Emotional self-regulation, impulsivity, 5-HTTLPR and tobacco use behavior among psychiatric inpatients.

BACKGROUND: While the serotonin transporter (SLC6A4) gene, 5-HTTLPR, interacts with the social environment to influence both emotional self-regulation and smoking behavior, less is known about interactions between emotional self-regulation and 5-HTTLPR or their joint influence on tobacco use. Here, we examined such interactions among psychiatric inpatients, the population with the highest rates of smoking. METHODS: Participants (506 adults) were psychiatric inpatients at The Menninger Clinic in Houston TX between 2012 and 16. Most were white (89%), male (55%), with a mean age of 32.3 years. Participants completed the Difficulties in Emotional Regulation Scale (DERS) at admission. We examined interactions with smoking among three DERS subscales and 5-HTTLPR, controlling for sex, race and age. RESULTS: Smoking rates were higher among those with the 5-HTTPLR L'L' genotype compared to peers carrying an S' allele (47.9% vs. 37.4%, respectively). Among S' allele carrying participants, impulse control difficulties (OR = 1.09; 95%CI: 1.03-1.14) and lack of emotion clarity (OR = 1.06; 95%CI: 1.00-1.11) increased risk for ever using tobacco, while accessing more ways to regulate emotion (OR = 0.95; 95%CI: 0.92-0.99) offered a protective effect against ever using tobacco. Neither demographic nor DERS covariates were associated with using tobacco among the L'L' group. LIMITATIONS: This ethnically homogenous sample limits generalizability and using a binary outcome can over-estimate a gene environment interaction effect. CONCLUSIONS: Emotional self-regulation exerts a stronger influence on using tobacco among carriers of an S' allele of 5-HTTLPR than peers with the L'L' genotype. Promoting emotional self-regulatory skills may have benefits for preventing tobacco use.

Illness-course modulates suicidality-related prefrontal gray matter reduction in women with bipolar disorder.

OBJECTIVE: Explore interrelationships between suicide attempt history (Objective 1) or suicide attempt severity (Objective 2) with prefrontal cortex gray matter (PFCGM ) volume and illness-course in patients with bipolar disorder (BD). METHOD: Ninety-three women with BD-I or -II diagnosis (51 with and 42 without suicide attempt history) underwent structural MRI and filled out questionnaires. Measured were GM volumes of 11 PFC regions, BD illness-course, and attempt history and severity. Effects were examined with repeated measures GLM or logit analyses. RESULTS: Objective 1: Attempt history was associated with increased trait impulsivity and aggression, and higher prevalence of BD-I, past drug use disorder, and past psychiatric hospitalization. PFCGM volume was lower in patients with than without attempt history in those with past psychiatric hospitalization. PFCGM volume was higher in patients with than without attempt history in those without hospitalization. Higher trait aggression predicted attempt history. Objective 2: Increased frontal pole volume and younger age at first hospitalization predicted many suicide attempts. CONCLUSION: Attempt history in patients with BD related to PFCGM volume reduction or increase. Volume modulation by psychiatric hospitalization could reflect effects of illness-course or care. Attempt severity was not related to volume reduction. Research on suicidality-brain relationships should include illness-course and attempt severity measures.

Psychostimulants given in adolescence modulate their effects in adulthood using the open field and the wheel-running assays.

