Antidepressant tolerability in anxious and depressed youth at high risk for bipolar disorder: a prospective naturalistic treatment study.

OBJECTIVE: Depressive and anxiety disorders are common in youth who are at risk for bipolar disorder (i.e., youth who have at least one parent with bipolar disorder) and antidepressants are commonly prescribed as treatment. However, there are few data regarding the safety and tolerability of antidepressants in this population. Therefore, we sought to prospectively examine the effects of these medications in children and adolescents who are diagnosed with depressive or anxiety disorders and have a parent with bipolar I disorder. METHODS: Youth aged 9-20 years, with at least one parent with bipolar I disorder [high risk (HR)], were recruited (n = 118) and assessed using semi-structured diagnostic interviews. Participants were prospectively evaluated using a modified version of the Longitudinal Interval Follow-up Evaluation to assess changes in affective and anxiety symptoms and were treated naturalistically. RESULTS: Over the course of 43-227 weeks (mean duration of follow-up: 106 ± 55 weeks), 21% (n = 25) of youth had antidepressant exposure and, of these, 57% (n = 12) had an adverse reaction (e.g., irritability, aggression, impulsivity, or hyperactivity) that led to antidepressant discontinuation. Those patients who experienced an adverse reaction were significantly younger than those who did not (p = 0.02) and discontinuation of antidepressant therapy secondary to an adverse event occurred at an average of 16.7 ± 17.4 weeks (median: 11 weeks, range: 2-57 weeks). Cox proportional hazard analyses yielded a hazard ratio of 0.725 (p = 0.03), suggesting that there is a 27% decrease in the likelihood of an antidepressant-related adverse event leading to discontinuation with each one-year increase in age. CONCLUSIONS: Antidepressant medications may be poorly tolerated in youth with a familial risk for developing mania. Controlled studies further assessing treatments for depression and anxiety in HR youth are urgently needed.

Conflict monitoring and adaptation in individuals at familial risk for developing bipolar disorder.

OBJECTIVE: To examine conflict monitoring and conflict-driven adaptation in individuals at familial risk for developing bipolar disorder. METHODS: We recruited 24 adolescents who had a parent with bipolar disorder and 23 adolescents with healthy parents. Participants completed an arrow version of the Eriksen Flanker Task that included trials with three levels of conflict: neutral, congruent, and incongruent flanks. Differences in performance were explored based upon the level of conflict in the current and previous trials. RESULTS: Individuals at risk for developing bipolar disorder performed more slowly than youth with healthy parents in all trials. Analyses evaluating sequential effects revealed that at-risk subjects responded more slowly than youth of healthy parents for all trial types when preceded by an incongruent trial, for incongruent trials preceded by congruent trials, and for neutral and congruent trials when preceded by neutral trials. In contrast to the comparison group, at-risk adolescents failed to display a response time advantage for incongruent trials preceded by an incongruent trial. When removing subjects with attention-deficit hyperactivity disorder (ADHD), differences between groups in response time fell below significant level, but a difference in sequence modulation remained significant. Subjects at risk for bipolar disorder also displayed greater intra-subject response time variability for incongruent and congruent trials compared with the comparison adolescents. No differences in response accuracy were observed between groups. CONCLUSIONS: Adolescents at risk for developing bipolar disorder displayed specific deficits in cognitive flexibility, which might be useful as a potential marker related to the development of bipolar disorder.

The effects of ziprasidone on prefrontal and amygdalar activation in manic youth with bipolar disorder.

