Results from a randomized, double-blind, placebo-controlled, crossover, multimodal-MRI pilot study of gabapentin for co-occurring bipolar and cannabis use disorders.

Disrupted brain gamma-aminobutyric acid (GABA)/glutamate homeostasis is a promising target for pharmacological intervention in co-occurring bipolar disorder (BD) and cannabis use disorder (CUD). Gabapentin is a safe and well-tolerated medication, FDA-approved to treat other neurological diseases, that restores GABA/glutamate homeostasis, with treatment studies supporting efficacy in treating CUD, as well as anxiety and sleep disorders that are common to both BD and CUD. The present manuscript represents the primary report of a randomized, double-blind, placebo-controlled, crossover (1-week/condition), multimodal-MRI (proton-MR spectroscopy, functional MRI) pilot study of gabapentin (1200 mg/day) in BD + CUD (n = 22). Primary analyses revealed that (1) gabapentin was well tolerated and adherence and retention were high, (2) gabapentin increased dorsal anterior cingulate cortex (dACC) and right basal ganglia (rBG) glutamate levels and (3) gabapentin increased activation to visual cannabis cues in the posterior midcingulate cortex (pMCC, a region involved in response inhibition to rewarding stimuli). Exploratory evaluation of clinical outcomes further found that in participants taking gabapentin versus placebo, (1) elevations of dACC GABA levels were associated with lower manic/mixed and depressive symptoms and (2) elevations of rBG glutamate levels and pMCC activation to cannabis cues were associated with lower cannabis use. Though promising, the findings from this study should be interpreted with caution due to observed randomization order effects on dACC glutamate levels and identification of statistical moderators that differed by randomization order (i.e. cigarette-smoking status on rBG glutamate levels and pMCC cue activation). Nonetheless, they provide the necessary foundation for a more robustly designed (urn-randomized, parallel-group) future study of adjuvant gabapentin for BD + CUD.

A Multimethod Examination of Sensitivity to Reward and Sensitivity to Punishment in Bipolar Disorder and Alcohol Dependence: Results from a 2 × 2 Factorial Design.

INTRODUCTION: Shared neurobehavioral characteristics of bipolar disorder (BD) and alcohol dependence (AD), including heightened sensitivity to reward (SR), may account for high rates of BD and AD co-occurrence (BD + AD). However, empirical research is lacking. The present multimethod investigation examined SR and sensitivity to punishment (SP) among these patient groups using a reliable and well-validated self-report questionnaire of SR and SP along with a laboratory task specifically designed to distinguish SR and SP activation. METHODS: One-hundred participants formed 4 groups: BD + AD (n = 40), BD (n = 18), AD (n = 25), and healthy controls (n = 17). Clinical interviews were administered, and participants completed the Sensitivity to Punishment and Sensitivity to Reward Questionnaire (SPSR-Q) and the Point Score Reaction Test behavioral task. Pearson correlations, hierarchical linear regression, and 2 × 2 factorial general linear modeling with Bonferroni-corrected pairwise comparisons were performed. RESULTS: BD and AD main effects were significant on self-reported SR and SP; however, BD × AD interactions were not. BD + AD individuals were significantly higher on self-reported SR than BD and AD individuals, yet all clinical groups were similar on SP. Behavioral response times did not distinguish groups nor did they associate with self-report data. DISCUSSION/CONCLUSION: BD and AD had additive, rather than interactive, effects on self-reported SR and SP. The methods employed, paired with their application to the present sample, may account for a lack of positive findings with behavioral data.

Identification and initial validation of empirically derived bipolar symptom states from a large longitudinal dataset: an application of hidden Markov modeling to the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study.

BACKGROUND: Although bipolar disorder (BD) is a fundamentally cyclical illness, a divided model of BD that emphasizes polarity over cyclicity has dominated modern psychiatric diagnostic systems since their advent in the 1980s. However, there has been a gradual return to conceptualizations of BD which focus on longitudinal course in the research community due to emerging supportive data. Advances in longitudinal statistical methods promise to further progress the field. METHODS: The current study employed hidden Markov modeling to uncover empirically derived manic and depressive states from longitudinal data [i.e. Young Mania Rating Scale and Montgomery-Asberg Depression Rating Scale responses across five occasions from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study], estimate participants' probabilities of transitioning between these states over time (n = 3918), and evaluate whether clinical variables (e.g. rapid cycling and substance dependence) predict participants' state transitions (n = 3229). RESULTS: Analyses identified three empirically derived mood states ('euthymic,' 'depressed,' and 'mixed'). Relative to the euthymic and depressed states, the mixed state was less commonly experienced, more temporally unstable, and uniquely associated with rapid cycling, substance use, and psychosis. Individuals assigned to the mixed state at baseline were relatively less likely to be diagnosed with BD-II (v. BD-I), more likely to present with a mixed or (hypo)manic episode, and reported experiencing irritable and elevated mood more frequently. CONCLUSIONS: The results from the current study represent an important step in defining, and characterizing the longitudinal course of, empirically derived mood states that can be used to form the foundation of objective, empirical attempts to define meaningful subtypes of affective illness defined by clinical course.

