Study of the Effects of Mecamylamine and Varenicline in Schizophrenia - Full Text View

Purpose

We are conducting this study to find out if blocking or partially stimulating the effects of nicotine in the brain can affect memory and concentration. Nicotine is the addictive drug found in tobacco products. Our subjects will be people with and without mental illness (schizophrenia), smokers and non-smokers.

We will use a medication called mecamylamine (Inversine) to block the effects of nicotine on the brains of our subjects. We will also use a medication called varenicline (Chantix) to partially increase the effects of nicotine on the brains of our subjects. This study also uses a placebo, a pill that does not have any active ingredients but looks exactly like the mecamylamine and varenicline pills. We will compare the effects of giving mecamylamine or placebo to people who have schizophrenia and people who do not have schizophrenia.

We know that people with schizophrenia smoke heavily and find it harder to stop smoking than most other people do. Studies have shown that people with schizophrenia may smoke more because nicotine helps their concentration and memory. We are interested in helping people with schizophrenia smoke less. Mecamylamine blocks the parts of the brain that react to nicotine and varenicline partially stimulates and partially blocks the parts of the brain that react to nicotine. Both medications may decrease the effects that smoking has on the body.

Condition	Intervention
Cognition in Schizophrenia	Drug: Mecamylamine Drug: Varenicline Drug: Placebo

MedlinePlus related topics:

Schizophrenia Smoking

Drug Information available for:

Varenicline Mecamylamine Mecamylamine hydrochloride

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Investigator), Crossover Assignment, Safety/Efficacy Study

Official Title:	Cognitive Effects of Mecamylamine and Varenicline in Schizophrenia

Further study details as provided by Massachusetts General Hospital:

Primary Outcome Measures:

Change from baseline reaction time for correct responses on the CPT-IP continuous performance task [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Effects of mecamylamine and varenicline compared with placebo in schizophrenia and control groups on response bias, reaction time, errors of commission and errors of omission [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]

Estimated Enrollment:	80
Study Start Date:	March 2007
Estimated Study Completion Date:	September 2008
Estimated Primary Completion Date:	September 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Mecamylamine: Active Comparator	Drug: Mecamylamine A single dose of 10 mg of mecamylamine (via two 5 mg capsules) is given at the start of the mecamylamine arm of the study. This is the only administration of mecamylamine given during the course of the study. Participants' blood pressure and vitals are checked regularly for five hours after drug administration for monitoring and safety assurance.
Varenicline: Active Comparator	Drug: Varenicline A single dose of 1 mg of varenicline (via two 0.5 mg capsules) is given at the start of the varenicline arm of the study. This is the only administration of varenicline given during the course of the study. Participants' blood pressure and vitals are checked regularly for five hours after drug administration for monitoring and safety assurance.
Placebo: Placebo Comparator	Drug: Placebo The placebo contains no active medication. The placebo dose is given via two capsules at the start of the placebo arm of the study. Participants' blood pressure and vitals are checked regularly for five hours after drug administration for monitoring and safety assurance. The placebo has no effects that last for any duration of time.

Show Detailed Description

Eligibility

Ages Eligible for Study:	18 Years to 64 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria for Patients with Schizophrenia:

Males or females ages 18-64
Axis I diagnosis of schizophrenia or schizoaffective disorder
Smoking or Non-smoking
Negative salivary screen for drugs of abuse
Stable psychiatric treatment for 4 weeks

Exclusion Criteria for Patients with Schizophrenia

Current (within the last 6 months) DSM-IV diagnosis of bipolar disorder, PTSD, organic mental disorder, or anorexia nervosa
Substance use disorder other than nicotine or caffeine in the past 6 months
Orthostatic blood pressure changes at 3 minutes of > 20 mm Hg systolic or 10 mm Hg diastolic
Blood Pressure: Women under 50 years of age: Supine baseline systolic blood pressure < 90 mm Hg; Men under 50 years of age: Supine baseline systolic blood pressure < 100 mm Hg; Women and men over 50 years of age: Supine baseline systolic blood pressure < 110 mm Hg
History of angina, MI within the past 2 years, CHF with LVEF < 40%
History of syncope or neurocardiogenic syncope
History of stroke or TIA's
Glaucoma
Pyloric Stenosis
Current pregnancy or lactation
Renal Insufficiency/Uremia
Known allergy to mecamylamine
Inability to give informed consent
Cognitive impairment secondary to head injury, dementia, general medical condition, or mental retardation
Current use of antibiotics or sulfa drugs, vasodilators such as alpha blocking agents and nitrates
Use of investigational medication or device within one month of randomization
Chronic use of antihypertensive drugs, including diuretics, will be considered on an individual basis

