressing for patients and complicate treatment. Our objective was to complete a follow-up review of published EPR cases reported for serotonergic antidepressants. DATA SOURCES: Published cases between January 1998 and May 2015 were collected through a medical literature search. Citation reference lists were also searched manually. STUDY SELECTION AND DATA EXTRACTION: Identified cases were reviewed for patient age, gender, psychiatric diagnosis, dosage, time to reaction onset, concurrent medications, and EPR description. Cases were excluded when there was not a clear description, if descriptions were not consistent with accepted definitions, or if the written English was poor. We included cases of akathisia, dystonia, dyskinesia, parkinsonism, or mixed EPRs. Authors scored each case using the Naranjo adverse drug reaction probability scale. DATA SYNTHESIS: We identified 86 published reports involving 91 patients; selective serotonin reuptake inhibitors were implicated in 80.2% of cases. All EPR types were reported: 17 akathisia cases, 18 dyskinesia cases, 27 dystonia cases, 19 parkinsonism cases, and 10 mixed EPR cases. EPRs typically occurred within 30 days of either treatment initiation or dose increase. Age, gender, antidepressant dosing, or concurrent antipsychotic treatment did not appear to broadly contribute to EPR risk. Naranjo scores ranged from 2 to 8. CONCLUSIONS: Case reports associating serotonergic antidepressants with EPRs continue to be published. Practitioners are advised that monitoring for such is important. Rigorous research efforts are needed to better understand the clinical risk factors for these adverse drug reactions.

Subjective well-being in schizophrenia: a randomised controlled open-label 12-month non-inferiority study comparing quetiapine XR with risperidone (RECOVER).

UNLABELLED: This randomised 12-month open study analysed the effectiveness of quetiapine XR (400-800 mg) versus risperidone (2-6 mg) on subjective well-being in schizophrenia (NCT00600756). Primary objective was to demonstrate non-inferiority of quetiapine XR to risperidone in 6-month responder rate using the Subjective Well-Being under Neuroleptics scale (SWN-K) (per-protocol at Month 6 [PP 6] population). Non-inferiority was defined as the lower limit of the 95% confidence interval (CI) greater than -9.7% for the adjusted difference between quetiapine XR and risperidone. Secondary objectives included non-inferiority of quetiapine XR versus risperidone (lower limit of 95% CI greater than -7.5 points) for SWN-K change from baseline to Month 12 (PP 12). 798 patients were randomised (quetiapine XR, n=395; risperidone, n=403); at Month 12, 212 (54%) and 227 (56%) patients, respectively, completed the study. At Month 6, SWN-K responder rate in the PP 6 population was 65% (136/210) with quetiapine XR and 68% (158/232) with risperidone (adjusted treatment difference: -5.7%; 95% CI: -15.1, 3.7); thus, non-inferiority could not be established. SWN-K change from baseline to Month 12 was 23.2 points for quetiapine XR and 21.1 points for the risperidone group; treatment difference was 2.1 (95% CI: -0.8; 5.0); non-inferiority was established (PP 12). CONCLUSION: SWN-K response at 6 months was comparable between the two antipsychotics. However, with a lower than expected responder rate and a lower than expected number of evaluable patients in the PP 6 population, non-inferiority was not demonstrated. A secondary objective (SWN-K total score) established non-inferiority of quetiapine XR to risperidone at Month 12.

Efficacy and safety of second-generation long-acting injections in schizophrenia: a meta-analysis of randomized-controlled trials.