Alcohol Cue Processing in Co-Occurring Bipolar Disorder and Alcohol Use Disorder.

Importance: Reward circuitry dysfunction is a candidate mechanism of co-occurring bipolar disorder and alcohol use disorder (BD + AUD) that remains understudied. This functional magnetic resonance imaging (fMRI) research represents the first evaluation of alcohol cue reward processing in BD + AUD. Objective: To determine how alcohol cue processing in individuals with BD + AUD may be distinct from that of individuals with AUD or BD alone. Design, Setting, and Participants: This cross-sectional case-control study (April 2013-June 2018) followed a 2 × 2 factorial design and included individuals with BD + AUD, AUD alone, BD alone, and healthy controls. A well-validated visual alcohol cue reactivity fMRI paradigm was administered to eligible participants following their demonstration of 1 week or more of abstinence from alcohol and drugs assessed via serial biomarker testing. Study procedures were completed at the Medical University of South Carolina. Analysis took place between June and August 2022. Main Outcomes and Measures: Past-week mood symptoms were rated by clinicians using the Montgomery-Åsberg Depression Rating Scale and Young Mania Rating Scale. The Alcohol Dependence Scale, Obsessive-Compulsive Drinking Scale, and Barratt Impulsiveness Scale were included questionnaires. Functional MRI whole-brain data were analyzed along with percent signal change within a priori regions of interest located in the ventral striatum, dorsal striatum, and ventromedial prefrontal cortex. Exploratory analyses of associations between cue reactivity and select behavioral correlates (alcohol craving, impulsivity, maximum number of alcohol drinks on a single occasion, and days since last alcohol drink) were also performed. Results: Of 112 participants, 28 (25.0%) had BD + AUD, 26 (23.2%) had AUD alone, 31 (27.7%) had BD alone, and 27 (24.1%) were healthy controls. The mean (SD) age was 38.7 (11.6) years, 50 (45.5%) were female, 33 (30%) were smokers, and 37 (34.9%) reported recent alcohol consumption. Whole-brain analyses revealed a BD × AUD interaction (F = 10.64; P = .001; η2 = 0.09) within a cluster spanning portions of the right inferior frontal gyrus and insula. Region of interest analyses revealed a main association of BD (F = 8.02; P = .006; η2 = 0.07) within the dorsal striatum. In each instance, individuals with BD + AUD exhibited reduced activation compared with all other groups who did not significantly differ from one another. These hypoactivations were associated with increased impulsivity and obsessive-compulsive alcohol craving exclusively among individuals with BD + AUD. Conclusion and Relevance: The findings of this study suggest conceptualizing reward dysfunction in BD + AUD by the potential interaction between blunted reward responsivity and deficient inhibitory control may help guide treatment development strategies. To this end, reduced right inferior frontal gyrus and insula alcohol cue reactivity represents a novel candidate biomarker of BD + AUD that may respond to pharmacological interventions targeting impulsivity-related neural mechanisms for improved executive control.

A randomized, double-blind, placebo-controlled clinical trial of acamprosate in alcohol-dependent individuals with bipolar disorder: a preliminary report.

BACKGROUND: Alcohol use disorders commonly co-occur with bipolar disorder and are associated with a more severe course of bipolar illness, yet treatment research in this important clinical population is scarce. The current study assessed the effects of acamprosate on alcohol use and mood symptoms in subjects with co-occurring bipolar disorder and active alcohol dependence. METHODS: Thirty-three adults meeting criteria for bipolar I or bipolar II disorder and current alcohol dependence were randomized to receive add-on acamprosate (1998 mg/day) or placebo while concurrently maintained on mood stabilizing medications. Participants were assessed weekly for frequency and quantity of alcohol consumption and general clinical severity for eight weeks. Depressive symptoms, manic symptoms, and alcohol craving were assessed biweekly. Biomarkers of alcohol use were assessed at study baseline and endpoint. RESULTS: Of the 33 subjects randomized, 23 (69.7%) completed all active phase visits. Over the trial as a whole, no statistically significant treatment differences were detected in drinking outcomes. Post-hoc analysis revealed lower Clinical Global Impression scores of substance use severity in acamprosate-treated participants in weeks 7-8 of the trial. No significant differences in depressive symptoms, manic symptoms, or adverse events were observed between groups. CONCLUSIONS: Acamprosate was well-tolerated, with no worsening of depressive or manic symptoms, and appeared to confer some clinical benefit in study completers in the last two weeks of the trial. Larger studies of longer duration are required to fully explore the utility of acamprosate in this population.

