Examination of preliminary behavioral and effective connectivity findings from treatment response to citalopram in cocaine use disorder: A dynamic causal modeling study.

We sought effective (directional) connectivity parameters associated with response to citalopram in cocaine use disorder (CUD) by conducting a functional magnetic resonance imaging (fMRI) experiment with participants diagnosed with CUD (n = 13) and matched healthy controls (HC; n = 17). CUD participants showed a positive correlation between bilateral DLPFC-to-putamen effective connectivity and treatment effectiveness score. These preliminary results support further investigation of prefrontal-striatal interactions in response to treatment in CUD.

INTEGRATIVE BAYESIAN ANALYSIS OF NEUROIMAGING-GENETIC DATA THROUGH HIERARCHICAL DIMENSION REDUCTION.

Advances in neuromedicine have emerged from endeavors to elucidate the distinct genetic factors that influence the changes in brain structure that underlie various neurological conditions. We present a framework for examining the extent to which genetic factors impact imaging phenotypes described by voxel-wise measurements organized into collections of functionally relevant regions of interest (ROIs) that span the entire brain. Statistically, the integration of neuroimaging and genetic data is challenging. Because genetic variants are expected to impact different regions of the brain, an appropriate method of inference must simultaneously account for spatial dependence and model uncertainty. Our proposed framework combines feature extraction using generalized principal component analysis to account for inherent short- and long-range structural dependencies with Bayesian model averaging to effectuate variable selection in the presence of multiple genetic variants. The methods are demonstrated on a cocaine dependence study to identify ROIs associated with genetic factors that impact diffusion parameters.

Variation within the serotonin (5-HT) 5-HT2C receptor system aligns with vulnerability to cocaine cue reactivity.

Cocaine dependence remains a challenging public health problem with relapse cited as a major determinant in its chronicity and severity. Environmental contexts and stimuli become reliably associated with its use leading to durable conditioned responses ('cue reactivity') that can predict relapse as well as treatment success. Individual variation in the magnitude and influence of cue reactivity over behavior in humans and animals suggest that cue-reactive individuals may be at greater risk for the progression to addiction and/or relapse. In the present translational study, we investigated the contribution of variation in the serotonin (5-HT) 5-HT2C receptor (5-HT2CR) system in individual differences in cocaine cue reactivity in humans and rodents. We found that cocaine-dependent subjects carrying a single nucleotide polymorphism (SNP) in the HTR2C gene that encodes for the conversion of cysteine to serine at codon 23 (Ser23 variant) exhibited significantly higher attentional bias to cocaine cues in the cocaine-word Stroop task than those carrying the Cys23 variant. In a model of individual differences in cocaine cue reactivity in rats, we identified that high cocaine cue reactivity measured as appetitive approach behavior (lever presses reinforced by the discrete cue complex) correlated with lower 5-HT2CR protein expression in the medial prefrontal cortex and blunted sensitivity to the suppressive effects of the selective 5-HT2CR agonist WAY163909. Our translational findings suggest that the functional status of the 5-HT2CR system is a mechanistic factor in the generation of vulnerability to cocaine-associated cues, an observation that opens new avenues for future development of biomarker and therapeutic approaches to suppress relapse in cocaine dependence.

Interactions between bipolar disorder and antisocial personality disorder in trait impulsivity and severity of illness.

OBJECTIVE: We investigated trait impulsivity in bipolar disorder and antisocial personality disorder (ASPD) with respect to severity and course of illness. METHOD: Subjects included 78 controls, 34 ASPD, 61 bipolar disorder without Axis II disorder, and 24 bipolar disorder with ASPD, by Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (SCID-I and -II). Data were analyzed using general linear model and probit analysis. RESULTS: Barratt Impulsiveness Scale (BIS-11) scores were higher in ASPD (effect sizes 0.5-0.8) or bipolar disorder (effect size 1.45) than in controls. Subjects with both had more suicide attempts and previous episodes than bipolar disorder alone, and more substance-use disorders and suicide attempts than ASPD alone. BIS-11 scores were not related to severity of crimes. CONCLUSION: Impulsivity was higher in bipolar disorder with or without ASPD than in ASPD alone, and higher in ASPD than in controls. Adverse effects of bipolar disorder in ASPD, but not of ASPD in bipolar disorder, were accounted for by increased impulsivity.

Evaluation of heterogeneity in pharmacotherapy trials for drug dependence: a Bayesian approach.

