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BACKGROUND: Psychotic depression (PD) is a severe disabling disorder with considerable morbidity and mortality. Electroconvulsive therapy and pharmacotherapy are each efficacious in the treatment of PD. Expert guidelines recommend the combination of antidepressant and antipsychotic medications in the acute pharmacologic treatment of PD. However, little is known about the continuation treatment of PD. Of particular concern, it is not known whether antipsychotic medication needs to be continued once an episode of PD responds to pharmacotherapy. This issue has profound clinical importance. On the one hand, the unnecessary continuation of antipsychotic medication exposes a patient to adverse effects, such as weight gain and metabolic disturbance. On the other hand, premature discontinuation of antipsychotic medication has the potential risk of early relapse of a severe disorder.

METHODS/DESIGN: The primary goal of this multicenter randomized placebo-controlled trial is to assess the risks and benefits of continuing antipsychotic medication in persons with PD once the episode of depression has responded to treatment with an antidepressant and an antipsychotic. Secondary goals are to examine age and genetic polymorphisms as predictors or moderators of treatment variability, potentially leading to more personalized treatment of PD. Individuals aged 18-85 years with unipolar psychotic depression receive up to 12 weeks of open-label treatment with sertraline and olanzapine. Participants who achieve remission of psychosis and remission/near-remission of depressive symptoms continue with 8 weeks of open-label treatment to ensure stability of remission. Participants with stability of remission are then randomized to 36 weeks of double-blind treatment with either sertraline and olanzapine or sertraline and placebo. Relapse is the primary outcome. Metabolic changes are a secondary outcome.

DISCUSSION: This trial will provide clinicians with much-needed evidence to guide the continuation and maintenance treatment of one of the most disabling and lethal of psychiatric disorders.

TRIAL REGISTRATION AND URL: NCT: NCT01427608.

Support for Institutional Animal Care and Use Committees (IACUCs) varies among those in animal use-related professions. The authors designed and carried out an anonymous survey to solicit opinions on the structure and organizational functions of IACUCs. They found that most respondents believed a single, institution-based IACUC was an appropriate venue for institutional approval of animal care and use, that their IACUCs represented their institutions' constituencies and that the unaffiliated IACUC members adequately represented their surrounding communities. Respondents believed that members came prepared for IACUC meetings, and a majority agreed that full committee reviews were more thorough than designated member reviews. The quality of veterinary care for animals was deemed to be very good. Participants reported that the status of the person submitting an animal use protocol, the perceived monetary value of a grant associated with a protocol and pressure for a rapid protocol review did not alter the quality of the protocol review. On many of the survey items, opinions of IACUC members differently significantly from those of non-members, and opinions of non-member IACUC administrators differed from those of IACUC chairpersons, perhaps owing to differences in responsibilities and perceived status.

A diverse panel convened in June 2011 to explore a dilemma in human research: some traits may make individuals or communities particularly vulnerable to a variety of harms in research; however, well-intended efforts to protect these vulnerable individuals and communities from harm may actually generate a series of new harms.

We have presented a consensus statement forged by the panel through discussion during a 2-day meeting and the article-writing process. We have identified practical problems that sometimes arise in connection with providing additional safeguards for groups labeled as vulnerable and offered recommendations on how we might better balance concerns for protection with concerns for justice and participant autonomy.

Clinician-researchers have responsibilities both to seek the best interests of the people they treat and to advance scientific knowledge. The purpose of this study was to examine researchers' beliefs and behaviors regarding areas of tension between their clinical and scientific roles. We conducted and analyzed 19 in-depth interviews with psychiatric clinical researchers to explore these issues. Responses usually indicated that researchers recognize limits on their abilities to be helpful to patients, since they cannot know in advance whether a specific research intervention will help and whether participation is in the patient's best interest. Hence, most researchers did not make special efforts to recruit patients doing poorly in standard care, although they occasionally tolerated minor deviations from recruitment and treatment protocols when they might be in participants' interests. Often respondents asked the IRB to approve these deviations or change the protocol for all subjects, though it was unclear how often they may have acted without this approval. Despite researchers' high regard for following the research protocol, clinical judgment remained the ultimate guide if patients were not doing well and needed alternative care. Hence, respondents expressed a strong commitment both to protecting patients' interests and to advancing science. In cases of direct conflict between the two, many of the researchers tended to promote patients' best interests even at some cost to scientific research.