Impact of depressive symptoms on future alcohol use in patients with co-occurring bipolar disorder and alcohol dependence: a prospective analysis in an 8-week randomized controlled trial of acamprosate.

BACKGROUND: Bipolar disorders and alcohol use disorders commonly co-occur, yet little is known about the proximal impact of bipolar symptoms on alcohol use in patients with this comorbidity. The present study examined the impact of depressive symptoms and alcohol craving on proximal alcohol use in patients with co-occurring bipolar disorder and alcohol dependence. METHODS: Data were collected during an 8-week randomized controlled trial of acamprosate for individuals with co-occurring bipolar disorder and alcohol dependence (n = 30). Depressive symptoms and alcohol craving were assessed biweekly using the Montgomery Asberg Depression Rating Scale (MADRS) and the Obsessive Compulsive Drinking Scale (OCDS), respectively. Daily alcohol use data were available via administration of the Time-line Follow-back interview at baseline and at subsequent weekly study visits. Correlational analyses and hidden Markov modeling were used to examine the prospective relationships between depressive symptoms, alcohol craving, and alcohol use. RESULTS: Depressive symptoms and alcohol craving were significantly correlated with proximal (i.e., 1 week later) alcohol use across a variety of alcohol consumption summary measures. In hidden Markov models, depressive symptoms (OR = 1.3, 95% credible interval = [1.1, 1.5]) and alcohol craving (OR = 1.6, 95% credible interval = [1.4, 1.9]) significantly predicted transitioning from a light to a heavy drinking state, or remaining in a heavy drinking state. CONCLUSIONS: The results from the present study suggest that depressive symptoms and alcohol craving increase proximal risk for alcohol use in individuals with co-occurring bipolar and alcohol use disorders.

Does alexithymia explain variation in cue-elicited craving reported by methamphetamine-dependent individuals?

Drug craving is an important motivational phenomenon among addicted individuals, and successful management of craving is essential to both the initiation and maintenance of abstinence. Although craving in response to drug cues is common in drug-dependent individuals, it is not universal. At the present time, it is not known why approximately 20-30% of all addicted persons fail to report appreciable craving in laboratory-based cue reactivity studies. This study examined the possibility that alexithymia, a personality attribute characterized by a difficulty identifying and describing emotions, may contribute to the impoverished cue-elicited craving experienced by some addicts. Specifically, we tested the hypothesis that alexithymia, as measured by the Toronto Alexithymia Scale (TAS), would be inversely related to the magnitude of cue-elicited craving obtained in a cue reactivity protocol. Forty methamphetamine-dependent individuals completed the TAS and provided craving ratings for methamphetamine after presentation of methamphetamine-associated cues. Thirteen participants (32%) reported no methamphetamine cue-elicited craving. Contrary to expectation, TAS factor 1 (a measure of difficulty identifying feelings) scores were positively associated with cue-elicited craving. Thus, the results suggest that increasing difficulty-identifying feelings may be associated with higher cue-elicited craving. Clinical implications for this finding are discussed.

Impaired cognitive performance in subjects with methamphetamine dependence during exposure to neutral versus methamphetamine-related cues.

BACKGROUND: Chronic methamphetamine abuse is associated with cognitive deficits that may impede treatment in methamphetamine-dependent patients. Exposure to methamphetamine-related cues can elicit intense craving in chronic users of the drug, but the effects of exposure to drug cues on cognitive performance in these individuals are unknown. OBJECTIVES: This study assessed whether exposure to methamphetamine-related visual cues can elicit craving and/or alter dual task cognitive performance in 30 methamphetamine-dependent subjects and 30 control subjects in the laboratory. METHODS: Reaction time, response errors, and inhibition errors were assessed on an auditory Go-No Go task performed by adult participants (total N = 60) while watching neutral versus methamphetamine-related video cues. Craving was assessed with the Within-Session Rating Scale modified for methamphetamine-dependent subjects. RESULTS: Exposure to methamphetamine-related cues elicited craving only in methamphetamine-dependent subjects. Even in the absence of methamphetamine cues, methamphetamine-dependent subjects exhibited slower reaction times and higher rates of both inhibition and response errors than control subjects did. Upon exposure to methamphetamine cues, rates of both response errors and inhibition errors increased significantly in methamphetamine-dependent subjects. Control subjects exhibited no increase in inhibition errors and only slightly increased rates of response errors upon exposure to methamphetamine cues. Response error rates, but not inhibition error rates or reaction times, during methamphetamine cue exposure were significantly associated with craving scores in methamphetamine-dependent subjects. CONCLUSIONS AND SIGNIFICANCE: Methamphetamine-dependent individuals exhibit cognitive performance deficits that are more pronounced during exposure to methamphetamine-related cues. Interventions that reduce cue reactivity may have utility in the treatment of methamphetamine dependence.

