Depressive and Anxiety Symptoms Predict Obsessive and Compulsive Cravings among Depressed Alcoholics.

Objectives: Alcohol craving is often associated with mood symptoms and predicts alcohol use in individuals with alcohol dependence. However, little is known about the impact of mood symptoms on alcohol craving in comorbid mood disorders and alcohol dependence. This study examines the predictive value of depressive and anxiety symptoms for obsessive and compulsive aspects of alcohol craving in adults with comorbid Major Depressive Disorder (MDD) and Alcohol Dependence. Methods: Fifty-five adults (47% female; mean age of 39.35 (SD=8.80)) with DSM-IV diagnoses of comorbid MDD and alcohol dependence were prospectively assessed over a six-month period. They completed the Hamilton Rating Scales for Depression and Anxiety, the Alcohol Timeline Followback, the Obsessive Compulsive Drinking Scale (OCDS), the Alcohol Dependence Scale (ADS), and the Addiction Severity Index (ASI). The linear mixed model analyses for repeated measures was used to test weather depressive and anxiety symptoms predict OCDS subscale scores. Results: Depressive and anxiety symptoms were strongly associated with obsessive and compulsive subscales of the OCDS. Baseline ASI-alcohol scores were associated with both the obsessive and compulsive and with the obsessive subscale scores in the predictive model including depressive symptoms, and that including anxiety symptoms respectively. Conclusions: Results suggest that depressive and anxiety symptoms predict obsessive and compulsive aspects of alcohol craving in adults with comorbid MDD and alcohol dependence. Assessing the severity of depressive and anxiety symptoms and alcohol use in this population may identify those more likely to experience intense alcohol craving states and at increased risk of relapse.

Drug use and hazardous drinking are associated with PTSD symptoms and symptom clusters in US Army Reserve/National Guard Soldiers.

BACKGROUND AND OBJECTIVES: There is strong evidence of the association between Posttraumatic Stress Disorder (PTSD) symptoms and substance use. Previous work has found sex differences in these associations. With revisions to the DSM, it is important to understand how overall PTSD symptoms and the new symptom clusters relate to substance use among Reserve/Guard soldiers-a high risk group. METHODS: Data are from the baseline assessment of Operation: SAFETY (Soldiers and Families Excelling Through the Years), a longitudinal study of US Army Reserve/National Guard (USAR/NG) soldiers (N = 389 males, N = 84 females). We examined associations between current substance use (drug use, hazardous drinking, and smoking) and overall PTSD symptoms, and symptom clusters. Additionally, we examined PTSD by sex interactions. RESULTS: Greater overall PTSD symptoms were associated with higher odds of drug use (OR = 1.08; 95%CI: 1.05, 1.12) and hazardous drinking (OR = 1.04; 95%CI: 1.02, 1.07). Greater individual symptom cluster scores were associated with higher odds of drug use (ps < .001) and hazardous drinking (ps < .01). Interaction models revealed no differences in these associations on the basis sex (ps > .05). There were no associations between PTSD symptoms or symptom clusters on smoking (ps > .05). DISCUSSION AND CONCLUSION: Soldiers experiencing PTSD symptoms are reporting current drug and hazardous alcohol use, suggestive of self-medication. SCIENTIFIC SIGNIFICANCE: It is imperative to consider the impact of PTSD on substance use broadly, as this work shows that overall symptoms and symptom clusters have an impact on male and female USAR/NG soldiers. (Am J Addict 2019;28:22-28).

Greater Prevalence of Proposed ICD-11 Alcohol and Cannabis Dependence Compared to ICD-10, DSM-IV, and DSM-5 in Treated Adolescents.