Inclusion Criteria for Healthy Controls:

Males or females ages 18-64
Smoking or Non-smoking
Negative salivary screen for drugs of abuse

Exclusion Criteria for Healthy Controls:

Current or lifetime Axis I DSM-IV diagnosis or family history of schizophrenia, schizoaffective disorder, or bipolar disorder
Current (within past 6 months) Axis I DSM-IV diagnosis of major depressive disorder, eating disorder, generalized anxiety disorder or PTSD
Substance use disorder other than nicotine or caffeine in the past 6 months
Orthostatic blood pressure changes at 3 minutes of > 20 mm Hg systolic or 10 mm Hg diastolic
Blood Pressure: Women under 50 years of age: Supine baseline systolic blood pressure < 90 mm Hg; Men under 50 years of age: Supine baseline systolic blood pressure < 100 mm Hg; Women and men over the age of 50: Supine baseline systolic blood pressure < 110 mm Hg
History of angina, MI within the past 2 years, CHF with LVEF < 40%
History of syncope or neurocardiogenic syncope
History of stroke or TIA's
Glaucoma
Pyloric Stenosis
Current pregnancy or lactation
Renal Insufficiency/Uremia
Known allergy to mecamylamine
Inability to give informed consent
Cognitive impairment secondary to head injury, dementia, general medical condition, or mental retardation
Current use of antibiotics or sulfa drugs, vasodilators such as alpha blocking agents and nitrates
Use of investigational medication or device within one month of randomization
Chronic use of antihypertensive drugs, including diuretics, will be considered on an individual basis

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00455650

Contacts


Contact: Priscilla Sinclair, B.A.	(617) 912-7829	psinclair1@partners.org

Contact: Alice Coakley, B.A.	(617) 912-7863	acoakley1@partners.org

Locations


United States, Massachusetts
	Freedom Trail Clinic, Massachusetts General Hospital	Recruiting
	Boston, Massachusetts, United States, 02114
	Contact: Priscilla Sinclair, B.A. 617-912-7829 psinclair1@partners.org
	Contact: Alice Coakley, B.A. (617) 912 - 7863 acoakley1@partners.org
	Principal Investigator: A. Eden Evins, M.D., M.P.H.
	Sub-Investigator: Catherine Fullerton, M.D., M.P.H.

Sponsors and Collaborators

Massachusetts General Hospital

National Alliance for Research on Schizophrenia and Depression

The Bowman Family Foundation

Investigators


Principal Investigator:	A. Eden Evins, MD, MPH	Massachusetts General Hospital

Study Director:	Catherine Fullerton, M.D., M.P.H.	Massachusetts General Hospital

More Information

Publications:

Breese CR, Lee MJ, Adams CE, Sullivan B, Logel J, Gillen KM, Marks MJ, Collins AC, Leonard S. Abnormal regulation of high affinity nicotinic receptors in subjects with schizophrenia. Neuropsychopharmacology. 2000 Oct;23(4):351-64.

Chambers RA, Krystal JH, Self DW. A neurobiological basis for substance abuse comorbidity in schizophrenia. Biol Psychiatry. 2001 Jul 15;50(2):71-83. Review.

Potter A, Corwin J, Lang J, Piasecki M, Lenox R, Newhouse PA. Acute effects of the selective cholinergic channel activator (nicotinic agonist) ABT-418 in Alzheimer's disease. Psychopharmacology (Berl). 1999 Mar;142(4):334-42.

Wilens TE, Biederman J, Spencer TJ, Bostic J, Prince J, Monuteaux MC, Soriano J, Fine C, Abrams A, Rater M, Polisner D. A pilot controlled clinical trial of ABT-418, a cholinergic agonist, in the treatment of adults with attention deficit hyperactivity disorder. Am J Psychiatry. 1999 Dec;156(12):1931-7.

Sacco KA, Termine A, Seyal A, Dudas MM, Vessicchio JC, Krishnan-Sarin S, Jatlow PI, Wexler BE, George TP. Effects of cigarette smoking on spatial working memory and attentional deficits in schizophrenia: involvement of nicotinic receptor mechanisms. Arch Gen Psychiatry. 2005 Jun;62(6):649-59.

George TP, Vessicchio JC, Termine A, Sahady DM, Head CA, Pepper WT, Kosten TR, Wexler BE. Effects of smoking abstinence on visuospatial working memory function in schizophrenia. Neuropsychopharmacology. 2002 Jan;26(1):75-85.

Skjei KL, Markou A. Effects of repeated withdrawal episodes, nicotine dose, and duration of nicotine exposure on the severity and duration of nicotine withdrawal in rats. Psychopharmacology (Berl). 2003 Jul;168(3):280-92. Epub 2003 Apr 24.

