Varenicline and Smoking Cessation in Schizophrenia (VSCS)

This study has been completed.
Sponsor:
Collaborators:
Information provided by (Responsible Party):
University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier:
NCT01111149
First received: April 23, 2010
Last updated: July 8, 2014
Last verified: July 2014
  Purpose

There is a strong association between smoking and schizophrenia with prevalence rates ranging from 74% to 90%, versus a national average of 30% in nonschizophrenic individuals. A number of hypotheses have been proposed to explain the relationship between high smoking rates and schizophrenia, mostly relating to self-medication primarily for the negative symptoms of schizophrenia. Smoking cessation rates among schizophrenic patients are considerably lower than for other psychiatric disorders. The negative health effects of smoking increase the morbidity and mortality in schizophrenic patients. Currently, the efficacy of bupropion HCl in the treatment of smoking by schizophrenic subjects is inconclusive, and there have not been any published studies of the efficacy of varenicline in schizophrenic subjects. As varenicline appears to be a promising treatment in non-psychiatric patients, it would be useful to expand these studies to examine its effects in schizophrenic patients. Identifying effective and safe means of smoking cessation for this vulnerable population has the potential to reduce morbidity and mortality among individuals with schizophrenia.


Condition Intervention Phase
Schizophrenia
Smoking Cessation
Other: Sugar Pill
Drug: Varenicline
Drug: Bupropion HCl
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Factorial Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Varenicline and Smoking Cessation in Schizophrenia

Resource links provided by NLM:


Further study details as provided by University of Minnesota - Clinical and Translational Science Institute:

Primary Outcome Measures:
  • Smoking Abstinence - Serum/Urine Measurements [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
    Measured by blood/urine tests for nicotine and its break-down product cotinine.

  • Smoking Abstinence - Number of Cigarettes Smoked [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
    Number of cigarettes smoked at week 12 of the study by self-report.

  • Smoking Abstinence - Exhaled Carbon Monoxide [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
    Exhaled carbon monoxide as a biochemical verification of smoking abstinence. Values below are for week 12.


Secondary Outcome Measures:
  • Reduction in Smoking [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
    Successful outcome will be defined as a 50% or greater reduction in self-reported cigarettes per day and a 30% greater reduction in carbon monoxide and cotinine levels. Measured at week 12

  • Negative Symptoms of Schizophrenia - SANS [ Time Frame: Week 12 ] [ Designated as safety issue: Yes ]
    Scale for the Assessment of Negative Symptoms (SANS) a well-established test, used to assess the presence of psychosis or negative symptoms of schizophrenia. It consists of 25 questions rated on a scale of 0 (none) to 5 (severe). With a total score range of 0 to 125 points. There are 6 subscales: Affective Flattening or Blunting - (minimum, 0; maximum 35); Inappropriate Affect (minimum, 0; maximum 5); Alogia (minimum 0; maximum 25); Avolition-Apathy (minimum 0; maximum 20); Anhedonia-Asociality (minimum 0; maximum 25); Attention (minimum 0; maximum 15). Each subscale (except for Inappropriate Affect) contains one additional question as a Global Rating - or overall measure for that particular subscale. The sum of these questions constitutes the Total Global Score (minimum 0, maximum 25). The global questions are included within the Total Composite score. In each case, the larger the score, the more severe the symptoms.

  • Impulsivity and Inattention [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
    Impulsivity and inattention will be measured using the continuous performance test. Individuals were tasked with 359 items divided six blocks (59 in block 1, 60 in blocks 2-6). Omissions result from the failure to respond to target letters. CPT% Omissions measures the percentage of responses that qualify as omissions made during the test. Higher scores indicate increased inattention. Commissions result from responses given to non-targets. CPT% Commissions measures the percentage of responses that qualify as commissions made during the test. Higher scores indicate increased inattention. Perseverations result from reaction time less than 100 ms. CPT% Perseveration % measures the percentage of responses that qualify as perseverations made during the test. The higher the score, the greater impulsivity.

