A longitudinal study of insomnia and other sleep complaints in adolescents with and without alcohol use disorders.

BACKGROUND: Sleep disturbances are both common and well-characterized in adults with alcohol use disorders (AUDs), but have received little study in adolescents with AUDs. Furthermore, a handful of studies suggest that sleep complaints are a risk factor for AUDs. However, no published studies have yet examined the longitudinal course of sleep complaints in adolescents with AUDs; in particular, it remains unclear how persistent AUD-associated sleep complaints are in this age group, and what types of sleep complaints are most relevant to alcohol-use symptoms. We investigated these questions in a 5-year longitudinal study of adolescents with and without AUDs at baseline. METHODS: Participants were 696 adolescents (age 12 to 19) from a longitudinal study at the Pittsburgh Adolescent Alcohol Research Center. At baseline, 347 participants had a current AUD (AUD+), while 349 had no current or past AUD (AUD-). We examined sleep and alcohol involvement at baseline as well as 1-, 3-, and 5-year follow-up visits. Sleep variables included self-reported insomnia and hypersomnia, as well as variability in weekday-weekend sleep duration, all at baseline. Covariates included sex, age, current alcohol symptoms, and depression severity. RESULTS: The AUD+ group reported more overall sleep disturbance at baseline, including greater insomnia and hypersomnia complaints, and greater variability in weekday-weekend sleep duration. Group differences in insomnia and hypersomnia complaints persisted to the 5- and 3-year follow-ups, respectively. In the AUD- group, greater insomnia complaints at baseline predicted an increase in alcohol symptoms at the 1-year follow-up, while greater variability in sleep duration at baseline predicted an increase in alcohol symptoms at the 3- and 5-year follow-ups. CONCLUSIONS: These results complement previous findings in other samples, indicating that insomnia and other sleep problems are a chronic predicament for adolescents with AUDs. The findings also suggest that sleep disturbances may place adolescents without AUDs at an elevated risk of developing alcohol problems.

Mirtazapine in Comorbid Major Depression and Alcohol Use Disorder: A Long-Term Follow-Up Study.

BACKGROUND/OBJECTIVE: To date, pharmacotherapy trials of depressed alcoholics (MDD/AUD) have focused on SSRI medications, with disappointing results, so effective treatments for that comorbid population are lacking. Mirtazapine is an FDA-approved medication for treating MDD with a unique pharmacological profile whose efficacy may exceed that of SSRIs. Results from our recent open label study suggest robust acute phase efficacy for mirtazapine for decreasing both the depression and the drinking of that population. However, to date, no studies have evaluated the longer-term efficacy of mirtazapine in that population. We now report findings from a first long-term (two-year) naturalistic follow-up evaluation involving subjects from the acute phase trial. We hypothesized that the improvements would persist at follow-up. METHODS: An eight-week open label study of mirtazapine and motivation therapy was conducted involving persons 18 to 55 years of age with DSM-IV diagnoses of comorbid MDD/AD. Two years after entry into the acute phase study, a long-term evaluation was conducted using the same instruments that had been used at baseline to assess whether the improvements seen during the acute phase trial had persisted. RESULTS: Ten of the twelve patients who entered the acute phase study participated in the follow-up study. The large magnitude improvements (p<.01) in depressive symptoms (BDI), drinking (TLFB), and sleep disturbance (HDRS) persisted at the follow-up evaluation. Two of the subjects demonstrated MDD on structured interview at follow-up, while all ten had demonstrated MDD at baseline. Six of the ten used antidepressants during the follow-up period. At baseline, three were employed, while at follow-up seven were employed. CONCLUSIONS: These findings suggest long-term efficacy for mirtazapine for decreasing the drinking and depression of depressed alcoholics. Double-blind, placebo-controlled studies are warranted to clarify the efficacy of mirtazapine in depressed alcoholics.

Mirtazapine in Comorbid Major Depression and Alcohol Dependence: An Open-Label Trial.