AIMS: Difficulty identifying effective pharmacotherapies for cocaine dependence has led to suggestions that subgroup differences may account for some of the heterogeneity in treatment response. Well-attested methodological difficulties associated with these analyses recommend the use of Bayesian statistical reasoning for evaluation of salient interaction effects. METHODS: A secondary data analysis of a previously published, double-blind, randomized controlled trial examines the interaction of decision-making, as measured by the Iowa Gambling Task, and citalopram in increasing longest sustained abstinence from cocaine use. RESULTS: Bayesian analysis indicated that there was a 99% chance that improved decision-making enhances response to citalopram. Given the strong positive nature of this finding, a formal, quantitative Bayesian approach to evaluate the result from the perspective of a skeptic was applied. CONCLUSIONS: Bayesian statistical reasoning provides a formal means of weighing evidence for the presence of an interaction in scenarios where conventional, Frequentist analyses may be less informative. [Supplementary materials are available for this article. Go to the publisher's online edition of The American Journal of Drug and Alcohol Abuse for the following free supplemental resource: Appendix 1].

Psychiatric aspects of impulsivity.

OBJECTIVE: The authors discuss the relationship of impulsivity to psychiatric disorders and present selected hypotheses regarding the reasons for these relationships. METHOD: Previous research has shown significantly higher levels of impulsivity among patients with conduct disorder, personality disorders, substance use disorders, and bipolar disorder, compared to other psychiatric patients or healthy comparison subjects. A literature review of the theoretical bases of the relationship between these disorders and impulsivity is presented. Measurements of impulsivity and treatment options are discussed in relation to the physiology of impulsivity and the disorders in which it is a prominent feature. RESULTS: Impulsivity, as defined on the basis of a biopsychosocial approach, is a key feature of several psychiatric disorders. Behavioral and pharmacological interventions that are effective for treating impulsivity should be incorporated into treatment plans for these disorders. CONCLUSIONS: The high comorbidity of impulsivity and selected psychiatric disorders, including personality disorders, substance use disorders, and bipolar disorder, is in a large part related to the association between impulsivity and the biological substrates of these disorders. Before treatment studies on impulsivity can move forward, measures of impulsivity that capture the core aspects of this behavior need to be refined and tested on the basis of an ideologically neutral model of impulsivity.

Dextroamphetamine for cocaine-dependence treatment: a double-blind randomized clinical trial.

A properly implemented agonist treatment regimen should improve retention and reduce illicit drug use. Cocaine-dependent subjects (N = 128) were enrolled in a 12-week randomized, double-blind, placebo-controlled trial. In the multistage dosing design, subjects initially received placebo (PBO) or 15 to 30 mg of dextroamphetamine sulfate, sustained-release capsules. At week 5, the dose doubled to 30 mg or 60 mg for active groups. Subjects attended the clinic twice a week, provided urine samples, obtained medication, and had one behavioral therapy session a week. Retention was best for the 15- to 30-mg group, whereas the proportion of benzoylecgonine-positive urine screens was, from lowest to highest, 30 to 60 mg, 15 to 30 mg, and PBO at study end. Dosing must be refined. The results provide support for additional examination of the agonist model in psychostimulant-dependence treatment.

Antisocial personality disorder, alcohol, and aggression.

Epidemiologic studies and laboratory research consistently link alcohol use with aggression. Not all people, however, exhibit increased aggression under the influence of alcohol. Recent research suggests that people with antisocial personality disorder (ASPD) may be more prone to alcohol-related aggression than people without ASPD. As a group, people with ASPD have higher rates of alcohol dependence and more alcohol-related problems than people without ASPD. Likewise, in laboratory studies, people with ASPD show greater increases in aggressive behavior after consuming alcohol than people without ASPD. The association between ASPD and alcohol-related aggression may result from biological factors, such as ASPD-related impairments in the functions of certain brain chemicals (e.g., serotonin) or in the activities of higher reasoning, or "executive," brain regions. Alternatively, the association between ASPD and alcohol-related aggression may stem from some as yet undetermined factor(s) that increase the risk for aggression in general.

Fluoxetine treatment of cocaine-dependent patients with major depressive disorder.