  • Side Effects [ Time Frame: Week 12 ] [ Designated as safety issue: Yes ]
    Side effects will be monitored by a physician and/or assistant and recorded (SEP). All patients withdrawn from the study because of emerging side effects will be followed until the side effects are resolved. Each item is scored based on a scale of 0=none; 1=mild; 2=moderate; and 3=severe. Below, the data are shown for participants experiencing symptoms on week 12 of the study.

  • Abstinence-related Symptoms - MNWS and FTND [ Time Frame: Week 12 ] [ Designated as safety issue: No ]

    Minnesota Nicotine Withdrawal Scale (MNWS), a patient-reported measure of nicotine withdrawal symptoms and cravings. Eight items are listed, including craving for cigarettes, irritability, frustration, or anger, anxiety, etc scored on a five point scale from 0 (normal) to 5 (severe). Patients are asked for responses for the past 24 hours and past seven days (minimum 0, maximum 32; for each subscale). The higher the score, the greater the dependence. Additionally, one question (minimum score 1, maximum score 4 measures the individual's confidence in resisting strong urges to smoke. The higher the score on this question, the greater the individual's confidence in resisting smoking urges.

    The Fagerstrom Test for Nicotine Dependence measures nicotine dependence and consists of six questions with a total minimum score of 0 and a maximum score of 10. The higher the score, the greater the dependence on nicotine.


  • Depression [ Time Frame: Week 12 ] [ Designated as safety issue: Yes ]
    Beck Depression Inventory (BDI), a self-report rating inventory measuring characteristic attitudes and symptoms of depression consisting of 21 items with each item rated on a four point scale (0=not present to 3=severe). The accepted ranges are as follows: 0 to 9 indicates no depression, 10 to 18 indicates mild to moderate depression, 19 to 29 indicates moderate to severe depression and 30 to 63 indicates severe depression.

  • Abnormal Movements - BAS and SAS [ Time Frame: Week 12 ] [ Designated as safety issue: Yes ]

    Barnes Akathisia Scale (BAS), a widely-used measurement of drug-induced akathisia. It consists of 4 questions with questions 1-3 scored on a scale of 0-3 with 0=normal and 3=severe (minimum score 0, maximum score 9; while item 4 is a global clinical assessment of akathisia rated on a scale of 0 (normal) to 5 (severe). The higher the score on each subsclae, the greater the severity of akathisia.

    Simpson-Angus Scale (SAS), a 10-item instrument used to evaluate patients experiencing neuroleptic-induced parkinsonism and other extrapyramidal side effects. Items are rated for severity on a 0-4 scale, with 0 being normal and 4 being severe. Minimum = 0; Maximum = 40. The higher the score, the greater the severity.


  • Vital Signs [ Time Frame: Week 12 ] [ Designated as safety issue: Yes ]
    blood pressure will be measured.

  • Vital Signs - Weight [ Time Frame: Week 12 ] [ Designated as safety issue: Yes ]
    Weight will be measured for each participant. Values listed below are for week 12.

  • Vital Signs - Pulse [ Time Frame: Week 12 ] [ Designated as safety issue: Yes ]
    Pulse will be measured. The values below were measured at week 12 of the study.

  • Suicidality [ Time Frame: Week 12 ] [ Designated as safety issue: Yes ]
    The Columbia-Suicide Severity Rating Scale (C-SSRS), is a survey intended to quantify the severity of suicidal ideation and behavior. The questionaire for suicidal ideation consists of 5 questions with yes (1) /no (0) answers. If answers to questions 1 and 2 are no, questions 3-5 are skipped. Minimum of 0; Maximum of 5. The questionaire for suicidal behavior consists of seven questions rated 0 for no and 1 for yes. The minimum score is 0 and the maximum score is 7. In each case, the higher the score, the greater the severity.