BACKGROUND: Proposed International Classification of Diseases, 11th edition (ICD-11), criteria for substance use disorder (SUD) radically simplify the algorithm used to diagnose substance dependence. Major differences in case identification across DSM and ICD impact determinations of treatment need and conceptualizations of substance dependence. This study compared the draft algorithm for ICD-11 SUD against DSM-IV, DSM-5, and ICD-10, for alcohol and cannabis. METHODS: Adolescents (n = 339, ages 14 to 18) admitted to intensive outpatient addictions treatment completed, as part of a research study, a Structured Clinical Interview for DSM SUDs adapted for use with adolescents and which has been used to assess DSM and ICD SUD diagnoses. Analyses examined prevalence across classification systems, diagnostic concordance, and sources of diagnostic disagreement. RESULTS: Prevalence of any past-year proposed ICD-11 alcohol or cannabis use disorder was significantly lower compared to DSM-IV and DSM-5 (ps < 0.01). However, prevalence of proposed ICD-11 alcohol and cannabis dependence diagnoses was significantly higher compared to DSM-IV, DSM-5, and ICD-10 (ps < 0.01). ICD-11 and DSM-5 SUD diagnoses showed only moderate concordance. For both alcohol and cannabis, youth typically met criteria for an ICD-11 dependence diagnosis by reporting tolerance and much time spent using or recovering from the substance, rather than symptoms indicating impaired control over use. CONCLUSIONS: The proposed ICD-11 dependence algorithm appears to "overdiagnose" dependence on alcohol and cannabis relative to DSM-IV and ICD-10 dependence, and DSM-5 moderate/severe use disorder, generating potential "false-positive" cases of dependence. Among youth who met criteria for proposed ICD-11 dependence, few reported impaired control over substance use, highlighting ongoing issues in the conceptualization and diagnosis of SUD.

Motivation deficits and use of alcohol and illicit drugs among individuals with schizophrenia.

This study examined the impact of substance use on intrinsic motivation and evaluated the association between intrinsic motivation and substance use recovery among individuals with schizophrenia. Alcohol and illicit drug use and intrinsic motivation were evaluated at baseline and 6-months for 1434 individuals with schizophrenia from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) using self-rated substance use assessments and a derived motivation measure from the Heinrichs-Carpenter Quality of Life Scale. Results revealed patients had moderate motivation deficits overall and a considerable number were using alcohol or illicit drugs at baseline (n=576; 40.2%). Regression models at baseline showed patients with low levels of motivation had higher odds of substance use and those who were using substances had greater motivation deficits. At 6-months, substance using patients continued to demonstrate greater motivation deficits; however, those with high levels of motivation exhibited a greater reduction in their use of substances. Findings remained significant after adjusting for clinical confounds and were consistent across any substance, alcohol, and cannabis use. Our results emphasize concerns about substance use compounding motivation deficits in schizophrenia, and suggest that disentangling the motivation-substance use relationship in schizophrenia may facilitate efforts aimed at ameliorating these challenges and improving outcomes.

Differential Impact of Depressive and Manic Mood States on Alcohol Craving in Comorbid Bipolar Alcoholism: Preliminary Findings.

OBJECTIVES: To examine the differential impact of depressive and manic mood states on alcohol craving in patients with bipolar disorder and comorbid alcoholism. METHODS: Forty-four men and women, ages 18-65, with DSM-IV-TR comorbid diagnoses of bipolar I disorder and alcohol dependence were assessed over a three-month period to examine the extent to which their depressive and manic symptoms were associated with alcohol cravings (i.e., desire to use and not to use alcohol) at each assessment point, controlling for age, ethnicity, socio-economic status, baseline alcohol use, and number of assessments. RESULTS: Both manic and depressive symptoms were associated with greater desire to use alcohol. Only depressive symptomatology was associated with reduced desire not to use alcohol, and desire not to use alcohol declined over the course of the three-month treatment period. CONCLUSION: Whereas enhanced desire to drink alcohol may be a conditioned reaction to both manic and depressed mood states, desire not to drink alcohol may be more of an indicator of treatment motivation, which is negatively affected by depressed mood. Depressive symptoms may warrant prioritization and aggressive targeting early in treatment given that desire to refrain from alcohol use was only influenced by depressive symptoms and declined over the course of treatment.

Mirtazapine in comorbid major depression and an alcohol use disorder: A double-blind placebo-controlled pilot trial.

This was a first double-blind, placebo-controlled pilot study to evaluate the efficacy of the novel antidepressant medication mirtazapine for treating both the depressive symptoms and the level of alcohol consumption of subjects with comorbid major depressive disorder and an alcohol use disorder (MDD/AUD). The results of two previous studies of mirtazapine in MDD/AUD subjects had suggested efficacy for mirtazapine for decreasing their level of depressive symptoms, but level of alcohol consumption had not been assessed in those studies. All subjects in this 12-week pilot study were randomized to either mirtazapine or placebo, and also received motivational enhancement therapy. Between-group analyses involving the outcome measures of depressive symptoms, level of alcohol consumption, and level of alcohol craving indicated no significant differences between groups, possibly because of limited sample size. However, within-group t tests in the mirtazapine group showed a significant decrease in depressive symptoms by week 2, also noted at all subsequent assessments (weeks 3, 4, 6, 8, 10, and 12) during the 12-week study. In contrast, no significant decrease in depressive symptoms was noted in the placebo group until week 8. No evidence of efficacy was found for mirtazapine for decreasing level of alcohol consumption in MDD /AUD subjects.