BACKGROUND: Prior research has found that manic adolescents with bipolar disorder exhibit neurofunctional changes in the amygdala and prefrontal cortex following treatment with some pharmacological agents. We examined the neurofunctional effects of ziprasidone in manic adolescents. METHOD: Manic adolescents with bipolar disorder (n=23) participated in a placebo-controlled study of ziprasidone and underwent a functional magnetic resonance imaging scanning session while performing a task of sustained attention at baseline, prior to treatment as well as on days 7 and 28 (or early termination) of treatment. A comparison group of healthy adolescents (n=10) participated in a single scanning session. Region of interest analyses were performed to assess activation changes associated with treatment in Brodmann Areas (BA) 10, 11 and 47 and in the amygdala. RESULTS: Compared with placebo, treatment with ziprasidone was associated with greater increases over time in right BA 11 and 47 activation. These effects were not associated with differences in symptom improvement between the treatment groups. Patients who subsequently responded to ziprasidone showed significantly greater deactivation in the right Brodmann area 47 at baseline than those who did not respond to ziprasidone. Similarly, among the bipolar adolescents who were treated with ziprasidone, baseline activation in right BA 47 was negatively correlated with improvement in Young Mania Rating Scale (YMRS) score. LIMITATIONS: The small sample size limits the ability to detect significant group differences in other regions of interest. Healthy comparison subjects were scanned only at a single timepoint, which limits the interpretation of the results. Ziprasidone is not currently approved by the United States Food and Drug Administration for the treatment of adolescents with mania, and, therefore, the clinical relevance of these results is limited. CONCLUSIONS: The increases in right BA 11 and 47 activation observed during sustained attention tasks following ziprasidone treatment and the association identified between lower baseline BA 47 activation and ziprasidone treatment response suggests that ziprasidone may correct prefrontal dysfunction in manic adolescents with bipolar disorder.

Impulsivity in adolescents with bipolar disorder and/or attention-deficit/hyperactivity disorder and healthy controls as measured by the Barratt Impulsiveness Scale.

OBJECTIVE: To compare the type and degree of impulsivity among adolescents with bipolar disorder (BD), adolescents with attention-deficit/hyperactivity disorder (ADHD), and healthy comparison subjects using the Barratt Impulsiveness Scale, Version 11 (BIS-11). METHODS: Manic adolescents with BD (n=31), adolescents with ADHD (n=30), and healthy subjects (n=25) completed the BIS-11, a 30-item, self-report scale with three subscales (cognitive, motor, and nonplanning). The BIS-11 total and subscale scores were compared among groups. We also examined associations among the BIS-11, Young Mania Rating Scale and co-occurring disruptive behavioral disorders (DBDs) within the BD group. RESULTS: Total and each subscale scores were significantly higher for the BD group than for the healthy controls (p<0.05). The total scores and the cognitive and motor subscale scores were significantly higher for the ADHD group than for the healthy control group (p<0.05). However, there was no statistically significant difference between the nonplanning subscale scores of the ADHD group and the healthy control group (p>0.05). There were no significant differences between the BD and ADHD groups or between the BD groups with and without ADHD. The BD patients with DBDs (i.e., oppositional defiant disorder or conduct disorder) scored significantly higher on the motor subscale than did BD patients without DBDs. There were no statistically significant associations between the Young Mania Rating Scale and BIS-11 scores within the BD group. CONCLUSION: Our findings suggest that impulsivity is elevated in adolescents with BD as well as adolescents with ADHD, except for nonplanning impulsivity, which was not significantly different between adolescents with ADHD and the healthy comparison group. This may suggest that nonplanning impulsivity is relatively specific to adolescents with BD. Additionally, our data indicate that elevations in impulsivity, as measured by the BIS-11, may be independent of symptoms severity and, therefore, may be a stable, trait-related component of BD.

Progression of amygdala volumetric abnormalities in adolescents after their first manic episode.

OBJECTIVE: Although previous neuroimaging studies suggest that adolescents with bipolar disorder exhibit smaller amygdala volumes compared with healthy adolescents, whether these abnormalities are present at illness onset or instead develop over time remains unclear. The aim of this study was to conduct a prospective longitudinal investigation comparing amygdala neurodevelopment among adolescents after their first manic episode, adolescents with attention-deficit/hyperactivity disorder (ADHD), and healthy adolescents. METHOD: A total of 30 adolescents hospitalized for their first manic/mixed episode associated with bipolar disorder, 29 adolescents with ADHD, and 24 demographically matched healthy teens underwent magnetic resonance imaging scanning at index assessment and approximately 12 months later. Adolescents with bipolar disorder were prospectively evaluated using diagnostic interviews and with symptom rating scales. RESULTS: Mixed models examining the group × time effect for both left (p = .005) and right (p = .002) amygdala volumes were statistically significant. Change in left (p = .01) and right (p = .0008) amygdala volumes from baseline to 12 months were significantly different among groups. Specifically, left amygdala volumes increased over time in healthy adolescents (p = .008) and adolescents with ADHD (p = .0009), but not in adolescents with bipolar disorder (p = .3). Right amygdala volume increased over time in adolescents with ADHD (p < .001), but not in healthy adolescents nor in adolescents with bipolar disorder (p = .1 and p = .3, respectively). In adolescents with bipolar disorder, baseline total amygdala volume was significantly greater in those who subsequently achieved symptomatic recovery as compared with those who did not achieve recovery (p = .02). CONCLUSIONS: Adolescents with mania do not exhibit normal increases in amygdala volume that occur during healthy adolescent neurodevelopment.