  • Positive Symptoms of Schizophrenia (SAPS) [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
    Scale for the Assessment of Positive Symptoms (SAPS), a well-established test, used to assess the presence of psychotic symptoms of schizophrenia. There are 34 items rated on a scale of 0-5 with 0=none and 5=severe for a minimum score of 0 and a maximum score of 170. There are 4 subscales: Hallucinations (minimum score 0; maximum score 35); Delusions (minimum score 0; maximum score 65); Bizarre Behavior (minimum score 0; maximum score 25); Positive Formal Thought Disorder (minimum score 0; maximum score 45). Each subscale contains one additional question as a Global Rating - or overall measure for that particular subscale. The sum of these questions constitutes the Total Global Score (minimum 0, maximum 20). The values for the Global items are included in the Total Composite score. In each case, the higher the score, the greater the severity of symptoms.

  • General Psychopathology [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
    Brief Psychiatric Rating Scale (BPRS), an 24-item scale measuring positive symptoms, general psychopathology, and affective symptoms commonly used for schizophrenia with each item rated on a scale of 1-7 with 1=not present and 7=severe. The minimum score is 24 and the maximum score is 168. We have used five subscales as recommended by Dingemans et al., 1995: Positive subscale (minimum score 6; maximum score 42); Negative subscale (minimum score 5; maximum score 35); Depressed subscale (minimum score 5; maximum score 35); Mania subscale (minimum score 6; maximum score 42); and Disorientation subscale (minimum score 2; maximum score 14) . For both the total score and the subscale scores, the higher the score, the greater the symptom severity. We used the BPRS version 4.0. Dingemans PMAJ, Linszen DH, Lenoir ME, Smeets RMW, 1995. Component structure of the expanded Brief Psychiatric Rating Scale (BPRS-E). Psychopharmacology 122:263-267.

  • Hit Reaction Time - CPT [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
    The hit reaction time is the average speed of correct responses for the entire test given in milliseconds. The higher the score, the slower the speed. The standard error is a measure of response speed consistency. The higher the overall standard error, the greater inconsistency in the response speed. The values below were measured at week 12.

  • Variability of Standard Error - CPT [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
    Variability of Standard Error (VSE) is a measure of response speed consistency. VSE measures "within respondent" variability. That is, the amount of variability the individual shows in 18 separate segments of the Continuous Performance Test in relation to his or her own overall standard error. Although VSE is a different measure than Overall Standard Error, typically the two measures produce comparable results. The higher the VSE, the greater the inconsistency in the response speed. The values shown below are the VSE for Week 12.

  • Detectibility (d') of Continuous Performance Test [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
    The value d' is a measure of the difference between the signal (non-X) and noise (X) distributions. As such, d' provides a means for assessing an individual's discriminative power since, in general, the greater the difference between the signal and noise distributions, the better the ability to distinguish and detect X and non-X stimuli. The lower the score, the better the detectability. Values shown below are for week 12.

  • Response Style Indicator (Beta) for CPT [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
    Beta represents an individual's response tendency: Some individuals are cautious and choose not to respond very often. Conceptually, such individuals want to make sure they are correct when they give a response. Higher values of Beta reflect this response style. The emphasis is on avoiding commission errors. Other individuals respond more freely to make sure they respond to most or all targets, and they tend to be less concerned about mistakenly responding to a non-target. Lower values of Beta are produced by this response style. Values shown below were obtained at week 12.

  • Abstinence Related Symptoms - WISDM [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
    The Wisconsin Inventory of Smoking Dependence Motives (WISDM) consists of 68 items regarding smoking. Each item is rated on a scale of 1 (not true of me at all) to 7 (extremely true of me) leading to a minimum score of 68 and a maximum score of 476. The higher the score, the greater the dependence. Four of the items are grouped into a Craving subscale (minimum 4, maximum 28), the greater the score, the greater the craving. Five of the items are grouped into a Cognition subscale (minimum 5, maximum 35), the higher the score, the greater reliance on cigarette smoking for cognitive enhancement. WISDM scoring based on the original article by Piper et al., 2004. A multiple motives approach to tobacco dependence: the Wisconsin inventory of smoking dependence motives (WISDM-68). Journal of Consulting and Clinical Psychology 72:139-154.

