Alcoholism, Depression, PTSD
Conditions
Keywords
SSRI, treatment, naltrexone, alcohol dependence, Desipramine, depression, PTSD
Brief summary
The purpose of this study is to evaluate the efficacy of naltrexone in combination with an SSRI to reduce alcohol consumption in alcoholic patients with comorbid PTSD and depression. We hypothesize that the combination of naltrexone and SSRI will exhibit a greater decrease in alcohol consumption than that seen with treatment with SSRI alone, or with a combination of another class of antidepressant and naltrexone. We also hypothesize that SSRI will be effective in treating PTSD and depressive symptoms and naltrexone will be well tolerated.
Detailed description
OBJECTIVE: Alcoholics with current comorbid mental disorders constitute the majority of alcoholics in clinical settings. Although there are two FDA approved medications for the treatment of alcoholism (naltrexone and disulfiram), there are no established pharmacotherapies for individuals with comorbid alcoholism and psychiatric illnesses. Studies suggest that the class of antidepressants known as serotonin selective reuptake inhibitors (SSRIs) is effective in reducing alcohol use in depressed individuals. In addition, a small open label study has shown that SSRIs have similar effects on individuals with comorbid PTSD and alcoholism. Preclinical studies have shown that the combination of a serotonergic agent and naltrexone was more effective than either medication alone in suppressing alcohol intake. To address this issue, we are conducting a 13 week randomized clinical trial evaluating the effects of paroxetine, desipramine and naltrexone in reducing alcohol use in alcohol dependent individuals who currently meet DSM-IV diagnosis for Depressive Disorder or PTSD. RESEARCH PLAN: One hundred and twenty subjects who are alcohol dependent patients with comorbid PTSD or Depressive Disorder will be recruited from the following West Haven VA sources: the Substance Abuse Treatment program, the PTSD clinic, the Women's clinic, clinical referrals and advertisement. These subjects will be randomized in a double-blind fashion to one of four cells. We will compare paroxetine versus desipramine and naltrexone versus placebo. The antidepressant will be started at a low dose and titrated upward on a fixed schedule. The target dose will be 40mg for paroxetine and 200mg for desipramine. Minimum dosage permitted for study retention will be 20mg for paroxetine and 150mg for desipramine. Pharmacological treatments will last 13 weeks. Psychosocial treatment will involve medication compliance therapy, using the Microelectric Event Monitoring (MEMS) bottle caps. The specific aim of the research is to compare the relative effectiveness of paroxetine versus desipramine and naltrexone versus placebo in reducing the quantity and frequency of alcohol consumption. METHODOLOGY: The primary outcome measures of major interest will include: frequency and quantity of alcohol consumption, self-reported craving, self-reported psychiatric and emotional distress, diagnostic assessment or psychiatric symptoms and side effects. These outcomes will be measured by the following: self-assessments, Timeline Followback, Hamilton Depression and anxiety scales, CAPS, ASI, Quality of Life, breathalyzer tests and monthly liver function tests.
Interventions
DRUGparoxetine
paroxetine (40mg/day)
DRUGdesipramine
200 mg per day
DRUGNaltrexone
50 mg per day
DRUGPlacebo
placebo
Sponsors
Yale University
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
21 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* DSM-IV diagnosis of alcohol dependence and current DSM-IV depressive disorder or PTSD * a recent episode of heavy drinking * outpatient, sober from alcohol and other abused substance for at least 2 days before randomization * stable medication regiment for at least 2 weeks * women on adequate methods of contraception
Exclusion criteria
* current opioid dependence or abuse * history (within the last 3 months) of opioid dependence or abuse * pregnant * history of psychotic disorders or current treatment with antipsychotic medications * medication thought to influence drinking including: acamprosate, disulfiram, naltrexone, ondansetron, valproic acid or tegretol * current (within the lst 6 months) use of MAO inhibitors * suicidal active ideation or intent * significant underlying medical condition * history of cardiac condition abnormalities