OBJECTIVE: The authors compared the predictive accuracy of two risk assessment methods that are feasible to use in routine clinical settings: brief risk assessment tools and patients' self-perceptions of risk.

METHODS: In 2002-2003, clinical interviewers met with 86 high-risk inpatients with co-occurring mental and substance use disorders (excluding schizophrenia) to carefully elicit the patients' global rating of their risk of behaving violently and to complete two brief risk assessment tools-the Clinically Feasible Iterative Classification Tree (ICT-CF) and the Modified Screening Tool (MST). Two months after discharge, patients were reinterviewed in the community to assess their involvement in violence.

RESULTS: Patients' self-perceptions of risk performed quite well in predicting serious violence (area under the curve [AUC]=.74, sensitivity=50%), particularly compared with the ICT-CF (AUC=.59, sensitivity=40%) and the MST (AUC=.66, sensitivity=30%). Self-perceived risk also added significant incremental utility to these tools in predicting violence.

CONCLUSIONS: Patients' self-perceptions hold promise as a method for improving risk assessment in routine clinical settings. Assuming it replicates and generalizes beyond the research context, this finding encourages a shift away from unaided clinical judgment toward a feasible method of risk assessment built on patient collaboration.

Utilization of novel approaches in imaging modalities are needed for enhancing diagnostic and therapeutic outcomes of persons suffering a traumatic brain injury (TBI). This study explored the feasibility of using functional magnetic resonance imaging (fMRI) in conjunction with behavioral measures to target dynamic changes in specific neural circuitries in an animal model of traumatic brain injury. Wistar rats were randomly assigned to one of two groups (traumatic brain injury / sham operation). TBI rats were subjected to the closed head injury (CHI) model. Any observable motor deficits and cognitive deficits associated with the injury were measured using Beam Walk and Morris Water Maze tests, respectively. fMRI was performed to assess the underlying post-traumatic cerebral anatomy and function in acute (24 hours after the injury) and chronic (7 and 21 days after the injury) phases. Beam Walk test results detected no significant differences in motor deficits between groups. Morris Water Maze test indicated that cognitive deficits persisted for the first week following injury and to a large extent, recovered thereafter. Resting state functional connectivity (rsFC) analysis detected initially diminished connectivity between cortical areas involved in cognition for the TBI group; however the connectivity patterns normalized at one week and remained so at three weeks post-injury timepoint. Taken together, we have demonstrated an objective in vivo marker for mapping functional brain changes correlated with injury-associated cognitive behavior deficits and offer an animal model for testing potential therapeutic interventions options.

Investigations into the specific association of amygdala volume, a critical aspect of the fronto-limbic emotional circuitry, and aggression have produced results broadly consistent with the 'larger is more powerful' doctrine. However, recent reports suggest that the ventral and dorsal aspects of the amygdala play functionally specific roles, respectively, in the activation and control of behavior. Therefore, parceling amygdala volume into dorsal and ventral components might prove productive in testing hypotheses regarding volumetric association to aggression, and impulsivity, a related aspect of self-control.

We sought to test this hypothesis in a group of 41 psychiatric patients who received standard magnetic resonance imaging and a psychometric protocol including aggression and impulsivity measures. Whole amygdala volumes were not associated with aggression or impulsivity, but significant correlations were found when dorsal/ventral amygdalae were analyzed separately. Specifically, left and right ventral amygdala volume was positively associated with motor impulsivity, and left dorsal amygdala was negatively associated with aggression.

Results are discussed in terms of an activation and control model of brain-behavior relations. Potential relevance to the continuum of amygdala hyper- to hypo-activation and aggression is discussed.