The aim of the present article is to test at a meta-analytical level the efficacy and safety of second-generation long-acting antipsychotic injections (SGLAI) in schizophrenia. Thirteen randomized-controlled trials comparing SGLAI with either placebo or oral antipsychotics were included in a quantitative meta-analysis (6313 patients). Efficacy and safety measures as well as demographic and clinical variables were extracted from each publication or obtained directly from authors. Publication bias was assessed with funnel plots and Egger's intercept. Heterogeneity was addressed with the Q statistic and the I² index. SGLAI were more effective than placebo injections [Hedges's g=0.336, 95% confidence interval (CI) 0.246-0.426, Z=7.325, P<0.001] in reducing the Positive and Negative Syndrome Scale (PANSS) scores, but no differences were observed compared with oral antipsychotics (Hedges's g=0.072, 95% CI -0.072 to 0.217, Z=0.983, P=0.326). There were more responders under SGLAI than placebo (47 vs. 24%, NNT 4, 95% CI 3-6), but no differences in comparison with oral antipsychotics [relative risk (RR)=0.962, P=0.094]. SGLAI and controls groups shared a common safety profile with respect to the number of deaths, overall number of treatment-adverse events, insomnia, QT prolongation, or pain in the injection site. There was a greater risk of developing extrapyramidal side effects with SGLAI than with placebo (RR=2.037, P<0.001) or with oral antipsychotics (RR=1.451, P=0.048). There was no evidence of publication bias (Egger's P=0.476), and sensitivity analysis confirmed the robustness of results. The present meta-analysis shows superior efficacy for the SGLAI over placebo on psychotic symptoms, although with a relatively small effect size; no evidence of superiority in efficacy over oral antipsychotics; and modest evidence of greater symptoms of extrapyramidal side effects. These data suggest that SGLAI lack an advantage in reducing psychotic symptoms over oral medications. Their potential effects on relapse prevention should be better addressed by future randomized-controlled trials.

Manganese alters rat brain amino acids levels.

Manganese (Mn) is an essential element and it acts as a cofactor for a number of enzymatic reactions, including those involved in amino acid, lipid, protein, and carbohydrate metabolism. Excessive exposure to Mn can lead to poisoning, characterized by psychiatric disturbances and an extrapyramidal disorder. Mn-induced neuronal degeneration is associated with alterations in amino acids metabolism. In the present study, we analyzed whole rat brain amino acid content subsequent to four or eight intraperitoneal injections, with 25 mg MnCl2/kg/day, at 48-h intervals. We noted a significant increase in glycine brain levels after four or eight Mn injections (p < 0.05 and p < 0.01, respectively) and arginine also after four or eight injections (p < 0.001). Significant increases were also noted in brain proline (p < 0.01), cysteine (p < 0.05), phenylalanine (p < 0.01), and tyrosine (p < 0.01) levels after eight Mn injections vs. the control group. These findings suggest that Mn-induced alterations in amino acid levels secondary to Mn affect the neurochemical milieu.

Are atypical antipsychotics safer than typical antipsychotics for treating behavioral and psychological symptoms of dementia?

Atypical antipsychotics seem to be preferable than conventional agents in treating psychological symptoms of dementia (BPSD), because they have substantially lower risks of extrapyramidal neurological effects with lower reported rates of parkinsonism and tardive dyskinesia. However, in the course of time, with the increase in their use, more and more side effects have been reported. The benefits and risks of antipsychotic treatment should be carefully evaluated according to the co-morbidity and the severity of the psychological and behavioral symptoms and their impact on the individual elderly patient. It is recommended to keep those medications in the lower range of therapeutic doses. Due to the complexity of the individual patient, no guidelines have been yet established. Therefore, clinical judgment should be used in applying the dose and the type of those drugs.

Second-generation antipsychotic drugs and extrapyramidal side effects: a systematic review and meta-analysis of head-to-head comparisons.

OBJECTIVE: While all second-generation antipsychotics (SGAs) are promoted for having a low risk of extrapyramidal side effects (EPS), clinical observations suggest differences between the various agents. Nevertheless, this question has never been examined in a systematic review and meta-analysis of head-to-head comparisons. METHODS: We searched the register of the Cochrane schizophrenia group (last search May 2007), supplemented by MEDLINE (last search July 2009) for randomized, blinded studies comparing the following SGAs in the treatment of schizophrenia or related disorders: amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone, and zotepine. At least 3 reviewers extracted the data independently. The primary outcome was "use of antiparkinson medication." The results were combined in a meta-analysis. RESULTS: We included 54 studies with 116 arms. Risperidone was associated with more use of antiparkinson medication than clozapine, olanzapine, quetiapine, and ziprasidone. Ziprasidone showed more use of antiparkinson medication than olanzapine and quetiapine and zotepine more than clozapine. There was no significant difference between amisulpride and its comparators (olanzapine, risperidone, or ziprasidone). Quetiapine showed significantly less use of antiparkinson medication than the 3 other SGAs it was compared with (olanzapine, risperidone, and ziprasidone). Scale-derived data (Barnes Akathisia Scale and Simpson Angus Scale) were limited. CONCLUSIONS: Our meta-analysis demonstrates that there are differences between the SGAs in their ability to induce EPS that clinicians consider warrant treatment with antimuscarinic drugs. Even though the differences were relatively small, they might be important for individual patients and should be taken into account in drug choice.