Developmental pathways from prenatal marijuana exposure to Cannabis Use Disorder in young adulthood.

BACKGROUND: Earlier studies reported an association between prenatal marijuana exposure (PME) and cognitive and behavioral problems in the offspring. A recent publication demonstrated the relation between PME and offspring marijuana use at age 22. There are no reports of the association between PME and Cannabis Use Disorder (CUD) at 22years, the age when use of marijuana and CUD peak. METHODS: Subjects are from the Maternal Health Practices and Child Development Study, a longitudinal study of PME and other exposures during pregnancy. The cohort of mothers and their offspring has been followed since the fourth prenatal month through 22years of age. A path analysis was conducted on 590 mother-child pairs, representing 77% of the birth cohort, to examine potential pathways from PME to CUD in offspring at 22years of age. RESULTS: There is no direct effect of PME on CUD. There are, however, two indirect pathways from PME to CUD. In the first, the pathway from PME to CUD goes through offspring early age of marijuana onset. In the second, offspring depression at age 10 and early age of marijuana onset predict CUD. CONCLUSIONS: Although there is no direct effect of PME on CUD, there are significant indirect pathways from PME to CUD that affect the rate of CUD in the population. Thus, PME, offspring depression, and an early age of marijuana initiation, are significant points for intervention. As marijuana is legalized in more states, the rates of marijuana use will increase significantly, including during pregnancy, and the consequences of the association between PME and CUD will become even more significant from a public health perspective.

Patterns of Substance Use During Cognitive Enhancement Therapy: An 18-Month Randomized Feasibility Study.

OBJECTIVE: Substance use problems are common among people with schizophrenia, as are significant cognitive impairments. Because of potential shared neurobiological pathways, it is possible that cognitive remediation interventions may be associated with improvements in both substance use and cognition. This study examined the impact of cognitive remediation on alcohol and cannabis use and the cognitive correlates of changes in substance use among outpatients with schizophrenia. METHODS: Individuals with schizophrenia who were receiving outpatient services at a psychiatric clinic and had moderate or higher addiction severity scores (N = 31) were randomized to 18 months of cognitive enhancement therapy (n = 22) or usual care (n = 9). Cognitive enhancement therapy is a cognitive remediation approach that integrates computer-based training in attention, memory, and problem solving with a group-based social cognition curriculum. Usual care was provided to all participants and consisted of routine psychiatric care. Primary outcomes included days of alcohol and cannabis use, assessed with the Timeline Followback method every six months and modeled using penalized quasi-likelihood growth curves. RESULTS: Participants were on average 38.23 (SD = 13.44) years of age, had been ill for 14.19 (SD = 11.28) years, and were mostly male (n = 22, 71%), and about half were Caucasian (n = 16, 52%). Temporal patterns of substance use days were highly variable and followed nonlinear trajectories. Intent-to-treat analyses indicated that, compared to patients only receiving usual care, those receiving cognitive enhancement therapy were significantly less likely to use alcohol (OR = .22; 95% CI: .05, .90; p = .036), but not cannabis (OR = 1.89; 95% CI: .02, 142.99; p = .774) over time, and they reduced their alcohol use at significantly accelerated rates (OR = 1.02; 95% CI: 1.01, 1.03; p = .003). Changes in cognition were variably associated with substance use outcomes, although improvements in visual learning and reasoning and problem solving were both consistently related to reduced alcohol and cannabis use. CONCLUSIONS: Cognitive remediation may be effective for improving some substance use problems in schizophrenia. Visual learning and problem-solving deficits may be particularly important targets of such interventions, given their association with reduced alcohol and cannabis use. This study is registered at clinicaltrials.gov under #NCT01292577.

Does the Transmissible Liability Index (TLI) assessed in late childhood predict suicidal symptoms at young adulthood?