OBJECTIVE: This was a first pilot study evaluating the acute phase (8-week) efficacy of the antidepressant medication mirtazapine for the treatment of depressive symptoms and drinking of subjects with comorbid major depressive disorder and alcohol dependence (MDD/AD). We hypothesized that mirtazapine would demonstrate within-group efficacy for the treatment of both depressive symptoms and drinking in these subjects. METHODS: We conducted a first open label study of the second generation antidepressant mirtazapine in 12 adult outpatient subjects with comorbid major depressive disorder/alcohol dependence. The pharmacological profile of that medication is unique among antidepressants, unrelated to tricyclics or selective serotonin reuptake inhibitors. RESULTS: Mirtazapine was well tolerated in this treatment population. Self-reported depressive symptoms decreased from 31.8 to 8.3 on the Beck Depression Inventory, a 74.0% decrease (p<0.001), and drinking decreased from 33.9 to 13.3 drinks per week, a 60.8% decrease (p<0.05). None of the subjects were employed full-time at baseline, but 9 of the 12 (75%) were employed full-time at end-of-study. CONCLUSIONS: These preliminary findings suggest efficacy for mirtazapine for treating both the depressive symptoms and excessive alcohol use of comorbid major depressive disorder and alcohol dependence. Double-blind studies are warranted to further clarify the efficacy of mirtazapine in this population.

Double-blind fluoxetine trial in comorbid MDD-CUD youth and young adults.

OBJECTIVE: This study compared the acute phase (12-week) efficacy of fluoxetine versus placebo for the treatment of the depressive symptoms and the cannabis use of adolescents and young adults with comorbid major depression (MDD) and a cannabis use disorder (CUD) (cannabis dependence or cannabis abuse). We hypothesized that fluoxetine would demonstrate efficacy versus placebo for the treatment of the depressive symptoms and the cannabis use of adolescents and young adults with comorbid MDD/CUD. METHODS: We conducted the first double-blind placebo-controlled study of fluoxetine in adolescents and young adults with comorbid MDD/CUD. All participants in both treatment groups also received manual-based cognitive behavioral therapy (CBT) and motivation enhancement therapy (MET) during the 12-week course of the study. RESULTS: Fluoxetine was well tolerated in this treatment population. No significant group-by-time interactions were noted for any depression-related or cannabis-use related outcome variable over the 12-week study. Subjects in both the fluoxetine group and the placebo group showed significant within-group improvement in depressive symptoms and in number of DSM diagnostic criteria for a CUD. Large magnitude decreases in depressive symptoms were noted in both treatment groups, and end-of-study levels of depressive symptoms were low in both treatment groups. CONCLUSIONS: Fluoxetine did not demonstrate greater efficacy than placebo for treating either the depressive symptoms or the cannabis-related symptoms of our study sample of comorbid adolescents and young adults. The lack of a significant between-group difference in these symptoms may reflect limited medication efficacy, or may result from efficacy of the CBT/MET psychotherapy or from limited sample size.

Double-blind placebo-controlled trial of fluoxetine in adolescents with comorbid major depression and an alcohol use disorder.

OBJECTIVE: This study compared the acute phase (12-week) efficacy of fluoxetine versus placebo for the treatment of the depressive symptoms and the drinking of adolescents with comorbid major depression (MDD) and an alcohol use disorder (AUD). We hypothesized that fluoxetine would demonstrate efficacy versus placebo for the treatment of both the depressive symptoms and the drinking of comorbid MDD/AUD adolescents. METHODS: We conducted the first double-blind placebo-controlled study of fluoxetine in adolescents with comorbid MDD/AUD. All participants in both treatment groups also received intensive manual-based Cognitive Behavioral Therapy (CBT) and Motivation Enhancement Therapy (MET). RESULTS: Fluoxetine was well tolerated in this treatment population. No significant group-by-time interactions were noted for any depression-related or drinking-related outcome variable. Subjects in both the fluoxetine group and the placebo group showed significant within-group improvement in both depressive symptoms and level of alcohol consumption. End-of-study levels of depression and drinking were low in both treatment groups. CONCLUSIONS: The lack of a significant between-group difference in depressive symptoms and in drinking may reflect limited medication efficacy, or may result from limited sample size or from efficacy of the CBT/MET psychotherapy. Large multi-site studies are warranted to further clarify the efficacy of SSRI medications in this adolescent MDD/AUD population.

Cannabis withdrawal is common among treatment-seeking adolescents with cannabis dependence and major depression, and is associated with rapid relapse to dependence.

