Neurostructural impact of co-occurring anxiety in pediatric patients with major depressive disorder: a voxel-based morphometry study.

BACKGROUND: Depressive and anxiety disorders are among the most frequently occurring psychiatric conditions in children and adolescents and commonly present occur together. Co-occurring depression and anxiety is associated with increased functional impairment and suicidality compared to depression alone. Despite this, little is known regarding the neurostructural differences between anxiety disorders and major depressive disorder (MDD). Moreover, the neurophysiologic impact of the presence of anxiety in adolescents with MDD is unknown. METHODS: Using voxel-based morphometry, gray matter volumes were compared among adolescents with MDD (and no co-morbid anxiety disorders, n=14), adolescents with MDD and co-morbid anxiety ("anxious depression," n=12), and healthy comparison subjects (n=41). RESULTS: Patients with anxious depression exhibited decreased gray matter volumes in the dorsolateral prefrontal cortex (DLPFC) compared to patients with MDD alone. Compared to healthy subjects, adolescents with anxious depression had increased gray matter volumes in the pre- and post-central gyri. LIMITATIONS: The current sample size was small and precluded an analysis of multiple covariates which may influence GMV. CONCLUSIONS: Gray matter deficits in the DLPFC in youth with anxious depression compared to patients with MDD and no co-occurring anxiety may reflect the more severe psychopathology in these patients. Additionally, the distinct gray matter fingerprints of MDD and anxious depression (compared to healthy subjects) suggest differing neurophysiologic substrates for these conditions, though the etiology and longitudinal trajectory of the differences remain to be determined.

Bipolar I disorder and major depressive disorder show similar brain activation during depression.

OBJECTIVES: Despite different treatments and courses of illness, depressive symptoms appear similar in major depressive disorder (MDD) and bipolar I disorder (BP-I). This similarity of depressive symptoms suggests significant overlap in brain pathways underlying neurovegetative, mood, and cognitive symptoms of depression. These shared brain regions might be expected to exhibit similar activation in individuals with MDD and BP-I during functional magnetic resonance imaging (fMRI). METHODS: fMRI was used to compare regional brain activation in participants with BP-I (n = 25) and MDD (n = 25) during a depressive episode as well as 25 healthy comparison (HC) participants. During the scans, participants performed an attentional task that incorporated emotional pictures. RESULTS: During the viewing of emotional images, subjects with BP-I showed decreased activation in the middle occipital gyrus, lingual gyrus, and middle temporal gyrus compared to both subjects with MDD and HC participants. During attentional processing, participants with MDD had increased activation in the parahippocampus, parietal lobe, and postcentral gyrus. However, among these regions, only the postcentral gyrus also showed differences between MDD and HC participants. CONCLUSIONS: No differences in cortico-limbic regions were found between participants with BP-I and MDD during depression. Instead, the major differences occurred in primary and secondary visual processing regions, with decreased activation in these regions in BP-I compared to major depression. These differences were driven by abnormal decreases in activation seen in the participants with BP-I. Posterior activation changes are a common finding in studies across mood states in participants with BP-I.

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.

A systematic review of the evidence for the treatment of acute depression in bipolar I disorder.

In this article, we examined evidence for the acute treatment of depression in bipolar I disorder, focusing on double-blind, placebo-controlled studies with a definite primary outcome measure and published in peer review journals. Quetiapine and olanzapine/fluoxetine are currently approved by the FDA for the treatment of bipolar depression, and a number of additional agents (including other atypical antipsychotics, mood stabilizers, antidepressants, and novel compounds) have been studied with varying degrees of efficacy. The medication with the most evidence for efficacy in bipolar depression is quetiapine, with five studies showing positive efficacy compared to placebo. In contrast, five studies of lamotrigine were negative, although meta-analyses of the pooled have found some treatment effects. Two studies of olanzapine and olanzapine/fluoxetine and three small studies of divalproex showed significant efficacy in treating bipolar depression. Two studies of aripiprazole found no differences compared to placebo. Early research on lithium in bipolar depression had significant methodological flaws, and only one study of lithium met our primary search criteria. To better understand the role of antidepressants, we also examined studies of antidepressants as adjunctive treatment of bipolar depression in participants taking mood stabilizers or atypical antipsychotics. These studies reported mixed results for a variety of antidepressants, but the majority found no differences compared to placebo. Other studies of adjunctive treatment were also discussed. There has been one positive adjunctive study each of lamotrigine, omega-3 fatty acids, modafinil, and armodafinil, while there was one negative trial each of omega-3 fatty acids, ziprasidone, and levetiracetam.

Neuroanatomic abnormalities in adolescents with generalized anxiety disorder: a voxel-based morphometry study.