OBJECTIVE: Our previous work demonstrated that the Transmissible Liability Index (TLI), an instrument designed as an index of liability for substance use disorder (SUD), is associated with risk of substance use disorder. This longitudinal study assessed whether TLI measured in 10-12-year-olds (late childhood) predicts suicidal behavior from age 12-14 (preadolescence) to age 25 (young adulthood). We hypothesized that TLI would predict number and severity of suicide attempts. METHODS: Subjects were sons of men who had lifetime history of SUD (n = 250), called the High Average Risk (HAR) group, and sons of men with no lifetime history of a SUD (n = 250), called the Low Average Risk (LAR) group. The TLI was delineated at baseline (age 10-12), and age-specific versions were administered at 12-14, 16, 19, 22, and 25 years of age. RESULTS: TLI was significantly associated with number and severity of lifetime suicide attempts. CONCLUSIONS: These findings confirm the hypothesis that TLI assessed at late childhood is a predictor of frequency and severity of suicidal behavior from preadolescence to young adulthood.

Telehealth Monitoring of Patients with Schizophrenia and Suicidal Ideation.

A telehealth system was developed to monitor risk following hospitalization for suicidal ideation. We hypothesized that 3 months of telehealth monitoring will result in a greater reduction in suicidal ideation. Veterans with schizophrenia admitted with recent suicidal ideation and/or a suicidal attempt were recruited into a discharge program of VA Usual Care with daily Health Buddy© monitoring (HB) or Usual Care (UC) alone. Fifteen of 25 were randomized to HB and 10 received UC. Daily adherence in the use of the HB system during months 1-3 was, respectively, 86.9%, 86.3%, and 84.1%. There were significant improvements in Beck Scale for Suicide Ideation scores in HB participants. There were no changes in depressive symptoms. Telehealth monitoring for this population of patients appears to be feasible.

Prenatal marijuana exposure predicts marijuana use in young adulthood.

BACKGROUND: Studies have reported effects of prenatal marijuana exposure (PME) on cognitive and behavioral outcomes. An earlier publication from this study found that PME predicted early onset of marijuana use and frequency of marijuana use at age 14. No study has reported the effects of PME on marijuana use in young adulthood. This is a developmental period when substance use peaks, and by which, initiation of substance use has largely occurred. METHODS: Subjects were from a longitudinal cohort. Women were interviewed initially in their fourth prenatal month and women and their offspring were followed through 22 years. Significant covariates of offspring marijuana use at 22 years were identified and controlled for using ordinal logistic regression. RESULTS: PME predicted marijuana use in the offspring at 22 years after controlling for significant covariates. Prenatal alcohol exposure, offspring race, gender, and age were also significant predictors, but family history of substance abuse or disorder, and sociodemographic and psychological characteristics of the mother and offspring were not. This association was not moderated by gender or race. CONCLUSIONS: PME is associated with subsequent marijuana use in young adulthood after considering the effects of other significant factors. These findings have important implications for public health given the recent trend toward legitimization of marijuana use.

Cognitive Enhancement Therapy Improves Frontolimbic Regulation of Emotion in Alcohol and/or Cannabis Misusing Schizophrenia: A Preliminary Study.

Individuals with schizophrenia who misuse substances are burdened with impairments in emotion regulation. Cognitive enhancement therapy (CET) may address these problems by enhancing prefrontal brain function. A small sample of outpatients with schizophrenia and alcohol and/or cannabis substance use problems participating in an 18-month randomized trial of CET (n = 10) or usual care (n = 4) completed posttreatment functional neuroimaging using an emotion regulation task. General linear models explored CET effects on brain activity in emotional neurocircuitry. Individuals treated with CET had significantly greater activation in broad regions of the prefrontal cortex, limbic, and striatal systems implicated in emotion regulation compared to usual care. Differential activation favoring CET in prefrontal regions and the insula mediated behavioral improvements in emotional processing. Our data lend preliminary support of CET effects on neuroplasticity in frontolimbic and striatal circuitries, which mediate emotion regulation in people with schizophrenia and comorbid substance misuse problems.

Cognitive Enhancement Therapy in substance misusing schizophrenia: results of an 18-month feasibility trial.