Sixty-eight male and female individuals with both DSM-IV diagnoses of cocaine dependence and major depressive disorder were randomly assigned to one of two medication conditions (placebo vs. 40 mg per day) as part of a double-blind, placebo-controlled clinical efficacy trial of fluoxetine for the treatment of this dual diagnosis. During the 12-week outpatient treatment phase all participants also received individual cognitive-behavioral psychotherapy targeting both cocaine use and depression. Depressive symptoms remitted as a function of time in treatment, with no significant medication effects found. Fewer cocaine positive urines were found during the first 6 weeks of treatment in the placebo group compared with the 40-mg group. Cocaine use and depressive symptoms during treatment were significantly correlated. The findings fail to support the role of fluoxetine for treatment of cocaine use and depression in dually-diagnosed patients.

Endogenous plasma testosterone levels and commission errors in women: A preliminary report.

A correlation between elevated testosterone and aggressive behavior has been demonstrated in animals and to a lesser degree in humans, primarily in the context of dominance. Some aggression, namely non-premeditated aggression, is characterized by impaired impulse control. Real-world aggressive histories and self-reported impulsivity have correlated with commission errors (failures to withhold responses to nontarget stimuli) in versions of the continuous performance test (CPT). To begin exploring whether testosterone may play a role in aggression due more to a direct relationship with impaired impulse control, we related plasma total testosterone concentrations of 27 psychiatrically healthy women to commission errors in two variants of the CPT - with and without interstimulus distracters. Controlling for age and IQ, testosterone did not relate to rates of correct detections in either task, but correlated positively with commission errors in the distracter CPT variant. In light of the fact previous studies find commission errors on the CPT are associated with impulsivity, the results of this study support a positive relationship between testosterone and impulsivity.

Plasma GABA levels correlate with aggressiveness in relatives of patients with unipolar depressive disorder.

Plasma gamma-aminobutyric acid (GABA) levels are decreased in some patients with depression, mania and alcoholism. Medications which increase plasma GABA improve symptoms of mood disorders and can decrease aggression. We examined the relationship between plasma GABA and aggressiveness on the Buss-Durkee Hostility Inventory in 77 psychiatrically healthy adults. In subjects selected for having a first-degree relative with primary unipolar depressive disorder (FH+, n=33), plasma GABA was negatively correlated with aggressiveness (beta=-0.338, P=0.036), as was age (beta=-0.483, P=0.005). A relationship between plasma GABA levels and aggressiveness was not observed in subjects with no such family history (FH-, n=44). Moreover, FH+ subjects had significantly lower plasma GABA concentrations than FH- subjects. These data suggest that low GABA levels may correlate with some aspects of aggressiveness and may be genetically regulated.

Measurement of inter-episode impulsivity in bipolar disorder.

We carried out a preliminary investigation of impulsivity in patients with bipolar I disorder not meeting criteria for active episodes. Barratt Impulsiveness Scale (BIS-11) scores were significantly higher in bipolar disorder than in control subjects. Laboratory measurements of impulsivity correlated with a BIS-11 score or severity of manic symptoms. Impulsivity in bipolar disorder may have both stable and state-dependent aspects.

The impact of impulsivity on cocaine use and retention in treatment.

To determine whether impulsivity was related to severity of drug use and treatment outcome, 50 cocaine dependent subjects underwent baseline measures of severity of current cocaine use and the Barratt Impulsiveness Scale (BIS-11). The hypothesis of the study was that there would be a significant correlation between impulsivity and cocaine use severity. As predicted, there was a significant correlation between BIS-11 total scores and self-reported average daily cocaine use as well as cocaine withdrawal symptoms. A subset of 35 patients underwent a 12-week double-blind placebo controlled trial of buspirone and group therapy. Subjects with high baseline impulsivity remained in the study a significantly shorter period than did subjects with lower baseline impulsivity. This study shows that impulsivity is a significant predictor of cocaine use and treatment retention, and suggests the need for targeting impulsivity in cocaine dependence treatment.

Effects of moderate and high doses of alcohol on attention, impulsivity, discriminability, and response bias in immediate and delayed memory task performance.

