Bryan K. Tolliver

Cognitive enhancers in the treatment of substance use disorders: Clinical evidence

Attenuation of drug reward has been the major focus of medication development in the addiction area to date. With the growth of research in the area of cognitive neuroscience, the importance of executive function and inhibitory cognitive control in addictive disorders is becoming increasingly apparent. An emerging strategy in the pharmacotherapy of addictions and other psychiatric disorders involves the use of medications that improve cognitive function. In particular, agents that facilitate inhibitory and attentional control, improve abstraction, planning and mental flexibility could be beneficial in the treatment of substance use disorders. Because there are multiple neurotransmitter systems involved in the regulation of cognitive function, agents from a number of drug classes have been tested. In particular, agents acting through the cholinergic, adrenergic and glutamatergic systems have shown potential for improving cognitive function in a number of psychiatric and neurologic disorders, but most of these agents have not been tested in the treatment of individuals with substance use disorders. This manuscript provides a review of clinical data supporting the use of the major classes of cognitive enhancing agents in substance use disorders. Agents that have shown promise in cognitive enhancement in other disorders, and have a theoretical or mechanistic rationale for application to substance use disorders are also highlighted.

Uses of Coercion in Addiction Treatment: Clinical Aspects

Coerced or involuntary treatment comprises an integral, often positive component of treatment for addictive disorders. By the same token, coercion in health care raises numerous ethical, clinical, legal, political, cultural, and philosophical issues. In order to apply coerced care effectively, health care professionals should appreciate the indications, methods, advantages, and liabilities associated with this important clinical modality. An expert panel, consisting of the Addiction Committee of the Group for the Advancement of Psychiatry, listed the issues to be considered by clinicians in considering coerced treatment. In undertaking this task, they searched the literature using Pubmed from 1985 to 2005 using the following search terms: addiction, alcohol, coercion, compulsory, involuntary, substance, and treatment. In addition, they utilized relevant literature from published reports. In the treatment of addictions, coercive techniques can be effective and may be warranted in some circumstances. Various dimensions of coercive treatment are reviewed, including interventions to initiate treatment; contingency contracting and urine testing in the context of psychotherapy; and pharmacological methods of coercion such as disulfiram, naltrexone, and the use of a cocaine vaccine. The philosophical, historical, and societal aspects of coerced treatment are considered.

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

Tolliver BK, DeSantis SM, Brown DG, Prisciandaro JJ, Brady KT. A randomized, double‐blind, placebo‐controlled clinical trial of acamprosate in alcohol‐dependent individuals with bipolar disorder: a preliminary report. Bipolar Disord 2012: 14: 54–63.

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.

Extinction of Drug Cue Reactivity in Methamphetamine-Dependent Individuals

Conditioned responses to drug-related environmental cues (such as craving) play a critical role in relapse to drug use. Animal models demonstrate that repeated exposure to drug-associated cues in the absence of drug administration leads to the extinction of conditioned responses, but the few existing clinical trials focused on extinction of conditioned responses to drug-related cues in drug-dependent individuals show equivocal results. The current study examined drug-related cue reactivity and response extinction in a laboratory setting in methamphetamine-dependent individuals. Methamphetamine cue-elicited craving was extinguished during two sessions of repeated (3) within-session exposures to multi-modal (picture, video, and in-vivo) cues, with no evidence of spontaneous recovery between sessions. A trend was noted for a greater attenuation of response in participants with longer (4-7 day) inter-session intervals. These results indicate that extinction of drug cue conditioned responding occurs in methamphetamine-dependent individuals, offering promise for the development of extinction- based treatment strategies.

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.

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.

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.

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.