Alcohol Dependence, Depression
Conditions
Keywords
treatment, alcohol dependence, depression, mecamylamine
Brief summary
The objective of this study is to evaluate the efficacy of mecamylamine (MEC, 10 mg/day) versus placebo in reducing depressive and alcohol symptoms in patients with depression and co-morbid alcohol dependence. The researchers hypothesize that MEC will significantly reduce depressive symptoms and decrease alcohol consumption compared to placebo in patients with depression and alcohol dependence who are on a stable dose of a selective serotonin reuptake inhibitor (SSRI).
Detailed description
Depression with co-morbid alcohol dependence is very prevalent and it is very costly to treat. The co occurrence of the two disorders leads to greater severity and worse long-term outcome, including suicide. Although a number of treatment strategies have been implemented for depressed patients with alcohol dependence the controversy concerning best treatment options for those patients persists. The clinical relationship between depression and alcohol dependence suggests some common mechanism underlying both disorders. It has been hypothesized that medications that block presynaptic nAChR may be effective in the treatment of alcoholism and depression. Mecamylamine (Inversine ®) is a noncompetitive, high affinity nAChR antagonist with low selectivity for the alpha-7 receptor. Mecamylamine has never been investigated as an effective adjunct treatment for dually diagnosed patients with depression and alcohol dependence. Methods: Thirty participants with a current diagnosis of depression and alcohol dependence will be recruited for this 12-week treatment study. Fifteen participants will be randomized to mecamylamine and fifteen to placebo. Participants will be included in the study if: they meet current DSM-IV criteria for Major Depression and Alcohol Dependence and have been on a stable SSRI dose for 2 weeks. All participants will come weekly to take their medications and complete weekly assessments. Weekly assessments will consist of questioners that will assess depressive symptoms and alcohol consumption over the entire treatment period. Significance: This study is the first to evaluate the efficacy of mecamylamine as an augmenting agent for treatment of depression and alcohol dependence.
Interventions
DRUGMecamylamine
mecamylamine 10mg/day for 12 weeks
DRUGPlacebo
Placebo pill
Sponsors
National Alliance for Research on Schizophrenia and Depression
Yale University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
21 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Individuals with the DSM-IV diagnosis of Major Depression (MD) and Alcohol Dependence (AD) (using the SCID). 2. Individuals who have been on a stable SSRI dose for 2 weeks. 3. Smokers and non-smokers (smokers are defined as smoking more than 5 cigarettes per day). 4. Individuals who have a history of substance dependence (other than alcohol, tobacco and cocaine) but have not met criteria for substance dependence in the past 30 days will be included (using the SCID). 5. Women of childbearing potential must have a negative pregnancy test and use an acceptable method of contraception. 6. Individuals who are able to participate psychologically and physically; give informed consent; complete the assessments; take the study medication; and otherwise participate in the trial. A post-consent test will be given to assess patient's capacity to give informed consent.