Recently, reports have suggested that cannabis withdrawal occurs commonly in adults with cannabis dependence, though it is unclear whether this extends to those with comorbid depression or to comorbid adolescents. We hypothesized that cannabis withdrawal would be common among our sample of comorbid adolescents and young adults, and that the presence of cannabis withdrawal symptoms would be associated with a self-reported past history of rapid reinstatement of cannabis dependence symptoms (rapid relapse). The participants in this study included 170 adolescents and young adults, including 104 with cannabis dependence, 32 with cannabis abuse, and 34 with cannabis use without dependence or abuse. All of these subjects demonstrated current depressive symptoms and cannabis use, and most demonstrated current DSM-IV major depressive disorder and current comorbid cannabis dependence. These subjects had presented for treatment for either of two double-blind, placebo-controlled trials involving fluoxetine. Cannabis withdrawal was the most commonly reported cannabis dependence criterion among the 104 subjects in our sample with cannabis dependence, being noted in 92% of subjects, using a two-symptom cutoff for determination of cannabis withdrawal. The most common withdrawal symptoms among those with cannabis dependence were craving (82%), irritability (76%), restlessness (58%), anxiety (55%), and depression (52%). Cannabis withdrawal symptoms (in the N=170 sample) were reported to have been associated with rapid reinstatement of cannabis dependence symptoms (rapid relapse). These findings suggest that cannabis withdrawal should be included as a diagnosis in the upcoming DSM-V, and should be listed in the upcoming criteria list for the DSM-V diagnostic category of cannabis dependence.

Substance use disorder trajectory classes: diachronic integration of onset age, severity, and course.

BACKGROUND: Substance use disorders (SUDs) may be characterized by onset age, severity, substance type, course, and outcomes. SUD phenotypes in the literature typically consider each of these features in isolation. Conceptual frameworks and data collection procedures for assessing SUD phenotypes are increasingly "diachronic" in approach, providing for characterizations "throughout time". The recent availability of statistical procedures for the identification of latent classes offers the possibility of developing SUD phenotypes integrating these developmental features. This article illustrates the utilization of SAS-TRAJ mixture modeling to characterize variations in SUD symptom trajectories to define phenotypes. METHODS: The subjects were 332 adult males with SUDs. Their course of symptoms from early adolescence through middle adulthood was retrospectively determined. Symptom trajectories were defined by the number of DSM-IV SUD symptoms by year of age. SAS-TRAJ mixture models identified trajectory classes. Model development, evaluation, and selection using this approach are discussed. RESULTS: Among these men with SUDs, six trajectory classes were identified, including groups characterized by early-onset and severe SUD symptoms persisting into adulthood, an early-onset group similar in adolescence but improving in adulthood, and other groups with symptoms emerging later with varying degrees of severity and persistence. The SUD trajectory classes were significantly different on comorbid psychopathology, particularly childhood disruptive behavior disorders. CONCLUSION: The results present a new method for the comprehensive depiction of heterogeneity in SUD symptoms. Future studies may determine the extent to which SUDs phenotypes based on the course of symptom development inform etiology, prevention and treatment research.

Fluoxetine for the treatment of childhood anxiety disorders: open-label, long-term extension to a controlled trial.

OBJECTIVE: To assess the efficacy of fluoxetine for the long-term treatment of children and adolescents with anxiety disorders, including generalized anxiety disorder, separation anxiety disorder, and/or social phobia. METHOD: Children and adolescents (7-17 years old) with anxiety disorders were studied in open treatment for 1 year after they completed a randomized, controlled trial (RCT) comparing fluoxetine and placebo. The follow-up phase assessments included clinician, parent, and child ratings with measures of global severity, global improvement, and anxiety symptoms. RESULTS: Subjects taking fluoxetine (n = 42) were compared with those taking no medication (n = 10) during follow-up on anxiety changes from the end of the RCT through the follow-up period. Statistical models included RCT assignment and follow-up psychological treatment. Excluded subjects took other medications (n = 4) or did not complete follow-up (n = 18). Compared with subjects taking no medication, subjects taking fluoxetine showed significantly superior follow-up outcomes on most measures, including clinician, parent, and child ratings. CONCLUSIONS: The results suggest that fluoxetine is clinically effective for the maintenance treatment of anxiety disorders in children and adolescents. A major limitation, however, was the lack of RCT methodology in the follow-up phase. RCTs are needed to determine the long-term risks and benefits of fluoxetine for this group.

