The subjects for this study were participants (n=88) who met current DSM-IV criteria for PTSD and AD (see ). The participants were middle aged (mean age=47.1, SD=8.9), predominately Caucasian (75%), and male (90.1%), and the majority were either separated or divorced (59.1% please see ). There were no differences in age, sex, ethnicity, or marital status, based on treatment assignment in this sample. However, there were site differences on the basis of ethnicity (χ12=8.3, p=0.015), with 62% (n=26/42) Caucasians of the sample in West Haven in comparison with 87% (n=40/46) of the sample in Bedford. The sample consisted primarily of veterans (81/88 or 92%) and some non-veterans (7/88 or 8%). Participants were not on any psychiatric medications before starting study, with the exception of sleep medications that were taken as needed (n=6).
Demographic and Drinking Characteristics of the Sample
For the drinking baseline variables, data was collected for 90 days. Comparisons were made for each drinking variable (number of drinking days, drinks per drinking days, heavy drinking days, and % heavy drinking days) over each 30-day period (three times). As there were no differences in the overall drinking patterns over the three separate months before randomization, data is presented for the 30-day period before enrollment in the study. The participants in this study were heavy drinkers who drank on average 23.5 (SD=19.3) standard drinks on a drinking day, drank on average 19.9 (SD=9.9) days in a month, with more than half of their drinking days (mean=18.16, SD=10.7) in the past 30 days being heavy drinking days (five or more standard drinks). As shown in , there were no significant differences between the treatment groups at baseline in drinking days, drinks per drinking days, heavy drinking days, percent heavy drinking days, GGT levels, or ADS scores. However, there were site differences based on ADS scores (F1,84=4.44, p=0.038); participants in West Haven had lower ADS scores (mean=19.52, SD=1.32) than participants in Bedford (mean=23.41, SD=1.29).
Medication Dosing and Treatment Retention
Antidepressant medication was increased using a taper for all participants according to the predetermined schedule outlined earlier to a maximum dose of 200
mg for desipramine and 40
mg for paroxetine. Participants who could not tolerate the highest dose in either condition were brought to lower doses. In the group taking desipramine, 74% were tapered to the maximum dose of 200
mg, whereas in the group taking paroxetine, 79% were tapered to the maximum dose of 40
mg, indicating that the majority of the participants were able to tolerate the medications. The average maintenance dose for subjects that were on medication for at least 4 weeks was 187.2 (SD=31.7) for desipramine and 39.7 (SD=1.4) for paroxetine.
In this sample of individuals, 49/88 or 55.7% completed the entire trial. There were significantly more completers in the desipramine group (n=30/46, 65%) than in the paroxetine group (n=19/42, 45% χ12=3.551, p=.05). Subjects in the desipramine group also took medication longer (mean=61.41 days, SD=31.2) than those in the paroxetine group (mean=45.48 days, SD=34.6; F1,84=4.99, p=0.02), and desipramine significantly increased the duration (days in the study) of study retention (χ12=3.7, p=0.053; please see ).
Survival curve of treatment retention comparing desipramine with paroxetine.
Naltrexone did not significantly influence the rate of study completion (χ12=.414, p=.52) and did not significantly increase the duration of study retention (naltrexone: 49.89±35.3 SD; placebo: 57.73 ±31.92; χ12=0.01, p=0.916). There were no significant differences among the treatment groups, based on rates of study retention (χ12=0.84, p=0.36).
PTSD Symptom Outcomes
The CAPS data were analyzed using change from baseline CAPS scores in the model to control for baseline symptoms of PTSD (please see ). There was a significant decrease in CAPS scores over time (F6108.8=2.175, p=0.051) and no significant interactions of treatment with time (desipramine/paroxetine by time F6108.8=1.249, p=0.287; naltrexone/placebo by time F6108.8=0.813, p=0.562), and no significant three-way interaction (please see ). Similarly, there was a significant decrease in each of the three CAPS subscale scores over time, but after Bonferonni adjustment was applied to the analysis (α=0.016), no treatment effects or interactions were significant.
PTSD and Depression Outcome Scores at Beginning and End of Treatment
Post-traumatic stress disorder (PTSD) symptoms measured using total clinician administered PTSD scale for DSM-IV (CAPS) scores over the entire 12 weeks of treatment for four treatment conditions.