Progressive neurostructural changes in adolescent and adult patients with bipolar disorder.

OBJECTIVES: Several lines of evidence suggest that bipolar disorder is associated with progressive changes in gray matter volume (GMV), particularly in brain structures involved in emotional regulation and expression. The majority of these studies however, have been cross-sectional in nature. In this study we compared baseline and follow-up scans in groups of bipolar disorder and healthy subjects. We hypothesized bipolar disorder subjects would demonstrate significant GMV changes over time. METHODS: A total of 58 bipolar disorder and 48 healthy subjects participated in structural magnetic resonance imaging (MRI). Subjects were rescanned 3-34 months after their baseline MRI. MRI images were segmented, normalized to standard stereotactic space, and compared voxel-by-voxel using statistical parametrical mapping software (SPM2). A model was developed to investigate differences in GMV at baseline, and associated with time and episodes, as well as in comparison to healthy subjects. RESULTS: We observed increases in GMV in bipolar disorder subjects across several brain regions at baseline and over time, including portions of the prefrontal cortex as well as limbic and subcortical structures. Time-related changes differed to some degree between adolescent and adult bipolar disorder subjects. The interval between scans positively correlated with GMV increases in bipolar disorder subjects in portions of the prefrontal cortex, and both illness duration and number of depressive episodes were associated with increased GMV in subcortical and limbic structures. CONCLUSIONS: Our findings support suggestions that widely observed progressive neurofunctional changes in bipolar disorder patients may be related to structural brain abnormalities in anterior limbic structures. Abnormalities largely involve regions previously noted to be integral to emotional expression and regulation, and appear to vary by age.

Abnormal FMRI brain activation in euthymic bipolar disorder patients during a counting Stroop interference task.

BACKGROUND: Bipolar disorder is characterized by disturbed mood homeostasis accompanied by cognitive impairments that appear to persist during euthymia. Cognitive probes, coupled with neuroimaging, provide an approach toward clarifying the neurophysiology of bipolar disorder. METHOD: Sixteen patients with euthymic bipolar disorder and 16 healthy subjects underwent functional magnetic resonance imaging (fMRI) while performing a counting Stroop interference task and a control condition. Task performance was correlated with regional brain activation differences between groups, and the effect on brain activation of receiving versus not receiving medications was evaluated. RESULTS: Bipolar patients exhibited impaired task performance relative to the healthy subjects. In addition, the two groups demonstrated significantly different patterns of brain activation during the interference task. Healthy subjects exhibited relatively increased activation in temporal cortical regions, middle frontal gyrus, putamen, and midline cerebellum. Bipolar subjects exhibited relatively greater activation in the medial occipital cortex. The groups demonstrated different associations between task performance and fMRI activation in these brain regions. No differences in activation in these regions were observed between patients who were versus those who were not receiving medications; however, patients receiving medications exhibited greater activation in the anterior cingulate and dorsolateral prefrontal cortex. CONCLUSIONS: These differences suggest that patients with euthymic bipolar disorder fail to activate brain regions associated with performance of an interference task, which may contribute to impaired task performance. Medications do not explain these differences but may influence activation of brain regions primarily associated with performing an interference task.

MRI analysis of cerebellar vermal abnormalities in bipolar disorder.