Clinical predictors of treatment in a population of adolescents with alcohol use disorders.

The purpose of this paper is to identify potential predictors of treatment utilization, among both psychiatric and drug and alcohol variables. The subjects were 393 adolescents and young adults, age 12.9 to 18.11 years, who met DSM-IV criteria for a lifetime history of either alcohol abuse or alcohol dependence at baseline assessment. DSM-IV psychiatric and AUD diagnoses were obtained by semi-structure interviews (K-SADS and SCID). Other alcohol and drug variables were obtained by the Alcohol Consumption Questionnaire and other self-reports. The results of these analyses suggest that there are few potential predictors associated with substance use disorder (SUD) treatment. For mental health (MH) treatment, depression in the form of Major Depressive Disorder was relatively strong associated at baseline and follow-up, while Attention Deficit Hyperactivity Disorder and Conduct Disorder appear to be associated with MH treatment at follow-up. For SUD treatments, there are essentially no variables strongly associated with treatment. The best potential predictors of who enters treatment and how long they stay may not be related to comorbidity or other dimensional variables of clinical severity. Rather, treatment utilization appears to be related to environmental factors, which may include family factors, adolescent and parental motivation, access to treatment, or to the use of appropriate treatment modalities.

Fluoxetine in adolescents with comorbid major depression and an alcohol use disorder: a 3-year follow-up study.

The goal of this 3-year follow-up evaluation was to determine whether the decreases in drinking and in depressive symptoms that were noted during our acute phase study with fluoxetine in comorbid adolescents persisted at a 3-year follow-up evaluation. At the 3-year follow-up evaluation, the group continued to demonstrate significantly fewer DSM criteria for an AUD and fewer BDI depressive symptoms and also consumed fewer standard drinks than they had demonstrated at the baseline of the acute phase study. However, 7 of the 10 participants demonstrated MDD at the 3-year follow-up assessment, and 4 demonstrated an AUD. The presence of a MDD was significantly correlated with the presence of an AUD at both the 1-year and the 3-year follow-up assessments. Four of the participants restarted SSRI medications during the follow-up period. Half of the subjects graduated from college during the 3-year assessment period, despite their residual depressive symptoms and drinking. We conclude that the long-term therapeutic effects of an acute phase trial of fluoxetine plus psychotherapy slowly decrease but did not disappear when fluoxetine is discontinued shortly after the acute phase trial. The high rate of MDD at follow-up suggests that longer term antidepressant medication treatment may be needed for at least some comorbid adolescents.

Multidimensional assessment of nicotine dependence in adolescents.

Despite the critical importance of adolescent smoking, the assessment of nicotine dependence during this developmental period has been the subject of relatively little research. In this study, 301 adolescents (ages 12 through 18 years) reporting daily smoking were recruited for a project on alcohol use disorders (AUDs). The sample included 140 females and 161 males, 251 subjects from clinical and 50 from community sources, and 176 subjects with AUDs at the baseline assessment. Subjects were evaluated with the Nicotine Dependence Syndrome Scale (NDSS), the Fagerstrom Test for Nicotine Dependence (FTND) and a determination of average number of cigarettes per day (cigarettes/day). A varimax factor analysis of 27 NDSS items revealed four factors: (1) Drive/Tolerance (13 items; Cronbach alpha = 0.91); (2) Continuity (five items; Cronbach alpha = 0.67); (3) Priority (three items; Cronbach alpha = 0.64); (4) Stereotypy (five items; Cronbach alpha = 0.66). The NDSS total score, refined by the removal of four items, was also examined (23 items; Cronbach alpha = 0.90). Predicting cigarettes/day at follow-up, initial smoking rate was the best predictor, with the FTND and NDSS Total score showing significant and similar predictive validity. The NDSS Total showed incremental validity in the prediction of smoking progression in a model including demographic characteristics, initial smoking rate and FTND. The findings suggest that the NDSS has acceptable psychometric properties when applied to adolescents, complementing smoking rate and FTND in a multidimensional smoking assessment.

Major depression associated with earlier alcohol relapse in treated teens with AUD.