BACKGROUND: Despite recent data implicating functional abnormalities in the neurocircuitry underlying emotional processing in pediatric anxiety disorders, little is known regarding neurostructural abnormalities within these systems. METHODS: Using voxel-based morphometry, gray and white matter volumes were compared in 15 medication-free adolescents with generalized anxiety disorder (GAD; and no comorbid major depressive disorder) and 28 age- and sex-matched healthy comparison subjects. RESULTS: Compared to healthy adolescents, youth with GAD had larger gray matter volumes in the right precuneus and right precentral gyrus and decreased gray matter volumes in the left orbital gyrus and posterior cingulate. White matter volumes were decreased in the left medial and superior frontal gyrus and were increased in the left inferior temporal gyrus in youth with GAD relative to healthy subjects. CONCLUSIONS: Adolescents with GAD, who are early in the course of their illness, exhibit abnormalities in neural structures that subserve threat appraisal, modulation of fear responses, attachment, and mentalization.

The six most essential questions in psychiatric diagnosis: a pluralogue. Part 4: general conclusion.

In the conclusion to this multi-part article I first review the discussions carried out around the six essential questions in psychiatric diagnosis - the position taken by Allen Frances on each question, the commentaries on the respective question along with Frances' responses to the commentaries, and my own view of the multiple discussions. In this review I emphasize that the core question is the first - what is the nature of psychiatric illness - and that in some manner all further questions follow from the first. Following this review I attempt to move the discussion forward, addressing the first question from the perspectives of natural kind analysis and complexity analysis. This reflection leads toward a view of psychiatric disorders - and future nosologies - as far more complex and uncertain than we have imagined.

The six most essential questions in psychiatric diagnosis: a pluralogue part 3: issues of utility and alternative approaches in psychiatric diagnosis.

In face of the multiple controversies surrounding the DSM process in general and the development of DSM-5 in particular, we have organized a discussion around what we consider six essential questions in further work on the DSM. The six questions involve: 1) the nature of a mental disorder; 2) the definition of mental disorder; 3) the issue of whether, in the current state of psychiatric science, DSM-5 should assume a cautious, conservative posture or an assertive, transformative posture; 4) the role of pragmatic considerations in the construction of DSM-5; 5) the issue of utility of the DSM - whether DSM-III and IV have been designed more for clinicians or researchers, and how this conflict should be dealt with in the new manual; and 6) the possibility and advisability, given all the problems with DSM-III and IV, of designing a different diagnostic system. Part 1 of this article took up the first two questions. Part 2 took up the second two questions. Part 3 now deals with Questions 5 & 6. Question 5 confronts the issue of utility, whether the manual design of DSM-III and IV favors clinicians or researchers, and what that means for DSM-5. Our final question, Question 6, takes up a concluding issue, whether the acknowledged problems with the earlier DSMs warrants a significant overhaul of DSM-5 and future manuals. As in Parts 1 & 2 of this article, the general introduction, as well as the introductions and conclusions for the specific questions, are written by James Phillips, and the responses to commentaries are written by Allen Frances.

The six most essential questions in psychiatric diagnosis: a pluralogue part 2: Issues of conservatism and pragmatism in psychiatric diagnosis.

In face of the multiple controversies surrounding the DSM process in general and the development of DSM-5 in particular, we have organized a discussion around what we consider six essential questions in further work on the DSM. The six questions involve: 1) the nature of a mental disorder; 2) the definition of mental disorder; 3) the issue of whether, in the current state of psychiatric science, DSM-5 should assume a cautious, conservative posture or an assertive, transformative posture; 4) the role of pragmatic considerations in the construction of DSM-5; 5) the issue of utility of the DSM--whether DSM-III and IV have been designed more for clinicians or researchers, and how this conflict should be dealt with in the new manual; and 6) the possibility and advisability, given all the problems with DSM-III and IV, of designing a different diagnostic system. Part I of this article took up the first two questions. Part II will take up the second two questions. Question 3 deals with the question as to whether DSM-V should assume a conservative or assertive posture in making changes from DSM-IV. That question in turn breaks down into discussion of diagnoses that depend on, and aim toward, empirical, scientific validation, and diagnoses that are more value-laden and less amenable to scientific validation. Question 4 takes up the role of pragmatic consideration in a psychiatric nosology, whether the purely empirical considerations need to be tempered by considerations of practical consequence. As in Part 1 of this article, the general introduction, as well as the introductions and conclusions for the specific questions, are written by James Phillips, and the responses to commentaries are written by Allen Frances.

A longitudinal functional connectivity analysis of the amygdala in bipolar I disorder across mood states.