Exclusion criteria
1. Females who are pregnant or lactating. 2. Patients may not be taking medications thought to influence drinking behavior, including: acamprosate, disulfiram, naltrexone, or ondansetron. 3. Patients with significant underlying medical conditions, such as cerebral, renal, thyroid, hepatic or cardiac pathology, which in the opinion of the physician would preclude the patient from fully cooperating or be of potential harm during the course of the study. 4. Patients with a history of glaucoma, prostatic hypertrophy, urethral obstruction, cerebral arteriosclerosis, pyloric stenosis, or a history of hypersensitivity to mecamylamine. 5. Patients who meet current SCID criteria for the following major Axis I diagnosis (Posttraumatic Stress Disorders (PTSD), Bipolar Disorders, Schizophrenia and Schizophrenia-type Disorders). 6. Patients with a current unstable medical condition such as neurological, cardiovascular, endocrine, renal, liver, or thyroid pathology (LFT more than 5 times normal, abnormal BUN and creatinine, and unmanaged hypertension with BP higher than 200/120). 7. Patients on pharmacological treatments for alcohol and/or nicotine dependence. (8) Patients taking bethanechol. (9) Patients at risk for suicide.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Drinking Days | 25 weeks | Measured with time line follow back measures |
| Depression - Measured Using the HAMD Total Score | 12 weeks | The Hamilton Depression Rating Scale (HAM-D) has proven useful for many years as a way of determining a patient's level of depression before, during, and after treatment. It should be administered by a clinician experienced in working with psychiatric patients. Although the HAM-D form lists 21 items, the scoring is based on the first 17. It generally takes 15-20 minutes to complete the interview and score the results. The Scale ranges from 0 (normal) to \>23 (Very Severe Depression) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Percentage of Number of Drinking Days by Smoking Status | 25 weeks | Two-way interaction between smoking and medication for percentage of drinking days captured by time line follow back surveys. Data are calculated as number of drinking days over the number of days in the study for smokers and nonsmokers receiving either mecamylamine or placebo. |
| Mean Percentage of Heavy Drinking Days by Smoking | 25 weeks | The two-way interaction between medication by smoking status to measure percentage of heavy drinking days measured by time line follow back survey. Data were calculated as number of heavy drinking days (heavy drinking days is defined as 5 drinks on a single occasion for men and 4 for women) over the number of days in the study for smokers and non smokers receiving either mecamylamine or placebo. |
Countries
United States
Participant flow
Pre-assignment details
284 subjects were assessed for eligibility, but 263 were excluded because they did not meet inclusion criteria or did not want to participate.
Participants by arm
| Arm | Count |
|---|---|
| Mecamylamine Mecamylamine is a noncompetitive, high-affinity nAChR antagonist with low selectivity for the alpha-7 receptor. Those receiving mecamylamine started at 2.5mg once daily (second dose was placebo). The dose was increased to 5.0 mg twice daily over 3 weeks.
Mecamylamine: mecamylamine 10mg/day for 12 weeks | 11 |
| Placebo Placebo capsules were prepared by the pharmacy and were identical in size and color to the medication capsules.
Placebo: Placebo pill | 10 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 7 | 2 |
Baseline characteristics
| Characteristic | Mecamylamine | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 50.91 years STANDARD_DEVIATION 8.43 | 48.20 years STANDARD_DEVIATION 9.84 | 49.62 years STANDARD_DEVIATION 9 |
| Cigarettes per day | 13.6 cigarettes STANDARD_DEVIATION 7.8 | 16.6 cigarettes STANDARD_DEVIATION 4.5 | 14.9 cigarettes STANDARD_DEVIATION 6.6 |
| Depression HAMD | 13.64 units on a scale STANDARD_DEVIATION 5.43 | 12.90 units on a scale STANDARD_DEVIATION 2.93 | 13.29 units on a scale STANDARD_DEVIATION 4.32 |
| Drinking days, past 30 | 22.55 drinking days STANDARD_DEVIATION 7.5 | 22.10 drinking days STANDARD_DEVIATION 8.57 | 22.33 drinking days STANDARD_DEVIATION 7.83 |
| Drinks per drinking day | 13.56 drinks per day STANDARD_DEVIATION 8.27 | 9.32 drinks per day STANDARD_DEVIATION 8.99 | 11.54 drinks per day STANDARD_DEVIATION 8.68 |
