Comparing TADS subjects who did not participate in SOFTAD and the four SOFTAD participants excluded from the present study because of prior AUD or SUD, to the current study participants, we found that participants and non-participants did not differ on percentages randomized to the four TADS treatment conditions (X2 (3, N = 439) = 1.70, p = 0.64). The percent of current study participants who had been randomized to each short-term treatment condition was COMB=25%, FLX=24%, CBT= 28%, and PBO= 23%.
includes comparisons of participants and non-participants on variables related to our hypotheses and on demographic and clinical variables at TADS baseline. There were no differences in percentage of TADS treatment responders (53.6% versus 51.0%, X2 (1, N = 439) = 0.30, p = 0.58), or percentages of symptom count responders (47% versus 44.5%, X2 (1, N = 439) = 0.24, p = 0.62). The only significant demographic differences were that study participants were somewhat younger than non-participants (M = 14. 3, SD = 1.5 versus M= 14.8, SD = 1.6, F (1, 437) = 9.22, p = .0025) and included a smaller percentage of minority adolescents (21.4% versus 30.0%, X2(1, N = 439) = 4.14, p = .04). The significant baseline clinical differences were that study participants were more likely than non-participants to have entered TADS during their initial episode of MDD (90.5% versus 82.5%; X2(1, N = 429) = 5.59, p = .02) and had fewer total comorbid disorders (Median = 0 versus 1; z = −2.51, p = .012). Participants' involvement with alcohol or drugs at baseline was also significantly lower than that of non-participants (PESQ Problem Severity M = 21.2, SD = 6.0 versus M = 23.0, SD = 7.7; F(1, 422) = 6.81, p = .009).
Rates of Subsequent AUD and SUD
Of the 192 participants, 49 (25.5%) developed an AUD or SUD during the 60 months following short-term depression treatment. As shown in , 37 (19.3%) developed an AUD and 34 (17.7%) developed an SUD. These rates are not significantly different from each other (McNemar test p = 0.70). Twenty-two adolescents (11.5%) developed both disorders. The mean onset age of AUD was 18.0 years (SD = 1.7) and for SUD, 17.4 years (SD = 1.7). As indicated in , one-third of those with initial SUD-only went on to develop AUD as well, whereas none of those with initial AUD-only proceeded to also develop SUD during the follow-up period. Perhaps related to the slightly older age of onset of AUD compared to SUD in this sample, initial diagnoses of AUD were about equally likely to be made in K-SADS interviews with only the adolescent (20 of 37 or 54.0%) or with the adolescent and a parent (17 of 37 or 45.9%), whereas initial diagnoses of SUD were more likely to be made in K-SADS interviews with the adolescent and a parent (22 of 34 or 64.7%) than in interviews with the adolescent alone (12 of 34 or 35.3%). Those who developed AUD did not differ from those who did not, on their average month of initial SOFTAD assessment (t(190) = 1.35, p = .178). Similarly, those who developed SUD did not differ from those who did not, on this measure (t(190) = 1.15, p = .251).
Onset of AUD and/or SUD in 192 Adolescents Over Five Years Following Treatment for MDD
Among the illicit drugs of abuse, marijuana was the most prevalent drug of abuse, accounting for 26 of the 34 SUD diagnoses. Cocaine, opiates, hallucinogens, other drugs or polydrug use accounted for the other diagnoses. As a verification of diagnoses, the median peak score for participants with an AUD on past month drinking frequency was 6–9 times versus a median of 1-2 times for those without AUD (z = 4.64, p < .0001). The median peak score for those with an SUD on past month drug use frequency was 10–19 times per month versus a median of no use for those without SUD (z = 5.35, p < .0001).
Treatment Response Analysis
Using logistic regression analysis, we tested whether response to short-term depression treatment reduced the probability of developing either AUD or SUD, using both the TADS response and the symptom count response measures. For AUD, the hypothesis was not confirmed using either definition of response. Among 103 TADS treatment responders, 18 (17.5%) developed AUD; among 89 non-responders, 19 (21.4%) developed AUD (X2(1, N = 192) = .46, OR = 1.28 [0.62–2.63], p = .498). Among 90 symptom count responders, 17 (18.9%) developed AUD; among 102 non-symptom count responders, 20 (19.6%) developed AUD (X2(1, N = 192) = .02, OR = 1.05 [0.51–2.15], p = .899).
