Extrapyramidal Adverse Reactions Research Articles

Alteration in the mRNA expression profile of the autophagy-related mTOR pathway in schizophrenia patients treated with olanzapine

BackgroundThe mammalian target of rapamycin protein (mTOR) signaling pathway is involved in the pathogenesis of schizophrenia and the mechanism of extrapyramidal adverse reactions to antipsychotic drugs, which might be mediated by an mTOR-dependent autophagy impairment. This study aimed to examine the expression of mTOR pathway genes in patients with schizophrenia treated with olanzapine, which is considered an mTOR inhibitor and autophagy inducer.MethodsThirty-two patients with acute schizophrenia who had been treated with olanzapine for four weeks (average dose 14.24 ± 4.35 mg/d) and 32 healthy volunteers were recruited. Before and after olanzapine treatment, the Positive and Negative Syndrome Scale (PANSS) was used to evaluate the symptoms of patients with schizophrenia, and the mRNA expression levels of mTOR pathway-related genes, including MTOR, RICTOR, RAPTOR, and DEPTOR, were detected in fasting venous blood samples from all subjects using real-time quantitative PCR.ResultsThe MTOR and RICTOR mRNA expression levels in patients with acute schizophrenia were significantly decreased compared with those of healthy controls and further significantly decreased after four weeks of olanzapine treatment. The DEPTOR mRNA expression levels in patients with acute schizophrenia were not significantly different from those of healthy controls but were significantly increased after treatment. The expression levels of the RAPTOR mRNA were not significantly different among the three groups. The pairwise correlations of MTOR, DEPTOR, RAPTOR, and RICTOR mRNA expression levels in patients with acute schizophrenia and healthy controls were significant. After olanzapine treatment, the correlations between the expression levels of the DEPTOR and MTOR mRNAs and between the DEPTOR and RICTOR mRNAs disappeared.ConclusionsAbnormalities in the mTOR pathway, especially DEPTOR and mTORC2, might play important roles in the autophagy mechanism underlying the pathophysiology of schizophrenia and effects of olanzapine treatment.

Extrapyramidal adverse reactions to metoclopramide. A pharmacovigilance survey

In 2013 the Chilean regulatory sanitary agency issued a warning concerning dose adjustment and use restriction to avoid severe adverse effects of metoclopramide such tardive dyskinesia. To study dyskinesia type adverse effects in a population using metoclopramide. A cross sectional observational study was conducted among patients pertaining to palliative care and diabetes mellitus programs and consuming 10 mg/day or more of metoclopramide. Patients were interrogated looking for extrapiramidal signs and symptoms using a questionnaire validated by two neurologists. In 40% of diabetic patients with gastroparesia and 35% of palliative care patients, extrapyramidal adverse reactions to metoclopramide were suspected. Palliative Care patients suffered the largest number of adverse events. The period of use and individual doses of the drug were largely above Chilean regulatory agency recommendations in all cases. A significant number of patients using metoclopramide could experience extrapyramidal adverse reactions.

Indicators of Conformance With Guidelines of Schizophrenia Treatment in Mental Health Services

The aim of this study was to develop indicators of conformance in clinical practice with guidelines for care in schizophrenia. Recommended guidelines rarely apply to all patients and need to allow for social ability, family context, and phase of the disorder. These indicators were therefore devised for tailoring to patient characteristics and allowing for factors that may justify the lack of adherence to clinical guidelines. A team of senior clinicians and methodologists reviewed three clinical guidelines (from the Schizophrenia Patient Outcomes Research Team, McEvoy and colleagues, and the National Institute for Health and Clinical Excellence) and defined criteria for their operationalization into clinical indicators. For each indicator, the team defined criteria for eligibility (requirements to be met to qualify for evaluation), conformance (criteria to be satisfied to comply with each recommendation), and moderators (factors that could justify the lack of application of a given recommendation). These indicators were tested with a random sample of 807 patients with schizophrenia or schizoaffective disorders in outpatient facilities, long-term residential facilities, and hospital units for acute care in the Piedmont region of Italy. A set of 15 indicators was derived, nine concerning pharmacological treatment and six for general care and psychosocial rehabilitation. Moderators such as patient or family refusal of antipsychotic treatment and the patient's level of disability helped to justify a considerable proportion of nonconformant care. The indicators developed are a simple and useful tool to monitor the conformance of care with recommended practices and to identify areas needing improvement.