Substance use is a frequent problem in schizophrenia, and although many substance misusing patients with the disorder also experience considerable cognitive impairments, such individuals have been routinely excluded from clinical trials of cognitive remediation that could support their functional and addiction recoveries. This study conducted a small-scale feasibility trial of Cognitive Enhancement Therapy (CET) in substance misusing schizophrenia patients to assess the feasibility and efficacy of implementing comprehensive neurocognitive and social-cognitive remediation in this population. A total of 31 schizophrenia outpatients meeting addiction severity criteria for alcohol and/or cannabis use were randomized to 18months of CET or usual care. Feasibility findings indicated high degrees of satisfaction with CET, but also presented significant challenges in the recruitment and retention of substance misusing patients, with high levels of attrition (50%) over the study period, primarily due to positive symptom exacerbation. Intent-to-treat efficacy analyses showed large and significant improvements in neurocognition (d=.86), social cognition (d=1.13), and social adjustment (d=.92) favoring CET. Further, individuals treated with CET were more likely to reduce alcohol use (67% in CET vs. 25% in usual care) during treatment (p=.021). These results suggest that once engaged and stabilized, CET is a feasible and potentially effective treatment for cognitive impairments in patients with schizophrenia who misuse alcohol and/or cannabis. Substance misusing patients who are able to engage in treatment may be able to benefit from cognitive remediation, and the treatment of cognitive impairments may help improve substance use outcomes among this underserved population.

Serotonin Transporter Genotype Linked to Adolescent Substance Use Treatment Outcome through Externalizing Behavior.

Meta-analyses suggest that the serotonin transporter linked polymorphic region (5-HTTLPR) short (S) allele, relative to the long (L) allele, is associated with risk for alcohol dependence, particularly among individuals with early onset antisocial alcoholism. Youth in substance use treatment tend to show antisocial or externalizing behaviors, such as conduct problems, which predict worse treatment outcome. This study examined a pathway in which 5-HTTLPR genotype is associated with externalizing behavior, and the intermediate phenotype of externalizing behavior serves as a link between 5-HTTLPR genotype and substance use treatment outcome in youth. Adolescents (n = 142) who were recruited from addictions treatment were genotyped for 5-HTTLPR polymorphisms (S and LG carriers vs. LALA), assessed for externalizing and internalizing behaviors shortly after starting treatment, and followed over 6-months. 5-HTTLPR genotype was not associated with internalizing behaviors, and was not directly associated with 6-month substance use outcomes. However, 5-HTTLPR genotype was associated with externalizing behaviors (S and LG > LALA), and externalizing behaviors predicted alcohol and marijuana problem severity at 6-month follow-up. Results indicated an indirect (p < 0.05) and non-specific (i.e., both alcohol and marijuana severity) effect of 5-HTTLPR genotype on youth substance use treatment outcomes, with externalizing behaviors as an important linking factor. Adolescents in substance use treatment with low expressing (S and LG) 5-HTTLPR alleles and externalizing behavior might benefit from intervention that addresses serotonergic functioning, externalizing behaviors, and substance use to improve outcomes.

Does stress mediate the development of substance use disorders among youth transitioning to young adulthood?

BACKGROUND: Stress is a well-documented factor in the development of addiction. However, no longitudinal studies to date have assessed the role of stress in mediating the development of substance use disorders (SUD). Our previous results have demonstrated that a measure called Transmissible Liability Index (TLI) assessed during pre-adolescent years serves as a significant predictor of risk for substance use disorder among young adults. However, it remains unclear whether life stress mediates the relationship between TLI and SUD, or whether stress predicts SUD. METHODS: We conducted a longitudinal study involving 191 male subjects to assess whether life stress mediates the relationship between TLI as assessed at age 10-12 and subsequent development of SUD at age 22, after controlling for other relevant factors. RESULTS: Logistic regression demonstrated that the development of SUD at age 22 was associated with stress at age 19. A path analysis demonstrated that stress at age 19 significantly predicted SUD at age 22. However, stress did not mediate the relationship between the TLI assessed at age 10-12 and SUD in young adulthood. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: These findings confirm that stress plays a role in the development of SUD, but also shows that stress does not mediate the development of SUD. Further studies are warranted to clarify the role of stress in the etiology of SUD.

The "S" Allele of the Serotonin Transporter Is Not Associated with Major Depression in a Sample OF Veterans.