We explored whether randomized treatment assignment, or response to a specific treatment reduced the probability of developing AUD. Across the four randomized treatment arms, rates of subsequent AUD were 20.8% (COMB), 14.9% (FLX), 20.8% (CBT), and 20.5% (PBO) (X2(3, N = 192) = 0.76, p = .86). Neither this overall comparison, nor a post-hoc comparison of FLX (which had the lowest rate) to the other three treatments indicated significant differences between treatments in reducing the probability of developing AUD. For the comparison of FLX to other treatments, the percentages developing subsequent AUD were 14.9% and 20.7%, respectively (X2(1, N = 192) = 0.76, p = .384). An exploratory logistic regression analysis including treatment assignment, treatment response and the interactions of treatment assignment and treatment response as predictors of AUD was not significant, regardless of whether the more global TADS measure of response, or the more restrictive symptom count response was used in the analysis. For the full model using the TADS response measure, X2 (7, N = 192) = 2.92, p = .892). With the symptom count response measure, X2 (7, N = 192) = 3.065, p = .879).
For SUD, the hypothesis was confirmed: response to MDD treatment reduced the probability of subsequent SUD. This finding occurred with both measures of response. Twelve of 103 TADS treatment responders (11.6%) developed an SUD versus 22 of 89 non-responders (24.7%) (X2(1, N = 192) = 5.38, OR = 2.49 [1.15–5.38], p = .02). Nine of 90 symptom count responders (10%) versus 25 of 102 non-symptom count responders (24.5%) developed an SUD (X2(1, N = 192) = 6.52, OR = 2.92 [1.28–6.66], p = .011).
Exploratory analyses showed no significant differences in rates of subsequent SUD across the four TADS treatment conditions, with SUD rates of 14.6% (COMB), 17.0% (FLX), 20.8% (CBT), and 18.2% (PBO) (X2(3, N = 192) = 0.68, p = .88). Neither this overall comparison, nor a post-hoc comparison of COMB (which had the lowest rate) to the other three treatments indicated significant differences between treatments in reducing the probability of developing SUD. For the comparison of COMB to other treatments, the percentages developing subsequent SUD were 14.6% and 18.8.7%, respectively (X2(1, N = 192) = 0.43, p = .514). When the four assigned treatments, treatment response, and the interactions between assigned treatments and response were entered into exploratory logistic regression analyses, the predictive models showed trends toward statistical significance, using either measure of response (with TADS response, X2(7, N = 192) = 12.11, p = .097); with symptom count response, X2(7, N = 192) = 12.23, p = .093). However, since neither model attained statistical significance, further analyses were not warranted.
Baseline Predictors Analysis
To evaluate the effects of MDD treatment on AUD and SUD in the context of possible significant baseline predictors, we next tested whether TADS baseline demographic and clinical variables predicted subsequent AUD or SUD. Because of skewed distributions, index episode duration, and number of comorbid disorders were natural log transformed. Results are depicted in .
Individual Logistic Regression Analyses: TADS Baseline Predictors of Subsequent Alcohol or Substance Use Disorder
For subsequent AUD, older age (X2 (1, N = 192) = 8.81, OR = 1.49 [1.14–1.93], p = .003) and higher alcohol or drug involvement (X2(1, N = 185) = 11.93, OR = 1.11 [1.05–1.18], p < .001) were significant individual predictors. Those who developed AUD averaged 15.0 years of age at baseline (SD = 1.4 years), versus 14.1 years (SD = 1.5 years) for other participants. Adolescents who developed AUD had mean baseline PESQ scores of 24.8 (SD = 8.2), whereas those who did not averaged 20.3 (SD = 4.9).
There was a trend for males to have lower risk for subsequent AUD than females. Among 84 males, 11 (13.1%) developed AUD whereas 26 of 108 females (24.1%) did so (X2(1, N = 192) = 3.56, OR = 0.48 [0.22–1.03], p = .059). There was also a trend for youths with longer episodes of MDD prior to TADS treatment to be more likely to develop later AUD (X2(1, N = 192) = 3.05, OR = 1.37 [0.96–1.95], p = .081).
