Cigarette Smoking, Schizophrenia
Conditions
Keywords
schizophrenia, smoking, nicotine, cognitive deficits, nicotinic receptors, Cognitive Deficits in Schizophrenia
Brief summary
This is a 8-week double-blind placebo controlled parallel group study of the efficacy of varenicline (Chantix) for smoking cessation in schizophrenic patients, and its effect on cognitive function in patients with schizophrenia.At some sits evaluation of smoking measures is extended to 12 weeks. Correlations will be made with biological predictors of efficacy: a) measures of nicotinic receptors in lymphocytes b) DNMT1 and GAD67 mRNA in lymphocytes. Subjects will be current cigarette smokers or history of regular smokers.
Detailed description
This was a double-blind placebo controlled study of varenicline and matched placebo in patients with a diagnosis of schizophrenia or schizoaffective psychosis who were treated with antipsychotic medication and were cigarette smokers. Three sites (2 U.S., 1 Israel) were supported by the Stanley grant. A similar independently supported study was conducted in Beijing, China. We were allowed to access these data and combine them for our analysis of results. Subjects at each site participated in a protocol which was approved by their institutional IRB. All subjects signed informed consent. The study evaluated multiple measures of cigarette smoking, cognitive functions by MATRICS battery (Measurement and Treatment Research to Improve Cognition in Schizophrenia), and psychiatric symptoms by PANSS (Positive and Negative Symptom Scale), SANS (Schedule For Assessment Of Negative Symptoms), and Calgary Depression scales. Lymphocytes were collected for measurement of epigenetically related mRNA's.
Interventions
DRUGVarenicline
Varenicline 1-2 mg/day
Placebo
Sponsors
Nathan Kline Institute for Psychiatric Research
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
Diagnosis of Schizophrenia or Schizoaffective Disorder Current Cigarette Smoker or History of Chronic Cigarette smoking Age 18-65 Currently taking antipsychotic medication
Exclusion criteria
prior history of hospitalization for acute myocardial infarction or stroke, or persistent angina pectoris with current symptoms Patients who have previously tried varenicline and have stopped taking it because of side-effects of severe nausea or vomiting suicide attempt in the last year and or have had prominent or serious suicidal thoughts in the past year Women who are pregnant, nursing, or unable to use reliable contraception significant renal impairment(Creatinine ≥ 1.5) baseline Hamilton Depression Scores is \>20
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cotinine Level | Baseline, 4 weeks, 8 weeks | plasma cotinine |
| Change From Baseline in Cognitive Performance | basline and 8 weeks (or end of study iif patient ended participation before the 8-weeks) | The MATRICS Consensus Cognitive Battery (MCCB)(Measurement and Treatment Research to Improve Cognition in Schizophrenia) was used to measure cognitive performance. Six Domain scores and a Composite score are calculated by the proprietary MCCB Computer Scoring Program (modified beta version) from raw scores on 10 individually administered subtests. The social cognition test was not assessed in this study. The Domain T-scores are percentile-ranked and range from \<20 (\<0.1 percentile) to \>80 (\>99.9 percentile). The Composite scores are also percentile-ranked and range from \<213 (T\<20, \<0.1 percentile) to \>487 (T\>80, \>99.9 percentile). Higher scores after baseline represent better outcomes. Here we report difference scores from post-treatment and baseline with positive difference scores representing better outcomes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Psychiatric Symptoms | baseline, 4 weeks, 8 weeks | The Positive and Negative Syndrome Scale (PANSS) was used to measure psychiatric symptoms. Item scores ranged from 1 (Absent) to 6 (Severe) for symptoms on the Positive Scale (total subscale range: 7-42), the Negative Scale (total subscale range: 7-42), and the General Psychopathology Scale (total subscale range:16-96). All three subscales were summed for the PANSS total score (total scale range: 30-180). Scores closer to 30 after baseline represented better outcomes. Here we report difference scores from post-treatment and baseline with negative difference scores representing better outcomes. |
| Change From Basellne in Calgary Depression Scale Score | baseline, 4 weeks, 8 weeks | The Calgary Depression Scale for Schizophrenia. The scale has 9 items with ratings of 0 to 3 on each item. Total score can vary from 0 to 27. Higher scores indicate more depression. Negative change scores indicate decreasing depression. |