Comorbid anxiety disorders and baseline medication regimens predict clinical outcomes in individuals with co-occurring bipolar disorder and alcohol dependence: Results of a randomized controlled trial.

Despite the high prevalence and detrimental impact of alcoholism on bipolar patients, the diagnostic and treatment factors associated with better or worse clinical outcomes in alcohol-dependent patients with bipolar disorder are not well understood. The present study investigated the prospective impact of baseline psychiatric comorbidities and treatment regimens on clinical outcomes in bipolar alcoholics. Data were drawn from an 8-week randomized controlled clinical trial of acamprosate for individuals (n=30) with co-occurring bipolar disorder and alcohol dependence. Depressive and manic symptoms, and alcohol craving and consumption were monitored longitudinally using standardized instruments. Path analysis was used to estimate the prospective associations between patient characteristics and outcomes. More than 50% of patients were diagnosed with at least one anxiety (76.7%) or drug dependence disorder (60.0%). Comorbid anxiety disorders were prospectively associated with increased depressive symptoms and alcohol use. Participants were prescribed an average of 2.6 psychotropic medications at baseline. Antipsychotics and anticonvulsants were prospectively associated with increased alcohol use; anticonvulsants and benzodiazepines were associated with increased alcohol craving. Antidepressants were associated with increased depressive symptoms. Conversely, lithium was associated with decreased alcohol craving and depressive symptoms. The findings from the present study suggest areas for future research in this population.

The impact of clinical and demographic variables on cognitive performance in methamphetamine-dependent individuals in rural South Carolina.

Inconsistencies in reports on methamphetamine (METH) associated cognitive dysfunction may be attributed, at least in part, to the diversity of study sample features (eg, clinical and demographic characteristics). The current study assessed cognitive function in a METH-dependent population from rural South Carolina, and the impact of demographic and clinical characteristics on performance. Seventy-one male (28.2%) and female (71.8%) METH-dependent subjects were administered a battery of neurocognitive tests including the Test of Memory Malingering (TOMM), Shipley Institute of Living Scale, Paced Auditory Serial Addition Test (PASAT), Symbol Digit Modalities Test (SDMT), Grooved Pegboard Test, California Verbal Learning Test (CVLT), and Wisconsin Card Sorting Test (WCST). Demographic and clinical characteristics (eg, gender, frequency of METH use) were examined as predictors of performance. Subjects scored significantly lower than expected on one test of attention and one of fine motor function, but performed adequately on all other tests. There were no predictors of performance on attention; however, more frequent METH use was associated with better performance for males and worse for females on fine motor skills. The METH-dependent individuals in this population exhibit very limited cognitive impairment. The marked differences in education, Intellectual Quotient (IQ), and gender in our sample when compared to the published literature may contribute to these findings. Characterization of the impact of clinical and/or demographic features on cognitive deficits could be important in guiding the development of treatment interventions.

Independent predictors for lifetime and recent substance use disorders in patients with rapid-cycling bipolar disorder: focus on anxiety disorders.

We set out to study independent predictor(s) for lifetime and recent substance use disorders (SUDs) in patients with rapid-cycling bipolar disorder (RCBD). Extensive Clinical Interview and Mini-International Neuropsychiatric Interview were used to ascertain DSM-IV Axis I diagnoses of RCBD, anxiety disorders, and SUDs. Data from patients enrolling into four similar clinical trials were used. Where appropriate, univariate analyses with t-test or chi-square were applied. Stepwise logistic regression was used to examine the relationship among predictor variables and lifetime and recent SUDs. Univariate analysis showed that patients with co-occurring anxiety disorders (n = 261) had significantly increased rates of lifetime (odds ratio [OR]= 2.1) and recent (OR = 1.9) alcohol dependence as well as lifetime (OR = 3.4) and recent (OR = 2.5) marijuana dependence compared to those without co-occurring anxiety disorder (n = 303). In logistic regression analyses, generalized anxiety disorder (GAD) was associated with increased risk for lifetime SUDs (OR = 2.34), alcohol dependence (OR = 1.73), and marijuana dependence (OR = 3.36) and recent marijuana dependence (OR = 3.28). A history of physical abuse was associated with increased risk for lifetime SUDs (OR = 1.71) and recent marijuana dependence (OR = 3.47). Earlier onset of first mania/hypomania was associated with increased risk for lifetime SUDs (5% per year), and recent marijuana dependence (12% per year) and later treatment with a mood stabilizer were also associated with increased risk for recent SUDs (8% per year). Positive associations between GAD, later treatment with a mood stabilizer, and early childhood trauma and history of SUDs suggest that adequate treatment of comorbid anxiety, early treatment with a mood stabilizer, and prevention of childhood trauma may reduce the risk for the development of SUDs in patients with bipolar disorder.

