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.

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.

Transdermal nicotine and haloperidol in Tourette's disorder: a double-blind placebo-controlled study.

BACKGROUND: Preclinical animal and open-trial clinical trials using nicotine gum and the transdermal nicotine patch found that treatment with nicotine potentiates the effects of neuroleptics in reducing the dyskinetic symptoms of Tourette's disorder. We sought to verify and expand these findings in a prospective double-blind placebo-controlled trial. METHOD: Seventy patients with DSM-IV Tourette's disorder were treated with either transdermal nicotine (7 mg/24 hours) or placebo patches in a 33-day, randomized, double-blind study. Each patient received an individually based optimal dose of haloperidol for at least 2 weeks prior to random assignment to nicotine or placebo treatment. A new patch was worn each day for the first 5 days. On the sixth day, the dose of haloperidol was reduced by 50%. Daily patch applications were then continued for an additional 2 weeks (through day 19), at which time the patch was discontinued, but the 50% dose of haloperidol was continued for an additional 2 weeks (through day 33). Clinical and safety assessments were made at each visit. RESULTS: Patients who completed all 19 days of nicotine (N = 27) or placebo (N = 29) patch treatment were used in efficacy analyses. As documented by the Clinician- and Parent-rated Global Improvement scales, transdermal nicotine was superior to placebo in reducing the symptoms of Tourette's disorder. The Yale Global Tic Severity Scale was less sensitive in detecting a placebo/drug difference than were the global improvement scores, suggesting that some of the improvement may not have been related to treatment-related changes in tic severity, but to the emotional and behavioral symptoms. The side effects of nausea and vomiting were significantly more common in the nicotine group (71% [N = 25] and 40% [N = 14]) than in the placebo group (17% [N = 6] and 9% [N = 3]) (nausea, p = .0001; vomiting, p = .004). CONCLUSION: Transdermal nicotine was superior to placebo in reducing behavioral symptoms when patients were receiving an optimal dose of haloperidol, when the dose of haloperidol was reduced by 50%, and when the patch had been discontinued for 2 weeks. These findings confirm earlier open-label findings and suggest that combining nicotinic receptor modulation and neuroleptics could be a therapeutic option for the treatment of Tourette's disorder. While side effects limit chronic use of nicotine, it may be useful on a p.r.n. basis. Further clinical research is warranted to investigate the use of novel nicotinic receptor modulating agents with improved safety profiles over nicotine.

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 Tourette's 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 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). 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.

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 Tourette's 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 Tourette's 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 Tourette's 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.

Mecamylamine in Tourette's syndrome: a two-year retrospective case study.

OBJECTIVE: To test the efficacy and safety of a nicotinic, acetylcholine antagonist, mecamylamine, in the treatment of Tourette's syndrome (TS). METHODS: This is a retrospective, open-label study of 24 patients; 18 of whom were not responding to accepted medication for treatment of their TS and six of whom were receiving no medication. All 24 of them received mecamylamine in 2.5-6.25 mgm/day dose, at varying starting dates during the years June 1997 to June 1999. There were four females, 20 males, with 19 patients under the age of 18 years and five over the age of 18. Efficacy was evaluated by the Clinical Global Impression Scale (CGI); safety by adverse events notes during the time mecamylamine was administered. RESULTS: The number of days each patient received mecamylamine varied from 8 days to 550 days; with nine patients more than 200 days, six patients from 100-200 days, five patients for 50-100 days, and four patients 0-50 days. Comparing baseline CGI with that obtained on the date of last evaluation for each patient, a significant improvement in clinical assessment of severity of illness was obtained for the total group (Wilcoxon signed rank test, p < 0.0001). The six patients who received mecamylamine only also significantly improved (Wilcoxon signed rank test, p < 0.2). Case vignettes are described. CONCLUSIONS: Mecamylamine at 2.5-6.25 mgm/day has no significant peripheral parasympathetic activity and may be safely taken long term (up to 550 days in this study). It has a significant effect in relieving motor and vocal tics and in mood and behavior disturbances of children, adolescents, and adults with TS.

Nicotine for the treatment of Tourette's syndrome.

Recent evidence has demonstrated that nicotine may obtund the symptoms of Tourette's 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.

Case study: long-term potentiation of neuroleptics with transdermal nicotine in Tourette's syndrome.

Sixteen Tourette's 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 Tourette's syndrome are discussed.

Children with autistic behavior in a self-contained unit in the public schools.

The diagnosis of "autism" has been used to encompass a heterogeneous group of children who may differ in etiology, clinical manifestations, prognosis, and needed treatment. This paper presents the results of a comprehensive evaluation, using strict diagnostic criteria, of 33 children comprising the entire population of a self-contained unit for "autistic" children in the public school system of Hillsborough County, Florida. Only five of the children fit the criteria for early infantile autism. Six were diagnosed as suffering from schizophrenia, two as atypical developmental disorders. Twelve of the 33 showed evidence of neurological or recognized genetic abnormality, five had specific developmental language disorders, and three were severely retarded, cause unknown. Of the 12 children with evidence of neurological disease, five had chromosome abnormalities evident on cytogenetic study, two had high serum Cux++, one had histidinemia, one had maternal rubella, and three had dyskinesis of unknown origin. The heterogeneous nature of this group underlines the need for comprehensive evaluation of the autistic syndrome.

Children in classes for the severely emotionally handicapped.

This report will describe the clinical findings of a collaborative program to provide appropriate neuropsychiatric skills for 60 children ages 8 to 14 (grade 3 to 8) and their teachers, comprising the entire population of two self-contained units (eight classes) for the treatment of children designated as severely emotionally handicapped but not autistic. Of the 60 children, 36 (60%) were suffering from learning disabilities. Eighteen of these had neurological signs suggestive of organic defect of the central nervous system; the remaining 18 children with learning disabilities had specific or development learning disabilities characterized by perceptual immaturity in spatial orientation and/or temporal organization, but the classical neurological examination administered to them was within normal limits. Ten additional children were classified as having an attentional deficit disorder, and 11 additional children were functioning at a borderline level of cognitive ability. Fifty-nine of the 60 children were suffering from diagnosable psychiatric disorders: 21 (35%) severely anxious, 13 (22%) clinically depressed, 12 (20%) conduct disorders, 6 (10%) oppositional, 3 (5%) schizophrenic, 2 (3%) obsessive-compulsive disorder, and 2 (3%) personality disorder. Applications of these findings are suggested.

A unifying concept for the neuropsychological organization of children with reading disability.

Normative studies successfully predicting reading failure in 5- and 6-year-old children suggest that if the neuropsychological functions relating to spatial orientation and temporal organization are not age-appropriate, that child will not have normal achievement in the language arts, particularly in reading. This concept unifying the diverse symptoms found in elementary school children with reading failure has been used to develop a test battery predictive of reading failure, valid to 1 to 3% false positives and 10% false negatives. Further, a simple clinical test, the arm Extension Test, suggests that in these children hemisphere specialization for language has not been established.