Indicators of Conformance With Guidelines of Schizophrenia Treatment in Mental Health Services

Indicators of Conformance With Guidelines of Schizophrenia Treatment in Mental Health Services

Affinity of cyamemazine, an anxiolytic antipsychotic drug, for human recombinant dopamine vs. serotonin receptor subtypes

Animal studies indicate that the anxiolytic properties of the antipsychotic agent cyamemazine may result from blockade of serotonin 5-HT 2C receptors and to a lesser extent from blockade of serotonin 5-HT 3 receptors. Here, we used human recombinant receptors to determine the relative affinity of cyamemazine for serotonin and dopamine receptor subtypes. In addition, cyamemazine was tested in other brain receptor types and subtypes which are considered to mediate central nervous systems effects of drugs. Hence, cyamemazine affinity was determined in human recombinant receptors expressed in CHO cells ( hD 2, hD 3, and hD 4.4 receptors, h5-HT 1A, h5-HT 2A, h5-HT 2C, and h5-HT 7, and hM 1, hM 2, hM 3, hM 4, and hM 5 receptors), L-cells ( hD 1 receptor), and HEK-293 cells ( h5-HT 3 receptors) or natively present in N1E-115 cells (5-HT 3 receptors) or in rat cerebral cortex (non-specific α 1- and α 2-adrenoceptors, GABA A and GABA B receptors, H 3 histamine receptors), and guinea-pig cerebellum (H 1 central and H 2 histamine receptors) membranes. Similarly to atypical antipsychotics, cyamemazine exhibited high affinity for: (i) h5-HT 2A receptors ( K i =1.5±0.7 nM, mean±SEM, N=3) and this was four times higher than for hD 2 receptors ( K i =5.8±0.8 nM), (ii) h5-HT 2C receptors ( K i =11.8±2.2 nM), and (iii) 5-HT 7 receptors ( K i =22 nM). Conversely, cyamemazine exhibited very low affinity for h5-HT 3 receptors ( K i =2.9±0.4 μM). In conclusion, similarly to atypical antipsychotic agents, cyamemazine, possesses high affinity for h5-HT 2A, h5-HT 2C, and h5-HT 7 receptors, a feature which can explain its low propensity to cause extrapyramidal adverse reactions in clinical practice. The high affinity for h5-HT 2C receptors, but not for h5-HT 3 receptors, can account for the anxiolytic activity of cyamemazine in human subjects.

Frequency of Extrapyramidal Adverse Reactions in Schizophrenic Outpatients Treated with Risperidone, Olanzapine, Quetiapine or Haloperidol : Results of the EIRE Study.

The EIRE (Estudio de Investigaciön de Resultados en Esquizofrenia - Outcomes Research Study in Schizophrenia) study was initiated in order to assess the frequency of adverse reactions [extrapyramidal symptoms (EPS), hyperprolactinaemia, sexual dysfunction and weight gain] caused by atypical antipsychotics and haloperidol in patients with schizophrenia during routine treatment in clinical practice. This paper presents the results of the assessment of extrapyramidal adverse reactions. Outpatients diagnosed with schizophrenia according to the Diagnostic and Statistical Manual of mental disorders, 4th edition (DSM-IV), criteria and receiving a single antipsychotic (risperidone, olanzapine, quetiapine or haloperidol) for at least 4 weeks were consecutively recruited. In this cross-sectional and non-interventional study data were collected in a single visit; this included demographic and clinical characteristics, current antipsychotic and concomitant treatment, and data on several adverse effects listed in a modified version of the UKU (Udvalg for Kliniske Undersogelser - Committee on Clinical Investigations) scale. For paired comparisons of the frequency of adverse reactions between treatments the Chi-squared (χ2) test was used. For estimation of the risk of a given adverse reaction with a given treatment a logistic regression method was used. 636 evaluable patients (of 669 recruited) were assessed. The frequency of EPS with haloperidol (78.3% of the cases) was higher than with risperidone (55.1%), quetiapine (39.5%) and olanzapine (35.8%) [χ2: p < 0.05], and the difference between risperidone and olanzapine was also statistically significant (χ2: p < 0.05). Very similar results were obtained in the individualised analysis of the items as regards the occurrence of akathisia, which was also more frequent in the haloperidol (36.8%) and risperidone (19.7%) groups than in the olanzapine (11.4%) and quetiapine (2.6%) groups (χ2: p < 0.05). Olanzapine, quetiapine and risperidone also showed a lower risk of EPS than haloperidol when adjusting by dose. Our results suggest that the atypical antipsychotics studied are less likely to induce extrapyramidal adverse reactions compared with haloperidol in stabilised patients, although these reactions are still common.

