Stephen M. Strakowski

The functional neuroanatomy of bipolar disorder: a review of neuroimaging findings

The authors review existing structural and functional neuroimaging studies of patients with bipolar disorder and discuss how these investigations enhance our understanding of the neurophysiology of this illness. Findings from structural magnetic resonance imaging (MRI) studies suggest that some abnormalities, such as those in prefrontal cortical areas (SGPFC), striatum and amygdala exist early in the course of illness and, therefore, potentially, predate illness onset. In contrast, other abnormalities, such as those found in the cerebellar vermis, lateral ventricles and other prefrontal regions (eg, left inferior), appear to develop with repeated affective episodes, and may represent the effects of illness progression and associated factors. Magnetic resonance spectroscopy investigations have revealed abnormalities of membrane and second messenger metabolism, as well as bioenergetics, in striatum and prefrontal cortex. Functional imaging studies report activation differences between bipolar and healthy controls in these same anterior limibic regions. Together, these studies support a model of bipolar disorder that involves dysfunction within subcortical (striatal–thalamic)–prefrontal networks and the associated limbic modulating regions (amygdala, midline cerebellum). These studies suggest that, in bipolar disorder, there may be diminished prefrontal modulation of subcortical and medial temporal structures within the anterior limbic network (eg, amygdala, anterior striatum and thalamus) that results in dysregulation of mood. Future prospective and longitudinal studies focusing on these specific relationships are necessary to clarify the functional neuroanatomy of bipolar disorder.

A Double-Blind, Randomized, Placebo-Controlled Study of Quetiapine as Adjunctive Treatment for Adolescent Mania

OBJECTIVES This randomized, double-blind, placebo-controlled study examined the efficacy and tolerability of quetiapine in combination with divalproex (DVP) for acute mania in adolescents with bipolar disorder. It was hypothesized that DVP in combination with quetiapine would be more effective than DVP alone for treating mania associated with adolescent bipolar disorder. Furthermore, it was hypothesized that quetiapine would be well tolerated. METHOD Thirty manic or mixed bipolar I adolescents (12-18 years) received an initial DVP dose of 20 mg/kg and were randomly assigned to 6 weeks of combination therapy with quetiapine, which was titrated to 450 mg/day (n = 15) or placebo (n = 15). Primary efficacy measures were change from baseline to endpoint in Young Mania Rating Scale (YMRS) score and YMRS response rate. Safety and tolerability were assessed weekly. RESULTS The DVP + quetiapine group demonstrated a statistically significantly greater reduction in YMRS scores from baseline to endpoint than the DVP + placebo group (F(1,27) = 5.04, p =.03). Moreover, YMRS response rate was significantly greater in the DVP + quetiapine group than in the DVP + placebo group (87% versus 53%; Fisher exact test, p =.05). No significant group differences from baseline to endpoint in safety measures were noted. Sedation, rated as mild or moderate, was significantly more common in the DVP + quetiapine group than in the DVP + placebo group. CONCLUSIONS The findings of this study indicate that quetiapine in combination with DVP is more effective for the treatment of adolescent bipolar mania than DVP alone. In addition, the results suggest that quetiapine is well tolerated when used in combination with DVP for the treatment of mania.

The expert consensus guideline series

Abstract Over the past decade, many new epilepsy treatments have been approved in the United States, promising better quality of life for many with epilepsy. However, clinicians must now choose among a growing number of treatment options and possible combinations. Randomized clinical trials (RCTs) form the basis for evidence-based decision making about best treatment options, but they rarely compare active therapies, making decisions difficult. When medical literature is lacking, expert opinion is helpful, but may contain potential biases. The expert consensus method is a new approach for statistically analyzing pooled opinion to minimize biases inherent in other systems of summarizing expert opinion. We used this method to analyze expert opinion on treatment of three epilepsy syndromes (idiopathic generalized epilepsy, symptomatic localization-related epilepsy, and symptomatic generalized epilepsy) and status epilepticus. For all three syndromes, the experts recommended the same general treatment strategy. As a first step, they recommend monotherapy. If this fails, a second monotherapy should be tried. Following this, the experts are split between additional trials of monotherapy and a combination of two therapies. If this fails, most agree the next step should be additional trials of two therapies, with less agreement as to the next best step after this. One exception to these recommendations is that the experts recommend an evaluation for epilepsy surgery after the third failed step for symptomatic localization-related epilepsies. The results of the expert survey were used to develop user-friendly treatment guidelines concerning overall treatment strategies and choice of specific medications for different syndromes and for status epilepticus.

Regional prefrontal gray and white matter abnormalities in bipolar disorder.

BACKGROUND Previous magnetic resonance imaging (MRI) studies indicate that compared with healthy volunteers, patients with bipolar disorder have structural and functional abnormalities in the prefrontal cortex. The aim of this study was to investigate differences in prefrontal subregions between bipolar patients and healthy subjects. METHODS Bipolar patients hospitalized for a manic episode (n = 17), and demographically matched healthy volunteers (n = 12) were recruited. Contiguous 1-mm coronal T1-weighted MRI slices were obtained using a Picker 1.5 Tesla scanner. The gray and white matter volumes of five prefrontal subregions of interest were measured: superior, middle, inferior, cingulate, and orbital. RESULTS Bipolar patients had smaller left prefrontal gray matter volumes, specifically in the middle and superior subregions and smaller right prefrontal gray matter volumes, specifically in the inferior and middle subregions. White matter differences were not observed in any of the prefrontal subregions. CONCLUSIONS The results suggest that bipolar patients have subregion-specific gray matter volume reductions in the prefrontal cortex as compared to healthy subjects. Further investigations into the role of specific prefrontal subregions in bipolar disorder are warranted.