Acute and chronic methylphenidate (MPD) were given to adults treated with MPD only in adulthood (adult I) and to adults that had been treated repeatedly during adolescence and adulthood (adult II). Two locomotor activity assays, the open field and the running wheel, were used in a dose response experiment to assess whether methylphenidate (MPD) treatment during adolescence would affect responses to MPD in adulthood. Each experiment lasted 11 days as follows: saline control on experimental day 1 (ED 1), followed by a single daily dose of saline, 0.6, 2.5, or 10mg/kg MPD for 6 days (ED 2 to ED 7), 3 washout days with no drug administration (ED 8 to ED 10), and saline or MPD challenge on ED 11 at a dose identical to that given on ED 2 to ED 7. Acute MPD elicited characteristic dose response increases in locomotion in both experimental assays of adult I and adult II groups. Adult I and adult II rats tested in the open field assay exhibited sensitization to 2.5mg/kg MPD and tolerance to 10mg/kg MPD, while in the wheel-running assay all the three MPD doses elicited sensitization in both adult I and adult II rats. MPD treatment in adolescence did not change the baseline activity when animal reached adulthood. However, the responses to MPD in adult II rat groups were significantly different from the adult I group. Similar observations were noted during washout days. At the low and moderate MPD treatment both experimental assay exhibited similar observations while following the high dose of MPD treatment, the open field assay indicated that tolerance to MPD was expressed, while the wheel-running assay indicated that behavioral sensitization was developed. The distinction between the two assays and adult I and II differences are discussed.

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.

Bilateral six-hydroxydopamine administration to PFC prevents the expression of behavioral sensitization to methylphenidate.

Psychostimulants like amphetamine and methylphenidate (MPD) are used to treat attention deficit hyperactivity disorder (ADHD), which is marked by developmentally inappropriate inattention, hyperactivity, and impulsivity. Neuropsychological analyses indicate that ADHD patients are impaired on tasks of behavioral inhibition, reward reversal, and working memory, which are functions of the prefrontal cortex (PFC) and are modulated by the mesocortical dopamine (DA) system. Non-specific electrical lesioning of PFC eliminated the expression of behavioral sensitization elicited by chronic MPD administration. Behavioral sensitization is the progressive augmentation of locomotor activity as a result of repetitive (chronic) exposure to the drug. It is believed that the sensitization to chronic drug treatment is caused due to an increase in DA in the mesocorticolimbic DA system, which includes the PFC. Therefore, this study investigated the role of PFC DA in mediating the behavioral sensitization to repeated administration of MPD in adult male Sprague-Dawley rats. On experimental day (ED) 1, the behavior was recorded post-saline injection. On ED 2, the rats were divided into three groups--control, sham and bilateral 6-OHDA treated group; and the sham and 6-OHDA treated groups underwent respective surgeries. After 5 days of rest following surgery, the post-surgery baseline was recorded on ED 8 following a saline injection. All three groups received 2.5 mg/kg MPD for 6 days (from ED 9 to ED 14), followed by a 3-day washout period (ED 15 to ED 18). On ED 19, a rechallenge injection of 2.5 mg/kg MPD was given and locomotor activity was recorded. It was found that the 6-OHDA lesion group failed to exhibit behavioral sensitization to MPD. The involvement of the dopaminergic afferents of PFC in behavioral sensitization to MPD is discussed.

Descending glutamatergic pathways of PFC are involved in acute and chronic action of methylphenidate.

Progressive augmentation of behavioral response following repeated psychostimulant administrations is known as behavioral sensitization, and is an indicator of a drug's liability for abuse. It is known that methylphenidate (MPD) (also known as Ritalin), a drug used to treat attention-deficit hyperactivity disorder (ADHD), induces sensitization in animals following repeated injections. It was recently reported that bilateral electric (non-specific) lesion of prefrontal cortex (PFC) prevented MPD elicited behavioral sensitization. Since PFC sends glutamatergic afferents to both ventral tegmental area (VTA) and nucleus accumbens (NAc), sites that are involved in induction and expression of behavioral sensitization respectively and glutamate from PFC is known to modulate dopamine cell activity in VTA and NAc, this study investigated the role of descending glutamate from PFC in MPD elicited behavioral sensitization. Locomotor activity of three groups of rats-control, sham operated and group with specific chemical lesion of glutamate neurons of PFC-was recorded using an open-field assay. On experimental day (ED) 1, the locomotor activity was recorded post a saline injection. The sham and lesion groups underwent respective surgeries on ED 2, and were allowed to recover for 5 days (from ED 3 to ED 7). The post-surgery baseline was recorded on ED 8 following a saline injection. On ED's 9 through 14, 2.5 mg/kg MPD was given, followed by a 4-day washout period (ED 15 -18). All three groups received a rechallenge injection of 2.5 mg/kg on ED 19 and their locomotor activity on various days was analyzed. It was found that ibotenic acid lesion modulated the acute and chronic effects of MPD and hence suggests that PFC glutamatergic afferents are involved in the acute effect of MPD as well as in its chronic effects such as behavioral sensitization to MPD.