Pizzagalli DA, Jahn AL, O'Shea JP. Toward an objective characterization of an anhedonic phenotype: a signal-detection approach. Biol Psychiatry. 2005 Feb 15;57(4):319-27.

Katner SN, Davis SA, Kirsten AJ, Taffe MA. Effects of nicotine and mecamylamine on cognition in rhesus monkeys. Psychopharmacology (Berl). 2004 Sep;175(2):225-40. Epub 2004 Apr 27.

Fonder MA, Sacco KA, Termine A, Boland BS, Seyal AA, Dudas MM, Vessicchio JC, George TP. Smoking cue reactivity in schizophrenia: effects of a nicotinic receptor antagonist. Biol Psychiatry. 2005 Apr 1;57(7):802-8.

Green A, Ellis KA, Ellis J, Bartholomeusz CF, Ilic S, Croft RJ, Phan KL, Nathan PJ. Muscarinic and nicotinic receptor modulation of object and spatial n-back working memory in humans. Pharmacol Biochem Behav. 2005 Jul;81(3):575-84.

Gitelman DR, Prohovnik I. Muscarinic and nicotinic contributions to cognitive function and cortical blood flow. Neurobiol Aging. 1992 Mar-Apr;13(2):313-8.

Little JT, Johnson DN, Minichiello M, Weingartner H, Sunderland T. Combined nicotinic and muscarinic blockade in elderly normal volunteers: cognitive, behavioral, and physiologic responses. Neuropsychopharmacology. 1998 Jul;19(1):60-9.

Newhouse PA, Potter A, Corwin J, Lenox R. Age-related effects of the nicotinic antagonist mecamylamine on cognition and behavior. Neuropsychopharmacology. 1994 Apr;10(2):93-107.

Newhouse PA, Potter A, Corwin J, Lenox R. Acute nicotinic blockade produces cognitive impairment in normal humans. Psychopharmacology (Berl). 1992;108(4):480-4.

Rose JE, Sampson A, Levin ED, Henningfield JE. Mecamylamine increases nicotine preference and attenuates nicotine discrimination. Pharmacol Biochem Behav. 1989 Apr;32(4):933-8.

Oncken C, Gonzales D, Nides M, Rennard S, Watsky E, Billing CB, Anziano R, Reeves K. Efficacy and safety of the novel selective nicotinic acetylcholine receptor partial agonist, varenicline, for smoking cessation. Arch Intern Med. 2006 Aug 14-28;166(15):1571-7.

Jorenby DE, Hays JT, Rigotti NA, Azoulay S, Watsky EJ, Williams KE, Billing CB, Gong J, Reeves KR; Varenicline Phase 3 Study Group. Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. JAMA. 2006 Jul 5;296(1):56-63.

Burstein AH, Fullerton T, Clark DJ, Faessel HM. Pharmacokinetics, safety, and tolerability after single and multiple oral doses of varenicline in elderly smokers. J Clin Pharmacol. 2006 Nov;46(11):1234-40.

Kumari V, Postma P. Nicotine use in schizophrenia: the self medication hypotheses. Neurosci Biobehav Rev. 2005;29(6):1021-34. Review.

Responsible Party:	Massachusetts General Hospital ( A. Eden Evins, M.D., MPH )
Study ID Numbers:	PHRC #2006-P-001361, CORRC#3-2007
First Received:	April 2, 2007
Last Updated:	September 29, 2008
ClinicalTrials.gov Identifier:	NCT00455650
Health Authority:	United States: Institutional Review Board

Keywords provided by Massachusetts General Hospital:

schizophrenia

cognition

nicotinic receptors

mecamylamine

varenicline

Study placed in the following topic categories:

Schizophrenia

Mental Disorders

Mecamylamine

Psychotic Disorders

Schizophrenia and Disorders with Psychotic Features

Additional relevant MeSH terms:

Ganglionic Blockers

Neurotransmitter Agents

Cholinergic Antagonists

Molecular Mechanisms of Pharmacological Action

Nicotinic Antagonists

Physiological Effects of Drugs

Cardiovascular Agents

Antihypertensive Agents

Cholinergic Agents

Pharmacologic Actions

Autonomic Agents

Therapeutic Uses

Peripheral Nervous System Agents

ClinicalTrials.gov processed this record on October 21, 2008

Sponsors and Collaborators:	Massachusetts General Hospital National Alliance for Research on Schizophrenia and Depression The Bowman Family Foundation
Information provided by:	Massachusetts General Hospital
ClinicalTrials.gov Identifier:	NCT00455650