This study evaluated whether the common comorbid diagnosis of major depressive disorder (MDD) is associated with an earlier relapse to alcohol use among adolescents with an alcohol use disorder (AUD). The study sample consisted of 116 adolescents between the ages of 14 and 18 with an AUD recruited from treatment facilities in the Pittsburgh area, 50 of whom demonstrated a current MDD. An extensive baseline interview was conducted, followed by monthly interviews of alcohol use conducted by telephone for the following year. Those with current comorbid MDD demonstrated a median survival time of only 19 days until the first drink, while those without MDD demonstrated a median survival time of 45 days, which was a significant difference (Kaplan-Meier survival analysis, Breslow Test Statistic=4.27, df=1, P=.039). These results suggest that the comorbid presence of MDD is associated with an earlier relapse to alcohol use among adolescents with an AUD.

Fluoxetine in depressed AUD adolescents: a 1-year follow-up evaluation.

The authors conducted the first naturalistic 1-year follow-up evaluation of 10 adolescents with comorbid major depressive disorder and an alcohol use disorder (AUD) who had previously participated in an acute phase study of open-label fluoxetine plus psychotherapy (Cornelius et al. 2001). The goal of this follow-up evaluation was to determine whether the decreases in drinking and in depressive symptoms that were noted during the acute phase study persisted at the follow-up evaluation. At the 1-year follow-up evaluation, the group continued to demonstrate significantly fewer depressive symptoms (according to the 24-item Hamilton Rating Scale for Depression) and a lower frequency of drinking (drinking days in the last 30 days) than they had demonstrated at the baseline of the acute phase study. Surprisingly, all of the subjects had chosen to discontinue their antidepressant medication by the second month of their naturalistic follow-up period. Three subjects had experienced a relapse of their major depression during the follow-up period, and three others demonstrated a persistence of their original depressive episode throughout the follow-up period. Also, the number of drinks per drinking day continued to be high (about five per day), which was not significantly different from the baseline level. Thus, the long-term therapeutic effects of an acute phase trial of fluoxetine plus psychotherapy were limited. The high rate of recurrence or persistence of major depression in our sample and in a previous sample of nonalcoholic adolescents with major depression (Emslie et al. 1998) and the significant levels of drinking of our comorbid adolescents suggest that longer term treatment may be needed for at least some adolescents with major depressive disorder and alcohol use disorder.

Psychopathology risk transmission in children of parents with substance use disorders.

OBJECTIVE: Children of fathers with substance use disorders are at increased risk for psychopathology, including conduct disorder, attention deficit hyperactivity disorder (ADHD), major depressive disorder, and anxiety disorders. This study examined the distinct influences of parent substance use disorder and other psychopathology in the transmission of the risk for psychopathology to their children. METHOD: The subjects were 1,167 children (ages 6-14 years; 62% were male, 38% were female) from 613 families recruited according to a high-risk paradigm. Of these families, 294 had fathers with a substance use disorder (high-risk group), and 319 had fathers without a substance use disorder or other mental disorder (low-risk group). In all families, father, mother, and children were directly assessed. Mixed-effects ordinal regression analyses controlled for the nested data structure. RESULTS: For conduct disorder, ADHD, major depression, and anxiety disorders, the results indicated that the predominant predictor of specific mental disorders in offspring was a history of the corresponding disorders in both parents. CONCLUSIONS: These results support specific parent-child transmission for childhood psychopathology.

Clinical practices in the pharmacological treatment of comorbid psychopathology in adolescents with alcohol use disorders.

This study examined the use of psychiatric medications in 277 adolescents in treatment for alcohol use disorders. Subjects were recruited from addictions treatment sites, psychiatric programs, and juvenile justice settings. Characteristics studied included the use of and indications for specific medications, changes in clinical practices from 1991 through 2000, and continuation of psychopharmacological treatment over a 1-year followup period. Among adolescents taking psychiatric medications at baseline (n = 51), indicated DSM-IV mental disorders were typically present, use of antidepressants was most common (n = 41), benzodiazepine prescription was rare, and about one third reported continuing pharmacological treatment at one-year followup. In those with comorbid major depressive disorder and alcohol use disorders (n = 110), antidepressant medication use increased significantly from 18% to 55% over the decade studied. The treatment setting did not significantly influence antidepressant prescribing practices. The common and increasing use of psychiatric medications in this population emphasizes the urgent need for empirically based clinical guidelines.