Alcohol Use Outcomes
Relative to paroxetine, desipramine significantly reduced the percentage of heavy drinking days (F1.84=7.22, p=0.009) and drinks per drinking days (F1.84=5.04, p=0.027). Participants significantly reduced their weekly alcohol consumption during the study (time: ATS6.82=4.3, p=0.0001), and 51% of participants remained abstinent throughout the study. Also, after adjusting for multiple comparisons, there was a significant interaction for time by desipramine/paroxetine treatment on the number of drinks per week (ATS6.82=2.46, p=0.018; please see ), indicating that the desipramine-treated subjects had a greater reduction in their drinking over time compared with the paroxetine-treated subjects.
Number of standard drinks per week during pre-treatment (4 weeks) and during active treatment (12 weeks) for the four treatment conditions.
There were no significant effects of naltrexone on any of the drinking outcomes, including average number of drinks per week, percentage of heavy drinking days, and drinks per drinking days.
OCDS total scores decreased significantly over time (F12104.8
=0.0001). Naltrexone, relative to placebo, significantly decreased craving (F1582.0
=0.012; naltrexone=19.88 (SD=12.89) at baseline, placebo=21.1 (SD=12.89) at baseline, compared with naltrexone=6.7 (SD=14.07) at endpoint, placebo=8.3 (SD=13.38) at endpoint). There were no significant differences in craving between the desipramine vs
paroxetine-treated subjects (desipramine=20.0 (SD=12.61) at baseline, paroxetine=21.0 (SD=13.19) at baseline, compared with desipramine=6.1 (SD=13.09) at endpoint, and paroxetine=9.4 (SD=14.45) at endpoint) and no significant two-way or three-way interactions. OCDS (obsessions and compulsions) subscale scores decreased significantly over time. After Bonferonni adjustment was applied to the analysis (α
=0.025), no treatment effects or interactions were significant.
GGT levels declined over time in the entire sample (F3121.8=3.3, p=0.022). This reduction was significantly greater in the desipramine-treated participants (F1229.5=5.08, p=0.02; desipramine baseline=55.2, paroxetine baseline=86.4; desipramine week 4=48.7, paroxetine week 4=46.1; desipramine week 8=41.7, paroxetine week 8=47.1; desipramine week 12=37.5, paroxetine week 12=57.1). Naltrexone did not significantly affect GGT levels.
Depression Symptom Outcomes
There was a significant decrease in the 17-item Hamilton Depression scores over time (F7405.6=8.57, p=0.0001) and no significant interactions of treatment with time (desipramine/paroxetine by time F7418.2=0.834, p=0.970; naltrexone/placebo by time F7418.1=0.152, p=0.994), and no significant three-way interaction (please see ).
There were five medical adverse events in this study; one in the desipramine+naltrexone group, two in the desipramine+placebo group, one in paroxetine+naltrexone group, and one in the paroxetine+placebo group. One study participant died in a work-related fatality that occurred 4 weeks after study medications were discontinued, and was deemed to be unrelated to the study. Among participants receiving desipramine, two reported dizziness or lightheadedness, one participant treated with this medication-developed tachycardia. These cases were managed by careful clinical monitoring and, in some cases, adjusting their desipramine dose. One participant in the paroxetine+placebo group experienced a seizure and study medication was discontinued.
There were four psychiatric adverse events in this study. Two participants were incarcerated related to alcohol intoxication (desipramine+placebo; paroxetine+naltrexone). One participant was hospitalized for severe anxiety (paroxetine+placebo). One participant (paroxetine+placebo) reported suicidal ideation 9 weeks after study medication was discontinued, which was deemed to be unrelated to study medication.
Desipramine-treated participants reported significantly more gastrointestinal symptoms (abdominal pain, nausea, vomiting, loss of appetite, constipation, diarrhea, aftertaste, dry mouth, coughing up blood, vomiting blood, black/bloody/light stool, yellow eyes, weight gain, and increased thirst) than paroxetine-treated subjects (F1.84=7.67, p=0.007). After adjustment for multiple comparisons (α=0.007), there were no other statistically significant differences in side effect reporting across the groups.