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Self-report Weekly Craving Via Obsessive Compulsive Drinking Scale (OCDS) | beginning of treatment (week 1), and end of treatment (13 weeks) | The OCDS is a 14-item (rated 0-4), self-administered questionnaire for characterizing and quantifying the obsessive and compulsive cognitive aspects of craving and heavy (alcoholic) drinking, such as drinking-related thought, urges to drink, and the ability to resist those thoughts and urges. A higher total score indicates higher craving and ranges from 0-48. |
| Clinician-Administered PTSD Scale (CAPS) | beginning of treatment (week 1), and end of treatment (13 weeks) | The CAPS is the gold standard in PTSD assessment. The CAPS-5 is a 30-item structured interview that can be used to: Make current (past month) diagnosis of PTSD Make lifetime diagnosis of PTSD Assess PTSD symptoms over the past week Clinician-Administered PTSD Scale for DSM-5 (CAPS-5). A higher score is associated with higher severity of PTSD. The score is interpreted as follows: 0-19=Asymptomatic/few symptoms 20-39=Sub-threshold/mild PTSD 40-59=Threshold PTSD/moderate 60-79=Severe PTSD \>80=Extreme PTSD |
| Hamilton Depression Rating Scale (HAM-D) | beginning of treatment (week 1), and end of treatment (13 weeks) | The HAM-D ranges from 0 (Normal) to \>23 (Very Severe Depression) |
| Mean Number of Side Effects | 12 weeks | Differences in mean number of side effects reported for each group. Side effects and common adverse symptoms were evaluated by the research staff weekly, using a modified version of the ystematic Assessment for Treatment Emergent Events. The symptoms that are known to be associated with treatment with desipramine, paroxetine, and naltrexone were specifically screened or on a weekly basis. The symptoms were then clustered into the following categories: gastrointestinal, emotional, cold and flu symptoms, skin, sexual, neurological, and cardiac. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Paroxetine and Naltrexone Paroxetine was started at 10 mg per day and the dose was gradually increased over 2 weeks to 40 mg per day. Naltrexone was started at 25 mg the first day and 50 mg per day for the rest of the treatment.
paroxetine: paroxetine (40mg/day)
Naltrexone: 50 mg per day | 22 |
| Paroxetine and Placebo Paroxetine was started at 10 mg per day and the dose was gradually increased over 2 weeks to 40 mg per day.
paroxetine: paroxetine (40mg/day)
Placebo: placebo | 20 |
| Desipramine and Naltrexone Desipramine was started at a dose of 25 mg per day. The dose was gradually increased over 2 weeks to 200 mg per day. Naltrexone was started at 25 mg the first day and 50 mg per day for the rest of the treatment.
desipramine: 200 mg per day
Naltrexone: 50 mg per day | 22 |
| Desipramine and Placebo Desipramine was started at a dose of 25 mg per day. The dose was gradually increased over 2 weeks to 200 mg per day.
desipramine: 200 mg per day
Placebo: placebo | 24 |
| Total | 88 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 2 | 0 |
| Overall Study | Lost to Follow-up | 3 | 3 | 2 | 3 |
| Overall Study | Moved | 0 | 1 | 0 | 0 |
| Overall Study | No Transportation | 2 | 0 | 0 | 0 |
| Overall Study | Poor Compliance | 0 | 0 | 2 | 0 |
| Overall Study | Time Constraint | 2 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Paroxetine and Naltrexone | Paroxetine and Placebo | Desipramine and Naltrexone | Desipramine and Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 45.14 years STANDARD_DEVIATION 6.71 | 49.15 years STANDARD_DEVIATION 8.95 | 47.05 years STANDARD_DEVIATION 9.96 | 47.04 years STANDARD_DEVIATION 9.72 | 47.1 years STANDARD_DEVIATION 8.9 |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 4 Participants | 3 Participants | 8 Participants |
| Sex: Female, Male Male | 22 Participants | 19 Participants | 18 Participants | 21 Participants | 80 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 22 | 1 / 20 | 2 / 22 | 2 / 24 |
| serious Total, serious adverse events | 1 / 22 | 2 / 20 | 0 / 22 | 0 / 24 |
Outcome results
Primary
Clinician-Administered PTSD Scale (CAPS)
The CAPS is the gold standard in PTSD assessment. The CAPS-5 is a 30-item structured interview that can be used to: Make current (past month) diagnosis of PTSD Make lifetime diagnosis of PTSD Assess PTSD symptoms over the past week Clinician-Administered PTSD Scale for DSM-5 (CAPS-5). A higher score is associated with higher severity of PTSD. The score is interpreted as follows: 0-19=Asymptomatic/few symptoms 20-39=Sub-threshold/mild PTSD 40-59=Threshold PTSD/moderate 60-79=Severe PTSD \>80=Extreme PTSD