OBJECTIVE: Bipolar I disorder is characterized by affective symptoms varying between depression and mania. The specific neurophysiology responsible for depression in bipolar I disorder is unknown but previous neuroimaging studies suggest impairments in corticolimbic regions that are responsible for regulating emotion. The amygdala seems to play a central role in this network and is responsible for appraisal of emotional stimuli. To further understand the role of the amygdala in the generation of mood symptoms, we used functional magnetic resonance imaging (fMRI) to examine a group of patients with bipolar I disorder longitudinally. METHODS: fMRI was used to study regional brain activation in 15 bipolar I disorder patients followed for up to one year. Patients received an fMRI scan during an initial manic episode and a subsequent depressive episode. During the scans, patients performed an attentional task that incorporated emotional pictures. Fifteen healthy comparison subjects were also scanned at baseline and then at four months. Whole-brain functional connectivity analysis was performed using the left and right amygdala as seed regions. RESULTS: Significant changes in amygdala functional connectivity were found between the manic and depressed phases of illness. The right amygdala was significantly more positively correlated with the left inferior frontal gyrus during mania and with the right insula during depression. There were no significant differences in left amygdala correlations across mood states in the bipolar I disorder group. CONCLUSIONS: In the transition from a manic/mixed episode to a depressive episode, subjects with bipolar I disorder showed unique changes in cortical-amygdala functional connectivity. Increased connectivity between the insula and right amygdala may generate excessive positive feedback, in that both of these regions are involved in the appraisal of emotional stimuli. Increased correlation between the right amygdala and the inferior frontal gyrus in mania is consistent with previous findings of decreased prefrontal modulation of limbic regions in mania. These differences in connectivity may represent neurofunctional markers of mood state as they occurred in the same individuals across manic and depressive episodes.

The six most essential questions in psychiatric diagnosis: a pluralogue part 1: conceptual and definitional issues in psychiatric diagnosis.

In face of the multiple controversies surrounding the DSM process in general and the development of DSM-5 in particular, we have organized a discussion around what we consider six essential questions in further work on the DSM. The six questions involve: 1) the nature of a mental disorder; 2) the definition of mental disorder; 3) the issue of whether, in the current state of psychiatric science, DSM-5 should assume a cautious, conservative posture or an assertive, transformative posture; 4) the role of pragmatic considerations in the construction of DSM-5; 5) the issue of utility of the DSM - whether DSM-III and IV have been designed more for clinicians or researchers, and how this conflict should be dealt with in the new manual; and 6) the possibility and advisability, given all the problems with DSM-III and IV, of designing a different diagnostic system. Part I of this article will take up the first two questions. With the first question, invited commentators express a range of opinion regarding the nature of psychiatric disorders, loosely divided into a realist position that the diagnostic categories represent real diseases that we can accurately name and know with our perceptual abilities, a middle, nominalist position that psychiatric disorders do exist in the real world but that our diagnostic categories are constructs that may or may not accurately represent the disorders out there, and finally a purely constructivist position that the diagnostic categories are simply constructs with no evidence of psychiatric disorders in the real world. The second question again offers a range of opinion as to how we should define a mental or psychiatric disorder, including the possibility that we should not try to formulate a definition. The general introduction, as well as the introductions and conclusions for the specific questions, are written by James Phillips, and the responses to commentaries are written by Allen Frances.

Preliminary evidence for increased frontosubcortical activation on a motor impulsivity task in mixed episode bipolar disorder.

BACKGROUND: Of all mood states, patients in mixed episodes of bipolar disorder are at the greatest risk for impulsive behaviors including attempted suicide. The aim of this study was to examine whether the neural correlates of motor impulsivity are distinct in patients with mixed mania. METHODS: Ten patients with bipolar disorder in a mixed episode (BP-M), 10 bipolar comparison participants in a depressed episode (BP-D), and 10 healthy comparison (HC) participants underwent functional MRI while performing a Go/No-Go task of motor impulsivity. RESULTS: Both patient groups had elevated, self-rated motor impulsiveness scores. The BP-M group also had a trend-level increase in commission errors relative to the HC group on the Go/No-Go task. While the full sample strongly activated a ventrolateral prefrontal-subcortical brain network, the BP-M group activated the amygdala and frontal cortex more strongly than the HC group, and the thalamus, cerebellum, and frontal cortex more strongly than the BP-D group. LIMITATIONS: This study is primarily limited by a relatively small sample size. CONCLUSIONS: Higher commission error rates on the Go/No-Go task suggest increased vulnerability to impulsive responding during mixed episodes of bipolar disorder. Moreover, the distinct pattern of increased brain activation during mixed mania may indicate a connection between behavioral impulsivity and a failure of neurophysiological "inhibition", especially in the amygdala.

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.

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.

Differential brain activation during response inhibition in bipolar and attention-deficit hyperactivity disorders.

