Effects of prophylactic anticholinergic medications to decrease extrapyramidal side effects in patients taking acute antiemetic drugs: a systematic review and meta-analysis.

OBJECTIVES: To determine the effectiveness of prophylactic anticholinergic medications in reducing extrapyramidal symptoms in patients taking acute antiemetics with a dopamine D2 receptor antagonist effect. METHODS: Systematic searches of all published studies through March 2017 were identified from PubMed, Cochrane library, Embase, Web of Science and Scopus. Only randomised controlled trials of patients receiving dopamine D2 antagonist antiemetic therapy for acute migraine in which an anticholinergic or placebo was compared were included. Pooled ORs were calculated for incidence of extrapyramidal symptoms and sedation. RESULTS: Four placebo-controlled randomised controlled trials consisting of 737 patients met the inclusion criteria for our meta-analysis. The effect of diphenhydramine differed depending on the method of administration of the antiemetic. When the antiemetic was delivered as a 2 min antiemetic bolus, the odds of extrapyramidal symptoms were significantly reduced in the diphenhydramine group compared with placebo (OR 0.42; 95% CI 0.22 to 0.81; P=0.01). However, when the antiemetic was given as a 15 min infusion, there was no significant difference in extrapyramidal symptoms with or without diphenhydramine (OR 1.06; 95% CI 0.58 to 1.91; P=0.85). The lowest incidence of extrapyramidal symptoms was observed in patients receiving a 15 min antiemetic infusion without diphenhydramine prophylaxis (9.8%). In two trials including 351 patients that dichotomously reported sedation scales, diphenhydramine had significantly higher rates of sedation (31.6%vs19.2%, OR 2.01, 95% CI 1.21 to 3.33; P=0.007). CONCLUSION: Prophylactic diphenhydramine reduces extrapyramidal symptoms in patients receiving bolus antiemetic therapy with a dopamine D2 antagonist effect, but not when it is given as an infusion. Because of significantly greater sedation with diphenhydramine, the most effective strategy is to administer the D2 antagonist antiemetic as a 15 min infusion without prophylaxis.

A Population Approach to Guide Amisulpride Dose Adjustments in Older Patients With Alzheimer's Disease.

OBJECTIVE: We have previously reported high dopamine D2/3 receptor occupancies at low amisulpride concentrations in older people with Alzheimer's disease (AD), during off-label treatment of AD-related psychosis. This post hoc analysis explored pharmacokinetic (concentration) and pharmacodynamic (prolactin, D2/3 occupancy) contributions to symptom reduction and extrapyramidal side effects (EPS) to inform AD-specific dose adjustments. METHODS: Population pharmacokinetic-pharmacodynamic models were developed by combining pharmacokinetic data from a phase 1 study in 20 healthy older people with pharmacokinetic prolactin, [¹8F]fallypride D2/3 receptor imaging, and clinical outcome data from 28 older patients prescribed open amisulpride (25-75 mg/d) to treat AD-related psychosis. Model predictions were used to simulate dose-response and dose-EPS. RESULTS: Symptom reduction (delusions) was associated with amisulpride concentration (P = 1.3e-05) and D2/3 occupancy (P < .01, caudate, putamen, thalamus). Model predictions suggested that across concentrations of 40-100 ng/mL, and occupancies of 40% to 70% in the caudate and thalamus and 30% to 60% in the putamen, there was a 50% to 90% probability of response and < 30% probability of EPS. Simulations, based on concentration-delusions and concentration-EPS model outputs, showed that 50 mg/d of amisulpride was the appropriate dose to achieve this target range in those aged > 75 years; increasing the dose to 75 mg/d increased the risk of EPS, particularly in those aged > 85 years of low body weight. CONCLUSIONS: These findings argue strongly for the consideration of age- and weight-based dose adjustments in older patients with AD-related psychosis and indicate that 50 mg/d of amisulpride may be both the minimal clinically effective dose and, in those aged > 75 years, the maximally tolerated dose.

[A differential approach to the improvement of prevention and correction of neuroleptic side extrapyramidal disorders with pantogam activ in patients with schizophrenia]. / Differentsirovannyi podkhod k usovershenstvovaniyu metodov preduprezhdeniya i korrektsii neirolepticheskikh pobochnykh ekstrapiramidnykh rasstroistv preparatom pantogam aktiv u bol'nykh shizofreniei.