Psychostimulant treatment for ADHD is modulated by prefrontal cortex manipulation.

The psychostimulant amphetamine (Amph) is widely used treatments for attention-deficit hyperactivity disorder (ADHD). Chronic intermittent exposure to psychostimulants induces behavioral sensitization. The objective of this study was to investigate the role of prefrontal cortex (PFC) in the acute and chronic effect of Amph using the open-field assay. Male Sprague-Dawley rats were assigned randomly to three groups, (1) an intact control group (2) a PFC sham-operated group, and (3) a PFC lesion group. All the three groups showed increases in locomotor activity after acute amphetamine injection (P<0.05), and activity levels were especially augmented in PFC lesion group. Following chronic amphetamine, the control group and sham-operated group exhibited behavioral sensitization (P<0.05). However, the PFC lesion group failed to exhibit behavioral sensitization and the pattern of locomotion was altered, which indicated that the nature of behavioral sensitization was changed. The results suggest that PFC lesion enhance the acute effects of amphetamine on locomotor activity and is required for development of behavior sensitization.

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.

[Prediction of treatment response in acute mania: controlled clinical trials with divalproex]. / Prédiction de la réponse au traitement dans la manie aiguë: les données des études contrôlées avec le divalproex.

OBJECTIVE: To determine predictive factors for response to mood stabilising treatment in manic episodes and to determine the mood stabilising properties of divalproex. METHODS: For predictive factors, 179 subjects in 3 parallel groups (divalproex, lithium, placebo) were evaluated over a period of 21 days by using structured interviews conducted by the clinician (SADS-C) and by nursing staff (ADRS). For the follow-on study, 372 stabilised patients were randomised to three groups: divalproex, lithium or placebo. RESULTS: The presence of depressive symptoms was associated with poor response to lithium, and patients with manic episodes with depressive symptoms or with rapid cycling exhibited good response to divalproex, while classical manic episodes showed good response to lithium and divalproex, and dysphoric or irritable manic episodes responded well to divalproex but not to lithium. A high number of both manic and depressive prior episodes is predictive of poor response to lithium and favourable response to divalproex. The effects of depressive and manic episodes appear to be independent and do not correlate with the duration of the illness or age at onset. Divalproex was superior to placebo in preventing all types of episodes, whether or not relapse was depressive or manic, and it was also superior to lithium in preventing depressive episodes. CONCLUSION: Specific features of the disease history and of the semiology of individual episodes help predict therapeutic response to mood stabilisers.

Is suicide contagious? A study of the relation between exposure to the suicidal behavior of others and nearly lethal suicide attempts.

This study sought to determine the association between nearly lethal suicide attempts and exposure to the suicidal behavior of parents, relatives, friends, or acquaintances and to accounts of suicide in the media. The authors conducted a population-based case-control study in Houston, Texas, from November 1992 through July 1995. They interviewed 153 victims of attempted suicide aged 13--34 years who had been treated at emergency departments in Houston and a random sample of 513 control subjects. After controlling for potentially confounding variables, the authors found that exposure to the suicidal behavior of a parent (adjusted OR = 1.5; 95% CI: 0.6, 3.6; p = 0.42) or a nonparent relative (adjusted OR = 1.2; 95% CI: 0.7, 2.0; p = 0.55) was not significantly associated with nearly lethal suicide attempts. Both exposure to the suicidal behavior of a friend or acquaintance (adjusted OR = 0.6; 95% CI: 0.4, 1.0; p = 0.05) and exposure to accounts of suicidal behavior in the media (adjusted OR = 0.2; 95% CI: 0.1, 0.3; p = 0.00) were associated with a lower risk of nearly lethal suicide attempts. Exposure to accounts of suicidal behavior in the media and, to a lesser extent, exposure to the suicidal behavior of friends or acquaintances may be protective for nearly lethal suicide attempts, but further research is needed to better understand the mechanisms underlying these findings.