Determinants of cue-elicited craving and physiologic reactivity in methamphetamine-dependent subjects in the laboratory.

OBJECTIVE: Craving for methamphetamine is commonly reported by heavy users of the drug and may increase the risk of relapse in newly abstinent individuals. Exposure to methamphetamine-associated cues in the laboratory can elicit measureable craving and autonomic reactivity in some individuals with methamphetamine dependence. In this study, clinical and demographic correlates of methamphetamine craving and the optimal conditions for its measurement in the laboratory are explored. METHODS: Subjective (craving) and physiologic (heart rate and skin conductance) reactivity to presentation of methamphetamine-associated photo, video, and paraphernalia cues were evaluated in 43 subjects with methamphetamine dependence. Association of cue reactivity with demographic and clinical characteristics including duration, frequency, amount, and recency of methamphetamine use were assessed. RESULTS: Craving was reported by fewer than half of subjects at baseline and by approximately 70% of subjects after methamphetamine cue exposure. Relative to baseline, subjective craving was increased by all three cue modalities to a similar extent. In general, physiological cue reactivity correlated poorly with cue-induced craving. Craving at baseline was strongly predictive of cue-induced craving. Differences in cue-induced craving were not associated with age, sex, education, employment, treatment status, or number of days using methamphetamine in the 60 days prior to study entry. In contrast, the degree of baseline craving was strongly associated with employment status and the number of days using methamphetamine in the past 60 days. CONCLUSIONS: Cue-induced craving for methamphetamine may be reliably measured in methamphetamine-dependent individuals in the laboratory. Further studies employing the cue reactivity paradigm in methamphetamine dependence are warranted.

Biologic Commonalities between Mental Illness and Addiction.

Epidemiologic studies indicate that co-occurring substance use disorders and psychiatric disorders are frequently found in clinical practice. From a neurobiologic perspective, what do these two seemingly different groups of disorders have in common? Currently, several hypotheses are postulated to explain the high rates of comorbidity. Chronic alcohol and drug use may lead to neuroadaptation in the biologic systems mediating psychiatric disorders. Conversely, co-occurring psychiatric and substance use disorders (SUDs) may represent phenotypic expressions of common premorbid neurobiologic abnormalities. Similar alterations in the dopamine-mediated reward system and various neurotransmitter systems including glutamate, γ-aminobutyric acid, and serotonin are found in both SUDs and numerous psychiatric disorders. Stress and chronic distress with the resultant activation of the hypothalamic-pituitary-adrenal axis and stress system has also been implicated in the pathophysiology of both psychiatric disorders and SUDs. Better understanding the commonalities between the two groups of disorders should lead to more efficacious treatments and targeted prevention strategies.

Delay discounting and reward sensitivity in a 2 × 2 study of bipolar disorder and alcohol dependence.

BACKGROUND AND AIMS: Separate studies have shown increased delay discounting in people with bipolar disorder (BD) and people with alcohol dependence (AD) relative to people without mental health problems. Delay discounting was compared in people with no mental health problems, AD, BD and AD plus BD. Associations of delay discounting with self-reported impulsivity and reward sensitivity were also assessed. DESIGN: The study was a two-by-two factorial comparative observational design. SETTING: Data were collected at baseline diagnostic visits as part of a neuroimaging study at a medical university in South Carolina, USA. PARTICIPANTS: Twenty-two BD + AD, 33 BD, 28 AD and 27 people without mental health problems participated. MEASUREMENTS: Diagnostic and clinician-rated symptom measures, self-report questionnaires and a computerized delay discounting task were administered. Two-by-two general linear univariate models were tested to examine between-group differences on discounting rates, and bivariate correlations and hierarchical regression analyses were performed to examine associations between discounting rates and self-reported reward sensitivity and impulsivity. FINDINGS: There was a significant main effect of AD (P = 0.006, η2  = 0.068). The main effect of BD and the BD × AD interaction terms were non-significant (P ≥ 0.293, η2  ≤ 0.010). Reward sensitivity and impulsivity were not significantly associated with discounting rates after adjustment for the other (P ≥ 0.089). CONCLUSIONS: People with alcohol dependence appear to have higher delay discounting, while previously found associations between bipolar disorder and delay discounting may be secondary to alcohol use disorder.