  • Urge to Smoke - MNWS [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
    The Minnesota Nicotine Withdrawal Scale (MNWS) includes two items where individuals are asked to 1) declare the percentage of time they had an urge to smoke (MNWS % Urge to Smoke); and 2) declare the percentage of time they had a strong urge to smoke (MNWS % Strong Urge). For each case, percentages range from 0% to 100% - the higher the percentage, the greater urge to smoke.

  • Abnormal Movements - AIMS [ Time Frame: Week 12 ] [ Designated as safety issue: Yes ]
    Abnormal Involuntary Movement Scale (AIMS), to assess abnormal involuntary movements associated with antipsychotic drugs. There are 10 questions, based on a five-point scale ranging from 0 (none) to 4 (severe). Items 11-14 are yes/no questions that have no impact on the score. The Total Score is the sum of questions 1-7 (minimum = 0; maximum = 28). The severity index consists of one question (item 8; rated 0=none to 4=severe) based on the rater's observation of abnormal movements The AIMS Global Score is the sum of three questions (each item rated 0=none to 4=severe) regarding abnormal movements overall (minimum score 0, maximum score 12). For the total score and subscores, the higher the score, the greater the severity of abnormal movements. Scoring is based on the chapter: Guy W (2000), Abnormal Involuntary Movement Scale (AIMS), in: Handbook of Psychiatric Measures (Rush AJ Jr, et al., eds). APA Publishing: Washington DC: pp. 166-167.


Enrollment: 24
Study Start Date: December 2009
Study Completion Date: August 2012
Primary Completion Date: August 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Sugar Pill
Sugar pill will be given to patients as a comparison group to the active varenicline group. In the fist week, one placebo pill will be given per patient, followed by 2 pills per day for the remaining 12 weeks of the study.
Other: Sugar Pill
Sugar pill created and masked by the pharmacy to be used as a control.
Experimental: Varenicline
Varenicline has not previously been examined for its efficacy and safety in subjects with schizophrenia. Subjects in the varenicline group will receive one 1mg pill/day for week 0, followed by two 1mg pills/day for the rest of the study. This is an experimental group to be compared against both placebo and bupropion HCl.
Drug: Varenicline
Subjects in the varenicline group will receive one 1mg pill/day for week 0, followed by two 1mg pills/day for the rest of the study.
Other Name: Chantix
Active Comparator: Bupropion HCl
Bupropion HCl is an established smoking cessation agent and will be used to compare its efficacy and safety against varenicline. Subjects in the Bupropion HCl group will receive one 150mg pill/day for week 0, followed by two 150mg pills/day for the rest of the study.
Drug: Bupropion HCl
in the Bupropion HCl group will receive one 150mg pill/day for week 0, followed by two 150mg pills/day for the rest of the study
Other Names:
  • Wellbutrin
  • Zyban

Detailed Description:

There is a strong association between smoking and schizophrenia with prevalence rates ranging from 74% to 90%, versus a national average of 30% in nonschizophrenic individuals. A number of hypotheses have been proposed to explain the relationship between high smoking rates and schizophrenia, mostly relating to self-medication primarily for the negative symptoms of schizophrenia. Smoking cessation rates among schizophrenic patients are considerably lower than for other psychiatric disorders. The negative health effects of smoking increase the morbidity and mortality in schizophrenic patients. The smoking cessation agent bupropion HCl has been tested in schizophrenics, but the results on its efficacy are inconclusive. Recent works by different laboratories have shown the safety and efficacy of varenicline, a partial alpha4beta2 and full alpha7 nicotinic acetylcholine receptor agonist, as a smoking cessation agent. However, to date, no published studies have tested the safety and efficacy of varenicline in treatment of nicotine dependence in schizophrenic patients. As varenicline appears to be a promising treatment in non-psychiatric patients, it would be beneficial to examine its effects in schizophrenic patients. The central hypothesis of this application is that treatment with varenicline will safely increase smoking abstinence rates in schizophrenic patients when compared to those receiving placebo. This central hypothesis will be tested and the objectives of this application accomplished by pursuing two Specific Aims: 1) Treatment with varenicline or bupropion HCl for a period of three months will increase smoking abstinence rates in schizophrenic patents when compared to placebo; and 2) Treatment with varenicline or bupropion HCl for a period of three months will not increase psychosis in schizophrenic patients when compared to placebo. For our General Investigational Plan, we will employ a double-blind randomized placebo controlled study to assess varenicline's safety and efficacy. It is our expectation that we will demonstrate that varenicline is safe and effective in decreasing smoking rates in schizophrenic patients without exacerbating psychotic symptoms. Such outcomes will be significant, because they will offer a new treatment for smoking cessation in this vulnerable population.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male or female subjects, 18-75 years old
  • Diagnosis of schizophrenia or schizoaffective disorder based on Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) criteria
  • Smoking at least 10 cigarettes per day
  • Weight of at least 100 lbs (45.4 kg)
  • Motivation to quit smoking
  • Stabilized psychotic symptoms
  • Provision of informed consent for testing and treatment

Exclusion Criteria:

  • Serious cardiac, renal, hypertensive, pulmonary, endocrine, or neurologic disorder
  • Seizure disorder, recent withdrawal from alcohol or anxiolytics
  • History of bulimia nervosa, anorexia nervosa, or dementia
  • History of depression, panic, or bipolar disorders
  • Pregnancy or lactation
  • Prior use of varenicline or bupropion HCl within three months prior to initiation of the study
  • Current use of other smoking cessation treatments
  • Regular use of non-cigarette tobacco products (> than once/week)
  • Past substance abuse (alcohol or non-nicotine containing drugs) in the preceding 6 months
  • Patients with suicidal ideations or plans
  • Florid psychosis or increasing psychosis following varenicline or bupropion HCl treatment
  • History of, or current, alcohol dependence/abuse
  • Current use of monoamine oxidase inhibitors (MAOI)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01111149

Locations
United States, Minnesota
University of Minnesota, University of Minnesota Medical Center
Minneapolis, Minnesota, United States, 55455
Sponsors and Collaborators
University of Minnesota - Clinical and Translational Science Institute
Investigators
Principal Investigator: S. Hossein Fatemi, M.D., Ph.D. University of Minnesota - Clinical and Translational Science Institute
  More Information

Publications:
Responsible Party: University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier: NCT01111149     History of Changes
Other Study ID Numbers: 0904M64601, R01DA024674
Study First Received: April 23, 2010
Results First Received: December 16, 2013
Last Updated: July 8, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Minnesota - Clinical and Translational Science Institute:
Schizophrenia
Smoking cessation
Varenicline
Bupropion

Additional relevant MeSH terms:
Schizophrenia
Schizophrenia and Disorders with Psychotic Features
Smoking
Mental Disorders
Habits
Contraceptives, Oral
Bupropion
Varenicline
Contraceptive Agents, Female
Contraceptive Agents
Reproductive Control Agents
Physiological Effects of Drugs
Pharmacologic Actions
Therapeutic Uses
Antidepressive Agents, Second-Generation
Antidepressive Agents
Psychotropic Drugs
Central Nervous System Agents
Dopamine Uptake Inhibitors
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Uptake Inhibitors
Nicotinic Agonists
Cholinergic Agonists
Cholinergic Agents

ClinicalTrials.gov processed this record on July 24, 2014