Co-administration of haloperidol and drugs affecting the angiotensin pathway: effect on the extrapyramidal system.

The present study investigates the extrapyramidal effects of co-administration of enalapril (angiotensin-converting enzyme inhibitor) or losartan (angiotensin receptor blocker) with haloperidol in mice. Enalapril/losartan (as a suspension in 1% gum acacia) was administered by oral gavage and haloperidol was administered as an intraperitoneal injection to all the animals for seven days. Catalepsy was measured 30 min after the administration of haloperidol (1 mg/kg i.p.) on days 1 and 7. Observations on day 1 constituted the acute study (single dose administration) and observations on day 7, constituted the chronic study (repeated dose administration). Both acute and chronic administration of enalapril/losartan produced an increase in the duration of haloperidol induced catalepsy at the highest dose (20 mg/kg). Enalapril produced a more pronounced increase in the duration of catalepsy as compared to losartan on both acute and chronic administration. Results of our study suggest that co-administration of anti-psychotics and drugs affecting the angiotensin system can lead to an increase in motor side effects and therefore should be used with caution in patients with these co-morbid conditions.

Effects of adjunct galantamine to risperidone, or haloperidol, in animal models of antipsychotic activity and extrapyramidal side-effect liability: involvement of the cholinergic muscarinic receptor.

The acetylcholine esterase inhibitor/cholinergic nicotinic receptor (nAChR) allosteric modulator galantamine (Gal) is used against cognitive impairment in Alzheimer's disease. Negative/cognitive and psychotic symptom improvement in schizophrenia by adjunct Gal to antipsychotic drugs (APDs) has been reported. Cognitive symptoms in schizophrenia may involve brain prefrontal hypo-dopaminergia. Experimental data by others indicate nAChR involvement in animal pro-cognitive effects of Gal. The role of nAChRs in antipsychotic effects by Gal has, however, not been elucidated. Using the conditioned avoidance response (CAR) and the catalepsy tests for antipsychotic activity and extrapyramidal side-effect (EPS) liability, respectively, we here investigated the effects of adjunct Gal (1.25 mg/kg) to the typical APD haloperidol (Hal) (0.05 mg/kg), or the atypical APD risperidone (Ris) (0.2 mg/kg), in rats. Adjunct Gal significantly enhanced APD-like effects by low doses of Hal or Ris, but showed a safe EPS liability profile only in combination with Ris. Pretreatment with the muscarinic receptor (mAChR) antagonist scopolamine, but not the nAChR antagonist mecamylamine, completely reversed the enhancing effects of adjunct Gal to Hal treatment, in the CAR test. While the nAChR-modulating properties of Gal probably contribute to pro-cognitive activity, as shown by others, the present data suggest that any contribution to antipsychotic activity by Gal is mediated primarily via mAChRs. This property combination of Gal may offer a unique, favourable therapeutic profile for schizophrenia treatment.

Low doses of risperidone and morphine interact to produce more analgesia and greater extrapyramidal effects in rats.

The search for non-narcotic drugs that will enhance the analgesic effects of opiates without enhancing their side effects has included the investigation of psychoactive drugs already approved for other uses. Some research has supported an analgesic effect of risperidone (RIS), an atypical neuroleptic. However, the analysis of the analgesic efficacy of RIS alone or as an adjuvant to morphine (MOR) has not considered the production of adverse motor effects that would limit its usefulness as a treatment for pain. We tested whether low doses of RIS would enhance the analgesic action of opiates without inducing untoward motor effects. The analgesia induced by a range of RIS doses (0.1-1.0 mg/kg, SC) was assessed alone and in combination with MOR (5 mg/kg, IP) in male Long-Evans (hooded) rats using two different algesiometric assays: hotplate and tail-flick test. The presence or absence of ptosis, vacuous chewing, and abnormal stationary postures was recorded to evaluate dyskinetic effects. No dose of RIS alone altered pain threshold. However, the highest dose of RIS, 1.0 mg/kg SC, significantly increased the analgesic effects of MOR. Dyskinetic effects of RIS were dose-dependent and enhanced in RIS+MOR treatment. These results do not support the hypothesis that RIS, alone or in combination with MOR, elevates pain threshold without also inducing motor side effects. These findings suggest caution in the use of RIS as either a primary treatment or opiate adjuvant treatment for pain.