AIM: To identify differential patterns of brain activation between adolescents with bipolar disorder and adolescents with attention-deficit hyperactivity disorder (ADHD) to better understand the neurophysiology of both disorders. We hypothesized that subjects with ADHD would show altered activation in brain regions involved in executive and sustained attention. In contrast, we hypothesized that bipolar subjects would show altered brain activation in regions responsible for emotionally homeostasis, including the striatum and amygdala. METHODS: Functional magnetic resonance imaging was performed during a continuous performance task with a response inhibition component in 11 adolescents with bipolar disorder during a manic episode, 10 adolescents with ADHD, and 13 healthy adolescents. RESULTS: There were no differences in behavioural performance among the three groups. Compared with bipolar subjects, subjects with ADHD showed increased activation in the superior temporal lobe during successful response inhibition. Although bipolar subjects did not show activation differences in the striatum or amygdala compared with ADHD subjects, increased left parahippocampal activation in the bipolar group was associated with increased manic symptoms. CONCLUSIONS: The patterns of brain activation observed in the current study support divergent patterns of neurophysiological dysfunction in individuals with bipolar disorder as compared with those with ADHD. Therefore, the impulsive behaviour seen in both disorders may be the consequence of dysfunction in different brain regions, and further research may help identify neurobiological markers that are specific to each condition.

The functional neuroanatomy of bipolar disorder.

In this manuscript, research articles using functional magnetic resonance imaging (fMRI) to study adult patients with bipolar disorder were reviewed. The findings from these studies identify altered brain activation in five regions in cortico-limbic pathways responsible for emotional regulation: portions of the prefrontal cortex; anterior cingulate cortex; amygdala; thalamus; and striatum. The most consistent findings were overactivation of amygdala, striatum, and thalamus. Findings in prefrontal cortex were less consistent, but most studies also showed increased activation in ventrolateral and dorsolateral prefrontal cortical areas. Excessive activation in brain regions associated with emotional regulation may contribute to the affective symptoms of bipolar disorder. However, there are several important limitations in this body of research. Even when similar tasks were used, brain activation was often discrepant among studies. Most fMRI studies examined small samples (ten or fewer bipolar subjects) limiting statistical power. Additionally, most studies were confounded by patients taking psychotropic medications. Nonetheless, from this work an anterior limbic over-activation model of bipolar disorder is emerging.

Expect psychiatric side effects from corticosteroid use in the elderly.

Psychiatric side effects including mania, depression, psychosis, and delirium, are extremely common in patients treated with corticosteroids. The elderly and those with previous psychiatric diagnoses are not at increased risk for these side effects, but females and those with prior corticosteroid-induced psychiatric side effects are. Depression and mania are the most frequent behavioral side effects, followed by psychosis and delirium. In the geriatric population, there is a long list of medical etiologies of psychosis, delirium, mania, and depression. These must be distinguished from corticosteroid side effects. Treatment involves stopping the corticosteroids, if possible, and targeting the specific psychiatric symptoms that develop.

Magnetic resonance imaging brain activation in first-episode bipolar mania during a response inhibition task.

AIMS: Impulsivity is common in bipolar disorder, especially during mania. Understanding the functional neuroanatomy of response inhibition, one component of impulsivity, might clarify the neural substrate of bipolar disorder. METHODS: Sixteen DSM-IV first-episode, manic bipolar patients and 16 matched healthy subjects were examined during a first manic episode using functional magnetic resonance imaging while performing a response inhibition task. All subjects were studied using a 4.0 Tesla Varian Unity INOVA Whole Body MRI/MRS system. The response inhibition task was presented using non-ferromagnetic goggles, and task performance was recorded during scan acquisition. Imaging data were analysed using analysis of functional neuroimages. Group contrasts were made for the specific response inhibition measure. RESULTS: The groups performed the task similarly, although both demonstrated relatively poor rates of target response, but high rates of successful 'stops'. Despite similar behavioural results, the groups showed significantly different patterns of functional magnetic resonance imaging brain activation. Specifically, during response inhibition, the healthy subjects exhibited significantly greater activation in anterior and posterior cingulate, medial dorsal thalamus, middle temporal gyrus, and precuneus. The bipolar patients exhibited prefrontal activation (BA 10) that was not observed in healthy subjects. CONCLUSIONS: Bipolar and healthy subjects exhibit different patterns of brain activation to response inhibition; these differences may reflect different functional neuroanatomic approaches to response inhibition between the two groups.

Morphometric magnetic resonance imaging in psychiatry.

Although advances in the clinical criteria of various axis I psychiatric disorders are continually being made, there is still considerable overlap in the clinical features, and diagnosis is often challenging. As a result, there has been substantial interest in using morphometric magnetic resonance imaging to better characterize these diseases and inform diagnosis. Region of interest and voxel-based morphometry studies are reviewed herein to examine the extent to which these goals are being met across various psychiatric disorders. It is concluded based on the studies reviewed that specific patterns of regional loss, although present in certain axis I disorders, are not, as yet, diagnostically useful. However, advances in outcome and treatment monitoring show considerably more promise for rapid application in psychiatry.