The treatment of tardive dyskinesia: A systematic review and meta-analysis

This systematic review aimed to collate randomized controlled trials (RCTs) of various interventions used to treat tardive dyskinesia (TD) and, where appropriate, to combine the data for mete-analysis, Clinical trials were identified by electronic searches, handsearches and contact with principal investigators. Data were extracted independently by two reviewers, for outcomes related to improvement, deterioration, side-effects and drop out rates. Data were pooled using the Mantel-Haenzel Odds Ratio (fixed effect model). For treatments that had significant effects, the number needed to treat (NNT) was calculated. From 296 controlled clinical trials, data were extracted from 47 trials. For most interventions, we could identify no RCT-derived evidence of efficacy. A meta-analysis showed that baclofen, deanol and diazepam were no more effective than a placebo. Single RCTs demonstrated a lack of evidence of any effect for bromocriptine, ceruletide, clonidine, estrogen, gamma linolenic acid, hydergine, lecithin, lithium, progabide, seligiline and tetrahydroisoxazolopyridinol. The meta-analysis found that five interventions were effective: L-dopa, oxypertine, sodium valproate, tiapride and vitamin E; neuroleptic reduction was marginally significant. Data from single RCTs revealed that insulin, alpha methyl dopa and reserpine were more effective than a placebo. There was a significantly increased risk of adverse events associated with baclofen, deanol, L-dopa, oxypertine and reserpine. Metaanalysis of the impact of placebo (n=485) showed that 37.3% of participants showed an improvement. Interpretation of this systematic review requires caution as the individual trials identified tended to have small sample sizes. For many compounds, data from only one trial were available, and where meta-analyses were possible, these were based on a small number of trials. Despite these concerns, the review facilitated the interpretation of the large and diverse range of treatments used for TD. Clinical recommendations for the treatment of TD are made, based on the availability of RCT-derived evidence, the strength of that evidence and the presence of adverse effects. (C) 1999 Elsevier Science B.V. All rights reserved.

Does the degree of smoking effect the severity of tardive dyskinesia? A longitudinal clinical trial

Background. - Tardive dyskinesia (TD) is a movement disorder observed after chronic neuroleptic treatment. Smoking is presumed to increase the prevalence of TD. The question of a cause-effect-relationship between smoking and TD, however, remains to be answered. Purpose of this study was to examine the correlation between the degree of smoking and the severity of TD with respect to differences caused by medication. Method. - We examined 60 patients suffering from schizophrenia and TD, We compared a clozapine-treated group With a group treated with typical neuroleptics. Movement disorders were assessed using the Abnormal-Involuntary-Movement-Scale and the technical device digital image processing, providing rater independent information on perioral movements. Results. - We found a strong correlation (.80 < r < .90, always p < .0001) between the degree of smoking and severity of TD. Repeated measurements revealed a positive correlation between changes in cigarette consumption and changes of the severity of TD (p < .0001). Analyses of covariance indicated a significant group-effect with a lower severity of TD in the clozapine-group compared to the typical-neuroleptics-group (p = .010). Interaction-analyses indicated a higher impact of smoking oil the severity of TD in the typical-neuroleptics-group compared to the clozapine-group (p = .033). Conclusion. - Concerning a possible cause-effect-relationship between smoking and TD, smoking is more of a general health hazard than neuroleptic exposure in terms of TD. (C) 2008 Elsevier Masson SAS. All rights reserved.

Reliability and clinical utility of a Portuguese version of the Abnormal Involuntary Movements Scale (AIMS) for tardive dyskinesia in Brazilian patients

The objective of the present study was to evaluate the reliability and clinical utility of a Portuguese version of the Abnormal Involuntary Movements Scale (AIMS). Videotaped interviews with 16 psychiatric inpatients treated with antipsychotic drugs for at least 5 years were evaluated. Reliability was assessed by the intraclass correlation coefficient (ICC) between three raters, two with and one without clinical training in psychopathology. Clinical utility was assessed by the difference between the scores of patients with (N = 11) and without (N = 5) tardive dyskinesia (TD). Patients with TD exhibited a higher severity of global evaluation by the AIMS (sum of scores: 4.2 ± 0.9 vs 0.4 ± 0.2; score on item 8: 2.3 ± 0.3 vs 0.4 ± 0.2, TD vs controls). The ICC for the global evaluation was fair between the two skilled raters (0.58-0.62) and poor between these raters and the rater without clinical experience (0.05-0.29). Thus, we concluded that the Portuguese version of the AIMS shows an acceptable inter-rater reliability, but only between clinically skilled raters, and that it is clinically useful.