An evaluation of the impact of co-occurring anxiety and substance use disorder on bipolar disorder illness outcomes in STEP-BD.

BACKGROUND: Anxiety disorder (AD) and substance use disorder (SUD) highly co-occur with bipolar disorder (BD). AD and/or SUD co-occurrence is associated with poorer clinical outcomes in BD. However, respective associations between AD and/or SUD diagnoses and BD outcomes require clarification. Baseline data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) were therefore utilized to investigate independent and simultaneous contributions of ADs and SUDs on clinical variables in BD. METHODS: Two latent factors, "pathological anxiety" and "substance use problems," were derived from presence/absence of lifetime AD and SUD diagnoses. Latent dimensions' associations with clinical variables, obtained from the Affective Disorders Evaluation, Mini-International Neuropsychiatric Interview and Range of Impaired Functioning, were estimated via structural equation modeling (SEM). RESULTS: Modeled independently, pathological anxiety and substance use problems were significantly associated with several variables. Yet when modeled simultaneously, pathological anxiety's associations with functional impairment, past-year rapid cycling, and past-year %time spent anxious and depressed remained while most variables' associations with substance use problems became non-significant. The only significant latent-factor interaction evidenced was for age of BD onset. LIMITATIONS: Analyses were limited to lifetime diagnoses and causality may not be inferred given cross-sectional data. CONCLUSIONS: ADs and SUDs impact on BD was mostly additive rather than synergistic. Findings highlight the potentially understated importance of treating inter-episodic anxiety in BD as it may exacerbate mood symptoms, increasing functional impairment and risk for subsequent mood episodes.

Differential interactions between comorbid anxiety disorders and substance use disorder in rapid cycling bipolar I or II disorder.

OBJECTIVE: Anxiety disorders (AD) and substance use disorders (SUD) commonly co-occur with bipolar disorder. This study was undertaken to assess AD-SUD-bipolar subtype interactions. METHODS: Extensive clinical interview and MINI were used to ascertain DSM-IV diagnoses of rapid cycling bipolar I (RCBPDI) or II (RCBPDII) disorder, SUDs, and ADs including generalized anxiety disorder (GAD), panic disorder (PD), and obsessive-compulsive disorder (OCD). Data at the initial assessment of four studies was used to compare the prevalence differences in ADs between RCBPDI and RCBPDII by using protocol-defined SUD categories, "Never," "Lifetime, but not recent," or "Recent." RESULTS: Five-hundred sixty-six of 568 patients (RCBPDI n=320, RCBPDII n=246) were eligible for analyses. In the "Never" group (n=191), patients with RCBPDI and RCBPDII had similar risk for ADs. In the "Lifetime, but not recent" group (n=195), RCBPDI patients had significantly higher risks for GAD (OR=3.29), PD (OR=2.95), but not OCD, compared with their RCBPDII counterparts. Similarly, in the "Recent" group (n=180), RCBPDI patients also had significantly higher risks for GAD (OR=3.6), PD (OR=3.8), but not OCD, compared with their RCBPDII counterparts. LIMITATIONS: Data were cross-sectional and not all ADs were included. CONCLUSION: In this large cohort of patients with rapid cycling bipolar disorder, risk for having GAD, PD, but not OCD increased significantly in patients with bipolar I disorder compared to their bipolar II counterparts when a history of SUD was present. However, there were no significant differences in the risk for GAD, PD, or OCD between the subtypes among patients without a history of SUD.

An item response theory evaluation of the young mania rating scale and the montgomery-asberg depression rating scale in the systematic treatment enhancement program for bipolar disorder (STEP-BD).

BACKGROUND: The Young Mania Rating Scale (YMRS) and Montgomery-Asberg Depression Rating Scale (MADRS) are among the most widely used outcome measures for clinical trials of medications for Bipolar Disorder (BD). Nonetheless, very few studies have examined the measurement characteristics of the YMRS and MADRS in individuals with BD using modern psychometric methods. The present study evaluated the YMRS and MADRS in the Systematic Treatment Enhancement Program for BD (STEP-BD) study using Item Response Theory (IRT). METHODS: Baseline data from 3716 STEP-BD participants were available for the present analysis. The Graded Response Model (GRM) was fit separately to YMRS and MADRS item responses. Differential item functioning (DIF) was examined by regressing a variety of clinically relevant covariates (e.g., sex, substance dependence) on all test items and on the latent symptom severity dimension, within each scale. RESULTS: Both scales: 1) contained several items that provided little or no psychometric information, 2) were inefficient, in that the majority of item response categories did not provide incremental psychometric information, 3) poorly measured participants outside of a narrow band of severity, 4) evidenced DIF for nearly all items, suggesting that item responses were, in part, determined by factors other than symptom severity. LIMITATIONS: Limited to outpatients; DIF analysis only sensitive to certain forms of DIF. CONCLUSIONS: The present study provides evidence for significant measurement problems involving the YMRS and MADRS. More work is needed to refine these measures and/or develop suitable alternative measures of BD symptomatology for clinical trials research.