AIM: To assess the efficacy and safety of pantogam active (PA) in prevention and correction of neurological side-effects during the course neuroleptic treatment of acute endogenous psychoses. MATERIAL AND METHODS: Eighty schizophrenic patients (mean age 33 years) with acute psychosis were examined. All patients received 28-day course treatment with typical and atypical neuroleptics. Two equal groups were studied: patients of the first group were treated with trihexyphenidyl (THP) in dose of 0,002-0,012 mg and patients of the second group received in addition PA in dose 0,9 mg/day. Clinical-observation, psychometric scales (PANSS, CGI-S, UKU) were administered at baseline and in 1st,3rd,7th, 14th, 21st, 28st day. RESULTS: PA in the combination with THP improved tolerability to neuroleptic therapy in whole and exerted the better correction effect on neuroleptic extrapyramidal disorders (EPD) compared to THP monotherapy. The number of patients with ERD was reduced by 1.5 times and prevention of EPD was observed 3 times more frequent in the group treated with PA. In the THP group, other adverse effects (AE) were 1,7 times more frequent and the total AE score was 2,5 times greater compared to the PA group (131 vs 50). Correction and preventive effects of the combined treatment on the clinically severe symptoms of EPD (akathisia, muscle dystonia) were more frequent in patients treated with typical neuroleptics. A less amount of THP (by 1,2 times) was used to stop EPD in the PA group. CONCLUSION: PA in the combination with THP has demonstrated the clear neuroprotective effect on the development, frequency and clinical presentations of neurological side-effects. The РА can be recommended as a drug of choice for correction and prevention of neuroleptic side-effects, it promotes their tolerability and improves quality of life during the course treatment.

[Augmentation of antipsychotics with glycine may ameliorate depressive and extrapyramidal symptoms in schizophrenic patients--a preliminary 10-week open-label study]. / Augmentacja leczenia przeciwpsychotycznego glicyna moze zmniejszac nasilenie objawów depresyjnych oraz pozapiramidowych u chorych na schizofrenie--wyniki wstepnego 10-tygodniowego badania otwartego.

AIM: The objective of this study was to analyze the changes in depressive and extrapyramidal symptomatology during glycine augmentation of antipsychotic treatment in patients with schizophrenia. MATERIALS AND METHODS: Twenty-nine schizophrenic patients (ICD-10) with predominant negative symptoms in stable mental state participated in a 10-week open-label prospective study. Patients received stable doses of antipsychotic drugs for at least 3 months before glycine application. During the next 6 weeks patients received augmentation of antipsychotic treatment with glycine (up to 60 g per day). The first and last two weeks of observation were used to assess stability of mental state. Symptom severity was assessed using the Hamilton Depression Rating Scale (HDRS), the Positive and Negative Syndrome Scale (PANSS), and the Simpson-Angus Extrapyramidal Symptom Rating Scale (SAS). RESULTS: In the studied group after 6 weeks of administration ofglycine a significant improvement in depressive symptoms (reduced scores by 25.8% in HDRS, p < 0.001) and reduced scoring in mood symptoms of PANSS were observed. In SAS a reduction of extrapyramidal symptoms' severity (p < 0.05) was also noted. Two weeks after the glycine augmentation the symptom severity in the HDRS, PANSS, and SAS remained at similar levels. CONCLUSIONS: Glycine augmentation of antipsychotic treatment may reduce the severity of depressive and extrapyramidal symptoms. Glycine use was safe and well tolerated.

Naturalistic pharmacotherapy of acute episodes of schizophrenic disorders in comparison to treatment guidelines.

INTRODUCTION: This study was designed to investigate to what extent guidelines regarding the pharmacological treatment of patients suffering from schizophrenia-like psychosis are adopted in a naturalistic treatment setting. METHODS: Medical records of n=819 patients undergoing inpatient treatment for schizophrenia-like psychosis in 11 psychiatric hospitals in northwestern Germany were retrospectively analyzed and findings were compared to current schizophrenia guideline recommendations. RESULTS: The prescription rate of second generation antipsychotics increased from 47.1% on admission to 62.5% at discharge. Only half the patients (52.3%) received antipsychotic monotherapy while 47.7% took between 2 and 4 antipsychotic substances at a time. Dosage increases occurred most frequently (in 60%) within the first week of inpatient treatment, 16.6% experienced an elevation between days 15 and 29. A change within the atypical medication was found in 19.3%. Clozapine prescriptions increased throughout the treatment but were combined with other antipsychotic substances in the majority of cases. CONCLUSION: Under naturalistic conditions guideline recommendations for treatment of schizophrenia-like psychosis are adhered to only partially. Combination therapy with 2 or more antipsychotic drugs is quite common despite a clear recommendation for monotherapy.

Comparative study between two animal models of extrapyramidal movement disorders: prevention and reversion by pecan nut shell aqueous extract.

