David E. Fleck

The impact of substance abuse on the course of bipolar disorder

BACKGROUND Substance abuse occurs at high rates in bipolar disorder. The reasons for this co-occurrence are unknown. Alcohol use disorders have been associated with both earlier and later age of onset of bipolar disorder, in part based on the temporal associations of the two conditions. Both drug and alcohol use disorders are associated with impaired outcome of bipolar illness. This influence may involve both direct effects of alcohol or drugs on the initiation of affective symptoms and indirect effects on treatment compliance. To extend these previous findings we examined the temporal associations of substance abuse and affective symptoms in patients with new onset bipolar disorder. METHODS Associations between affective symptoms and alcohol and cannabis use disorder symptoms were evaluated using regression and time-series correlative methods in 50 new-onset bipolar patients. RESULTS The duration of alcohol abuse during follow-up was associated with the time patients experienced depression. The duration of cannabis abuse was associated with the duration of mania. Several subgroups could be identified with different temporal relationships among these disorders. CONCLUSIONS Although the relationships among substance use and bipolar disorders are complex, systematic study of the courses of the disorders might clarify how these conditions interact longitudinally. As the numbers of subjects in specific subgroups are relatively small in this study, these results should be considered preliminary.

Impulsivity across the course of bipolar disorder

OBJECTIVE To determine whether abnormalities of impulse control persist across the course of bipolar disorder, thereby representing potential state markers and endophenotypes. METHODS Impulse control of 108 bipolar I manic or mixed patients was measured on three tasks designed to study response inhibition, ability to delay gratification, and attention; namely, a stop signal task, a delayed reward task, and a continuous performance task, respectively. Barrett Impulsivity Scale (BIS-11) scores were also obtained. Patients were then followed for up to one year and reassessed with the same measures if they developed depression or euthymia. Healthy comparison subjects were also assessed with the same instruments on two occasions to assess measurement stability. RESULTS At baseline, bipolar subjects demonstrated significant deficits on all three tasks as compared to healthy subjects, consistent with more impulsive responding in the bipolar manic/mixed group. In general, performance on the three behavioral tasks normalized upon switching to depression or developing euthymia. In contrast, BIS-11 scores were elevated during mania and remained elevated as bipolar subjects developed depression or achieved euthymia. CONCLUSIONS Bipolar I disorder patients demonstrate deficits on laboratory tests of various aspects of impulsivity when manic, as compared to healthy subjects, that largely normalize with recovery and switching into depression. However, elevated BIS-11 scores persist across phases of illness. These findings suggest that impulsivity has both affective-state dependent and trait components in bipolar disorder.

Concord Grape Juice Supplementation and Neurocognitive Function in Human Aging

Polyphenol compounds found in berry fruits, in particular flavonoids, have been associated with health benefits including improvement in cognition and neuronal function with aging. Concord grape juice contains polyphenols, including anthocyanins and flavanols, and previous research has shown improvement in a number of human health conditions with grape juice supplementation. In the current study, older adult subjects with mild cognitive impairment consumed Concord grape juice or placebo for 16 weeks and were administered assessments of memory function and brain activation pre- and postintervention. Participants who consumed grape juice showed reduced semantic interference on memory tasks. Relatively greater activation in anterior and posterior regions of the right hemisphere was also observed with functional magnetic resonance imaging in the grape juice treated subjects. These findings provide further evidence that Concord grape juice can enhance neurocognitive function in older adults with mild memory decline.

Functional magnetic resonance imaging brain activation in bipolar mania: evidence for disruption of the ventrolateral prefrontal-amygdala emotional pathway.

BACKGROUND Bipolar I disorder is defined by the occurrence of mania. The presence of mania, coupled with a course of illness characterized by waxing and waning of affective symptoms, suggests that bipolar disorder arises from dysfunction of neural systems that maintain emotional arousal and homeostasis. We used functional magnetic resonance imaging (fMRI) to study manic bipolar subjects as they performed a cognitive task designed to examine the ventrolateral prefrontal emotional arousal network. METHODS We used fMRI to study regional brain activation in 40 DSM-IV manic bipolar I patients and 36 healthy subjects while they performed a continuous performance task with emotional and neutral distracters. Event-related region-of-interest analyses were performed to test the primary hypothesis. Voxelwise analyses were also completed. RESULTS Compared with healthy subjects, the manic subjects exhibited blunted activation to emotional and neutral images, but not targets, across most of the predefined regions of interest. Several additional brain regions identified in the voxelwise analysis also exhibited similar differences between groups, including right parahippocampus, right lingual gyrus, and medial thalamus. In addition to these primary findings, the manic subjects also exhibited increased activation in response to targets in a number of brain regions that were primarily associated with managing affective stimuli. Group differences did not appear to be secondary to medication exposure or other confounds. CONCLUSIONS Bipolar manic subjects exhibit blunted brain fMRI response to emotional cues throughout the ventrolateral prefrontal emotional arousal network. Disruption of this emotional network may contribute to the mood dysregulation of bipolar disorder.