Systematic review of cholinergic drugs for neuroleptic-induced tardive dyskinesia: a meta-analysis of randomized controlled trials

The authors evaluated the efficacy of cholinergic drugs in the treatment of neuroleptic-induced tardive dyskinesia (TD) by a systematic review of the literature on the following agents: choline, lecithin, physostigmine, tacrine, 7-methoxyacridine, ipidacrine, galantamine, donepezil, rivastigmine, eptastigmine, metrifonate, arecoline, RS 86, xanomeline, cevimeline, deanol, and meclofenoxate. All relevant randomized controlled trials, without any language or year limitations, were obtained from the Cochrane Schizophrenia Group's Register of Trials. Trials were classified according to their methodological quality. For binary and continuous data, relative risks (RR) and weighted or standardized mean differences (SMD) were calculated, respectively. Eleven trials with a total of 261 randomized patients were included in the meta-analysis. Cholinergic drugs showed a minor trend for improvement of tardive dyskinesia symptoms, but results were not statistically significant (RR 0.84, 95% confidence interval (CI) 0.68 to 1.04, p=0.11). Despite an extensive search of the literature, eligible data for the meta-analysis were few and no results reached statistical significance. In conclusion, we found no evidence to support administration of the old cholinergic agents lecithin, deanol, and meclofenoxate to patients with tardive dyskinesia. In addition, two trials were found on novel cholinergic Alzheimer drugs in tardive dyskinesia, one of which was ongoing. Further investigation of the clinical effects of novel cholinergic agents in tardive dyskinesia is warranted. (C) 2004 Elsevier Inc. All rights reserved.

Étude exploratoire sur la corrélation entre les indices buccaux et l'intensité de la dyskinésie buccale tardive

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the treatment of schizophrenia and related disorders

Background: The Royal Australian and New Zealand College of Psychiatrists is co-ordinating the development of clinical practice guidelines (CPGs) in psychiatry, funded under the National Mental Health Strategy (Australia) and the New Zealand Health Funding Authority. This paper presents CPGs for schizophrenia and related disorders. Over the past decade schizophrenia has become more treatable than ever before. A new generation of drug therapies, a renaissance of psychological and psychosocial interventions and a first generation of reform within the specialist mental health system have combined to create an evidence-based climate of realistic optimism. Progressive neuroscientific advances hold out the strong possibility of more definitive biological treatments in the near future. However, this improved potential for better outcomes and quality of life for people with schizophrenia has not been translated into reality in Australia. The efficacy-effectiveness gap is wider for schizophrenia than any other serious medical disorder. Therapeutic nihilism, under-resourcing of services and a stalling of the service reform process, poor morale within specialist mental health services, a lack of broad-based recovery and life support programs, and a climate of tenacious stigma and consequent lack of concern for people with schizophrenia are the contributory causes for this failure to effectively treat. These guidelines therefore tackle only one element in the endeavour to reduce the impact of schizophrenia. They distil the current evidence-base and make recommendations based on the best available knowledge. Method: A comprehensive literature review (1990-2003) was conducted, including all Cochrane schizophrenia reviews and all relevant meta-analyses, and a number of recent international clinical practice guidelines were consulted. A series of drafts were refined by the expert committee and enhanced through a bi-national consultation process. Treatment recommendations: This guideline provides evidence-based recommendations for the management of schizophrenia by treatment type and by phase of illness. The essential features of the guidelines are: (i) Early detection and comprehensive treatment of first episode cases is a priority since the psychosocial and possibly the biological impact of illness can be minimized and outcome improved. An optimistic attitude on the part of health professionals is an essential ingredient from the outset and across all phases of illness. (ii) Comprehensive and sustained intervention should be assured during the initial 3-5 years following diagnosis since course of illness is strongly influenced by what occurs in this 'critical period'. Patients should not have to 'prove chronicity' before they gain consistent access and tenure to specialist mental health services. (iii) Antipsychotic medication is the cornerstone of treatment. These medicines have improved in quality and tolerability, yet should be used cautiously and in a more targeted manner than in the past. The treatment of choice for most patients is now the novel antipsychotic medications because of their superior tolerability and, in particular, the reduced risk of tardive dyskinesia. This is particularly so for the first episode patient where, due to superior tolerability, novel agents are the first, second and third line choice. These novel agents are nevertheless associated with potentially serious medium to long-term side-effects of their own for which patients must be carefully monitored. Conventional antipsychotic medications in low dosage may still have a role in a small proportion of patients, where there has been full remission and good tolerability; however, the indications are shrinking progressively. These principles are now accepted in most developed countries. (vi) Clozapine should be used early in the course, as soon as treatment resistance to at least two antipsychotics has been demonstrated. This usually means incomplete remission of positive symptomatology, but clozapine may also be considered where there are pervasive negative symptoms or significant or persistent suicidal risk is present. (v) Comprehensive psychosocial interventions should be routinely available to all patients and their families, and provided by appropriately trained mental health professionals with time to devote to the task. This includes family interventions, cognitive-behaviour therapy, vocational rehabilitation and other forms of therapy, especially for comorbid conditions, such as substance abuse, depression and anxiety. (vi) The social and cultural environment of people with schizophrenia is an essential arena for intervention. Adequate shelter, financial security, access to meaningful social roles and availability of social support are essential components of recovery and quality of life. (vii) Interventions should be carefully tailored to phase and stage of illness, and to gender and cultural background. (viii) Genuine involvement of consumers and relatives in service development and provision should be standard. (ix) Maintenance of good physical health and prevention and early treatment of serious medical illness has been seriously neglected in the management of schizophrenia, and results in premature death and widespread morbidity. Quality of medical care for people with schizophrenia should be equivalent to the general community standard. (x) General practitioners (GPs)s should always be closely involved in the care of people with schizophrenia. However, this should be truly shared care, and sole care by a GP with minimal or no special Optimal treatment of schizophrenia requires a multidisciplinary team approach with a consultant psychiatrist centrally involved.