OBJECTIVE: The authors sought to expand previous findings of vermal abnormalities in bipolar disorder patients. METHOD: Magnetic resonance imaging (MRI) morphometry was used to quantify vermal subregion volumes in 18 subjects with first-episode bipolar disorder, 21 subjects with multiple-episode bipolar disorder, and 32 healthy subjects. RESULTS: Vermal subregion V2 volume was significantly smaller in multiple-episode bipolar disorder subjects than in first-episode patients and healthy subjects. Vermal subregion V3 was significantly smaller in multiple-episode bipolar disorder subjects than in healthy subjects. CONCLUSIONS: These results suggest that posterior-inferior cerebellar vermal abnormalities are present in patients with multiple-episode bipolar disorder.

Comorbid ADHD is associated with altered patterns of neuronal activation in adolescents with bipolar disorder performing a simple attention task.

OBJECTIVES: Bipolar disorder is increasingly recognized as a significant source of psychiatric morbidity in children and adolescents. Younger bipolar patients symptomatically differ from adults, and frequently present with comorbid disorders, particularly attention-deficit hyperactivity disorder (ADHD). The neurophysiological relationship between these two disorders, however, remains unclear. In this study we utilized functional magnetic resonance imaging (fMRI) to compare activation patterns during performance of a simple attention task between bipolar adolescents with and without ADHD. METHODS: Eleven bipolar adolescents with comorbid ADHD and 15 bipolar adolescents without comorbidity were recruited to participate in fMRI scans. A single-digit continuous performance task alternated with a control task in a block-design paradigm. between-group comparisons were made using voxel-by-voxel analysis. Follow-up correlations were made between performance and activation. RESULTS: Group performance did not significantly differ in percentage correct (p = 0.36) or discriminability (p = 0.11). ADHD comorbidity was associated with less activation in the ventrolateral prefrontal cortex (Brodmann 10) and anterior cingulate, and greater activation in posterior parietal cortex and middle temporal gyrus. Comorbid ADHD was associated with substantial differences in patterns of correlation between performance and voxel-by-voxel activation. CONCLUSIONS: Our findings suggest that comorbid ADHD in bipolar adolescents is associated with activation of alternative pathways during performance of a simple attention task. The pattern of differences suggests that bipolar adolescents with comorbid ADHD demonstrate decreased activation of prefrontal regions, compared with bipolar adolescents without ADHD, and preferentially recruit portions of posterior parietal and temporal cortex.

Parametric neurocognitive task design: a pilot study of sustained attention in adolescents with bipolar disorder.

BACKGROUND: Disruption in attention is one of the core features of bipolar disorder (BP). Therefore, neurocognitive paradigms assessing brain function in response to tasks of increasing attentional difficulty may be useful to clarify the neurophysiology of bipolar disorder. The aim of this study was to obtain pilot performance data using a parametric task of sustained attention that might be useful as an experimental paradigm for future functional neuroimaging studies. We hypothesized that task performance would worsen as task difficulty increased in manic and euthymic bipolar and healthy subjects. Additionally, we hypothesized that the groups would exhibit a similar decline in task performance as level of task difficulty increased and that within each level of task difficulty there would be similar performance among groups. METHODS: A novel parametric Continuous Performance Task-Identical Pairs (CPT-IP) version was administered to manic (N=10) and euthymic (N=10) adolescents with bipolar disorder and healthy controls (N=10). RESULTS: There were no statistically significant group differences in task performance as measured by discriminability, percent correct, false positive hits, and reaction time. However, within each group, performance on all measures worsened with increased attentional difficulty (p<0.0001). There were no statistically significant task difficulty by group interactions. Furthermore, medication exposure and comorbid attention-deficit hyperactivity disorder were not associated with most measures of task performance. However, BP subjects who were treated with medications had slower task performance compared with BP subjects who were unmedicated. LIMITATIONS: Larger studies examining the effects of specific medication classes on task performance are necessary. CONCLUSIONS: The results of this pilot study suggest that manic and euthymic BP patients do not exhibit attentional dysfunction as compared to healthy adolescents using a novel parametric version of the CPT-IP. Furthermore, our parametric CPT-IP version may be useful as a novel parametric neurocognitive paradigm for future functional neuroimaging studies of bipolar adolescents.

Voxel-based morphometry in adolescents with bipolar disorder: first results.