BACKGROUND: Prior studies that examined the effects of alcohol on Continuous Performance Test (CPT) performance have resulted in inconsistent outcomes. Most studies that examined the effects of alcohol on concentrated attention tasks (like the CPT) found little effect of alcohol on performance measures, even when doses that exceeded 0.8 g/kg were used. One likely reason for these inconsistencies is the varying difficulty (and sensitivity) of the task used, and as a result, comparisons between studies are difficult. This study is one in a series that examines the effects of alcohol on attention by using a difficult version of the CPT (Immediate and Delayed Memory Task--IMT/DMT). Our purpose for these studies has been two-fold, examining the effects of alcohol (1) on concentrated attention (i.e., correct detections) and (2) on errors (i.e., commission errors) previously correlated with impulsive behaviors. The first is important because previous studies have shown little effect of alcohol on attention, and the second is important because commission errors have been related to impulsive behaviors. METHODS: In the IMT/DMT, participants respond to a briefly displayed number when it is identical to the one displayed before it. The procedure includes immediate and delayed conditions where successive stimuli to be matched are delayed by 0.5 sec or by 3.5 sec. The three stimulus types included target (identical match), catch (four of five digits match), and filler (no match) stimuli. Twenty subjects completed this task after consuming either a placebo drink or a drink that contained 0.5 g/kg or 1.0 g/kg of alcohol on different days. RESULTS: The main findings were that (1) alcohol decreased the percentage of correct identifications of target stimuli; (2) alcohol increased the percentage of commission errors in relation to the number of correct target responses; and (3) alcohol decreased discriminability whereas response bias became more conservative. CONCLUSIONS: These results clearly demonstrated a time-course effect of the 1.0 g/kg alcohol dose on attention, impulsivity, discrimination, and response criteria when a variety of dependent measures are used.

The Brief Psychiatric Rating Scale as an acute inpatient outcome measurement tool: a pilot study.

BACKGROUND: Recent guidelines for length of stay at psychiatric hospitals may have an unacceptable impact on patient outcome at discharge. A valid measurement tool is needed to evaluate significant patient change during brief hospitalization, typically 7 days, and to provide early prediction of unfavorable short-term outcome. This study examines the utility of the Brief Psychiatric Rating Scale (BPRS) as such a tool. METHOD: During a 2-month testing period, the BPRS was administered to 87 successive adults admitted to an acute general psychiatric inpatient unit at admission, 2 days, 7 days, and weekly thereafter until discharge. Total BPRS scores and 4 subscores were used in the data analysis, which included paired t tests and correlation analyses. RESULTS: Mean BPRS total scores demonstrate significant (p < .001) patient improvement at days 2, 7, and 14 of the hospital stay. Changes in subscores and their relationship to eventual outcome vary across diagnostic groups. CONCLUSION: The BPRS appears to be a useful inpatient outcome measure since it is capable of demonstrating significant change during brief stays of 1 week or less. Subscale scores may provide more specific prediction of change and may help clarify outcome in individual patients who show insignificant change by total score.

Low dose zolmitriptan as a 5-HT neuroendocrine challenge agent in humans.

The 5-HT1B/D agonist sumatriptan has been used in a number of studies as a neuroendocrine challenge agent. Whether its neuroendocrine effects are centrally mediated is unclear, however, since sumatriptan shows minimal penetration of the central nervous system. Zolmitriptan shows a greater penetration into the central nervous system than sumatriptan, and has recently been shown to be an effective challenge agent. In order to determine the neuroendocrine, temperature and side effects of a 2.5 mg oral dose of zolmitriptan, 17 healthy volunteers underwent a placebo controlled, repeated measures, double blind neuroendocrine challenge. Zolmitriptan or placebo were administered, and cortisol, growth hormone, prolactin, blood pressure and temperature, were measured over four hours after the dose of zolmitriptan. Zolmitriptan at this dose was well tolerated by all subjects, with minimal side effects and only minor effects on blood pressure. There was a significant increase in serum growth hormone after zolmitriptan compared to placebo, however there were no significant effects on cortisol, prolactin or oral temperature. The neuroendocrine effects of 2.5 mg of orally administered zolmitriptan are similar to previously reported effects of sumatriptan, with minimal side effects.

Differential behavioral effects of plasma tryptophan depletion and loading in aggressive and nonaggressive men.

Preliminary findings indicate that men with high trait hostility may be prone to aggression increases following plasma tryptophan (Trp) depletion. We measured laboratory aggression in men selected for presence (n = 12) or absence (n = 12) of aggressive histories. Testing occurred before and after plasma Trp depletion, Trp loading, and under a food-restricted control condition. Subjects were provoked by subtractions of money, and aggression was measured as the responses the subject made to ostensibly subtract money from the instigator of the subtractions. When subjects were highly provoked, there was a significant Trp condition x aggression history interaction effect on aggressive responding. In particular, laboratory aggression in aggressive men was elevated under Trp-depleted conditions relative to Trp-loaded conditions, whereas the opposite occurred in nonaggressive men. Moreover, plasma total Trp levels after Trp loading were significantly higher in nonaggressive men, and plasma free (but not total) Trp levels after Trp loading correlated negatively with aggressive responses in the aggressive men. These data corroborate earlier findings that aggressive men may be more prone to aggression induced by reductions in plasma Trp.