CYP1A2*1C, CYP2E1*5B, and GSTM1 polymorphisms are predictors of risk and poor outcome in head and neck squamous cell carcinoma patients

Head and neck squamous cell carcinoma (HNSCC) is associated with environmental factors, especially tobacco and alcohol consumption. Most of the carcinogens present in tobacco smoke are converted into DNA-reactive metabolites by cytochrome P450 (CYPs) enzymes and detoxification of these substances is performed by glutathione S-transferases (GSTs). It has been suggested that genetic alterations, such as polymorphisms, play an important role in tumorigenesis and HNSCC progression. The aim of this study was to investigate CYP1A1, CYP1A2, CYP2E1, GSTM1, and GSTT1 polymorphisms as risk factors in HNSCC and their association with clinicopathologic data. The patients comprised 153 individuals with HNSCC (cases) and 145 with no current or previous diagnosis of cancer (controls). Genotyping of the single nucleotide polymorphisms (SNPs) of the CYP1A1, CYP1A2, and CYP2E1 genes was performed by PCR-RFLP and the GSTM1 and GSTT1 copy number polymorphisms (CNPs) were analyzed by PCR-multiplex. As expected, a significant difference was detected for tobacco and alcohol consumption between cases and controls (P < 0.001). It was observed that the CYP1A2*1D (OR = 16.24) variant and GSTM1 null alleles (OR = 0.02) confer increased risk of HNSCC development (P < 0.001). In addition, head and neck cancer alcohol consumers were more frequently associated with the CYP2E1*5B variant allele than control alcohol users (P < 0.0001, OR = 190.6). The CYP1A2*1C polymorphism was associated with tumor recurrence (log-rank test, P = 0.0161). The CYP2E1*5B and GSTM1 null alleles were significantly associated with advanced clinical stages (T3 + T4; P = 0.022 and P = 0.028, respectively). Overall, the findings suggested that the genetic polymorphisms studied are predictors of risk and are also associated with tumor recurrence, since they are important for determining the parameters associated with tumor progression and poor outcomes in HNSCC. (C) 2009 Elsevier Ltd. All rights reserved.

Substance misuse in patients with schizophrenia: epidemiology and management

Substance misuse in individuals with schizophrenia is very common, especially in young men, in communities where use is frequent and in people receiving inpatient treatment. Problematic use occurs at very low intake levels, so that most affected people are not physically dependent (with the exception of nicotine). People with schizophrenia and substance misuse have poorer symptomatic and functional outcomes than those with schizophrenia alone. Unless there is routine screening, substance misuse is often missed in assessments. Service systems tend to be separated, with poor inter-communication, and affected patients are often excluded from services because of their comorbidity. However, effective management of these disorders requires a fully integrated approach because of the close inter-relationship of the disorders. Use of atypical antipsychotics may be especially important in this population because of growing evidence (especially on clozapine and risperidone) that nicotine smoking, alcohol misuse and possibly some other substance misuse is reduced. Several pharmacotherapies for substance misuse can be used safely in people with schizophrenia, but the evidence base is small and guidelines for their use are necessarily derived from experience in the general population.

