Functional MRI of sustained attention in bipolar mania.

We examined sustained attention deficits in bipolar disorder and associated changes in brain activation assessed by functional magnetic resonance imaging (fMRI). We hypothesized that relative to healthy participants, those with mania or mixed mania would (1) exhibit incremental decrements in sustained attention over time, (2) overactivate brain regions required for emotional processing and (3) progressively underactivate attentional regions of prefrontal cortex. Fifty participants with manic/mixed bipolar disorder (BP group) and 34 healthy comparison subjects (HC group) received an fMRI scan while performing a 15-min continuous performance task (CPT). The data were divided into three consecutive 5-min vigilance periods to analyze sustained attention. Composite brain activation maps indicated that both groups activated dorsal and ventral regions of an anterior-limbic network, but the BP group exhibited less activation over time relative to baseline. Consistent with hypotheses 1 and 2, the BP group showed a marginally greater behavioral CPT sustained attention decrement and more bilateral amygdala activation than the HC group, respectively. Instead of differential activation in prefrontal cortex over time, as predicted in hypothesis 3, the BP group progressively decreased activation in subcortical regions of striatum and thalamus relative to the HC group. These results suggest that regional activation decrements in dorsolateral prefrontal cortex accompany sustained attention decrements in both bipolar and healthy individuals. Stable amygdala overactivation across prolonged vigils may interfere with sustained attention and exacerbate attentional deficits in bipolar disorder. Differential striatal and thalamic deactivation in bipolar disorder is interpreted as a loss of amygdala (emotional brain) modulation by the ventrolateral prefrontal-subcortical circuit, which interferes with attentional maintenance.

Experiences that matter in bipolar disorder: a qualitative study using the capability, comfort and calm framework.

BACKGROUND: When assessing the value of an intervention in bipolar disorder, researchers and clinicians often focus on metrics that quantify improvements to core diagnostic symptoms (e.g., mania). Providers often overlook or misunderstand the impact of treatment on life quality and function. We wanted to better characterize the shared experiences and obstacles of bipolar disorder within the United States from the patient's perspective. METHODS: We recruited 24 individuals diagnosed with bipolar disorder and six caretakers supporting someone with the condition. Participants were involved in treatment or support services for bipolar disorder in central Texas. As part of this qualitative study, participants discussed their everyday successes and obstacles related to living with bipolar disorder during personalized, open-ended interviews. Audio files were transcribed, and Nvivo software processed an initial thematic analysis. We then categorized themes into bipolar disorder-related obstacles that limit the patient's capability (i.e., function), comfort (i.e., relief from suffering) and calm (i.e., life disruption) (Liu et al., FebClin Orthop 475:315-317, 2017; Teisberg et al., MayAcad Med 95:682-685, 2020). We then discuss themes and suggest practical strategies that might improve the value of care for patients and their families. RESULTS: Issues regarding capability included the struggle to maintain identity, disruptions to meaningful employment, relationship loss and the unpredictable nature of bipolar disorder. Comfort related themes included the personal perception of diagnosis, social stigma and medication issues. Calm themes included managing dismissive doctors, finding the right psychotherapist and navigating financial burdens. CONCLUSIONS: Qualitative data from patients with bipolar disorder helps identify gaps in care or practical limitations to treatment. When we listen to these individuals, it is clear that treatments must also address the unmet psychosocial impacts of the condition to improve patient care, capability and calm.

Validity and severity thresholds for the depression subscale of the affective self rating scale: An equipercentile equating study using classical test theory.

BACKGROUND: The Affective Symptoms Scale (ASRS) is a unique instrument designed to separately measure depressive and manic symptoms in mood disorders. We validated the ASRS against the Patient Health Questionnaire (PHQ-9) and the Quick Inventory of Depressive Symptomatology (QIDS-16). METHODS: A retrospective study of 258 patients who completed the PHQ-9, QIDS-16 and ASRS as part of routine clinical care. To establish meaningful clinical thresholds for the depression subscale of the ASRS, it was equated with the QIDS and the PHQ-9. RESULTS: The depression subscale of the ASRS had significant positive correlations with the QIDS-16 and the PHQ-9 (respectively, r= 0.8, t[253] = 19.8, p < 0.001, and r= 0.8, t[245] = 28.2, p < 0.001). The equipercentile equating method with the PHQ-9 indicated that the thresholds corresponded to ASRS depression subscale scores of 5.4, 10.6, 16.1, and 23. Equating with the QIDS indicated that thresholds corresponded to ASRS depression subscale scores of 5.1, 11, 18.4, and 27.5. LIMITATIONS: Limitations include a small sample size that did not allow more detailed statistical analysis, such as Item Response Theory. The population is a heterogenous population at a university outpatient setting. CONCLUSIONS: The ASRS depression subscale significantly correlated with the PHQ-9 and QIDS-16. Our proposed threshold scores for the ASRS are 5, 11, 16 and 23 to indicated mild, moderate, severe and very severe depression respectively.