Eight-month functional outcome from mania following a first psychiatric hospitalization

The aim of this study was to identify how different areas of function (role performance, interpersonal relationships, sexual activity and recreational enjoyment) differentially recover from a manic episode during the 8 months following a first psychiatric hospitalization. Fifty patients with bipolar disorder, 16-45 years of age, who met the criteria for a current manic episode were recruited during their first psychiatric hospitalization. Forty-two (84%) of these participated in follow-up. Patients were evaluated using structured and semi-structured clinical instruments and the four areas of functional outcome were assessed with the LIFE interview. Recovery of the four areas of function were compared using survival and correlational analyses. Logistic regression identified factors associated with functional outcome. The four aspects of function were not significantly intercorrelated at baseline or during follow-up. Moreover, the survival curves for the different areas of function significantly differed. Specifically, patients demonstrated better recovery of sexual activity and worse recovery of recreational enjoyment than the other areas of function. Different clinical and demographic variables predicted recovery of the different areas of function. In conclusion, following a first manic episode, recovery of psychosocial function can be divided into separate components, i.e., role function, interpersonal relationships, sexual activity and recreational enjoyment, that appear to be relatively independent. Further clarification of recovery of these different areas of function may lead to better integrated treatments that maximize functional improvement early in the course of bipolar disorder.

Ethnicity and first-rank symptoms in patients with psychosis.

Previous studies suggested that African-American patients with psychotic disorders present more commonly with first-rank symptoms. However, it was unclear whether these results reflected true differences among African- and Euro-Americans in symptom presentation or instead resulted from raters being more likely to assign first-rank symptoms to African-American patients. In this study, a total of 195 African- and Euro-American patients presenting for hospitalization with psychosis were evaluated using structured diagnostic and symptom rating instruments; this evaluation was audiotaped. The tapes were transcribed and all cues indicating the patients ethnicity were edited from the transcript and from medical records. Two board-certified psychiatrists then evaluated the transcripts and medical records in order to make consensus expert diagnosis and rate first-rank symptoms. Ratings of first-rank symptoms in African- and Euro-American patients were compared between ethnicity-blinded expert consensus assessments and the unblinded structured interview. African-American men received higher first-rank symptom ratings than the remaining patient groups by both ethnicity-blinded expert consensus and unblinded structured interview. African-American men also had significantly more total psychotic symptoms than Euro-American men. However, the ethnically blinded expert consensus did not find an increased rate of schizophrenia in the African-American men. These findings indicate that psychotic symptom presentation should be evaluated in the context of other symptoms (e.g., affective symptoms) in diagnostic assessments in order to prevent misdiagnoses of schizophrenia.

Characterizing impulsivity in mania

OBJECTIVE To determine whether specific aspects of impulsivity (response disinhibition, inability to delay gratification, inattention) differ between healthy and bipolar manic subjects, and whether these aspects of impulsivity were associated with each other and severity of affective symptoms. METHODS Performance of 70 bipolar I manic or mixed patients was compared to that of 34 healthy subjects on three tasks specifically designed to study response inhibition, ability to delay gratification, and attention; namely, a stop signal task, a delayed reward task, and a continuous performance task, respectively. Correlations among tasks and with symptom ratings were also performed. RESULTS Bipolar subjects demonstrated significant deficits on all three tasks as compared to healthy subjects. Performance on the three tasks was largely independent. Task performance was not significantly associated with the severity of affective symptom ratings. However, measures of response inhibition and attention were sensitive to medication effects. Differences in the delayed reward task were independent of medication effects or symptom ratings. During the delayed reward task, although bipolar patients made their choices more slowly than healthy subjects, they were significantly more likely to choose a smaller, but more quickly obtained reward. Moreover, performance on this task was not associated with performance on the other impulsivity measures. Manic patients showed more impulsive responding than mixed patients. CONCLUSIONS Bipolar I manic patients demonstrate deficits on tests of various aspects of impulsivity as compared to healthy subjects. Some of these differences between groups may be mediated by medication effects. Findings suggested that inability to delay gratification (i.e., delayed reward task) was not simply a result of the speed of decision making or inattention, but rather that it reflected differences between bipolar and healthy subjects in the valuation of reward relative to delay.

Reaction time measures of sustained attention differentiate bipolar disorder from schizophrenia.

