Multicenter, Double-Blind, Placebo-Controlled Study of Mecamylamine Monotherapy for Tourette's Disorder
The safety and efficacy of mecamylamine as a monotherapy in children and adolescents with Tourette's disorder (TD) was investigated in an 8-week multicenter, double-blind, placebo-controlled study.
Eligible subjects included subjects with TD (DSM-IV), with a naturalistic mix of comorbid diagnoses, nonsmokers, aged 8 to 17 years, whose behavioral and emotional symptoms (according to parents) were more disturbing than tics. After a washout period of all psychotropic medication, subjects were randomly assigned to either mecamylamine (n = 29) or placebo (n = 32). Mecamylamine doses ranged from 2.5 to 7.5 mg/day. Primary efficacy measures included the Tourette's Disorder Scale-Clinician Rated (TODS-CR) and 21-point Clinical Global Improvement scale; secondary efficacy measures included the Yale Global Tic Severity Scale and a rage-attack scale (RAScal).
Of the 61 subjects who were randomized, 50 (82%) completed at least 3 weeks on medication and 38 (62%) completed the full 8-week trial. Study withdrawals included 12/29 on mecamylamine and 11/32 on placebo. For the total sample, mecamylamine was no more effective than placebo on any of the outcome measures. However, an item analysis of the TODS-CR suggested that mecamylamine may have reduced sudden mood changes and depression in moderately to severely affected subjects. Except for a slight increase in heart rate during the 1st week in both the mecamylamine and the placebo groups, there where no significant mecamylamine-related changes in vital signs, electrocardiogram, complete blood cell count, or blood chemistry values.
Mecamylamine, in doses up to 7.5 mg/day, is well tolerated in children and adolescents, but as a monotherapy it does not appear to be an effective treatment for tics or for the total spectrum of symptoms associated with TD. However, further studies should be conducted to investigate its possible therapeutic effects in subjects with comorbid mood disorders and as an adjunct to neuroleptic medication.
Available from: Marina R Picciotto
- "This was spontaneously reported by parents, and was sufficiently convincing that treatment was continued in these cases. Clearly additional studies are needed to establish the validity of the findings in trials designed to assess ARBS-specific outcomes, as both nicotine and mecamylamine have been described as effective for aggression and agitation in studies where they had no effect on the primary outcome (D'Souza and Markou, 2012; Silver et al., 2001b). Finally, studies should include both nicotinic agonists and antagonists, which might identify a preferred agent for a given indication. "
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ABSTRACT: The co-morbidity between smoking and mood disorders is striking. Preclinical and clinical studies of nicotinic effects on mood, anxiety, aggression, and related behaviors, such as irritability and agitation, suggest that smokers may use the nicotine in tobacco products as an attempt to self-medicate symptoms of affective disorders. The role of nicotinic acetylcholine receptors (nAChRs) in circuits regulating mood and anxiety is beginning to be elucidated in animal models, but the mechanisms underlying the effects of nicotine on aggression-related behavioral states (ARBS) are still not understood. Clinical trials of nicotine or nicotinic medications for neurological and psychiatric disorders have often found effects of nicotinic medications on ARBS, but few trials have studied these outcomes systematically. Similarly, the increase in ARBS resulting from smoking cessation can be resolved by nicotinic agents, but the effects of nicotinic medications on these types of mental states and behaviors in non-smokers are less well understood. Here we review the literature on the role of nAChRs in regulating mood and anxiety, and subsequently on the closely related construct of ARBS. We suggest avenues for future study to identify how nAChRs and nicotinic agents may play a role in these clinically important areas. This article is part of a Special Issue entitled 'Nicotinic Acetylcholine Receptor'.
Copyright © 2015. Published by Elsevier Ltd.