Design and methods for the Better Resiliency Among Veterans and non-Veterans with Omega-3's (BRAVO) study: A double blind, placebo-controlled trial of omega-3 fatty acid supplementation among adult individuals at risk of suicide.

Suicide remains the 10th leading cause of death among adults in the United States (U.S.). Annually, approximately 30 per 100,000 U.S. military Veterans commit suicide, compared to 14 per 100,000 U.S. civilians. Symptoms associated with suicidality can be treatment resistant and proven-effective pharmaceuticals may have adverse side-effects. Thus, a critical need remains to identify effective approaches for building psychological resiliency in at-risk individuals. Omega-3 highly unsaturated fatty acids (n-3 HUFAs) are essential nutrients, which must be consumed in the diet. N-3 HUFAs have been demonstrated to reduce symptoms of depression, anxiety, and impulsivity - which are associated with suicide risk. Here we present the design and methods for the Better Resiliency Among Veterans and non-Veterans with Omega-3's (BRAVO) study, which is a double blind, randomized, controlled trial among individuals at risk of suicide of an n-3 HUFA versus placebo supplementation in the form of all natural fruit juice beverages. The BRAVO study seeks to determine if dietary supplementation with n-3 HUFAs reduces the risk for serious suicidal behaviors, suicidal thinking, negative emotions, and symptoms associated with suicide risk. Sub-analyses will evaluate efficacy in reducing depressive symptoms, alcohol, and nicotine use. A sub-study utilizes functional magnetic resonance imaging (fMRI) to evaluate the neuropsychological and neurophysiological effects of n-3 HUFAs. We also outline selection of appropriate proxy outcome measures for detecting response to treatment and collection of ancillary data, such as diet and substance use, that are critical for interpretation of results.

Assessment and treatment of mood disorders in the context of substance abuse.

Recognition and management of mood symptoms in individuals using alcohol and/or other drugs represent a daily challenge for clinicians in both inpatient and outpatient treatment settings. Diagnosis of underlying mood disorders in the context of ongoing substance abuse requires careful collection of psychiatric history, and is often critical for optimal treatment planning and outcomes. Failure to recognize major depression or bipolar disorders in these patients can result in increased relapse rates, recurrence of mood episodes, and elevated risk of completed suicide. Over the past decade, epidemiologic research has clarified the prevalence of comorbid mood disorders in substance-dependent individuals, overturning previous assumptions that depression in these patients is simply an artifact of intoxication and/or withdrawal, therefore requiring no treatment. However, our understanding of the bidirectional relationships between mood and substance use disorders in terms of their course(s) of illness and prognoses remains limited. Like-wise, strikingly little treatment research exists to guide clinical decision making in co-occurring mood and substance use disorders, given their high prevalence and public health burden. Here we overview what is known and the salient gaps of knowledge where data might enhance diagnosis and treatment of these complicated patients.

El reconocimiento y manejo de los síntomas anímicos en los sujetos que emplean alcohol ylu otras drogas es un desafío diario para los clínicos en el tratamiento tanto de pacientes ambulatorios como hospitalizados. El diagnóstico de los trastornos del ánimo que están a la base de un abuso de sustancias requiere de una recopilación cuidadosa de la historia psiquiátrica, y a menudo es clave para lograr una planificación terapéutica y resultados óptimos. Una falla en el reconocimiento en estos pacientes de la depresión mayor o de los trastornos bipolares puede traducirse en un aumento en la frecuencia de recaídas, recurrencias y episodios anímicos, y un riesgo elevado de suicidio consumado. Durante la última década la investigación epidemiológica ha clarificado la prevalencia de los trastornos del ánimo comórbidos en sujetos con dependencia de sustancias, dando un vuelco en los supuestos previos acerca de que la depresión en estos pacientes era simplemente un artefacto de la intoxicación ylo de la abstinencia, y que por tanto no requería de tratamiento. Sin embargo, aun es limitada nuestra comprensión acerca de las relaciones bidireccionales entre los trastornos del ánimo y el abuso de sustancias en cuanto a los cursos y pronósticos de la enfermedad. Asimismo, llama la atención que existe poca investigación terapéutica para guiar la toma de decisiones clínicas cuando co-ocurren trastornos del ánimo y por uso de sustancias, dada su alta prevalencia y la carga para la salud pública. En este artículo se repasa lo que se sabe y los vacíos más destacados del conocimiento donde los datos podrían mejorar el diagnóstico y el tratamiento de estos pacientes complicados.