Bipolar disorder is an increasingly recognized cause of significant morbidity in the pediatric age group. However, there is still a large degree of uncertainty regarding the underlying neurobiological deficits. In this preliminary study, we performed automated volumetric studies and whole-brain voxel-based morphometry (VBM) on gray matter. Imaging data from 10 adolescents with bipolar disorder were compared with data from 52 age- and gender-matched healthy controls. Previously defined brain parcellations and optimized VBM protocols were used, based on custom-made pediatric reference data. An additional, exploratory whole-brain comparison was also implemented. The volumetric region-of-interest study revealed significantly greater gray matter volume in central gray matter structures bilaterally (including the basal ganglia and the thalamus) and the left temporal lobe in the bipolar group. VBM confirmed bilaterally larger basal ganglia. Localized gray matter deficits in bipolar subjects were found in the medial temporal lobe, orbito-frontal cortex, and the anterior cingulate, confirming and extending earlier studies.

Magnetic resonance imaging analysis of amygdala and other subcortical brain regions in adolescents with bipolar disorder.

OBJECTIVES: Few studies have examined the abnormalities that underlie the neuroanatomy of bipolar disorder in youth. The aim of this study was to evaluate brain regions that are thought to modulate mood utilizing quantitative analyses of thin-slice magnetic resonance imaging (MRI) scans of adolescents with bipolar disorder. We hypothesized that adolescents with bipolar disorder would exhibit abnormalities in brain regions that are involved in the regulation of mood including the amygdala, globus pallidus, caudate, putamen, and thalamus. METHODS: Bipolar adolescents (n = 23) and healthy subjects (n = 20) matched for age, race, sex, socioeconomic status, IQ, education and Tanner stage, were evaluated using the Washington University at St Louis Kiddie-Schedule for Affective Disorders and Schizophrenia (WASH-U K-SADS). Contiguous 1 mm axial T1-weighted MRI slices were obtained using a GE 1.5 T MR scanner. Regions of interest (ROI) included total cerebral volume, amygdala, globus pallidus, caudate, putamen, and thalamus. RESULTS: Total cerebral volume was smaller in bipolar adolescents than in healthy adolescents. A MANCOVA revealed a significant group difference in overall ROI volumes after adjusting for total cerebral volume. Specifically, adolescents with bipolar disorder exhibited smaller amygdala and enlarged putamen compared with healthy subjects. CONCLUSIONS: Our findings indicate that adolescents with bipolar disorder exhibit abnormalities in some of the brain regions that are thought to be involved in the regulation of mood. Additional structural and functional neuroimaging investigations of children, adolescents, and adults with bipolar disorder are necessary to clarify the role of these brain regions in the neurophysiology of adolescent bipolar disorder.

Ventricular and periventricular structural volumes in first- versus multiple-episode bipolar disorder.

OBJECTIVE: Ventriculomegaly has been reported in bipolar disorder, although whether it occurs at illness onset or progresses during the course of the disorder is unknown. In addition, it is unknown whether ventriculomegaly in bipolar disorder reflects acquired volume loss or underdevelopment of periventricular structures. METHOD: Magnetic resonance imaging was used to measure the volumes of the lateral and third ventricles and periventricular structures (caudate, putamen, thalamus, hippocampus). Patients with DSM-IV bipolar disorder, 18 who were having a first episode and 17 with multiple episodes, were compared with 32 healthy subjects. RESULTS: The lateral ventricles were significantly larger in the patients with multiple-episode bipolar disorder than in the first-episode patients or the healthy subjects, even after periventricular and total cerebral volumes were taken into account. Having larger lateral ventricles was associated with a higher number of prior manic episodes. The multiple-episode patients had a smaller total cerebral volume than the healthy subjects but not the first-episode patients. The putamen was significantly larger in the first-episode patients (and nearly so in the multiple-episode patients) than in the healthy subjects, although there was no difference between patient groups. CONCLUSIONS: Lateral ventriculomegaly was greater in bipolar disorder patients who had had repeated manic episodes, but it does not appear to be secondary to small critical periventricular structures. A larger than normal striatum, which has been reported in previous studies, was observed in first-episode patients. These results support the importance of prospectively studying neuroanatomic changes in bipolar disorder.