Differential patterns of brain activation over time in adolescents with and without attention deficit hyperactivity disorder (ADHD) during performance of a sustained attention task.

OBJECTIVE: Recent morphometric studies suggest that children with ADHD may demonstrate differential or delayed brain development compared with children without ADHD. This study examines the developmental course of brain activation patterns during the performance of an attention task. METHOD: Ten adolescents with ADHD and 14 healthy comparison adolescents performed a continuous performance task in an fMRI twice, one year apart. RESULTS: In the absence of performance differences, children with ADHD and healthy comparison subjects activated frontal-parietal regions while performing an attention task at initial testing. Children with ADHD appeared to require continued use of the right middle frontal gyrus during administration of testing one year apart while healthy comparison subjects did not activate this region at the time of the second testing. CONCLUSIONS: There appear to be developmental differences in brain activation patterns on an attentional task between ADHD and healthy controls. More research is needed for examining the longitudinal course of functional brain activation in children with ADHD.

The influence of religious affiliation on time to first treatment and hospitalization.

UNLABELLED: Longer duration of untreated psychosis (DUP) has been associated with treatment-refractory illness, significant cognitive decline, and poorer long-term outcomes. There are many factors, including social and cultural, that promote longer DUP. To date, there have been no studies to evaluate religion's effect on DUP. In this study, we evaluated the effect of certain religious affiliations and degree of religious practice on the DUP. METHODS: A total of 195 patients were recruited aged 18 to 45 years with the presence of at least 1 psychotic symptom (delusions, hallucinations, or prominent thought disorder). Patients were evaluated on their religious practice prior to the index episode using a Likert-style scale. Using a similar scale, patients were asked about their religious affiliation categorized as Catholic, Protestant, or neither. RESULTS: Correlational analysis revealed that the time to first treatment and time to first hospitalization were both was negatively related to degree of religious practice (r = -0.15, N = 161, p < 0.05 and r = -0.18, N = 161, p < 0.05, respectively). Between-group comparisons revealed longer DUP in the Protestant group compared to the no affiliation and Catholic groups (p = 0.05). CONCLUSION: From our results, it appears that the degree of religious practice does not affect length of time to treatment in psychotic patients. However, having a Protestant religious affiliation is strongly associated with having a greater delay in treatment seeking for psychosis. Factors contributing to a longer DUP in this group warrant further study.

Brain magnetic resonance imaging of structural abnormalities in bipolar disorder.

BACKGROUND: The neuropathogenesis of bipolar disorder remains poorly described. Previous work suggests that patients with bipolar disorder may have abnormalities in neural pathways that are hypothesized to modulate human mood states. We examined differences in brain structural volumes associated with these pathways between patients with bipolar disorder hospitalized with mania and healthy community volunteers. METHODS: Twenty-four patients with bipolar disorder and mania were recruited from hospital admission records. Twenty-two healthy volunteers were recruited from the community who were similar to the patients in age, sex, race, height, handedness, and education. All subjects were scanned using a 3-dimensional radio-frequency-spoiled Fourier acquired steady state acquisition sequence on a 1.5-T magnetic resonance imaging scanner. Scans were analyzed using commercial software. Prefrontal, thalamic, hippocampal, amygdala, pallidal, and striatal volumetric measurements were compared between the 2 groups. RESULTS: Patients with bipolar disorder demonstrated a significant (A = 0.64; F6,37 = 3.4; P = .009) overall difference in structural volumes in these regions compared with controls. In particular, the amygdala was enlarged in the patients. Brain structural volumes were not significantly associated with duration of illness, prior medication exposure, number of previous hospital admissions, or duration of substance abuse. Separating patients into first-episode (n = 12) and multiple-episode (n = 12) subgroups revealed no significant differences in any structure (P>.10). CONCLUSION: Patients with bipolar disorder exhibit structural abnormalities in neural pathways thought to modulate human mood.

Twelve-month outcome after a first hospitalization for affective psychosis.