The lifetime cost of bipolar disorder in the US: an estimate for new cases in 1998.

OBJECTIVE: To develop a cost model that estimates the total and per case lifetime cost of bipolar disorder for 1998 incident cases in the US. STUDY DESIGN: Lifetime cost simulation model. PERSPECTIVE: Societal. METHODS: Age- and gender-specific incidence of bipolar disorder in 1998 was estimated by simulation based on existing prevalence data. The course of illness and mental health service cost of 6 clinically defined prognostic groups was estimated based on the research literature and the judgement of panels of experts. Excess cost of general medical care was estimated based on claims data from a large insurer. Indirect cost was projected including excess unemployment and reduced earnings reported in the National Comorbidity Survey. Comorbidity treatment and indirect cost related to alcohol (ethanol) and drug abuse was added based on a National Institute on Drug Abuse study. RESULTS: The present value of the lifetime cost of persons with onset of bipolar disorder in 1998 was estimated at 24 billion US dollars ($US). Average cost per case ranged from $US11,720 for persons with a single manic episode to $US624,785 for persons with nonresponsive/chronic episodes. CONCLUSION: The model indicates the potential cost savings of preventing a case of bipolar disorder and underscores the importance of achieving a stable outcome in new cases to limit the economic consequences of the disorder.

Texas Medication Algorithm Project: development and feasibility testing of a treatment algorithm for patients with bipolar disorder.

BACKGROUND: Use of treatment guidelines for treatment of major psychiatric illnesses has increased in recent years. The Texas Medication Algorithm Project (TMAP) was developed to study the feasibility and process of developing and implementing guidelines for bipolar disorder, major depressive disorder, and schizophrenia in the public mental health system of Texas. This article describes the consensus process used to develop the first set of TMAP algorithms for the Bipolar Disorder Module (Phase 1) and the trial testing the feasibility of their implementation in inpatient and outpatient psychiatric settings across Texas (Phase 2). METHOD: The feasibility trial answered core questions regarding implementation of treatment guidelines for bipolar disorder. A total of 69 patients were treated with the original algorithms for bipolar disorder developed in Phase 1 of TMAP. RESULTS: Results support that physicians accepted the guidelines, followed recommendations to see patients at certain intervals, and utilized sequenced treatment steps differentially over the course of treatment. While improvements in clinical symptoms (24-item Brief Psychiatric Rating Scale) were observed over the course of enrollment in the trial, these conclusions are limited by the fact that physician volunteers were utilized for both treatment and ratings. and there was no control group. CONCLUSION: Results from Phases 1 and 2 indicate that it is possible to develop and implement a treatment guideline for patients with a history of mania in public mental health clinics in Texas. TMAP Phase 3, a recently completed larger and controlled trial assessing the clinical and economic impact of treatment guidelines and patient and family education in the public mental health system of Texas, improves upon this methodology.

Major system toxicities and side effects of anticonvulsants.

The use of anticonvulsants is expanding in the treatment of bipolar and related disorders. Although they have characteristics in common, the anticonvulsants currently used are quite diverse and vary in their spectrum of activity, quality of supporting evidence, and organ toxicities. Common side effects of anticonvulsants that can limit tolerability but are not physiologically severe include sedation and other cognitive impairments, tremor, and gastrointestinal side effects. Possibly less common, but of more physiologic significance, are effects on body weight and metabolism and dose-related hepatic and hematologic effects. Severe, but rare, toxicities include skin, bone marrow, and hepatic toxicity due to hypersensitivity. The most important aspect of successful management of severe toxicities is early detection, discontinuation of the medicine, and vigorous treatment of the toxicity. Anticonvulsants can also be associated with fetal toxicity, especially neural tube defects. In general, anticonvulsants are well tolerated and their effectiveness greatly outweighs risk or annoyance from side effects, but side effects must be kept in mind when choosing and monitoring treatment.