Countries
China, Israel, United States
Participant flow
Pre-assignment details
Overall, 93 subjects were consented, 2 withdrew consent before randomization, and 87 provided evaluable data on at least one outcome measure. The number enrolled 93, is less than the number started 91, because 2 patients withdrew consent before randomization
Participants by arm
| Arm | Count |
|---|---|
| Varenicline Varenicline 1-2 mg/day
Varenicline: Varenicline 1-2 mg/day | 42 |
| Matched Placebo placebo for varenicline
Placebo for varenicline: Placebo | 45 |
| Total | 87 |
Baseline characteristics
| Characteristic | Varenicline | Matched Placebo | Total |
|---|---|---|---|
| Age, Continuous | 46.6 years STANDARD_DEVIATION 8.9 | 43.6 years STANDARD_DEVIATION 10.6 | 44.7 years STANDARD_DEVIATION 9.9 |
| Race/Ethnicity, Customized black-AA | 15 Participants | 17 Participants | 32 Participants |
| Race/Ethnicity, Customized chinese han | 8 Participants | 8 Participants | 16 Participants |
| Race/Ethnicity, Customized hispanic | 5 Participants | 7 Participants | 12 Participants |
| Race/Ethnicity, Customized white | 14 Participants | 13 Participants | 27 Participants |
| Region of Enrollment China | 8 participants | 8 participants | 16 participants |
| Region of Enrollment Israel | 12 participants | 10 participants | 22 participants |
| Region of Enrollment United States | 22 participants | 27 participants | 49 participants |
| Sex: Female, Male Female | 7 Participants | 6 Participants | 13 Participants |
| Sex: Female, Male Male | 35 Participants | 39 Participants | 74 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 45 | 0 / 46 |
| serious Total, serious adverse events | 2 / 45 | 1 / 46 |
Outcome results
Primary
Change From Baseline in Cognitive Performance
The MATRICS Consensus Cognitive Battery (MCCB)(Measurement and Treatment Research to Improve Cognition in Schizophrenia) was used to measure cognitive performance. Six Domain scores and a Composite score are calculated by the proprietary MCCB Computer Scoring Program (modified beta version) from raw scores on 10 individually administered subtests. The social cognition test was not assessed in this study. The Domain T-scores are percentile-ranked and range from \<20 (\<0.1 percentile) to \>80 (\>99.9 percentile). The Composite scores are also percentile-ranked and range from \<213 (T\<20, \<0.1 percentile) to \>487 (T\>80, \>99.9 percentile). Higher scores after baseline represent better outcomes. Here we report difference scores from post-treatment and baseline with positive difference scores representing better outcomes.
Time frame: basline and 8 weeks (or end of study iif patient ended participation before the 8-weeks)
Population: N's varied from 25-32 in varenicline group and 29-35 in placebo group because all subjects did not complete all parts of MATRICS battery.Maximum number of participants is entered for number of participants because this cell entry does not allow entry of variable number of participations ( e.g. 25-32). for different scores..
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Varenicline | Change From Baseline in Cognitive Performance | MATRICS attention-vigilance diff from baseline | 2.49 T scores from MATRICS battery | Standard Error 1.99 |
| Varenicline | Change From Baseline in Cognitive Performance | MATRICS visual learning diff from baseline | 4.75 T scores from MATRICS battery | Standard Error 2.26 |
| Varenicline | Change From Baseline in Cognitive Performance | MATRICS composite score diff from baseline | -0.19 T scores from MATRICS battery | Standard Error 2.14 |
| Varenicline | Change From Baseline in Cognitive Performance | MATRICS Speed of Processing diff from baseline | 3.03 T scores from MATRICS battery | Standard Error 1.52 |
| Varenicline | Change From Baseline in Cognitive Performance | MATRICS working memory diff from baseline | 0.95 T scores from MATRICS battery | Standard Error 1.82 |
| Varenicline | Change From Baseline in Cognitive Performance | MATRICS verbal learning diff from baseline | 0.94 T scores from MATRICS battery | Standard Error 1 |
| Varenicline | Change From Baseline in Cognitive Performance | MATRICS reasoning-rob sol diff from baseline | 0.38 T scores from MATRICS battery | Standard Error 0.78 |
| Matched Placebo | Change From Baseline in Cognitive Performance | MATRICS visual learning diff from baseline | 7.85 T scores from MATRICS battery | Standard Error 2.3 |
| Matched Placebo | Change From Baseline in Cognitive Performance | MATRICS working memory diff from baseline | 5.29 T scores from MATRICS battery | Standard Error 1.88 |
| Matched Placebo | Change From Baseline in Cognitive Performance | MATRICS reasoning-rob sol diff from baseline | 2.79 T scores from MATRICS battery | Standard Error 0.81 |
