Efficacy of maintenance use of anticholinergic agents. Treatment of tardive dyskinesia with galantamine: a randomized controlled crossover trial. A randomized, placebo-controlled trial of the discontinuation of long-term antipsychotics in dementia. Time course of physical and psychological responses to selegiline monotherapy in newly diagnosed, idiopathic parkinsonism. Clozapine versus placebo in Huntington's disease: a double blind randomised comparative study. Effect of antipsychotic withdrawal on behavior and sleep/wake activity in nursing home residents with dementia: a randomized, placebo-controlled, double-blinded study. The Bergen District Nursing Home Study. A double-blind study of combination of clozapine with risperidone in patients with schizophrenia: effects on cognition. Anticholinergic challenge and neuroleptic withdrawal. Changes in dyskinesia and symptom measures. A double-blind controlled study of clinical efficacy of maprotiline and amitriptyline in depression.
Twenty-seven long-term psychiatric inpatients maintained on neuroleptics with concomitant antiparkinsonian medication were entered into a study in which anticholinergic medication was gradually withdrawn in a randomized double-blind within-subjects design. The extrapyramidal symptoms of each patient were compared when taking their usual anticholinergic medication, when taking placebo and when taking no antiparkinsonian drug. The relapse rate on no medication was 14%, and if patients relapsed on no medication they also relapsed on placebo. The relapse rate was not significantly different on active medication. Nor were there significant differences in ratings of parkinsonism or dyskinesia. The lack of difference between double-blind and overt withdrawal does not mean that studies that find a much higher relapse rate are necessarily unaffected by nonspecific factors, as significant unblinding may occur in clinical trials. Recent evidence suggests that tar-dive dyskinesia may result from antipsychotic-induced damage to striatal cholinergic neurons. To test whether cholinesterase inhibitors compensate for diminished cholinergic activity, we conducted a 30-week randomized, double-blind, placebo-controlled crossover trial of galantamine in patients with tardive dyskinesia.
                Patients with tardive dyskinesia were recruited between June 2001 and June 2004. After a 2-week baseline period, 35 male schizophrenia patients, on stable doses of antipsychotics, were randomly assigned to receive galantamine (8-24 mg) or placebo for two 12-week phases separated by a 4-week washout period. Patients were evaluated every 2 weeks for changes in extrapyramidal symptoms and before and after each treatment for effects on psychiatric symptoms and cognition.
                Galantamine reduced mean total Abnormal Involuntary Movement Scale (AIMS) scores more than placebo, but this difference was not statistically significant (p = .08). However, patients initially randomly assigned to galantamine showed a reversal of AIMS scores after switching to placebo. Simpson-Angus Scale ratings of parkinsonism were significantly higher with galantamine than placebo (p = .0005) and correlated with age. There were no significant differences between groups in akathisia, cognition, or psychiatric symptoms. More patients dropped out while receiving galantamine, but this outcome did not significantly influence the results.
                In contrast to previous reports, reductions in tardive dyskinesia associated with galantamine were not statistically significant compared with placebo in this trial. However, galantamine was associated with a modest rebound in dyskinesia scores after discontinuation and clinically minor but statistically higher ratings of parkinsonism. These findings support the need for further investigations of cholinergic mechanisms underlying tardive dyskinesia and extrapyramidal effects of cholinesterase inhibitors when used in combination with antipsychotics in susceptible patients.
                ClinicalTrials.gov identifier NCT00164242. The objectives of this randomized clinical trial were to investigate the impact of the discontinuation of long-term antipsychotics in residents with dementia in chronic care institutions and to identify clinical predictors of safe discontinuation. Subjects included 34 residents with dementia who were on antipsychotics for more than 6 months and whose behavior was currently stable. Subjects were randomized to either continue receiving their regular dosage of antipsychotics or to receive placebo for 6 months. Early withdrawal from the study was not statistically different between the groups (relative risk [RR] = 1.57, 95% confidence interval [CI] 0.76-3.26), and though not significantly different, subjects in the placebo group were more likely to be withdrawn from the study because of worsening behavior (RR = 1.25, 95% Cl 0.33-4.76). Three subjects in the placebo group were withdrawn from the study due to worsening of extrapyramidal symptoms. The active treatment group had more behavioral problems (e.g., physical aggression towards others, p < .05) compared to the placebo group. The placebo group developed more apathy, but balancing this outcome was a relative improvement in cognitive functioning. Baseline antipsychotic dose was predictive of behavioral worsening upon discontinuation of long-term antipsychotic drugs. The primary limitation of the study was the small sample size. In conclusion, a trial of discontinuation of antipsychotics should be considered in this population. Poor specificity of face-value endpoints and the poor sensitivity of gross clinical examination may have militated against demonstrating prophylaxis by selegiline.