Alcohol increases commission error rates for a continuous performance test.

BACKGROUND: Studying the effects of alcohol on Continuous Performance Test (CPT) performance was of interest for two reasons, i.e., (1) perhaps because of the ease of the task used in previous experiments, alcohol has not been found to impair performance, and (2) CPT commission errors (described below) have been related to impulsive behavior. METHODS: In this study, the CPT featured both an Immediate Memory Task (IMT) and a more difficult Delayed Memory Task (DMT). We compared the performance of 18 subjects under both alcohol and placebo conditions, using a within-subject design. Both the IMT (0.5-sec delay) and the DMT (3.5-sec delay, with distracter stimuli at 0.5-sec intervals) required the subject to respond if a briefly displayed number was identical to the one presented before it. Stimuli included target (identical match), catch (4 of 5 digits matched), and novel (random number) stimuli. On 2 separate days, subjects performed between administrations of three hourly placebo drinks or three hourly drinks containing 0.20 g/kg of alcohol (producing peak breath alcohol concentrations of approximately 0.035%). RESULTS: The main finding was that alcohol consumption increased responses to catch stimuli (i.e., commission errors) in the DMT. In contrast, performance in the IMT (the easier task) was unaffected by alcohol. Commission errors measured during peak breath alcohol concentrations were significantly correlated with scores on the Barratt Impulsivity Scale for both the IMT and DMT. Discriminability (A') between target and catch stimuli was reduced by alcohol for the DMT only. CONCLUSIONS: These data indicate that even small amounts of alcohol can produce measurable changes in CPT performance parameters if the task is of sufficient difficulty and that commission errors can be increased by alcohol consumption.

The effects of a cumulative alcohol dosing procedure on laboratory aggression in women and men.

OBJECTIVE: This study directly compared the effects of cumulative alcohol dosing procedure on aggression in both women and men. METHOD: Thirteen women and 13 men consumed three beverages 1 hour apart. There were two experimental conditions: (1) a placebo day, when subjects consumed three 240 ml beverages, each containing only 1 ml of alcohol; and (2) an alcohol day, when subjects consumed three 240 ml beverages, each containing 0.35 g/kg of 95% alcohol. Alcohol doses for women were reduced by 8%. Prior to beverage consumption, and periodically after consumption, subjects participated in 25-minute laboratory testing sessions designed to measure aggression. In this paradigm, subjects could earn points by responding on a button, or aggress toward a fictitious opponent who ostensibly subtracted earnings from them. RESULTS: Both women and men showed an increase in aggressive responding after drinking alcohol but not placebo. As a group the greatest increases were observed after consuming the second alcohol drink (BAC = 0.08%). Aggressive responding, however, remained elevated for several hours after alcohol consumption. A post hoc analysis of the data indicated that subjects with high aggression levels under placebo conditions showed the greatest increases in aggression under alcohol conditions. CONCLUSIONS: These results indicate that at least under these conditions, alcohol does increase aggression in both women and men. The aggression-increasing effects of alcohol appear to be long-lasting and specific to individuals with the higher aggressive tendencies while sober.

Laboratory measures of aggression and impulsivity in women with borderline personality disorder.

To characterize how severe negative affect in women is reflected in objective measures of aggression and impulsivity, the aggressive and impulsive behavior of 14 hospitalized women with borderline personality disorder (BPD) was compared with that of 17 controls. In an impulsivity task, subjects experienced two sets of 50 trials during which they could choose a smaller, immediate monetary reward or a larger but progressively delayed reward. In a separate task (PSAP), subjects earned monetary reinforcers with repeated button presses, and were provoked by the subtraction of money which was blamed on a fictitious other participant. Subjects could respond by ostensibly subtracting money from the fictitious subject (the aggressive response). While selection frequency of the short-delay responses was similar in patients and controls, BPD patients responded to avoid longer delay of reward across trials, and had higher Barratt Impulsiveness Scale total scores and attentional subscale scores. BPD patients responded to the money losses with roughly three times as many aggressive responses as controls and had higher Buss-Durkee Hostility Inventory (BDHI), Brown History of Violence, and Retrospective Overt Aggression Scale scores than controls. Aggressive responding rates correlated positively with BDHI scores. These results extend previous findings that negative affect in women is reflected in laboratory behavioral measures.