Neuropharmacology 01/2015; 96(Pt B). DOI:10.1016/j.neuropharm.2014.12.028 · 5.11 Impact Factor
Available from: Michael G Aman
- "In each of those cases, the parents stated that they noticed the greatest improvement in their child's irritability and hyperactivity, but also mentioned increased verbalization. The improved irritability would be compatible with the mood improvements reported by Silver et al. (2001b). However, these anecdotal improvements were not confirmed on a group basis by ABC irritability or hyperactivity scores or by Expressive Vocabulary Test (Table 2b). "
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ABSTRACT: To explore possible benefits of a nicotinic acetylcholine receptor (nAChR) agent for autistic symptoms based on postmortem observation of nAChR abnormalities (deficient α4β2 nAChRs, excess α7 nAChRs) in brains of patients with autism.
Mecamylamine, because of its safety record in children with other disorders, was chosen for this first exploration. Twenty children with autism spectrum disorder age 4-12 years were randomly assigned for 14 weeks to placebo (n=8) or mecamylamine (n=12) in ascending fixed doses: 0.5 mg/day for 6 weeks, 2.5 mg for 2 weeks, then 5 mg/day for 6 weeks. Improvement was rated by a blinded independent evaluator. Because of small sample, data analysis was descriptive.
Eighteen participants (10 mecamylamine, 8 placebo) completed the study. All doses were well tolerated; the only side effect of note was constipation (50% compared with 25% of placebo group). Three children had clinically nonsignificant electrocardiographic QT prolongation. Both groups showed modest to moderate improvement, but differences between groups were negligible. On the primary outcome measure, the Ohio Autism Clinical Impressions Scale, 90% of the active treatment group showed improvement at some point (but only 40% sustained it), compared with 62% on placebo. Of the four in active treatment that sustained improvement, three had a maximum dose of 0.13-0.15 mg/kg/day, while those who regressed had doses ≥0.18 mg/kg/day. Graphed means suggested better outcome with lower mg/kg and longer medication duration. Four parents spontaneously reported reduced hyperactivity and irritability and better verbalization and continued mecamylamine at their own expense.
Mecamylamine appeared to be safe, but not very effective in autism. The suggestion of better results at lower doses and longer exposure warrants consideration for future trials. The next step would be exploration of a more specific α4β2 nAChR agonist, such as varenicline.
Journal of child and adolescent psychopharmacology 04/2012; 22(3):198-205. DOI:10.1089/cap.2011.0056 · 2.93 Impact Factor
Available from: Joseph F McGuire
- "It is important to note that the mechanism of change (i.e., the intervention type) is not a factor as long as the YGTSS cutoff reflects what is clinically viewed as treatment response. Mecamylamine, a non-selective antagonist of the nicotinic acetylcholine receptors, was well-tolerated in doses up to 7.5 mg/day but not efficacious relative to placebo (Silver et al. 2001). Aripiprazole, an atypical antipsychotic, was well-tolerated in children with tics and associated with significant tic reduction (Murphy et al. 2009). "
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ABSTRACT: To examine the optimal Yale Global Tic Severity Scale (YGTSS) percent reduction and raw cutoffs for predicting treatment response among children and adolescents with tic disorders.
Youth with a tic disorder (N=108; range=5-17 years) participated in several clinical trials involving varied medications or psychosocial treatment, or received naturalistic care. Assessments were conducted before and after treatment and included the YGTSS and response status on the Clinical Global Impressions-Improvement Scale (CGI-I).
A 35% reduction on the YGTSS total tic severity score or a YGTSS raw total tic severity score change of 6 or 7 points were the best indicators of clinical treatment response in youth with tic disorders.
A YGTSS total tic severity score reduction of 35% or a raw total tic severity score change of 6 or 7 appears optimal for determining treatment response. A consistent definition of treatment response on the YGTSS may facilitate cross-study comparability. Practitioners can use these values for treatment planning decisions (e.g., change medications, etc.).
Journal of child and adolescent psychopharmacology 11/2011; 21(6):621-7. DOI:10.1089/cap.2010.0149 · 2.93 Impact Factor
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