Antipsychotics in the treatment of schizophrenia: an overview.

Schizophrenia is characterized by positive, negative, cognitive, disorganization, and mood symptoms. Antipsychotics are the mainstay in the pharmacologic treatment of schizophrenia. Findings concerning efficacy for positive symptoms and disorganization suggest no consistent differences among available antipsychotics, with the exception of clozapine's superior efficacy for treatment-resistant schizophrenia. Efficacy for negative, depressive, and cognitive symptoms appears to be determined by (1) the extent to which reduction in positive symptoms brings about improvement in these other domains and (2) the extent to which extrapyramidal side effects (EPS) and anticholinergic effects (of the antipsychotic and of agents used to treat EPS) exacerbate them. Thus, the ability of antipsychotics to produce a potent antipsychotic effect without EPS and need for concomitant anticholinergic therapy yields multiple therapeutic benefits. In contrast to their broadly similar efficacy, antipsychotics differ markedly in their propensity to cause various adverse effects. Although second-generation antipsychotics (SGAs) have generally been believed to be associated with a lower risk of EPS but a higher risk of metabolic adverse effects than first-generation agents (FGAs), the substantial variation in these and other side effects among agents within both classes indicates that it is not clinically useful to make a categorical distinction between FGAs and SGAs. Choice of antipsychotic medication should be based on individual preference, prior treatment response and side effect experience, medical history and risk factors, and adherence history, with side effect profile a major determinant of antipsychotic choice.

Dose-related effects of clozapine and risperidone on the pattern of brain regional serotonin and dopamine metabolism and on tests related to extrapyramidal functions in rats.

The present study was designed to evaluate the behavioral and neurochemical profiles of clozapine and risperidone in rats in a dose-dependent manner. Animals injected intraperitoneally (i.p.) with clozapine (2.5, 5.0 and 10.0 mg kg-1) or risperidone (1.0, 2.5 and 5.0 mg kg-1) were sacrificed 1 h later to collect brain samples. Hypolocomotive effects (home cage activity and catalepsy) were successively monitored in each animal after the drug or saline administration. Both drugs significantly (p < 0.01) decreased locomotor activity at high doses and in a dose-dependent manner. Maximum (100%) cataleptic potential was achieved at a high dose (5.0 mg kg-1) of risperidone. Neurochemical estimations were carried out by HPLC with electrochemical detection. Both drugs, at all doses, significantly (p < 0.01) increased the concentration of homovanillic acid (HVA), a metabolite of dopamine (DA), in the striatum. Dihydroxyphenylacetic acid (DOPAC) levels increased in the striatum and decreased in the rest of the brain, particularly in clozapine-injected rats. 5-Hydroxyindoleacetic acid (5-HIAA), the predominant metabolite of serotonin, significantly (p < 0.01) decreased in the striatum. 5-Hydroxytryptamine (5-HT) was significantly (p < 0.01) increased by risperidone and decreased by clozapine in the rest of the brain. Striatal tryptophan (TRP) was significantly (p < 0.01) decreased by risperidone and increased in the rest of the brain. The striatal HVA/DA ratio increased and the 5-HT turnover rate remained unchanged in the rest of the brain. Results suggest that the affinity of the two drugs towards D2/5-HT1A receptors interaction is involved in lower incidence of extrapyramidal side effects. Role of 5-HT1A receptors in the treatment of schizophrenia is discussed.

Responses of limbic and extrapyramidal substance P systems to nicotine treatment.