| Matched Placebo | Change From Baseline in Cognitive Performance | MATRICS composite score diff from baseline | 1.97 T scores from MATRICS battery | Standard Error 1.86 |
| Matched Placebo | Change From Baseline in Cognitive Performance | MATRICS verbal learning diff from baseline | 0.01 T scores from MATRICS battery | Standard Error 1.04 |
| Matched Placebo | Change From Baseline in Cognitive Performance | MATRICS Speed of Processing diff from baseline | 4.08 T scores from MATRICS battery | Standard Error 1.56 |
| Matched Placebo | Change From Baseline in Cognitive Performance | MATRICS attention-vigilance diff from baseline | 4.33 T scores from MATRICS battery | Standard Error 1.95 |
Primary
Cotinine Level
plasma cotinine
Time frame: Baseline, 4 weeks, 8 weeks
Population: Data were available for cotinine analysis in mixed model analysis of co covariance on 34 participants in the varenicline arms and 36 participants in the placebo arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Varenicline | Cotinine Level | week4 | 176.0 cotinine ng/ml | Standard Error 16 |
| Varenicline | Cotinine Level | week8 | 147.0 cotinine ng/ml | Standard Error 17.9 |
| Varenicline | Cotinine Level | baseline | 257.9 cotinine ng/ml | Standard Error 15.9 |
| Matched Placebo | Cotinine Level | baseline | 258.6 cotinine ng/ml | Standard Error 18.4 |
| Matched Placebo | Cotinine Level | week4 | 252.1 cotinine ng/ml | Standard Error 18.7 |
| Matched Placebo | Cotinine Level | week8 | 264.6 cotinine ng/ml | Standard Error 18.9 |
Secondary
Change From Baseline in Psychiatric Symptoms
The Positive and Negative Syndrome Scale (PANSS) was used to measure psychiatric symptoms. Item scores ranged from 1 (Absent) to 6 (Severe) for symptoms on the Positive Scale (total subscale range: 7-42), the Negative Scale (total subscale range: 7-42), and the General Psychopathology Scale (total subscale range:16-96). All three subscales were summed for the PANSS total score (total scale range: 30-180). Scores closer to 30 after baseline represented better outcomes. Here we report difference scores from post-treatment and baseline with negative difference scores representing better outcomes.
Time frame: baseline, 4 weeks, 8 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Varenicline | Change From Baseline in Psychiatric Symptoms | PANSS Total wk4 -baseline diff | -3.56 units on a scale | Standard Error 1.29 |
| Varenicline | Change From Baseline in Psychiatric Symptoms | PANSS Depression Factor wk4-basline diff | -0.67 units on a scale | Standard Error 0.24 |
| Varenicline | Change From Baseline in Psychiatric Symptoms | PANSS Total wk8-baseline diff | -3.05 units on a scale | Standard Error 1.35 |
| Varenicline | Change From Baseline in Psychiatric Symptoms | PANSS depressor factor wk8-baseline diff | -0.67 units on a scale | Standard Error 0.25 |
| Matched Placebo | Change From Baseline in Psychiatric Symptoms | PANSS depressor factor wk8-baseline diff | -0.10 units on a scale | Standard Error 0.25 |
| Matched Placebo | Change From Baseline in Psychiatric Symptoms | PANSS Total wk4 -baseline diff | -0.86 units on a scale | Standard Error 1.42 |
| Matched Placebo | Change From Baseline in Psychiatric Symptoms | PANSS Total wk8-baseline diff | -0.97 units on a scale | Standard Error 1.4 |
| Matched Placebo | Change From Baseline in Psychiatric Symptoms | PANSS Depression Factor wk4-basline diff | 0.23 units on a scale | Standard Error 0.26 |
Secondary
Change From Basellne in Calgary Depression Scale Score
The Calgary Depression Scale for Schizophrenia. The scale has 9 items with ratings of 0 to 3 on each item. Total score can vary from 0 to 27. Higher scores indicate more depression. Negative change scores indicate decreasing depression.
Time frame: baseline, 4 weeks, 8 weeks
Population: Not all patients had relevant responses on Calgary Depression Scale. Data are analyzed for 36 subjects randomized to varenicline and 38 subjects randomized to placebo (total N=74).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Varenicline | Change From Basellne in Calgary Depression Scale Score | Calgrapy Dep totl wk4-baseline diff | -0.63 Scores on a scale | Standard Error 0.24 |
| Varenicline | Change From Basellne in Calgary Depression Scale Score | calgrapy dep wk8-baseline diff | -0.79 Scores on a scale | Standard Error 0.26 |
| Matched Placebo | Change From Basellne in Calgary Depression Scale Score | Calgrapy Dep totl wk4-baseline diff | -0.72 Scores on a scale | Standard Error 0.27 |
| Matched Placebo | Change From Basellne in Calgary Depression Scale Score | calgrapy dep wk8-baseline diff | -0.88 Scores on a scale | Standard Error 0.26 |