Fluoxetine and Tics in an Adolescent

To describe a case of tics associated with fluoxetine. A depressed adolescent was treated with fluoxetine. The patient had not been exposed to any other pharmacologic agents prior to this treatment. Following eight months of fluoxetine therapy the patient developed numerous tics. The movements subsided six months after discontinuation of fluoxetine. Antidopaminergic effects have been reported in patients treated with fluoxetine. Because fluoxetine is a specific serotonin reuptake inhibitor, one plausible explanation for the extrapyramidal symptoms observed in these patients is that serotonin modulates dopaminergic neurons. Extrapyramidal symptoms have been reported in patients receiving fluoxetine, although never previously in an adolescent. This case report provides further evidence that fluoxetine may be associated with severe extrapyramidal adverse reactions.

Acute Dystonia Induced by Sulpiride

We report a 15-year-old boy who, after the administration of 100 mg i.v. of sulpiride, presented an acute dystonic reaction consisting of oculogyric crises, retrocollis, opysthotonus, and dystonic postures in the left arm and hand. The symptoms were reversed after the injection of biperiden. This side effect has not been described previously. Sulpiride can induce the same extrapyramidal adverse reactions as the classical neuroleptic drugs.

High-dose metoclopramide + lorazepam versus low-dose metoclopramide + lorazepam + dehydrobenzperidol in the treatment of cisplatin-induced nausea and vomiting

In a randomized double-blind, cross-over trial of 34 patients receiving cisplatin-based chemotherapy (20-100 mg/m2), the antiemetic effect of high-dose metoclopramide (HDM) (10 mg/kg iv. loading dose + 7 hours continuous infusion) + lorazepam (L) (2.5 mg x 4 po) was compared with low-dose metoclopramide (LDM) (70 mg) + L (2.5 mg x 2 po) + dehydrobenzperidol (5 mg x 2 im). Among the 29 patients who completed the cross-over, HDM significantly reduced the number of vomiting episodes (p = 0.002) and the degree of nausea (p = 0.004). Seventeen patients preferred the HDM and 4 the LDM regimen (p = 0.01). Sedation was seen in all but 1 patient, and was graded as severe in 6 patients receiving the HDM and in 2 patients receiving the LDM regimen. No extrapyramidal adverse reactions were seen. We conclude that high-dose metoclopramide + lorazepam is a safe antiemetic regimen and significantly superior to low-dose metoclopramide + lorazepam + dehydrobenzperidol. Owing to the severe sedation which occurs in some patients, the dose of lorazepam should be individually adjusted.

Clozapine: a novel antipsychotic agent.

Clozapine is an antipsychotic without the extra-pyramidal adverse effects associated with currently marketed antipsychotics. In animals, this drug has not been shown to induce catalepsy and only weakly antagonizes the stereotypic movements induced by apomorphine and the amphetamines. Clozapine is rapidly absorbed after both single and repeated oral doses, with steady-state concentrations attained within eight to ten days after beginning therapy. It is metabolized to N-oxideclozapine and N-desmethylclozapine, which have less pharmacological activity than the parent compound and are excreted in the urine and, to a lesser extent, in the feces. Clozapine has overall therapeutic efficacy and/or superiority to currently marketed antipsychotics in the treatment of refractory schizophrenia. Usual doses (25-900 mg/d) of clozapine cause fewer extrapyramidal adverse reactions than available antipsychotics. Hypotension, dizziness, salivation, and sedation are the most frequently reported adverse effects and tend to subside over time. Agranulocytosis is the most serious adverse reaction, and those receiving clozapine should undergo weekly white blood cell count determinations. Clozapine is useful for those treatment-resistant patients who have not responded to adequate trials of other antipsychotics.