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.

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.

Alcohol consumption and nearly lethal suicide attempts.

We conducted a case-control study of the association between nearly lethal suicide attempts and facets of alcohol consumption; namely, drinking frequency, drinking quantity, binge drinking, alcoholism, drinking within 3 hours of suicide attempt, and age began drinking. Subjects were 13-34 years of age. In bivariable analyses, all measures were associated with nearly lethal suicide attempts. Odds ratios ranged from 2.4 for alcoholism to 7.0 for drinking within 3 hours of attempt. All exposure variables except age began drinking exhibited a J-shaped relationship between alcohol exposure and nearly lethal suicide attempt. After controlling for potential confounders and other measures of alcohol exposure, drinking within 3 hours of attempt remained most strongly (odds ratios > 6) associated. Alcoholism remained significantly associated in most models, but at lower strength.

The influence of geographic mobility on nearly lethal suicide attempts.

Teenagers and young adults are very mobile and mobility has been identified as a potential risk factor for suicidal behavior. We conducted a population-based, case-control study of nearly lethal suicide attempts with 153 cases and 513 controls. Study participants were asked about changing residence over the past 12 months. Results indicate that moving in the past 12 months is positively associated with a nearly lethal suicide attempt (adjusted odds ratio of 2.1, with 95% confidence interval of 1.4-3.3), as are specific characteristics of the move (e.g., frequency, recency, distance, and difficulty staying in touch). These findings confirm and extend prior ecologic research by demonstrating a relationship, at the individual level, between the geographic mobility of adolescents and young adults and nearly lethal suicide attempts.

Characteristics of impulsive suicide attempts and attempters.

Suicide attempts often are impulsive, yet little is known about the characteristics of impulsive suicide. We examined impulsive suicide attempts within a population-based, case-control study of nearly lethal suicide attempts among people 13-34 years of age. Attempts were considered impulsive if the respondent reported spending less than 5 minutes between the decision to attempt suicide and the actual attempt. Among the 153 case-subjects, 24% attempted impulsively. Impulsive attempts were more likely among those who had been in a physical fight and less likely among those who were depressed. Relative to control subjects, male sex, fighting, and hopelessness distinguished impulsive cases but depression did not. Our findings suggest that inadequate control of aggressive impulses might be a greater indicator of risk for impulsive suicide attempts than depression.

Integration of suicide prevention into outpatient management of bipolar disorder.

Suicide prevention is a critical objective in the treatment of bipolar disorder. This article describes practical mechanisms by which monitoring and management of suicide risk can be integrated into the routine care of patients with bipolar disorder. Suicide risk is assessed in terms of inclination (the drive to commit a self-destructive act) and opportunity (access to lethal means). Intervention strategies are adapted to the needs of bipolar patients across 3 phases of treatment: the acute episode; the continuation phase, when symptom reduction has occurred but adaptive recovery has not; and the maintenance phase, in which optimization of adaptive function and vigilance against impending relapse are paramount. Integration of suicide prevention into the outpatient management plan begins with a routine discussion of suicide risk at the initiation of a treatment relationship, even in the absence of other known risk factors. This discussion paves the way for ongoing assessment of suicidality. Just as the recommended routine monitoring of every euthymic bipolar patient includes at least some minimal assessment for prodromal symptoms of acute mania or depression, every clinical visit can include sufficient probes to determine the need for new interventions specific to suicide prevention. Ongoing assessment of risk and protective factors can be linked to a range of individualized interventions designed to meet the varying needs of patients over time. The intensity of monitoring and interventions reflects the clinician's knowledge of risk factors and may be life saving, but it is also important that patients and others involved in their care understand that monitoring cannot guarantee safety.