BACKGROUND: We studied the 12-month course of illness after a first hospitalization for affective psychosis to identify potential outcome predictors in this rarely studied patient population. METHODS: For this study, 109 patients consecutively admitted for their first psychiatric hospitalization for treatment of affective psychosis were recruited. Diagnostic, symptomatic, and functional evaluations were obtained at the index hospitalization and at 2, 6, and 12 months after discharge to assess syndromic, symptomatic, and functional outcome predictors. Factors associated with outcome were identified by means of multivariate analyses. RESULTS: Fifty-six percent of the patients achieved syndromic recovery during the 12-month follow-up. Full treatment compliance was associated with more frequent and rapid syndromic recovery. Full compliance was more common in white patients and in patients without substance abuse. Only 35% of these patients achieved symptomatic recovery during this same 12-month interval, and, similarly, only 35% achieved functional recovery. Symptomatic recovery was delayed in patients with substance abuse and was associated with higher socioeconomic status. Higher socioeconomic status was also associated with functional recovery, as was good premorbid function. CONCLUSIONS: Few patients achieved a favorable outcome in the year after a first hospitalization for an affective psychosis. Low socioeconomic status, poor premorbid function, treatment noncompliance, and substance abuse were associated with lower rates or delayed onset of recovery.

D3 dopamine receptor, behavioral sensitization, and psychosis.

Behavioral sensitization is a progressive, enduring enhancement of behaviors that develops following repeated stimulant administration. It is mediated in part by dopaminergic pathways that also modulate a number of psychiatric conditions including the development of psychosis. We propose that down-regulation of D3 dopamine receptor function in critical brain regions contributes to sensitization. Rodent locomotion, a sensitizable behavior, is regulated by the opposing influence of dopamine receptor subtypes, with D3 stimulation opposing concurrent D1 and D2 receptor activation. The D3 dopamine receptor has a 70-fold greater affinity for dopamine than D1 or D2 dopamine receptors. This imbalance in ligand affinity dictates greater occupancy for D3 than D1 or D2 receptors at typical dopamine concentrations following stimulant drug administration, resulting in differences in the relative tolerance at D3 vs D1 and D2 receptors. Sensitization may therefore result in part from accommodation of the inhibitory D3 receptor 'brake' on D1/D2 mediated behaviors, leading to a progressive locomotion increase following repeated stimulant exposure. The requirement for differential tolerance at D3 vs D1 and D2 receptors may explain the observed development of sensitization following application of cocaine, but not amphetamine, directly into nucleus accumbens. If correct, the 'D3 Dopamine Receptor Hypothesis' suggests D3 antagonists could prevent sensitization, and may interrupt the development of psychosis when administered during the prodromal phase of psychotic illness. Additional study is needed to clarify the role of the D3 dopamine receptor in sensitization and psychosis.

Progressive behavioral response to repeated d-amphetamine challenge: further evidence for sensitization in humans.

BACKGROUND: Behavioral sensitization is the process whereby intermittent stimulant exposure produces a time-dependent, enduring, and progressive behavioral response. Although animal models of sensitization are well established, the phenomenon has been relatively little studied in humans. In a previous study, we reported enhanced responses following a second as compared to a first amphetamine dose in eye-blink rate and ratings of increased motor activity/energy, increased speech, and elevated mood in normal human volunteers. This current study extends those findings in a new sample of normal volunteers. METHODS: Eleven normal human volunteers were administered three single oral doses of d-amphetamine (0.25 mg/kg) at 48-hour intervals, alternating with matched placebo in a randomized, double-blind trial. Hourly behavioral ratings included eye-blink rate, symptoms (elevated mood, increased speech, increased motor activity/energy), and subjective drug effects. RESULTS: Eye-blink rate and increased motor activity/energy ratings progressively increased following each challenge with the third amphetamine dose response significantly greater than all other conditions 4 hours postadministration. Similar, although less pronounced, responses were observed for elevated mood and subjective drug effect. CONCLUSIONS: These results provide further evidence for sensitization of some amphetamine-induced behaviors in human subjects.

Enhanced behavioral response to repeated d-amphetamine and personality traits in humans.

BACKGROUND: This study examined whether the magnitude of the behavioral response to repeated d-amphetamine administration previously demonstrated in a double-blind study in humans was associated with certain personality characteristics. METHODS: Eleven normal volunteers completed the Tridimensional Personality Questionnaire (TPQ) prior to being administered three doses of d-amphetamine (0.25 mg/kg) alternating with three doses of placebo over 6 consecutive days. Behavioral measures included eye-blink rates as well as ratings of elevated mood, increased motor activity/energy, and increased speech. These variables were assessed once prior to dosing, then hourly for 5 hours. RESULTS: A greater magnitude of change in elevated mood over the three amphetamine doses significantly correlated with ratings of the Novelty Seeking on the TPQ. CONCLUSIONS: These results suggest that similar to findings in animal models, there are certain intrinsic behavioral characteristics that are associated with amphetamine sensitivity in humans.