It is now recognized that a number of cognitive, behavioral, and mental health outcomes across the lifespan can be traced to fetal development. Although the direct mediation is unknown, the substantial variance in fetal growth, most commonly indexed by birth weight, may affect lifespan brain development. We investigated effects of normal variance in birth weight on MRI-derived measures of brain development in 628 healthy children, adolescents, and young adults in the large-scale multicenter Pediatric Imaging, Neurocognition, and Genetics study. This heterogeneous sample was recruited through geographically dispersed sites in the United States. The influence of birth weight on cortical thickness, surface area, and striatal and total brain volumes was investigated, controlling for variance in age, sex, household income, and genetic ancestry factors. Birth weight was found to exert robust positive effects on regional cortical surface area in multiple regions as well as total brain and caudate volumes. These effects were continuous across birth weight ranges and ages and were not confined to subsets of the sample. The findings show that (i) aspects of later child and adolescent brain development are influenced at birth and (ii) relatively small differences in birth weight across groups and conditions typically compared in neuropsychiatric research (e.g., Attention Deficit Hyperactivity Disorder, schizophrenia, and personality disorders) may influence group differences observed in brain parameters of interest at a later stage in life. These findings should serve to increase our attention to early influences.

BACKGROUND: Research exploring Bipolar Disorder (BD) phenotypes and mitochondrial dysfunction, particularly in younger subjects, has been insufficient to date. Previous studies have found abnormal cerebral pH levels in adults with BD, which may be directly linked to abnormal mitochondrial activity. To date no such studies have been reported in children with BD.

METHODS: Phosphorus Magnetic Resonance Spectroscopy ((31)P MRS) was used to determine pH, phopshocreatine (PCr) and inorganic phosphate (Pi) levels in 8 subjects with BD and 8 healthy comparison subjects (HCS) ages 11 to 20 years old.

RESULTS: There was no significant difference in pH between the patients and HCS. However, frontal pH values for patients with BD increased with age, contrary to studies of HCS and the pH values in the frontal lobe correlated negatively with the YMRS values. Global Pi was significantly lower in subjects with BD compared with HCS. There were no significant differences in PCr between the groups. Global PCr-to-Pi ratio (PCr/Pi) was significantly higher in subjects with BD compared with HCS.

CONCLUSIONS: The change in Pi levels for the patients with BD coupled with the no difference in PCr levels, suggest an altered mitochondrial phosphorylation. However, our findings require further investigation of the underlying mechanisms with the notion that a mitochondrial dysfunction may manifest itself differently in children than that in adults.

LIMITATIONS: Further investigations with larger patient populations are necessary to draw further conclusions.

This study examined the convergent and divergent validity of heart-rate (HR)-based response discrepancy scores as measures of denial. After standardizing measures of stressor-related anxiety, hostility, and HR, response discrepancy scores were calculated by subtracting each measure of negative affect from the HR value. Analyses revealed the response discrepancy scores to correlate positively with measures of denial, negatively with a measure of trait anger, and to not correlate with measures of the nondefensive need for approval and the positive trait of curiosity. These findings support the construct validity of response discrepancy scores as markers of denial.

A meta-analysis of 295 relevant effect sizes obtained from 25,469 participants confirmed expectations that elevated blood pressure (BP) and essential hypertension (EH) would be associated with lower affect expression but with more negative affectivity and defensiveness. The strongest associations occurred for defensiveness and measures of anger and affect expression linked to an interpersonal context(s). However, a number of other factors also were found to moderate associations of BP with personality measures, including awareness of BP status, gender, occupation, and diastolic versus systolic BP assessment. Given these moderators, the authors conclude that a traditional view of personality causing EH is untenable and that, not incorporating multifactorial, synergistic approaches is likely to obscure associations of personality-behavior with EH.

This meta-analytic review predicted and confirmed that interpersonal contact between mental health employees or students and persons diagnosed with psychiatric disorders is associated with improved attitudes toward the latter group. As also predicted, the amount of attitude change was found to be smaller, although still significant, when the evaluative measure described a group of the "mentally ill" rather than specific individuals, and when the respondents were mental health employees rather than students. Contrary to predictions, contact interventions of longer duration were not associated with greater attitude changes. It is concluded that contact interventions occurring in mental health settings are effective in promoting attitude changes toward persons with psychiatric disorders, and methodological refinements that should strengthen the effectiveness of future contact interventions are outlined.

We investigated psychosocial treatment interventions, mood symptoms, and substance use among 24 patients with bipolar disorder and substance dependence. Patients were assessed for 6 months following hospital discharge. Psychotherapy and Alcoholics Anonymous (AA) attendance decreased over time. Moreover, the focus of patients' psychotherapy changed over time, with decreasing emphasis on the patients' specific disorders. Mood symptoms and substance use did not change significantly over time, although there was a trend toward more frequent drug use over time. These findings point to infrequent utilization over time of psychosocial treatments focusing specifically on bipolar and substance use disorder.