Time frame: beginning of treatment (week 1), and end of treatment (13 weeks)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Paroxetine and Naltrexone | Clinician-Administered PTSD Scale (CAPS) | Beginning of Treatment | 73.54 units on a scale | Standard Error 5.007 |
| Paroxetine and Naltrexone | Clinician-Administered PTSD Scale (CAPS) | End of Treatment | 40.024 units on a scale | Standard Error 5.53 |
| Paroxetine and Placebo | Clinician-Administered PTSD Scale (CAPS) | End of Treatment | 36.591 units on a scale | Standard Error 5.57 |
| Paroxetine and Placebo | Clinician-Administered PTSD Scale (CAPS) | Beginning of Treatment | 69.810 units on a scale | Standard Error 5.166 |
| Desipramine and Naltrexone | Clinician-Administered PTSD Scale (CAPS) | Beginning of Treatment | 62.500 units on a scale | Standard Error 5.047 |
| Desipramine and Naltrexone | Clinician-Administered PTSD Scale (CAPS) | End of Treatment | 26.751 units on a scale | Standard Error 5.353 |
| Desipramine and Placebo | Clinician-Administered PTSD Scale (CAPS) | Beginning of Treatment | 77.833 units on a scale | Standard Error 4.832 |
| Desipramine and Placebo | Clinician-Administered PTSD Scale (CAPS) | End of Treatment | 41.392 units on a scale | Standard Error 4.949 |
p-value: 0Mixed Models Analysis
Primary
Hamilton Depression Rating Scale (HAM-D)
The HAM-D ranges from 0 (Normal) to \>23 (Very Severe Depression)
Time frame: beginning of treatment (week 1), and end of treatment (13 weeks)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Paroxetine and Naltrexone | Hamilton Depression Rating Scale (HAM-D) | Beginning of Treatment | 13.273 units on a scale | Standard Error 1.112 |
| Paroxetine and Naltrexone | Hamilton Depression Rating Scale (HAM-D) | End of Treatment | 9.328 units on a scale | Standard Error 1.256 |
| Paroxetine and Placebo | Hamilton Depression Rating Scale (HAM-D) | End of Treatment | 8.238 units on a scale | Standard Error 1.299 |
| Paroxetine and Placebo | Hamilton Depression Rating Scale (HAM-D) | Beginning of Treatment | 10.950 units on a scale | Standard Error 1.167 |
| Desipramine and Naltrexone | Hamilton Depression Rating Scale (HAM-D) | Beginning of Treatment | 11.195 units on a scale | Standard Error 1.132 |
| Desipramine and Naltrexone | Hamilton Depression Rating Scale (HAM-D) | End of Treatment | 8.563 units on a scale | Standard Error 1.201 |
| Desipramine and Placebo | Hamilton Depression Rating Scale (HAM-D) | Beginning of Treatment | 13.167 units on a scale | Standard Error 1.065 |
| Desipramine and Placebo | Hamilton Depression Rating Scale (HAM-D) | End of Treatment | 8.943 units on a scale | Standard Error 1.117 |
Primary
Mean Number of Side Effects
Differences in mean number of side effects reported for each group. Side effects and common adverse symptoms were evaluated by the research staff weekly, using a modified version of the ystematic Assessment for Treatment Emergent Events. The symptoms that are known to be associated with treatment with desipramine, paroxetine, and naltrexone were specifically screened or on a weekly basis. The symptoms were then clustered into the following categories: gastrointestinal, emotional, cold and flu symptoms, skin, sexual, neurological, and cardiac.
Time frame: 12 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Paroxetine and Naltrexone | Mean Number of Side Effects | Gastrointestinal symptoms | 3.651 side effects | Standard Error 0.487 |
| Paroxetine and Naltrexone | Mean Number of Side Effects | Sexual Symptoms | .877 side effects | Standard Error 0.241 |
| Paroxetine and Naltrexone | Mean Number of Side Effects | Skin Symptoms | 1.002 side effects | Standard Error 0.24 |
| Paroxetine and Naltrexone | Mean Number of Side Effects | Emotional Symptoms | 4.874 side effects | Standard Error 0.686 |
| Paroxetine and Naltrexone | Mean Number of Side Effects | Cardiac Symptoms | .416 side effects | Standard Error 0.093 |
| Paroxetine and Naltrexone | Mean Number of Side Effects | Neurological Symptoms | 6.212 side effects | Standard Error 1.058 |
| Paroxetine and Naltrexone | Mean Number of Side Effects | Cold Symptoms | 2.182 side effects | Standard Error 0.49 |
| Paroxetine and Placebo | Mean Number of Side Effects | Sexual Symptoms | .932 side effects | Standard Error 0.252 |
