Archie A. Silver

Nicotinic acetylcholine receptors as targets for antidepressants

While the monoamine deficiency hypothesis of depression is still most commonly used to explain the actions of antidepressant drugs, a growing body of evidence has accumulated that is not adequately explained by the hypothesis. This article draws attention to contributions from another apparently common pharmacological property of antidepressant medications—the inhibition of nicotinic acetylcholine receptors (nAChR). Evidence is presented suggesting the hypercholinergic neurotransmission, which is associated with depressed mood states, may be mediated through excessive neuronal nicotinic receptor activation and that the therapeutic actions of many antidepressants may be, in part, mediated through inhibition of these receptors. In support of this hypothesis, preliminary evidence is presented suggesting that the potent, centrally acting nAChR antagonist, mecamylamine, which is devoid of monoamine reuptake inhibition, may reduce symptoms of depression and mood instability in patients with comorbid depression and bipolar disorder. If this hypothesis is supported by further preclinical and clinical research, nicotinic acetylcholine receptor antagonists may represent a novel class of therapeutic agents for treating mood disorders.

Nicotine for the treatment of Tourette's syndrome.

Recent evidence has demonstrated that nicotine may obtund the symptoms of Tourettes syndrome (TS). TS is a neuropsychiatric disorder characterized by motor and vocal tics, obsessions and compulsions, and frequently with impulsivity, distractibility, and visual-motor deficits. While neuroleptics, such as haloperidol, are most effective for treatment of the motor and vocal tics of TS, these medications have many side effects. In this article, we review the evidence, consistent with findings in animals, that administration of nicotine (either 2 mg nicotine gum or 7 mg transdermal nicotine patch) potentiates the therapeutic properties of neuroleptics in treating TS patients and that a single patch may be effective for a variable number of days. These findings suggest that transdermal nicotine could serve as an effective adjunct to neuroleptic therapy for TS.

Multicenter, Double-Blind, Placebo-Controlled Study of Mecamylamine Monotherapy for Tourette's Disorder

OBJECTIVE The safety and efficacy of mecamylamine as a monotherapy in children and adolescents with Tourettes disorder (TD) was investigated in an 8-week multicenter, double-blind, placebo-controlled study. METHOD 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 Tourettes 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). RESULTS 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. CONCLUSIONS 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.

Case Study: Long-Term Potentiation of Neuroleptics with Transdermal Nicotine in Tourette's Syndrome

Sixteen Tourettes syndrome patients, aged 9 to 15 years, whose symptoms were not controlled with neuroleptics, were followed for various lengths of time after the application of a transdermal nicotine patch (TNP) (7 mg/24 hours) as part of an ongoing case study. While there was a broad range in individual response, application on the TNP produced significant reductions (p < .001) in Yale Global Tic Severity Scale scores relative to baseline, with an average duration of effect lasting between 1 and 2 weeks. Side effects, for the most part, were transient. Clinical implications for the use of TNP as an adjunct to neuroleptic treatment of Tourettes syndrome are discussed.

Mecamylamine (Inversine ): an old antihypertensive with new research directions

Mecamylamine (Inversine®), the first orally available antihypertensive agent, is now rarely used. Although celebrated in the 1950s, mecamylamine fell out of favour because of its widespread ganglionic side effects at antihypertensive doses (30–90 mg/day). However, recent studies suggest that mecamylamine is very effective at relatively low doses (2.5–5 mg b.i.d.) for blocking the physiological effects of nicotine and improving abstinence rates in smoking cessation studies, particularly for women. When these lower doses of mecamylamine are given, patients do not experience the severity of side effects that made the drug unpopular for the treatment of hypertension. Tobacco smoking is a strong risk factor for cardiovascular morbidity, including accelerated atherosclerosis and increased risk of heart attacks. Though currently untested, the available evidence suggests that low-dose mecamylamine therapy might reduce blood pressure variability and atherogenetic lipid profile in smokers. With this in mind, mecamylamine should be an important research tool in the field of hypertension research, particularly in recalcitrant smokers with mild to moderate hypertension.

The Tourette's Disorder Scale (TODS): development, reliability, and validity.

To address the lack of a simple and standardized instrument to assess overall illness severity of Tourettes disorder (TD), the authors developed and tested a 15-item scale to measure a broad range of common symptoms including tics, inattention, hyperactivity, obsessions, compulsions, aggression, and emotional symptoms. Independent investigators used the 15-item Tourettes Disorder Scale (TODS) to assess 60 TD patients who were taking part in a double-blind placebo-controlled multicenter 8-week treatment study. Interrater reliability, internal consistency, convergent and discriminant validity, and sensitivity to change were examined. The TODS was associated with good interrater reliability, excellent internal consistency, and favorable levels of validity and sensitivity to change. Individual TODS items showed good convergent and discriminant validity against other measures. The TODS is a simple, efficient way for clinicians and parents to rate the severity of multiple symptoms commonly found in patients with Tourettes disorder.