BACKGROUND: Bipolar disorder (BPD) is the Axis I disorder with the highest risk for coexisting substance use disorder. One explanation for this phenomenon is the 'self-medication hypothesis', which states that some patients experience improvement in psychiatric symptoms as a result of substance use. We thus investigated reasons for substance use and perceived substance-induced improvement in BPD symptoms among patients with current BPD and substance dependence.

METHODS: A total of 45 patients received six monthly assessments; 21 also received integrated group therapy (IGT), focusing simultaneously on BPD and substance dependence, while 24 did not receive IGT. Patients reported at intake their current reasons for initiating substance use (including BPD symptoms) and the effects of substance use on those symptoms.

RESULTS: Nearly all patients initiated substance use because of at least one BPD symptom, especially depression (77.8%) and racing thoughts (57.8%); most (66.7%) reported improvement in at least one BPD symptom as a result of substance use. Among patients reporting substance-induced improvement in BPD symptoms, those receiving IGT reported fewer days of drug use over the 6-month study period than those not receiving IGT; this difference was not significant among patients without substance-induced improvement in BPD symptoms.

LIMITATIONS: The study is limited by its small sample size and by the potential inaccuracy of self-reports regarding the effects of substance use on mood.

CONCLUSIONS: Substance dependent patients who report that substance use improves their BPD symptoms may benefit from treatment that focuses simultaneously on both disorders.

Little is known about the impact of sexual or physical abuse history on response to alcohol treatment. This prospective study investigated the relationships between sexual and physical abuse histories, participants' characteristics, and response to inpatient alcohol treatment. Forty-one women and 59 men were assessed monthly for 1 year following hospitalization for alcohol dependence. Survival analyses showed that sexual abuse history was associated with shorter times to first drink and relapse. Physical abuse history was not associated with poorer drinking outcomes. Although women were more likely than men to have a history of sexual abuse, no gender differences were found in drinking outcomes. Poorer drinking outcomes were found among participants who at baseline were not married, had less than a college education, were not employed full time, or carried a diagnosis of depression or other psychiatric disorder. When adjusted for these characteristics, the associations between sexual abuse history and times to first drink and relapse were no longer statistically significant. While sexual abuse history is a clinically meaningful predictor of return to drinking we note the importance of considering patients' background and clinical characteristics in examining the impact of sexual abuse history on drinking outcomes following treatment.

Bipolar and substance use disorders are known to co-occur frequently, but limited attention has been paid to anxiety disorders that may accompany this dual diagnosis. Therefore, we examined the prevalence and nature of anxiety disorders among treatment-seeking patients diagnosed with current bipolar and substance use disorders, and investigated the association between anxiety disorders and substance use. Among 90 participants diagnosed with bipolar disorder I (n = 75, 78%) or II (n = 15, 22%), 43 (48%) had a lifetime anxiety disorder, with post-traumatic stress disorder (PTSD) occurring most frequently (n = 21, 23%). We found that those with PTSD, but not with the other anxiety disorders assessed, began using drugs at an earlier age and had more lifetime substance use disorders, particularly cocaine and amphetamine use disorders, than those without PTSD. Further examination revealed that (1) most participants with PTSD were women, (2) sexual abuse was the most frequently reported index trauma, and (3) the mean age of the earliest index trauma occurred before the mean age of initiation of drug use. Our findings point to the importance of further investigating the ramifications of a trauma history among those who are dually diagnosed with bipolar and substance use disorders.

OBJECTIVE: Although bipolar disorder and substance use disorder frequently co-occur, there is little information on the effectiveness of behavioral treatment for this population. Integrated group therapy, which addresses the two disorders simultaneously, was compared with group drug counseling, which focuses on substance use. The authors hypothesized that patients receiving integrated group therapy would have fewer days of substance use and fewer weeks ill with bipolar disorder.