fMRI of neuronal activation with symptom provocation in unmedicated patients with obsessive compulsive disorder

BACKGROUND Previous studies suggest that a neural circuit involving over-activation of cortical, paralimbic, limbic, and striatal structures may underlie OCD symptomatology, but results may have been limited by medication use in those studies. To address this, we examined the effects of symptom induction on fMRI neural activation in medication-free patients with OCD. METHODS Seven outpatients with OCD were exposed to individually tailored provocative and innocuous stimuli during fMRI scans. Self-ratings of OCD symptoms were performed prior to each scan and after exposure to stimuli. Images were analyzed as composite data sets and individually. RESULTS Stimulus presentation was associated with significant increases in OCD self-ratings. Significant activation was demonstrated in several regions of the frontal cortex (orbitofrontal, superior frontal, and the dorsolateral prefrontal); the anterior, medial and lateral temporal cortex; and the right anterior cingulate. Right superior frontal activation inversely correlated with baseline compulsion symptomatology and left orbitofrontal cortical activation was inversely associated with changes in OCD self-ratings following provocative stimuli. CONCLUSIONS These results in unmedicated patients are consistent with those from previous studies with medicated patients and suggest that OCD symptomatology is mediated by multiple brain regions including the anterior cingulate as well as frontal and temporal brain regions.

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.

A preliminary FMRI study of sustained attention in euthymic, unmedicated bipolar disorder.

The symptoms of bipolar disorder suggest dysfunction of anterior limbic networks that modulate emotional behavior and that reciprocally interact with dorsal attentional systems. Bipolar patients maintain a constant vulnerability to mood episodes even during euthymia, when symptoms are minimal. Consequently, we predicted that, compared with healthy subjects, bipolar patients would exhibit abnormal activation of regions of the anterior limbic network with corresponding abnormal activation of other cortical areas involved in attentional processing. In all, 10 unmedicated euthymic bipolar patients and 10 group-matched healthy subjects were studied with fMRI while performing the Continuous Performance Task-Identical Pairs version (CPT-IP). fMRI scans were obtained on a 3.0 T Bruker system using an echo planar imaging (EPI) pulse sequence, while subjects performed the CPT-IP and a control condition to contrast group differences in regional brain activation. The euthymic bipolar and healthy subjects performed similarly on the CPT-IP, yet showed significantly different patterns of brain activation. Specifically, bipolar patients exhibited increased activation of limbic, paralimbic, and ventrolateral prefrontal areas, as well as visual associational cortices. Healthy subjects exhibited relatively increased activation in fusiform gyrus and medial prefrontal cortex. In conclusion, these differences suggest that bipolar patients exhibit overactivation of anterior limbic areas with corresponding abnormal activation in visual associational cortical areas, permitting successful performance of an attentional task. Since the differences occurred in euthymia, they may represent trait, rather than state, abnormalities of brain function in bipolar disorder.

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.

MRI Analysis of the Cerebellum in Bipolar Disorder: A Pilot Study

Since qualitative CT studies have suggested decreased cerebellar size in patients with bipolar disorder, we performed a quantitative analysis of the cerebellum in patients with bipolar disorder to determine whether high-resolution, thin slice magnetic resonance imaging (MRI) morphometry would reveal similar results. Bipolar patients hospitalized for a first manic episode (n = 16), bipolar patients with prior manic episodes hospitalized for a manic episode (n = 14), and normal volunteers (n = 15) matched for age, sex, race, and education were recruited and anatomic brain scans were acquired using a Picker 1.5 Tesla MRI scanner. Right and left cerebellar hemisphere volumes and vermal areas V1 (lobules I-V), V2 (lobules VI-VII), and V3 (lobules VIII-X) were measured. ANCOVA comparing each ROI, adjusting for race, sex, age, total cerebral volume, and substance abuse duration, revealed a significant group effect for vermal V3 area. Specifically, V3 area was significantly smaller in multiple-episode patients than in first-episode patients or healthy volunteers. Number of previous episodes of depression may contribute to this finding. These results suggest that cerebellar vermal atrophy may be a later neurodegenerative event in patients with bipolar disorder who have had multiple affective episodes. The confounding effects of medications are considered.

Differences and similarities in mixed and pure mania

The aim of this study was to examine the relationship between mixed and pure mania using both narrow (DSM-III-R) and broad (Cincinnati) operational diagnostic criteria to define mixed mania regarding the degree of associated depression. Hospitalized patients aged > or = 12 years and meeting DSM-III-R criteria for bipolar disorder, manic or mixed, were compared regarding demographics, phenomenology, course of illness, comorbidity, family history, and short-term outcome. Seventy-one patients were recruited during a 1-year period. Twenty-four patients (34%) met DSM-III-R criteria for mixed bipolar disorder; 28 (40%) met the broader definition (which required three associated depressive symptoms rather than full syndromal DSM-III-R depression). Compared with pure manic patients, DSM-III-R mixed patients had significantly more depressive symptoms, were more likely to be female, experienced more prior mixed episodes, displayed higher rates of comorbid obsessive-compulsive disorder, and had longer hospitalizations. However, when mixed mania was defined more broadly, differences in gender and hospitalization length were lost. Also, regardless of the definition used, mixed and pure manic patients were similar on most other variables assessed. We conclude that mixed and pure mania differ in some respects but have many similarities, especially when mixed mania is defined by lesser degrees of depression. The use of dimensional rather than categoric systems to describe the degree of associated depression may be a more meaningful method of classifying mania.