La reconnaissance et la prise en charge des troubles de l'humeur chez les personnes consommant de l'alcool et/ou d'autres substances sont des défis quotidiens pour les médecins, que ce soit dans le cadre hospitalier ou ambulatoire. Le diagnostic des troubles de l'humeur sous-jacents dans le contexte d'une toxicomanie existante nécessite un recueil soigneux des antécédents psychiatriques ; il est souvent déterminant pour une organisation et des résultats optimaux du traitement. Une absence de reconnaissance de la dépression majeure ou des troubles bipolaires chez ces patients peut entraîner une augmentation des taux de rechute, une récidive des troubles thymiques et un risque élevé de suicide réussi. Ces 10 dernières années, la recherche épidémiologique a clarifié la prévalence des troubles comorbides de l'humeur chez les personnes dépendantes d'une substance, infirmant les hypothèses antérieures considérant la dépression chez ces patients comme un simple artéfact de l'intoxication et/ou du sevrage, ne nécessitant donc aucun traitement. Cependant, notre compréhension des relations bidirectionnelles entre troubles de l'humeur et troubles de l'usage d'une substance en termes d'évolution de la maladie et de pronostic reste limitée. De même, le peu de recherche thérapeutique pour guider la décision clinique en cas de troubles concomitants de l'humeur et de l'usage de substances est marquant, compte tenu de leur haute prévalence et de leur poids dans la santé publique. Nous analysons ici ce qui est connu ainsi que les lacunes importantes dans nos connaissances dans ce domaine ; des résultats de recherche pourraient améliorer le diagnostic et le traitement de ces patients compliqués.

Evidence for the involvement of cyclooxygenase activity in the development of cocaine sensitization.

Phospholipase A2 (PLA(2)) activation generates the release of arachidonic acid (AA) and platelet-activating factor (PAF), two compounds which may be involved in neuroplasticity. In previous studies, we found that PLA(2) activation is involved in the development of stimulant sensitization. In the present study, we have examined the roles of AA and PAF in the development of stimulant sensitization using agonists and antagonists selective for PAF receptors or the induction of various AA cascade-mediated eicosanoids. Sprague-Dawley rats were treated for 5 days with cocaine (30 mg/kg) or D-amphetamine (1 mg/kg) preceded 15 min earlier by various antagonists, and then tested following a 10-day withdrawal period for cocaine (15 mg/kg) or D-amphetamine (0.5 mg/kg)-induced locomotion. Consistent with our earlier work, pretreatment with the PLA(2) inhibitor quinacrine (25 mg/kg) blocked the development of cocaine and amphetamine sensitization. The lipoxygenase (LOX) inhibitors nordihydroguaiaretic acid (NDGA) (5-10 mg/kg) and MK-886 (1 mg/kg) had no effect on cocaine sensitization. The PAF receptor antagonist WEB 2086 (5-10 mg/kg) reduced the development of cocaine sensitization. The cyclooxygenase (COX) inhibitors indomethacin (1-2 mg/kg), piroxicam (0.5-1 mg/kg), 6-methoxy-2-napthylacetic acid (6-MNA; 0.5-1 mg/kg), and NS-398 (0.5-1 mg/kg) blocked the development of cocaine sensitization. The COX inhibitors indomethacin (2 mg/kg) and 6-MNA (1 mg/kg) also reduced the development of amphetamine sensitization. Rats were administered bilateral intraventral tegmental area (VTA) injections of D-amphetamine (5 microg/side) or saline coadministered with indomethacin (0.5 microg/side) or vehicle three times over 5 days and were then tested after a 10-day withdrawal for D-amphetamine (0.5 mg/kg ip)-induced locomotion. Intra-VTA amphetamine induced a robust form of amphetamine sensitization, which was blocked by coadministration of indomethacin. Unilateral intra-VTA injections of PAF (1 microg) did not significantly alter cocaine (15 mg/kg ip)-induced locomotion when tested after a 3-day withdrawal. These findings suggest that COX, and possibly PAF, activity is involved in the development of stimulant sensitization. Neuroanatomical studies demonstrate that this may occur at the level of the VTA.