                Objective measures of the four cardinal signs were used as primary outcome criteria in a randomised, double-blind, placebo-controlled, parallel group study of selegiline monotherapy in 25 newly diagnosed elderly sufferers from idiopathic parkinsonism, stratified for sex and Hoehn and Yahr functional staging.
                There was a significant interaction between time and nature of treatment with respect to rigidity. The effect of time during active treatment was highly significant: rigidity decreased by 1.3% per week. The worsening of rigidity on placebo was not statistically significant. Neuronal rescue is a possible explanation for the long term, progressive improvement produced by selegiline. No significant treatment effect was seen on the other cardinal signs. However, there was a significant quadratic time trend for arousal on active treatment suggesting tolerance to this effect.
                The difference in time course between the psychostimulant and physical effects suggests more than one mode of action. To establish the effect of the atypical neuroleptic clozapine on chorea, voluntary motor performance, and functional disability in patients with Huntington's disease.
                Thirty three patients with Huntington's disease participated in a double blind randomised trial. A maximum of 150 mg/day clozapine or placebo equivalent was given for a period of 31 days. Assessments were performed in the week before and at the last day of the trial. Chorea was scored using the abnormal involuntary movement scale (AIMS), the chorea score of the unified Huntington's disease rating scale (UHDRS), and judgement of video recordings. Voluntary motor performance was assessed using the UHDRS motor scale. Patients and their partners completed a questionnaire regarding functional disability. Twelve patients already used other neuroleptic medication, which was kept unchanged during the trial period. Results of neuroleptic naive and neuroleptic treated patients were analysed separately.
                Clozapine tended to reduce chorea in neuroleptic naive patients only (AIMS); improvement seemed more pronounced in patients receiving higher doses of clozapine. Other measures of chorea (UHDRS chorea score, video ratings) showed no improvement. Clozapine had no beneficial effect on chorea in patients already receiving neuroleptic medication. Voluntary motor performance did not improve with clozapine. Neuroleptic naive patients reported aggravation of functional disability, possibly reflecting the frequent occurrence of side effects. Adverse reactions forced trial termination in six patients and dose reduction in another eight, and consisted mainly of drowsiness, fatigue, anticholinergic symptoms, and walking difficulties.
                Clozapine has little beneficial effect in patients with Huntington's disease, although individual patients may tolerate doses high enough to reduce chorea. Because adverse reactions are often encountered, clozapine should be used with restraint in this patient group. To explore the effect on sleep/wake activity and on behavioral and psychological symptoms of the withdrawal of antipsychotic medications from nursing home (NH) patients with dementia.
                Randomized, placebo-controlled, double-blind trial.
                NHs in Bergen, Norway.
                Thirty patients (mean age 83.5) taking haloperidol, risperidone, or olanzapine for nonpsychotic symptoms. Intervention: Study participants were randomly assigned to withdrawal (intervention group) or continued treatment with antipsychotic medications (reference group) for 4 consecutive weeks.
                Behavioral rating using the Neuropsychiatric Inventory Questionnaire (NPI-Q) and actigraphy.
                After antipsychotic withdrawal, behavioral scores remained stable or improved in 11 of 15 patients, whereas four had worsening scores. Actigraphy revealed decreased sleep efficiency after drug discontinuation and increased 24-hour and night activity in both groups. Actigraphy records of nighttime and daytime activity indicated sleep problems and restlessness, in terms of the NPI-Q. One patient was restarted on antipsychotics.
                Antipsychotic drug withdrawal affected activity and sleep efficiency over the short term. Increases in total activity and impaired sleep quality after drug discontinuation should be monitored, because the long-term effect of these changes is not known. The NPI-Q and actigraphy are feasible tools that disclose relevant changes occurring during antipsychotic withdrawal in NH patients with dementia. Their use in clinical practice should be substantiated by larger studies. Atypical antipsychotic drugs produce improvement in some domains of cognition as well as psychopathology in patients with schizophrenia. However, the effect of combinations of atypical antipsychotic drugs on cognitive function is unknown. The aim of this study was to compare the effect of risperidone or placebo on cognitive function in patients with schizophrenia who were previously treated with clozapine monotherapy.