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.

Placebo effect in randomized, controlled studies of acute bipolar mania and depression.

Randomized, double-blind, placebo-controlled, parallel group clinical trials have been the standard methodology for establishing the efficacy of new treatments for patients with bipolar disorder in manic, mixed, or depressive episodes. We examine the placebo response rate in acute treatment trials of acute mania (and mixed states) and bipolar depression. Also addressed are potential variables associated with placebo response, strategies to minimize placebo response, the optimum duration of placebo-controlled acute treatment trials, possible alternatives to the use of placebo, and the ramifications of these issues with regard to the design of studies in children, adolescents, and older adults with bipolar disorder.

Placebo effect in randomized, controlled maintenance studies of patients with bipolar disorder.

The prevention of mood episodes is an important goal of the maintenance treatment of patients with bipolar disorder. The rate of relapse on placebo compared with that on active treatment is an important issue in the design of future clinical trials of maintenance treatment. We examine the range and time course of placebo relapse rates in studies of patients with bipolar I disorder. In addition, we address the potential variables associated with placebo response, strategies to minimize placebo response, the optimum duration of placebo-controlled maintenance trials, possible alternatives to placebo control groups, and the impact of these considerations in maintenance studies of children, adolescents, and older adults with bipolar disorder.

Enhanced response to repeated d-amphetamine challenge: evidence for behavioral sensitization in humans.

Behavioral sensitization is the process whereby intermittent stimulant exposure produces a time-dependent, enduring, and progressively more robust behavioral response. This process serves as an important model of neural plasticity and has also been proposed as a model for a variety of psychiatric syndromes; however, there are no published controlled studies of behavioral sensitization in human subjects. The authors report results from a double-blind, placebo-controlled study of repeated d-amphetamine challenges in a sample of normal human volunteers. Eleven consecutively recruited normal volunteers participated in this 4-day protocol. Each subject received two daily doses of d-amphetamine (0.25 mg/kg) separated by 48 hours that alternated with two daily doses of matched placebo. Symptoms (activity/energy level, mood, rate, and amount of speech) and eye-blink rates were measured hourly for 5 hours following drug administration. All four measures demonstrated significantly enhanced increases following the second amphetamine dose as compared to the first amphetamine dose and both placebo conditions. These findings suggest that behavioral sensitization is measurable in human subjects.

Lack of enhanced response to repeated d-amphetamine challenge in first-episode psychosis: implications for a sensitization model of psychosis in humans.

Behavioral sensitization is the process whereby intermittent stimulant exposure produces a time-dependent, enduring, and progressively more robust behavioral response. This process serves as a model for the development of psychosis, but has been little studied in humans. The authors report results from a double-blind, placebo-controlled study of repeated d-amphetamine challenges in 13 patients with first-episode manic or schizophrenic psychosis. Each patient received two daily doses of d-amphetamine (0.25 mg/kg) separated by 48 hours that alternated with two daily doses of matched placebo. Symptoms (activity/energy level, mood, rate and amount of speech, and severity of psychosis) and eye-blink rates were measured hourly for 5 hours following drug administration. In contrast to results from previous work in normal volunteers, none of the measures demonstrated the progressive increase following the second amphetamine dose as compared to the first dose that characterizes sensitization. These results suggest that patients with psychosis are already maximally sensitized, so cannot exhibit progressive behavioral enhancement following repeated stimulant challenges, or that patients with psychosis do not sensitize.

Structural brain abnormalities in first-episode mania.

Using magnetic resonance imaging (MRI), we studied brain morphometric differences between patients with first-episode mania (n = 17) and normal control subjects (n = 16). Patients were admitted for their first psychiatric hospitalization and met DSM-III-R criteria for bipolar disorder, manic or mixed. Diagnoses were made using the Structured Clinical Interview for DSM-III-R. Patients and control subjects were matched for age, gender, height, past history of substance abuse, and handedness, although control subjects had attained higher levels of education. MRI inversion recovery coronal scans were used for measurements. Volumetric measurements were obtained for cerebral hemispheres, lateral and third ventricles, caudate, thalamus, and cingulate gyrus. Patients with first-episode mania demonstrated significantly larger third-ventricular volumes, possibly increased lateral ventricular volumes, and differences in gray/white matter distribution compared with normal control subjects. The possible pathophysiological meaning of these findings is discussed.