RATIONALE: Neuropeptides are linked to the psychopathology of stimulants of abuse, principally through dopamine mechanisms. Substance P (SP) is one of these neuropeptides and is associated with both limbic and extrapyramidal dopaminergic pathways and likely contributes to the pharmacology of these stimulants. The effects of nicotine on these dopamine systems have also been extensively studied; however, its effects on the associated SP pathways have received little attention. OBJECTIVES: In the present study, we elucidated the effects of nicotine treatment on limbic and extrapyramidal SP systems by measuring changes in associated SP tissue concentrations. MATERIALS AND METHODS: Male Sprague-Dawley rats received (+/-)nicotine 4.0 mg/kg/day (0.8 mg/kg, intraperitoneally; five injections at 2-h intervals) in the presence or absence of selective dopamine D1 and D2 receptor antagonists or a nonselective nicotinic acetylcholine receptor antagonist. RESULTS: The nicotine treatment significantly but temporarily decreased substance P-like immunoreactivity (SPLI) content in the ventral tegmental area (VTA) and substantia nigra 12-18 h after drug exposure. The nicotine-mediated changes in SPLI were selectively blocked by pretreatment with mecamylamine as well as a dopamine D1, D2, or both receptor antagonists. Other brain areas that also selectively demonstrated nicotine-related declines in SPLI content included prefrontal cortex, the nucleus accumbens shell, and the very posterior caudate. CONCLUSIONS: These findings indicate that some limbic and basal ganglia SP systems are significantly affected by exposure to nicotine through processes mediated by nicotinic and dopaminergic receptors, suggesting a role for SP pathways in nicotine's limbic and extrapyramidal effects.

Classifying antipsychotic agents : need for new terminology.

Converging data from multiple lines of research provide growing understanding of the pharmacological basis of the efficacy and tolerability of antipsychotic agents. This review highlights some of the drawbacks of the current practice of classifying antipsychotic agents into first- and second-generation agents, and argues that much of what is known about an antipsychotic agent in terms of its efficacy and tolerability can be predicted from its binding affinity at different receptors. This makes a case for a new system of classification that reflects the receptor binding affinity profiles of individual antipsychotic agents. In its quest to make a compelling case, the review provides detailed explanations for the pharmacological basis of antipsychotic efficacy, antipsychotic-induced weight gain and diabetes mellitus, cognitive effects and other adverse effects.

Dopamine transporter inhibitory and antiparkinsonian effect of common flowering quince extract.

Common flowering quince (FQ) is the fruit of Chaenomeles speciosa (Sweet) Nakai. FQ-containing cocktails have been applied to the treatment of neuralgia, migraine, and depression in traditional Chinese medicine. The present study assessed whether FQ is effective in dopamine transporter (DAT) regulation and antiparkinsonism by utilizing in vitro and in vivo assays, respectively. FQ at concentrations of 1-1000 microg/ml concentration-dependently inhibited dopamine uptake by Chinese hamster ovary (CHO) cells stably expressing DAT (D8 cells) and by synaptosomes. FQ had a slight inhibitory action on norepinephrine uptake by CHO cells expressing the norepinephrine transporter and no inhibitory effect on gamma-aminobutyric acid (GABA) uptake by CHO cells expressing GABA transporter-1 or serotonin uptake by the serotonin transporter. A viability assay showed that FQ mitigated 1-methyl-4-phenylpyridinium-induced toxicity in D8 cells. Furthermore, in behavioral studies, FQ alleviated rotational behavior in 6-hydroxydopamine-treated rats and improved deficits in endurance performance in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. Furthermore, immunohistochemistry revealed that FQ markedly reduced the loss of tyrosine hydroxylase-positive neurons in the substantia nigra in MPTP-treated mice. In summary, FQ is a selective, potent DAT inhibitor and has antiparkinsonian-like effects that are mediated possibly by DAT suppression. FQ has the potential to be further developed for Parkinson's disease treatment.

Rivastigmine-induced dystonia.