                This prospective, randomized, double-blind, placebo-controlled, 6-week study included 30 patients with DSM-IV schizophrenia. Patients whose psychopathology was no more than partially responsive to clozapine treatment were randomly assigned to receive adjunctive treatment with risperidone (N = 16) up to 6 mg/day or placebo (N = 14). Cognitive test scores for verbal learning and memory, verbal fluency, attention, executive function, verbal working memory, and motor function were the primary outcome measures. Secondary outcome measures included assessment of psychopathology, extrapyramidal side effects, and global functioning. Data were collected between November 2001 and July 2003.
                Significant improvement was found in both treatment groups in a variety of cognitive measures, but there was significantly greater improvement in the placebo-augmented group on measures of initial learning acquisition and attention. The improvement in cognition was not correlated with improvement in psychopathology. There were significant correlations between improvement in verbal working memory, verbal learning and memory, and attention and quality of life and global functioning in the placebo-augmented but not the risperidone-augmented group.
                Adjunctive treatment with risperidone for 6 weeks in patients with schizophrenia who had received chronic treatment with clozapine does not significantly improve cognitive function. Benztropine mesylate (intravenous [IV] and oral) challenge was compared with brief neuroleptic withdrawal on dyskinesia ratings and symptom measures. Thirty-six neuroleptic-treated patients underwent a placebo-controlled acute IV challenge with 2 mg benztropine and a placebo-controlled two-week trial of oral benztropine mesylate (2 mg three times a day), followed by a double-blind placebo-controlled neuroleptic withdrawal involving four weeks of dose tapering and six weeks of placebo treatment. Benztropine given IV had no significant effect. Orally administered benztropine, however, led to statistically significant increases in dyskinesia and dysphoric mood. The brief neuroleptic withdrawal significantly increased dyskinesia scores and dysphoria and resulted in early termination of therapy in 12 of 36 patients (33%) due to symptom exacerbation. There was a striking absence of correlation between dyskinesia change measures brought about by benztropine and changes following neuroleptic withdrawal. Therefore anticholinergic challenge does not appear to be a fruitful procedure for identifying patients with covert dyskinesia. A multiclinic double-blind controlled study was performed on the effects of MAP in both inpatients and outpatients with AMT as control drug. 1. Subjects consisted of 41 male and 45 female patients suffering from various types of depression. MAP was assigned to 42 cases and AMT to 44 cases. Of these patients, 14 MAP cases and 10 AMT cases were subsequently dropped for a variety of reasons to obtain 28 MAP cases and 34 AMT cases as evaluable. 2. The global improvement ratings were compared and found not significantly different for any week between the two treatments. 3. The global improvement ratings by the characteristic features of patients did not show any significant difference in any items studied between the two treatments. 4. The symptomatic improvement ratings (on the Hamilton R.S. for assessment by the physician) indicated that AMT was more effective on "anxiety (psychic)." 5. The symptomatic improvement ratings (on the Beck self-assessment scale by the patient) indicated that MAP was more effective on "work" and AMT on "pathos", "feeling of satisfaction", "withdrawal" and "loss of libido." 6. During the treament period, 74.3 percent of the MAP group and 76.9 percent of the AMT group of patients showed some side effects of accompanying symptoms, with no significant difference recognized between the two treatments. Itemwise, however, the incidence of tremor was significantly lower (p-=0.06) in the MAP group. Moreover, the MAP group tended to be less liable to such anticholinergic side effects as dry mouth, constipation, trouble of accomodation, urinary disturbance and palpitation. 7. On the basis of the above findings, it is concluded that MAP is as effective against depression as AMT and less liable to the anticholinergic side effects. It is, therefore, a very useful antidepressant.
As monotherapy or as an adjunct to other antiparkinsonian drugs, anticholinergics are more effective than placebo in improving motor function in Parkinson´s disease. Neuropsychiatric and cognitive adverse events occur more frequently on anticholinergics than on placebo and are a more common reason for withdrawal than lack of efficacy.Results regarding a potentially better effect of the anticholinergic drug on tremor than on other outcome measures are conflicting and data do not strongly support a differential clinical effect on individual parkinsonian features.Data is insufficient to allow comparisons in efficacy or tolerability between individual anticholinergic drugs.