Although continuous performance tasks (CPTs) are becoming more common in psychiatric research, it remains unclear which performance measures best differentiate psychiatric patient groups and along which psychological dimensions. To address this the authors examined sustained attention decrements in patients with bipolar disorder and schizophrenia using CPT measures of perceptual sensitivity, response bias, and psychomotor processing speed. Patients with bipolar disorder with psychotic features (N=20), schizophrenia (N=20), and healthy controls (N=20) were evaluated using structured clinical interviews. These patients were rated with the Scale for the Assessment of Positive Symptoms and the Young Mania Rating Scale before completing a degraded-stimulus version of the CPT. Psychomotor processing speed was the only measure that reliably differentiated the groups across the entire vigilance period and was the strongest predictor of group membership. These findings suggest that reaction time measures may be sensitive to differences in the sustained attention abilities of patients with bipolar disorder and schizophrenia. By incorporating reaction time measures into CPT assessments, discriminant ability may be enhanced.

Placebo effect of medication cost in Parkinson disease: A randomized double-blind study

Objective: To examine the effect of cost, a traditionally “inactive” trait of intervention, as contributor to the response to therapeutic interventions. Methods: We conducted a prospective double-blind study in 12 patients with moderate to severe Parkinson disease and motor fluctuations (mean age 62.4 ± 7.9 years; mean disease duration 11 ± 6 years) who were randomized to a “cheap” or “expensive” subcutaneous “novel injectable dopamine agonist” placebo (normal saline). Patients were crossed over to the alternate arm approximately 4 hours later. Blinded motor assessments in the “practically defined off” state, before and after each intervention, included the Unified Parkinsons Disease Rating Scale motor subscale, the Purdue Pegboard Test, and a tapping task. Measurements of brain activity were performed using a feedback-based visual-motor associative learning functional MRI task. Order effect was examined using stratified analysis. Results: Although both placebos improved motor function, benefit was greater when patients were randomized first to expensive placebo, with a magnitude halfway between that of cheap placebo and levodopa. Brain activation was greater upon first-given cheap but not upon first-given expensive placebo or by levodopa. Regardless of order of administration, only cheap placebo increased activation in the left lateral sensorimotor cortex and other regions. Conclusion: Expensive placebo significantly improved motor function and decreased brain activation in a direction and magnitude comparable to, albeit less than, levodopa. Perceptions of cost are capable of altering the placebo response in clinical studies. Classification of evidence: This study provides Class III evidence that perception of cost is capable of influencing motor function and brain activation in Parkinson disease.

Influence of Patient Race and Ethnicity on Clinical Assessment in Patients With Affective Disorders

CONTEXT Rates of clinical diagnoses of schizophrenia in African American individuals appear to be elevated compared with other ethnic groups in the United States, contradicting population rates derived from epidemiologic surveys. OBJECTIVE To determine whether African American individuals would continue to exhibit significantly higher rates of clinical diagnoses of schizophrenia, even after controlling for age, sex, income, site, and education, as well as the presence or absence of serious affective disorder, as determined by experts blinded to race and ethnicity. A secondary objective was to determine if a similar pattern occurred in Latino subjects. DESIGN Ethnicity-blinded and -unblinded diagnostic assessments were obtained in 241 African American individuals (mean [SD] age, 34.3 [8.1] years; 57% women), 220 non-Latino white individuals (mean [SD] age, 32.7 [8.5] years; 53% women), and 149 Latino individuals (mean [SD] age, 33.5 [8.0] years; 58% women) at 6 US sites. Logistic regression models were used to determine whether elevated rates of schizophrenia in African American individuals would persist after controlling for various confounding variables including blinded expert consensus diagnoses of serious affective illness. SETTINGS Six academic medical centers across the United States. PARTICIPANTS Six hundred ten psychiatric inpatients and outpatients. MAIN OUTCOME MEASURE Relative odds of unblinded clinical diagnoses of schizophrenia in African American compared with white individuals. RESULTS A significant ethnicity/race effect (χ(2)(2)=10.4, P=.01) was obtained when schizophrenia was narrowly defined, controlling for all other predictors. The odds ratio comparing African American with non-Latino white individuals was significant (odds ratio=2.7; 95% CI, 1.5-5.1). Similar differences between African American and white individuals occurred when schizophrenia was more broadly defined (odds ratio=2.5; 95% CI, 1.4-4.5). African American individuals did not differ significantly from white individuals in overall severity of manic and depressive symptoms but did evidence more severe psychosis. CONCLUSIONS African American individuals exhibited significantly higher rates of clinical diagnoses of schizophrenia than non-Latino white subjects, even after controlling for covariates such as serious affective disorder.