| Paroxetine and Placebo | Mean Number of Side Effects | Cold Symptoms | 2.393 side effects | Standard Error 0.512 |
| Paroxetine and Placebo | Mean Number of Side Effects | Neurological Symptoms | 5.078 side effects | Standard Error 1.106 |
| Paroxetine and Placebo | Mean Number of Side Effects | Skin Symptoms | .859 side effects | Standard Error 0.252 |
| Paroxetine and Placebo | Mean Number of Side Effects | Cardiac Symptoms | .474 side effects | Standard Error 0.101 |
| Paroxetine and Placebo | Mean Number of Side Effects | Emotional Symptoms | 3.963 side effects | Standard Error 0.719 |
| Paroxetine and Placebo | Mean Number of Side Effects | Gastrointestinal symptoms | 2.688 side effects | Standard Error 0.513 |
| Desipramine and Naltrexone | Mean Number of Side Effects | Cold Symptoms | 1.891 side effects | Standard Error 0.483 |
| Desipramine and Naltrexone | Mean Number of Side Effects | Gastrointestinal symptoms | 3.052 side effects | Standard Error 0.475 |
| Desipramine and Naltrexone | Mean Number of Side Effects | Emotional Symptoms | 3.727 side effects | Standard Error 0.689 |
| Desipramine and Naltrexone | Mean Number of Side Effects | Neurological Symptoms | 4.201 side effects | Standard Error 1.047 |
| Desipramine and Naltrexone | Mean Number of Side Effects | Skin Symptoms | .591 side effects | Standard Error 0.236 |
| Desipramine and Naltrexone | Mean Number of Side Effects | Sexual Symptoms | .737 side effects | Standard Error 0.238 |
| Desipramine and Naltrexone | Mean Number of Side Effects | Cardiac Symptoms | .389 side effects | Standard Error 0.089 |
| Desipramine and Placebo | Mean Number of Side Effects | Neurological Symptoms | 4.566 side effects | Standard Error 0.97 |
| Desipramine and Placebo | Mean Number of Side Effects | Cardiac Symptoms | .356 side effects | Standard Error 0.076 |
| Desipramine and Placebo | Mean Number of Side Effects | Sexual Symptoms | .736 side effects | Standard Error 0.219 |
| Desipramine and Placebo | Mean Number of Side Effects | Emotional Symptoms | 5.248 side effects | Standard Error 0.629 |
| Desipramine and Placebo | Mean Number of Side Effects | Gastrointestinal symptoms | 3.653 side effects | Standard Error 0.431 |
| Desipramine and Placebo | Mean Number of Side Effects | Skin Symptoms | 1.057 side effects | Standard Error 0.215 |
| Desipramine and Placebo | Mean Number of Side Effects | Cold Symptoms | 2.253 side effects | Standard Error 0.447 |
Comparison: Gastrointestinal symptoms comparedp-value: 0.007ANOVA
Primary
Mean Self-report Weekly Craving Via Obsessive Compulsive Drinking Scale (OCDS)
The OCDS is a 14-item (rated 0-4), self-administered questionnaire for characterizing and quantifying the obsessive and compulsive cognitive aspects of craving and heavy (alcoholic) drinking, such as drinking-related thought, urges to drink, and the ability to resist those thoughts and urges. A higher total score indicates higher craving and ranges from 0-48.
Time frame: beginning of treatment (week 1), and end of treatment (13 weeks)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Paroxetine and Naltrexone | Mean Self-report Weekly Craving Via Obsessive Compulsive Drinking Scale (OCDS) | Week 1 | 21.273 units on a scale | Standard Error 2.547 |
| Paroxetine and Naltrexone | Mean Self-report Weekly Craving Via Obsessive Compulsive Drinking Scale (OCDS) | Week 13 | 10.013 units on a scale | Standard Error 3.009 |
| Paroxetine and Placebo | Mean Self-report Weekly Craving Via Obsessive Compulsive Drinking Scale (OCDS) | Week 13 | 9.690 units on a scale | Standard Error 3.025 |
| Paroxetine and Placebo | Mean Self-report Weekly Craving Via Obsessive Compulsive Drinking Scale (OCDS) | Week 1 | 20.700 units on a scale | Standard Error 2.672 |
| Desipramine and Naltrexone | Mean Self-report Weekly Craving Via Obsessive Compulsive Drinking Scale (OCDS) | Week 1 | 18.500 units on a scale | Standard Error 2.547 |
| Desipramine and Naltrexone | Mean Self-report Weekly Craving Via Obsessive Compulsive Drinking Scale (OCDS) | Week 13 | 4.296 units on a scale | Standard Error 2.847 |
| Desipramine and Placebo | Mean Self-report Weekly Craving Via Obsessive Compulsive Drinking Scale (OCDS) | Week 1 | 21.458 units on a scale | Standard Error 2.439 |
| Desipramine and Placebo | Mean Self-report Weekly Craving Via Obsessive Compulsive Drinking Scale (OCDS) | Week 13 | 7.489 units on a scale | Standard Error 2.483 |