Acute buspirone abolishes the expression of behavioral dopaminergic supersensitivity in mice

Previous studies have shown that rats withdrawn from long-term treatment with dopamine receptor blockers exhibit dopaminergic supersensitivity, which can be behaviorally evaluated by enhanced general activity observed in an open-field. Recently, it has been reported that co-treatment with the non-benzodiazepine anxiolytic buspirone attenuates the development of haloperidol-induced dopaminergic supersensitivity measured by open-field behavior of rats. The aims of the present study were: 1) to determine, as previously reported for rats, if mice withdrawn from long-term neuroleptic treatment would also develop dopaminergic supersensitivity using open-field behavior as an experimental paradigm, and 2) to examine if acute buspirone administration would attenuate the expression of this behavioral dopaminergic supersensitivity. Withdrawal from long-term haloperidol treatment (2.5 mg/kg, once daily, for 20 days) induced a significant (30%) increase in ambulation frequency (i.e., number of squares crossed in 5-min observation sessions) but did not modify rearing frequency or immobility duration in 3-month-old EPM-M1 male mice observed in the open-field apparatus. Acute intraperitoneal injection of buspirone (3.0 and 10 but not 1.0 mg/kg, 12-13 animals per group) 30 min before open-field exposure abolished the increase in locomotion frequency induced by haloperidol withdrawal. These data suggest that the open-field behavior of mice can be used to detect dopaminergic supersensitivity, whose expression is abolished by acute buspirone administration.

The influence of drug-induced dyskinesias on manual tracking in Parkinson's disease

The influence of peak-dose drug-induced dyskinesia (DID) on manual tracking (MT) was examined in 10 dyskinetic patients (OPO), and compared to 10 age/gendermatched non-dyskinetic patients (NDPD) and 10 healthy controls. Whole body movement (WBM) and MT were recorded with a 6-degrees of freedom magnetic motion tracker and forearm rotation sensors, respectively. Subjects were asked to match the length of a computer-generated line with a line controlled via wrist rotation. Results show that OPO patients had greater WBM displacement and velocity than other groups. All groups displayed increased WBM from rest to MT, but only DPD and NDPO patients demonstrated a significant increase in WBM displacement and velocity. In addition, OPO patients exhibited excessive increase in WBM suggesting overflow DID. When two distinct target pace segments were examined (FAST/SLOW), all groups had slight increases in WBM displacement and velocity from SLOW to FAST, but only OPO patients showed significantly increased WBM displacement and velocity from SLOW to FAST. Therefore, it can be suggested that overflow DID was further increased with increased task speed. OPO patients also showed significantly greater ERROR matching target velocity, but no significant difference in ERROR in displacement, indicating that significantly greater WBM displacement in the OPO group did not have a direct influence on tracking performance. Individual target and performance traces demonstrated this relatively good tracking performance with the exception of distinct deviations from the target trace that occurred suddenly, followed by quick returns to the target coherent in time with increased performance velocity. In addition, performance hand velocity was not correlated with WBM velocity in DPO patients, suggesting that increased ERROR in velocity was not a direct result of WBM velocity. In conclusion, we propose that over-excitation of motor cortical areas, reported to be present in DPO patients, resulted in overflow DID during voluntary movement. Furthermore, we propose that the increased ERROR in velocity was the result of hypermetric voluntary movements also originating from the over-excitation of motor cortical areas.

The impact of drug-induced dyskinesias on rapid alternating movements in patients with Parkinson's disease

We investigated the likelihood that hypokinesia/bradykinesia coexist with druginduced dyskinesias (DID) in patients with Parkinson's disease (PD). The influence of dyskinesias on rapid alternating movements (RAM) was investigated in ten dyskinetic patients (DPD). Their motor performance was compared to that of ten age/gendermatched non-dyskinetic patients (NDPD) and ten healthy control subjects. Whole-body magnitude (WBM) and fast pronation-supination at the wrist were recorded using 6- degrees of freedom magnetic motion tracker and forearm rotational sensors, respectively. Subjects were asked to pronate-supinate their dominant hand for 10s. Pre- and postmeasures were taken in a neutral position for 20s. RANGE (measure of hypokinesia), DURATION (measure of bradykinesia). VELOCITY (measure of bradykinesia) and IRREGULARITY (measure of fluctuations in movement amplitude) were used to assess RAM performance. Results showed that DPD patients had greater WBM than NDPD and control groups during rest and RAM performance. There were no differences in performance between NDPD and DPD groups for RANGE, DURATION and VELOCITY, despite significant longer disease duration for the DPD group (DPD = 15.5 ± 6.2 years versus NDPD = 6.6 ± 2.6 years). However, both the NDPD and DPD groups showed lower RANGE, longer DURATION, and reduced VELOCITY compared to controls,, suggesting the presence of bradykinesia and hypokinesia. In the case of IRREGULARITY, DPD patients showed clear fluctuations in movement amplitude compared to the NDPD and control groups. However, the lack of correlation between WBM and IRREGULARITY within the DPD group (Spearman's rank order, Rho - 0.31, p > 0.05), suggests that DID was not the primary cause of the fluctuating movementamplitude observed in that group. In conclusion, these findings suggest that DID may coexists with bradykinesia and hypokinesia, but that they are not inevitably accompanied with worsening motor performance.