The results of some studies suggest that the serotonin transporter-linked polymorphic region (5-HTTLPR) short (S) allele, relative to the long (L) allele, is associated with risk for Major Depressive Disorder (MDD), and thus serves as a biomarker for MDD, while results from other studies do not support that conclusion. Persons with an S allele demonstrate a 2- to 2.5 fold decrease in serotonin transcription rate compared to the L-allele, which may increase their risk for MDD. Differences in study populations may help explain the differences in findings between those meta-analyses. To date, there have been no published reports which have addressed the possible association between the S allele and MDD among military veterans. This manuscript describes a first study to assess the possible association of the S allele with MDD among a study population of veterans in treatment for a substance use disorder. We hypothesized that the S allele would be associated with MDD in our study sample. Subjects signing informed consent were 101 Veterans recruited from VA behavioral health and substance use treatment clinics in the VA Pittsburgh Healthcare System, and 91 of those subjects were genotyped for 5-HTTLPR polymorphisms. The study sample from whom genetic material was collected included 82 males and 9 females, of whom 53 were white, 38 were black, and one was "other". Fifty-four members of the study sample (59%) met DSM-IV criteria for an MDD on the SCID. Forty-five of the subjects demonstrated one or two S alleles, while 46 did not do so. The presence of the S allele of the serotonin transporter was not found to be significantly associated with the diagnosis of major depressive disorder in our sample (Chi-square=0.1.63, df=1, p=0.199). That finding, in combination with other recent negative findings from other researchers involving non-veterans, raises questions regarding the clinical utility of utilizing genetics tests involving the assessment of the alleles of the serotonin transporter as a possible biomarker for MDD.

The "S" Allele of the Serotonin Transporter Is Not Associated with Major Depression or Alcohol Use Disorders in a Veteran Sample.

The results of some studies suggest that the serotonin transporter-linked polymorphic region (5-HTTLPR) short (S) allele, relative to the long (L) allele, is associated with risk for Major Depressive Disorder (MDD) and for Alcohol Use Disorder (AUD), and thus serves as biomarker for those disorders, while results from other studies do not support that conclusion. Persons with an S allele demonstrate a 2- to 2.5 fold decrease in serotonin transcription rate compared to the L-allele, which may increase their risk for MDD. Differences in study populations may help explain the differences in findings between those meta-analyses. To date, there have been no published reports which have addressed the possible association between the S allele and MDD among military veterans. This manuscript describes a first study to assess the possible association of the S allele with MDD or with AUD among a study population of veterans in treatment for a substance use disorder. We hypothesized that the S allele would be associated with MDD in our study sample. Subjects signing informed consent were 101 Veterans recruited from VA behavioral health and substance use treatment clinics in the VA Pittsburgh Healthcare System, and 91 of those subjects were genotyped for 5-HTTLPR polymorphisms. The study sample from whom genetic material was collected included 82 males and 9 females, of whom 53 were white, 38 were black, and one was "other". Fifty-four members of the study sample (59%) met DSM-IV criteria for an MDD on the SCID. Forty-five of the subjects demonstrated one or two S alleles, while 46 did not do so. The presence of the S allele of the serotonin transporter was not found to be significantly associated with the diagnosis of major depressive disorder or with alcohol use disorders in our sample. Those findings, in combination with other recent negative findings from other researchers involving non-veterans, raise questions regarding the clinical utility of utilizing genetics tests involving the assessment of the alleles of the serotonin transporter as a possible biomarker for MDD or for AUD.

Paradoxical Decrease in Striatal Activation on an fMRI Reward Task Following Treatment in Youth with Co-morbid Cannabis Dependence/Major Depression.

Reward behavior, including reward behavior involving drugs, has been shown to be mediated by the ventral striatum and related structures of the reward system. The aim of this study was to assess reward-related activity as shown by fMRI before and after treatment among youth with comorbid cannabis dependence and major depression. We hypothesized that the reward task (Delgado et al., 2003) would elicit activation in the reward system, and that the level of activation in response to reward would increase from the beginning to the end of the 12-week treatment study as levels of depressive symptoms and cannabis use decreased. Six subjects were recruited from a larger treatment study in which all received Cognitive Behavioral Therapy/Motivational Enhancement Therapy (CBT/MET), and also were randomized to receive either fluoxetine or placebo. Each of the six subjects completed an fMRI card- guessing/reward task both before and after the 12-week treatment study. As hypothesized, the expected activation was noted for the reward task in the insula, prefrontal, and striatal areas, both before and after treatment. However, the participants showed lower reward-related activation after treatment relative to pre-treatment, which is opposite of what would be expected in depressed subjects who did not demonstrate a comorbid substance use disorder. These paradoxical findings suggest that the expected increase in activity for reward associated with treatment for depression was overshadowed by a decrease in reward-related activation associated with treatment of pathological cannabis use in these comorbid youth. These findings emphasize the importance of comorbid disorders in fMRI studies.