Acute reserpine and subchronic haloperidol are animal models of extrapyramidal disorders often used to study parkinsonism, akinesia and tardive dyskinesia. In humans, these usually irreversible and disabling extrapyramidal disorders are developed by typical antipsychotic treatment, whose pathophysiology has been related to oxidative damages development. So far, there is no treatment to prevent these problems of the psychiatric clinic, and therefore further studies are needed. Here we used the animal models of extrapyramidal disorders cited above, which were performed in two distinct experiments: orofacial dyskinesia (OD)/catalepsy induced by acute reserpine and subchronic haloperidol after (experiment 1) and before (experiment 2) oral treatment with pecan shell aqueous extract (AE), a natural and promissory antioxidant. When administered previously (exp.1), the AE prevented OD and catalepsy induced by both reserpine and haloperidol. When reserpine and haloperidol were administered before the extract (exp.2), the animals developed OD and catalepsy all the same. However, the orofacial parameter (but not catalepsy) in both animal models was reversed after 7 and 14 days of AE treatment. These results indicate that, acute reserpine and subchronic haloperidol administrations induced similar motor disorders, although through different mechanisms, and therefore are important animal models to study the physiopathology of extrapyramidal disorders. Comparatively, the pecan shell AE was able to both prevent and reverse OD but only to prevent catalepsy. These results reinforce the role of oxidative stress and validate the two animal models used here. Our findings also favor the idea of prevention of extrapyramidal disorders, rather than their reversal.

Addressing adverse effects of antipsychotic treatment in young patients with schizophrenia.

Children and adolescents are at a greater risk than adults for antipsychotic-induced adverse effects such as extrapyramidal symptoms, prolactin elevation, sedation, weight gain, and metabolic effects, which can have long-term health consequences for young patients. Clinicians should complete careful baseline assessments and perform dietary and lifestyle counseling when initiating antipsychotic treatment and then proactively monitor for adverse effects to optimize physical as well as psychiatric outcomes. Strategies to manage adverse effects that occur or worsen during treatment include switching medications, lowering the dosage of medications, and initiating targeted treatments to address clinically relevant changes.

Basal ganglia neuroprotection with anticonvulsants after energy stress: a comparative study.

The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model provides a valuable paradigm of the energy deficiency disorders found in childhood. In such disorders, anticonvulsants may provide neuroprotection by modulating cellular energy consumption and by exerting favorable pleiotropic effects on neuronal survival. To verify such hypothesis, we tested the effects of levetiracetam, vigabatrin, gabapentine, pregabaline, tiagabine, clonazepam and lamotrigine on neuroprotection in the MPTP mouse model. The membrane dopamine transporter (DAT) density, which provides a reliable index of dopaminergic neurons survival in the basal ganglia, was assessed by semi-quantitative autoradiography of the striatum. Unlike all other anticonvulsants tested, lamotrigine provided a significant and dose-dependent neuroprotection in these experimental conditions. Lamotrigine, a widely used and well-tolerated molecule in children, could provide neuroprotection in various energy deficiency disorders.

Aripiprazole differentially affects mesolimbic and nigrostriatal dopaminergic transmission: implications for long-term drug efficacy and low extrapyramidal side-effects.

Aripiprazole has been used effectively to treat schizophrenia in the clinic; however, its mechanisms of action are not clear. This study examined how short- and long-term aripiprazole treatment affects dopaminergic transmission in mesolimbic and nigrostriatal pathways. For comparison, the effects of haloperidol and olanzapine treatment were also examined. Aripiprazole significantly increased D2 receptor mRNA expression and decreased tyrosine hydroxylase (TH) mRNA expression in the ventral tegmental area (VTA) after 1- and 12-wk treatment, but had no effect in substantia nigra (SN) and nucleus accumbens (NAc). Aripiprazole also decreased dopamine transporter (DAT) binding density in NAc (for 1- and 12-wk treatment) and VTA (1-wk treatment). In contrast, haloperidol significantly increased D2 receptor binding density and decreased DAT binding density in NAc and caudate putamen (CPu) after 1- and 12-wk treatment, and it also decreases DAT binding in VTA after 12-wk treatment. Olanzapine had less widespread effects, namely an increase in D2 receptor mRNA in VTA after 12-wk treatment and decreased DAT binding in NAc after 1-wk treatment. These results suggest that aripiprazole has selective effects on the mesolimbic dopaminergic pathway. Selectively reducing dopamine synthesis in VTA is a possible therapeutic mechanism for the long-term efficacy of aripiprazole in controlling schizophrenia symptoms with reduced extrapyramidal side-effects.

CYP 2D6 polymorphism and antipsychotic therapy.

One of the most challenging problems in clinical psychiatry are inter-individual differences in clinical response to antipsychotic treatment. Several studies were investigating the impact of the polymorphic cytochrome P450 2D6 gene (CYP 2D6) on the psychopathological and extrapyramidal symptoms, but the results were conflicting. There is a lack of clinical studies of the impact of CYP2D6 polymorphism on therapeutic efficacy, especially in the long-term treatment of schizophrenia. The aim of the presentation was to evaluate the impact of CYP2D6 genotype on psychopathological and extrapyramidal symptoms in a group of Slovenian outpatients with schizophrenia or schizoaffective disorder in stable remission, who were receiving long-term maintenance therapy.