PURPOSE: A case of acute dystonia related to rivastigmine use is reported. SUMMARY: A 61-year-old Caucasian woman who had suffered from bipolar II disorder with rapid cycling for over 30 years was admitted to an inpatient psychiatry unit. In addition to bipolar II disorder, the patient had been previously diagnosed with early-stage Alzheimer's disease, posttraumatic stress disorder, and various anxiety disorders. During the current hospitalization, she was taking clonazepam, dextroamphetamine, lamotrigine, lansoprazole, levothyroxine, memantine, quetiapine, risperidone, rivastigmine, tranylcypromine, trazodone, and zolpidem. Soon after hospital admission, she began to complain of a tightening in her chest. A review of her records revealed similar complaints during previous hospitalizations. Rivastigmine was discontinued due to concerns of interactions with her antipsychotic regimen. Although these symptoms were previously attributed to anxiety, they appeared worse during this hospitalization. During these events she would be witnessed lying in bed in a supine position with her head canted posteriorly. Benztropine was given to help determine if she was having a dystonic reaction. Within 30 minutes, her chest discomfort began to resolve, and her symptoms resolved completely over the next 48 hours. Three days later, rivastigmine was restarted by the attending psychiatrist because of concerns about the patient's memory, and the dystonia-like symptoms returned within 2 hours of her morning dose. Rivastigmine was discontinued, and benztropine was given and then discontinued, with no return of symptoms for the remainder of her two-week hospitalization. CONCLUSION: A patient with bipolar II disorder and mild-to-moderate Alzheimer's disease developed dystonia, possibly caused by rivastigmine. However, the patient was taking various other medications that could have lowered the threshold for extrapyramidal syndromes.

Association of the RGS2 gene with extrapyramidal symptoms induced by treatment with antipsychotic medication.

OBJECTIVES: To investigate the role of genes encoding regulators of G protein signaling in early therapeutic response to antipsychotic drugs and in susceptibility to drug-induced extrapyramidal symptoms. As regulators of G protein signaling and regulators of G protein signaling-like proteins play a pivotal role in dopamine receptor signaling, genetically based, functional variation could contribute to interindividual variability in therapeutic and adverse effects. METHODS: Consecutively hospitalized, psychotic patients with Diagnostic and Statistical Manual of Mental Disorder-IV schizophrenia (n=121) were included in the study if they received treatment with typical antipsychotic medication (n=72) or typical antipsychotic drugs and risperidone (n=49) for at least 2 weeks. Clinical state and adverse effects were rated at baseline and after 2 weeks. Twenty-four single nucleotide polymorphisms were genotyped in five regulators of G protein signaling genes. RESULTS: None of the single nucleotide polymorphisms were related to clinical response to antipsychotic treatment at 2 weeks. Five out of six single nucleotide polymorphisms within or flanking the RGS2 gene were nominally associated with development or worsening of parkinsonian symptoms (PARK+) as measured by the Simpson Angus Scale, one of them after correction for multiple testing (rs4606, P=0.002). A GCCTG haplotype encompassing tagging single nucleotide polymorphisms within and flanking RGS2 was significantly overrepresented among PARK+ compared with PARK--patients (0.23 vs. 0.08, P=0.003). A second, 'protective', GTGCA haplotype was significantly overrepresented in PARK--patients (0.13 vs. 0.30, P=0.009). Both haplotype associations survive correction for multiple testing. CONCLUSIONS: Subject to replication, these findings suggest that genetic variation in the RGS2 gene is associated with susceptibility to extrapyramidal symptoms induced by antipsychotic drugs.

Polymorphisms in dopamine receptor DRD1 and DRD2 genes and psychopathological and extrapyramidal symptoms in patients on long-term antipsychotic treatment.

DRD(1) and DRD(2) receptor gene variants have been associated with clinical aspects of schizophrenia; however only specific features were analyzed in different samples. To assess the complex interaction between genetic and clinical factors, we studied the possible cross-interactions between DRD1 and DRD2 dopamine receptor gene polymorphisms, symptomatology of schizophrenia and schizoaffective disorders, and the occurrence of treatment induced side effects taking into consideration possible clinical confounding variables. One hundred thirty one outpatients in stable remission meeting the DSMIV criteria for schizophrenia spectrum disorders and receiving long-term maintenance therapy with haloperidol, fluphenazine, zuclopenthixole, or risperidone were genotyped for DRD1 A-48G, DRD2 Ins-141CDel, and DRD2 Ser311Cys polymorphisms. Psychopathological symptoms were assessed with the positive and negative syndrome scale for schizophrenia (PANSS). Extrapyramidal side effects were assessed with the Simpson-Angus extrapyramidal side effects scale (EPS), the Barnes Akathisia scale (BARS), and the abnormal involuntary movement scale (AIMS). Drug dosage was included as covariant because it was associated with the severity of symptomatology, akathisia, and parkinsonism. No association was observed for DRD1 and DRD2 polymorphisms and extrapyramidal side effects, or with the other clinical variables considered. Our study suggests that DRD1 and DRD2 variants are not liability factors for tardive dyskinesia.