The McLean-Harvard first-episode project: 6-month symptomatic and functional outcome in affective and nonaffective psychosis.

BACKGROUND: The McLean-Harvard First-Episode Project recruited affective and nonaffective patients at their first lifetime psychiatric hospitalization. METHODS: Baseline evaluation and 6-month follow-up in 257 cases yielded recovery outcomes defined by syndromal (absence of DSM-IV criteria for a current episode) and functional (vocational and residential status at least at baseline levels) status. Time to recovery was assessed by survival analysis, and risk factors by multivariate logistic regression. RESULTS: Syndromal recovery was attained by 77% of cases over an average of 84 days. By diagnostic group, syndromal recovery rates ranked (p = .001) major affective disorders (81%) > nonaffective acute psychoses (74%) > schizoaffective disorders (70%) > schizophrenia (36%). Functional recovery was significantly associated to syndromal recovery, diagnosis, shorter hospitalization normalized to year, and older age at onset. Average hospital stay declined across the study period, but recovery did not vary with year of entry. CONCLUSIONS: Syndromal recovery was achieved by nearly one half of patients within 3 months of a first lifetime hospitalization for a psychotic illness, but functional recovery was not achieved by 6 months in nearly two thirds of patients who had attained syndromal recovery.

Differences in thyroid function between bipolar manic and mixed states.

BACKGROUND: High rates of thyroid axis abnormalities have been reported in most studies of patients with rapid-cycling bipolar disorder. Mixed states share similarities with rapid-cycling, including close temporal occurrence of manic and depressive symptoms, predominance in women, poor outcome, and less robust response to lithium compared with pure mania; however, thyroid axis abnormalities have not been well studied in mixed mania. METHODS: To test the hypothesis that mixed states are associated with a higher prevalence of hypothyroidism than pure mania, immunoreactive triiodothyronine (T3), thyroxine (T4), and thyroid-stimulating hormone (TSH) concentrations were determined from serum obtained at the time of admission in 37 consecutive patients with DSM-III-R bipolar disorder, manic or mixed. RESULTS: The mean TSH concentration was significantly higher, and the mean T4 concentration was significantly lower in patients with mixed mania compared with pure mania. There were no significant differences in T3 concentration or in previous lithium exposure. CONCLUSIONS: These findings suggest thyroid axis dysfunction is more common in bipolar mixed than in bipolar manic patients.

Differences in cerebral activation during smooth pursuit and saccadic eye movements using positron-emission tomography.

BACKGROUND: Abnormalities of smooth pursuit eye movements occur commonly in schizophrenia, but the pathophysiological significance of these abnormalities is unknown. To address this, the authors conducted a pilot study in which we examined differences in regional cerebral activation using positron-emission tomography (PET) in normal volunteers as they performed two types of eye movements. METHODS: Cerebral activation in 10 normal volunteers was studied using C15O2 PET while subjects tracked a visual target using smooth pursuit and saccadic eye movements. A left-hand movement comparison task provided a physiologic landmark for verification of the location of the frontal eye fields (FEFs). RESULTS: Subjects exhibited FEF activation during both smooth pursuit and saccadic eye movements, which was greater in the latter. During smooth pursuit, subjects also exhibited increased cerebral activation in the left temporal-occipital border and left superior frontal cortex and decreased activation in medial superior parietal and insular regions relative to saccades. Other cortical visual and eye-movement brain regions also demonstrated differences in activation between the two visual tasks. CONCLUSIONS: Significant fEF activation appears to underlie both smooth pursuit and saccadic eye movements but may be more critical in the former. Dysfunction of the frontal lobe, and possibly of other areas in the pursuit pathway such as the temporo-occipital motion area, may contribute to observed eye-movement abnormalities in patients with schizophrenia.

Symptom correlates of attentional improvement following hospitalization for a first episode of affective psychosis.

BACKGROUND: This study examined patients with a first-episode of affective psychosis during acute and compensated states in order to determine whether changes in attentional functioning over time were accompanied by changes in the severity of psychotic or affective symptoms. METHODS: Attentional performance was measured in patients (n = 27) using the degraded-stimulus continuous Performance Test (CPT) and symptoms were assessed at the time of index hospitalization, and 2 months after discharge. A comparison group of normal volunteers (n = 31) also performed the CPT two months apart. RESULTS: Patients performed significantly worse than controls at the initial testing but not at follow-up. The improvement in attentional performance significantly correlated with decreased severity of manic symptoms. CONCLUSIONS: Results suggest attentional dysfunction is a state-dependent characteristic of mania, and may provide an additional measure of clinical improvement following treatment.