METHOD: A randomized controlled trial compared 20 weeks of integrated group therapy or group drug counseling with 3 months of posttreatment follow-up. Sixty-two patients with bipolar disorder and current substance dependence, treated with mood stabilizers for >or=2 weeks, were randomly assigned to integrated group therapy (N=31) or group drug counseling (N=31). The primary outcome measure was the number of days of substance use. The primary mood outcome was the number of weeks ill with a mood episode.

RESULTS: Intention-to-treat analysis revealed significantly fewer days of substance use for integrated group therapy patients during treatment and follow-up. Groups were similar in the number of weeks ill with bipolar disorder during treatment and follow-up, although integrated group therapy patients had more depressive and manic symptoms.

CONCLUSIONS: Integrated group therapy, a new treatment developed specifically for patients with bipolar disorder and substance dependence, appears to be a promising approach to reduce substance use in this population.

BACKGROUND: We examined a modified version of the Hamilton Depression Rating Scale (HDRS) among treatment-seeking patients with co-occurring bipolar disorder and substance dependence in order to elucidate key features of depression in this specific population of patients.

METHODS: Patients with current bipolar disorder and substance dependence who were prescribed mood stabilizers (n=105) completed a 27-item version of the HDRS that was subjected to item and principal components analyses. Preliminary validity analysis consisted of comparing the derived total and component scores to the depressed mood indicators from the Addiction Severity Index (ASI).

RESULTS: Eleven items representing two related components labeled "melancholia" and "anxiety" were retained. The 11-item HDRS total and component scores were higher for those who reported serious depression, serious anxiety, cognitive problems, and suicidal ideation on the ASI than for those who did not report these problems.

LIMITATIONS: We conducted the analyses with a relatively small sample of patients who were primarily white and were diagnosed with bipolar I disorder, thus limiting the generalizability of findings. Moreover, we obtained limited data regarding construct validity of the 11-item scale.

CONCLUSIONS: Our psychometric evaluation of the HDRS led us to retain 11 items representing primarily melancholic and neurovegetative symptoms of depression. These findings suggest that sample-specific item characteristics of the HDRS need to be evaluated prior to using this scale to assess depressive symptom severity among patients with complex diagnostic and treatment characteristics.

Despite decades of theory and research implicating suppressed anger in the development of cardiovascular disorders involving cardiovascular reactivity (CVR), to date the theoretical components of low anger expression, guilt feelings over agonistic reactions, and defensive strivings to avoid social disapproval have not been used conjointly to profile suppressed anger for the prediction of CVR. The purpose of this study, then, was to cluster analyze measures of anger expression, hostility guilt, and social defensiveness to create a suppressed anger profile (low anger expression, high hostility guilt, high social defensiveness) and a non-suppressed profile from a sample of college males. Social evaluative threat may be a potent stressor for people who defensively suppress anger expression. Thus, to examine the combined effects of suppressed anger and social evaluative threat, participants, prior to telling a story to a Thematic Apperception Card (TAT), were randomly assigned to either a high-threat (story will be compared to stories created by the mentally ill) or a low-threat condition (story used to study effects of talking on cardiovascular responses). Blood pressure (BP) and heart rate (HR) were monitored during a rest period and the subsequent TAT card period. As predicted, suppressed anger males in the high-threat condition showed the highest levels of diastolic BP and HR change from the rest period. The suppressed anger group's systolic BP reactivity was independent of threat manipulation. Research implications are discussed.

Few individuals with substance use disorders limit their intake to one substance of abuse; however, many studies focus on a single substance. Unfortunately, the optimal method to determine the principal substance is unclear. In particular, this issue is problematic in patients with co-occurring psychiatric illness, who commonly use multiple substances. Hence we compared three methods for assessing the principal substance of abuse in 150 subjects with bipolar disorder and substance dependence: 1) the Addiction Severity Index interview, 2) a self-administered questionnaire, and 3) the most frequently used substance. While most subjects were concordant on the interview and the other two methods, we found substantial disagreement (9.3% between the interview and the questionnaire, and 12.7% between the interview and the most frequently used substance) and partial agreement (14.0%). These findings from a comorbid population demonstrate that different methods to assess principal substance of abuse could lead to different conclusions about treatment outcomes. Hence studies of comorbid patients may benefit from 1) using more than one method to assess principal substance and 2) reporting use of all substances as well as a targeted substance.