A Pilot Controlled Trial of Transdermal Nicotine in the Treatment of Attention Deficit Hyperactivity Disorder

Summary: Objective: To test the hypothesis that transdermal nicotine would be efficacious for the treatment of children and adolescents with attention deficit hyperactivity disorder (ADHD). Method: This was a double-blind, placebo-controlled, randomized, pilot trial that compared the effects of daily transdermal nicotine (5 mg/16 hrs) to placebo in children and adolescents with ADHD. There was a three-day washout period of all psychotropic medication followed by a one-week treatment period. Results: All 10 subjects enrolled (six males, four females; mean age = 10 years, SEM = 0.8) completed the study. As assessed by the 48-item Conners Parent Rating Scale at endpoint and during the trial, there was a significantly greater reduction in ADHD symptoms on “Learning Problems” and “Hyperactivity” subfactors. Nausea, stomach ache, itching under patch and dizziness were the most frequently reported adverse effects associated with transdermal nicotine. Conclusions: While the results of this study support previous research indicating that nicotinic receptor modulation may be a potentially useful strategy for the treatment of ADHD, therapeutic uses of nicotine are limited due to side effects. Thus, future research should investigate ways of improving the therapeutic index of nicotinic ligands in the treatment of ADHD, such as testing selective nicotinic antagonists alone or in combination with cholinergic agonists.

Transdermal nicotine for Tourette's syndrome

The present review evaulates the therapeutic response to the transdermal nicotine patch (TNP) in Tourettes syndrome (TS) patients. Twenty TS patients (17 children and adolescents, 3 adults), in 18 of whom tic symptoms were not controlled with neuroleptics and 2 of whom were free of medication, were followed for various lenghts of time following the application of two TPs (each 7mg/24 hours). While there was a broad range in individual response, it was determined that each application of a single TNP produced a significant reduction in Yale Global Tic Severity Scale mean scores for an average duration of approximately 1 to 2 weeks post‐application. Individual case reports are discusssed as well as the possible therapeutic mechanisms of transdermal nicotine in reducing the symptoms of TS. Although our data should be viewed as preliminary until controlled studies are completed, the present open‐trial findings suggest that transdermal nicotine is an effective adjunct to neuroleptic theraphy of TS. Drug Dev. Res. 38:290–298.

Comorbid bipolar disorder in Tourette's syndrome responds to the nicotinic receptor antagonist mecamylamine (Inversine).

BACKGROUND We have previously proposed that the therapeutic effect of transdermal nicotine in Tourettes syndrome may involve nicotinic receptor inactivation resulting from a prolonged continuous exposure to nicotine. In vitro studies with nicotine and preliminary positive experience with mecamylamine (Inversine), a nicotinic receptor antagonist, in the clinical treatment of Tourettes syndrome patients, further supports the receptor inactivation hypothesis. METHODS We retrospectively documented an unexpected therapeutic response to mecamylamine (2.5-7.5 mg/day) in two Tourettes syndrome patients who were subsequently found to have comorbid bipolar disorder as defined by DSM-IV criteria. RESULTS In patient 1, the mood-stabilizing effect of mecamylamine was noticed by the patient during the course of mecamylamine treatment and brought to our attention, whereas for patient 2, manic symptoms were only apparent clinically following cessation of mecamylamine treatment. CONCLUSIONS The clinical observations presented here suggest that nicotinic antagonists might be potential therapeutic agents for the treatment of bipolar disorder. Double-blind, placebo-controlled studies are now necessary to investigate these observations under more rigorous conditions.

Family Impact of Tourette's Syndrome

Tourettes syndrome (TS) is a neuropsychological disorder characterized by vocal and motor tics. TS is also associated with several behavior disorders such as Attention Deficit Hyperactivity Disorder, Oppositional Defiant Disorder, conduct disorder, and Obsessive-Compulsive Disorder. We examined the impact of Tourettes syndrome with and without comorbid psychiatric disorders on the family. TS complicated by comorbid disorders had a greater impact on the family than uncomplicated TS. Tourettes symptom severity was significantly correlated with the level of impact on the family and with the number of comorbid disorders. TS is a disorder with effects that extend beyond motor and vocal tics.