Metoclopramide and extrapyramidal symptoms: a case report.

Metoclopramide is a useful medication in the anesthesia provider's armamentarium. Its primary indication in the preoperative phase is to reduce gastric contents and increase lower esophageal sphincter tone for pharmacologic pulmonary aspiration prophylaxis. Metoclopramide can precipitate extrapyramidal symptoms (EPS)/drug-induced movement disorders (DIMD). Tardive dyskinesia and Parkinsonism is generally seen after long-term use, whereas dystonia and akathisia can occur after a single dose of metoclopramide. Recognition of dystonia and/or akathisia by the perianesthesia nurse after the administration of metoclopramide is important for prompt treatment of this distressing condition. It is imperative that the perianesthesia nurse is knowledgeable in metoclopramide's basic pharmacology, uses as an anesthetic adjunct, guidelines for administration, and EPS/DIMD associated reactions, as well as measures that may reduce the incidence and/or facilitate treatment of this medication-induced condition. This case report presents a male patient in his 40s experiencing akathisia after a single 10-mg dose of metoclopramide.

Assessing and maximizing the safety and tolerability of antipsychotics used in the treatment of children and adolescents.

When taking antipsychotic medications, children and adolescents seem to have a higher risk than adults for experiencing adverse events such as extrapyramidal symptoms, prolactin elevation, sedation, weight gain, and metabolic effects. Side effects may be predicted by the pharmacologic binding profiles of antipsychotics to certain neuroreceptors. Data from 7 recently completed randomized placebo-controlled trials in adolescent schizophrenia and pediatric bipolar disorder that included a total of 1480 patients extend prior results and provide numbers-needed-to-harm as a clinically useful measure of risk. Results from these pediatric studies indicate that adverse effect profiles differ among commonly used antipsychotics. However, more detailed data are needed, as information is lacking regarding carryover or withdrawal effects from prior medications and regarding the masking of effects by adjunctive treatments used to treat agitation, insomnia, or extrapyramidal symptoms and akathisia in these studies. Moreover, randomized head-to-head trials and large-scale studies that investigate predictors of adverse effects as well as the safety and efficacy of interventions aimed at preventing and reversing negative effects of antipsychotics with relevant impact on psychological, psychiatric, and physical functioning are lacking. When choosing an antipsychotic treatment, patients and their families should be included in a careful risk-benefit assessment. Consideration of adverse effects, as well as dietary and lifestyle counseling, should be part of any antipsychotic treatment initiation and continuation. Routine, proactive monitoring of side effects is essential to optimize patient outcomes. In all treatment decisions, the benefits of improving often severe and debilitating manic, psychotic, and aggressive symptomatology must be balanced against the varying risks of adverse effects associated with specific antipsychotic agents in child and adolescent patients.

[Risperidone use in child and adolescent psychiatric patients]. / Prescription de la rispéridone chez l'enfant et l'adolescent.

In a plural and multidisciplinary process of care, it would be fruitful to ally complementary, pharmacologic and psychodynamic approaches. We have done a review of the literature on the effectiveness and the cautions for prescription of risperidone, a second generation antipsychotic drug. Risperidone has proved helpful in treating children and adolescents with autism spectrum, conduct and bipolar disorders, Tourette's syndrome, and schizophrenia. The principal side effects are sedation, weight gain, and metabolic disturbances. Extrapyramidal symptoms, QTc prolongation, and hyperprolactemia with clinical signs are infrequent and not clinically significant. The benefit/risk is clearly in favor of the prescription when it is accompanied with the precautions and with the adequate monitoring.

Health monitoring for patients who have schizophrenia. Summary of the Mount Sinai Conference recommendations.

Schizophrenia is associated with several chronic medical illnesses and a reduced life expectancy. This paper summarizes findings and recommendations from "The Mount Sinai Conference," held at the Mount Sinai School of Medicine in New York on October 17-18, 2002, and discusses the implications for improving medical monitoring of patients with schizophrenia who are managed in outpatient settings from the initiation of treatment. The Mount Sinai Conference involved a diverse panel of experts, including specialists on schizophrenia, obesity, diabetes, cardiology, endocrinology, and ophthalmology. Consensus recommendations included baseline measurement and regular monitoring of body mass index, blood glucose, lipid profiles, signs of prolactin elevation or sexual dysfunction, and movement disorders. Information from such measurements should be considered when selecting or switching antipsychotic agents and should trigger an evaluation of medication when abnormalities are detected.