When baseline PESQ score, MDD episode duration, age, and gender were entered into a stepwise model, older age (X2(1, N = 185) = 5.13, OR = 1.37 [1.04–1.81], p = 0.024) and higher PESQ score (X2(1, N = 185) = 9.16, OR = 1.10 [1.03–1.16], p = 0.002) were retained as significant predictors of subsequent AUD. No further multivariable model was tested because MDD treatment response had not proven to be a significant predictor.
For subsequent SUD, significant individual baseline predictors included the total number of comorbid disorders (X2 (1, N = 192) = 5.78, OR = 2.39 [1.17–4.85], p = .016) and the PESQ Problem Severity score (X2(1, N = 185) = 7.13, OR = 1.08 [1.02–1.14], p = 0.008). Depressed adolescents who later developed SUD had a mean of 1.1 comorbid disorders, (SD= 1.3), compared to a mean of 0.6 comorbid disorders (SD = 0.9) for those who did not. They also had higher PESQ scores at baseline (M = 24.1, SD = 8.4) than other adolescents (M = 20.6, SD = 5.2).
When these two predictors were entered into a stepwise multivariable model, both were retained as significant predictors (PESQ, X2(1, N = 185) = 7.25, OR = 1.08 [1.02–1.14], p = .007; number of comorbid disorders (X2(1, N = 185) = 4.17, OR = 2.23 [1.03–4.79], p = .04).
We then tested whether poor treatment response predicted subsequent SUD when the two significant baseline predictors were included in overall models, using the two definitions of treatment response. Results indicated that it did. With TADS treatment response in the final model, all three predictors were significant (TADS treatment response, X2(1, N = 185) = 3.84, OR [.999–5.28], p = .050; PESQ, X2(1, N = 185) = 6.48, OR = 1.07 [1.02–1.14], p = .011; Number of comorbid disorders, X2(1, N = 185) = 4.12, OR = 2.23 [1.03–4.86], p = .042). Similarly, with symptom count response in the model, all three predictors remained significant (Symptom count response, X2(1, N = 185) = 4.65, OR = 2.61 [1.09–6.24, p = .031; PESQ, X2(1, N = 185) = 6.95, OR = 1.07 [1.02–1.14, p = .008; Number of comorbid disorders, X2(1, N = 185) = 4.28, OR = 2.29 [1.04–5.02], p = .038). Characteristics of adolescents who developed AUD, SUD or neither are described in .
Characteristics of Adolescents Who Developed AUD, SUD, or Neither, Following Treatment for MDD
MDD Course Analysis
The course of MDD for study participants through the end of SOFTAD was as follows: 98 (51.0%) recovered from their index episode with no recurrence; 87 (45.3%) recovered but had at least one recurrence; and 7 (3.7%) experienced chronic MDD. AUD was diagnosed in 10 of the 98 recovery cases (10.2%), in 25 of the 87 recovery and recurrence cases (28.7%), and in 2 of the 7 persistent depression cases (28.6%). Comparing the 98 recovery cases to the 94 cases with either chronic or recurrent MDD, a logistic regression indicated that depression recovery was negatively associated with onset of AUD (X2(1, N = 192) = 9.8, OR = 0.28 [0.13–0.62], p = 0.002).
SUD was diagnosed in 13 of the 98 recovery cases (13.3%), in 19 of the 87 recovery and recurrence cases (21.8%), and in 2 of the 7 chronic depression cases (28.6%). Logistic regression indicated a trend for the depression recovery group to have fewer cases of SUD onset (X2(1, N = 192) = 2.77, OR = 0.53 [0.24–1.14], p = 0.103).
Lastly, we explored the timing of MDD recurrence in relation to AUD or SUD onset. Among the 87 participants with recurrent MDD, 62 (71.3%) did not develop AUD, one (1.1%) had MDD recurrence before AUD onset, and 24 (27.6%) had MDD recurrence after AUD onset. In this latter group the onset of first MDD recurrence was, on average, 22.7 months (SD = 11.8) after the AUD onset. A similar pattern was observed for MDD recurrence and SUD: 68 participants with recurrent MDD (78.2%) did not develop SUD, two (2.3%) had MDD recurrence before SUD onset, and 17 (19.5%) had MDD recurrence after SUD onset. Onset of the first recurrence was, on average, 19 months (SD = 9.9) after SUD onset.