| Heavy drinking days, past 30 | 21.73 days STANDARD_DEVIATION 7.38 | 18.00 days STANDARD_DEVIATION 11.62 | 19.95 days STANDARD_DEVIATION 9.57 |
| Race/Ethnicity, Customized African American | 4 participants | 1 participants | 5 participants |
| Race/Ethnicity, Customized Caucasian | 7 participants | 9 participants | 16 participants |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 6 Participants |
| Sex: Female, Male Male | 9 Participants | 6 Participants | 15 Participants |
| Smoking Status Non-Smokers | 4 participants | 5 participants | 9 participants |
| Smoking Status Smokers | 7 participants | 5 participants | 12 participants |
| Total Alcohol Dependence Scale (ADS) score | 17.70 units on a scale STANDARD_DEVIATION 10.34 | 21.7 units on a scale STANDARD_DEVIATION 9.72 | 19.70 units on a scale STANDARD_DEVIATION 9.98 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 11 | 4 / 10 |
| serious Total, serious adverse events | 0 / 11 | 0 / 10 |
Outcome results
Primary
Depression - Measured Using the HAMD Total Score
The Hamilton Depression Rating Scale (HAM-D) has proven useful for many years as a way of determining a patient's level of depression before, during, and after treatment. It should be administered by a clinician experienced in working with psychiatric patients. Although the HAM-D form lists 21 items, the scoring is based on the first 17. It generally takes 15-20 minutes to complete the interview and score the results. The Scale ranges from 0 (normal) to \>23 (Very Severe Depression)
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Depression - Measured Using the HAMD Total Score | 8.212 units on a scale | Standard Deviation 1.592 |
| Mecamylamine | Depression - Measured Using the HAMD Total Score | 8.10 units on a scale | Standard Deviation 1.6 |
Comparison: Comparison of baseline and post-treatmentp-value: 0.0001Mixed Models Analysis
Primary
Number of Drinking Days
Measured with time line follow back measures
Time frame: 25 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Number of Drinking Days | 17.6 days | Standard Deviation 6.57 |
| Mecamylamine | Number of Drinking Days | 12.6 days | Standard Deviation 6.57 |
Comparison: Comparison is between baseline and during treatment.p-value: 0.014Mixed Models Analysis
Secondary
Mean Percentage of Heavy Drinking Days by Smoking
The two-way interaction between medication by smoking status to measure percentage of heavy drinking days measured by time line follow back survey. Data were calculated as number of heavy drinking days (heavy drinking days is defined as 5 drinks on a single occasion for men and 4 for women) over the number of days in the study for smokers and non smokers receiving either mecamylamine or placebo.
Time frame: 25 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Mean Percentage of Heavy Drinking Days by Smoking | Smokers | 15.14 percentage of Heavy Drinking Days | Standard Deviation 19.48 |
| Placebo | Mean Percentage of Heavy Drinking Days by Smoking | Non-Smokers | 3.57 percentage of Heavy Drinking Days | Standard Deviation 6.19 |
| Mecamylamine | Mean Percentage of Heavy Drinking Days by Smoking | Smokers | 1.68 percentage of Heavy Drinking Days | Standard Deviation 2.47 |
| Mecamylamine | Mean Percentage of Heavy Drinking Days by Smoking | Non-Smokers | 31.67 percentage of Heavy Drinking Days | Standard Deviation 29.03 |
p-value: 0.019Mixed Models Analysis
Secondary
Mean Percentage of Number of Drinking Days by Smoking Status
Two-way interaction between smoking and medication for percentage of drinking days captured by time line follow back surveys. Data are calculated as number of drinking days over the number of days in the study for smokers and nonsmokers receiving either mecamylamine or placebo.
Time frame: 25 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Mean Percentage of Number of Drinking Days by Smoking Status | Smokers | 21.34 Percentage of Drinking Days | Standard Deviation 21.96 |
| Placebo | Mean Percentage of Number of Drinking Days by Smoking Status | Non-Smokers | 14.76 Percentage of Drinking Days | Standard Deviation 18.63 |
| Mecamylamine | Mean Percentage of Number of Drinking Days by Smoking Status | Smokers | 4.57 Percentage of Drinking Days | Standard Deviation 6.19 |
| Mecamylamine | Mean Percentage of Number of Drinking Days by Smoking Status | Non-Smokers | 48.81 Percentage of Drinking Days | Standard Deviation 35.22 |
p-value: 0.025Mixed Models Analysis