Earle E. Bain

Reduced Serotonin Type 1A Receptor Binding in Panic Disorder

Recent animal models suggest that disturbances in serotonin type-1A receptor (5-HT1AR) function may contribute to chronic anxiety, although it is not clear at all whether such models constitute relevant models for panic disorder (PD) in humans. The selective 5-HT1AR radioligand [18F]trans-4-fluoro-N-2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide (FCWAY) permits in vivo assessment of central 5-HT1AR binding using positron emission tomography (PET). We studied 16 unmedicated symptomatic outpatients with PD and 15 matched healthy controls. Seven patients had an additional diagnosis of a current major depressive episode, however PD was the primary diagnosis. A 120 min PET study of 5-HT1AR binding was acquired using a GE Advance scanner in three-dimensional mode. Using quantitative PET image analysis, regional values were obtained for [18F]-FCWAY volume of distribution (DV), corrected for plasma protein binding, and K1, the delivery rate of [18F]-FCWAY from plasma to tissue. MRI scanning was performed using a GE Signa Scanner (3.0 Tesla) to provide an anatomical framework for image analysis and partial volume correction of PET data. PD patients showed lower DV in the anterior cingulate (t = 4.3; p < 0.001), posterior cingulate (t = 4.1; p < 0.001), and raphe (t = 3.1; p = 0.004). Comparing patients with PD, patients with PD and comorbid depression, and healthy controls revealed that DVs did not differ between PD patients and PD patients with comorbid depression, whereas both patient groups differed significantly from controls. These results provide for the first time in vivo evidence for the involvement of 5-HT1ARs in the pathophysiology of PD.

Reduced hippocampal volume in unmedicated, remitted patients with major depression versus control subjects

BACKGROUND Hippocampal volumes obtained from a group of medication-free, remitted subjects with recurrent major depressive disorder (MDD) were compared against corresponding measures from healthy controls. METHODS Thirty-one subjects with recurrent MDD in full remission, and 57 healthy controls underwent high resolution magnetic resonance imaging (MRI) on a GE 3T scanner. Eight patients with MDD were medication-naive, and twenty-three MDD patients were off antidepressant medications for a mean of 30 months at the time of the MRI study. RESULTS Patients showed smaller total and posterior hippocampal volume relative to controls. Anterior hippocampal volume did not differ between patients and controls. CONCLUSIONS Recurrent depression is associated with smaller hippocampal volume which is most prominent in the posterior hippocampus. Smaller hippocampal volume appears to be a trait characteristic for MDD.

Habenula Volume in Bipolar Disorder and Major Depressive Disorder: A High-Resolution Magnetic Resonance Imaging Study

BACKGROUND Increased activity of the habenula has been implicated in the etiology of major depressive disorder (MDD), in which reductions in habenula volume are present after death. We conducted the first magnetic resonance imaging analysis of habenula volume in MDD and bipolar disorder (BD). METHODS High-resolution images (resolution approximately .4 mm(3)) were acquired with a 3T scanner, and a pulse sequence was optimized for tissue contrast resolution. The habenula was manually segmented by one rater blind to diagnosis. Seventy-four healthy control subjects (HC) were compared with both medicated (lithium/divalproex, n = 15) and unmedicated, depressed BD (n = 22) patients; unmedicated, depressed MDD patients (n = 28); and unmedicated MDD patients in remission (n = 32). RESULTS The unmedicated BD patients displayed significantly smaller absolute (p < .01) and normalized (p < .05) habenula volumes than the HC subjects. In post hoc assessments analyzing men and women separately, the currently-depressed women with MDD had smaller absolute (p < .05) habenula volumes than the HC women. None of the other psychiatric groups differed significantly from the HC group. CONCLUSIONS We provide further evidence for the involvement of the habenula in affective illness but suggest that a reduction in volume might be more pronounced in unmedicated, depressed BD subjects and female currently depressed MDD subjects. The habenula plays major roles in the long-term modification of monoamine transmission and behavioral responses to stress and in the suppression of dopamine cell activity after the absence of an expected reward. A reduction in habenula volume might thus have functional consequences that contribute to the risk for developing affective disease.

Normal Prefrontal Gamma-Aminobutyric Acid Levels in Remitted Depressed Subjects Determined by Proton Magnetic Resonance Spectroscopy

BACKGROUND There is growing evidence that the brain gamma-aminobutyric acid (GABA) system is involved in depression. Lowered plasma GABA levels were identified as a traitlike abnormality found in patients with remitted unipolar depression and in healthy first-degree relatives of patients with unipolar depression. Major depressive disorder has been associated with neuroimaging and neuropathological abnormalities in the prefrontal cortex by various types of evidence. As a result, the current study investigates whether GABA levels in the prefrontal cortex differ between unmedicated subjects with remitted major depressive disorder (rMDD) and healthy control subjects. METHODS Sixteen rMDD subjects and 15 healthy control subjects underwent magnetic resonance spectroscopy. We used a 3 Tesla GE whole body scanner with a homogeneous resonator coil providing a homogenous radiofrequency field and capability of obtaining measurement from the prefrontal cortex. Gamma-aminobutyric acid levels were measured in the ventromedial prefrontal cortex and dorsolateral/anterior medial prefrontal cortex. RESULTS There was no difference in GABA concentrations between rMDD subjects and healthy control subjects in the ventromedial prefrontal cortex and dorsolateral/anterior medial prefrontal cortex. Secondary analyses provided preliminary evidence for a negative relationship between the glutamate/glutamine (Glx)/GABA ratio and age of onset of major depression in the ventromedial prefrontal cortex. CONCLUSIONS This result suggests that GABA levels in the prefrontal cortex, if found to be reduced in symptomatic depression, do not represent a persistent characteristic of major depression. Further research is needed to determine brain GABA levels in different brain regions, in different stages of depressive illness, and in different depressive subtypes.

AMYGDALA VOLUME IN DEPRESSED PATIENTS WITH BIPOLAR DISORDER ASSESSED USING HIGH RESOLUTION 3T MRI: THE IMPACT OF MEDICATION

MRI-based reports of both abnormally increased and decreased amygdala volume in bipolar disorder (BD) have surfaced in the literature. Two major methodological weaknesses characterizing extant studies are treatment with medication and inaccurate segmentation of the amygdala due to limitations in spatial and tissue contrast resolution. Here, we acquired high-resolution images (voxel size=0.55 x 0.55 x 0.60 mm) using a GE 3T MRI scanner, and a pulse sequence optimized for tissue contrast resolution. The amygdala was manually segmented by one rater blind to diagnosis, using coronal images. Eighteen unmedicated (mean medication-free period 11+/-10 months) BD subjects were age and gender matched with 18 healthy controls, and 17 medicated (lithium or divalproex) subjects were matched to 17 different controls. The unmedicated BD patients displayed smaller left and right amygdala volumes than their matched control group (p<0.01). Conversely, the BD subjects undergoing medication treatment showed a trend towards greater amygdala volumes than their matched HC sample (p=0.051). Right and left amygdala volumes were larger (p<0.05) or trended larger, respectively, in the medicated BD sample compared with the unmedicated BD sample. The two control groups did not differ from each other in either left or right amygdala volume. BD patients treated with lithium have displayed increased gray matter volume of the cortex and hippocampus relative to untreated BD subjects in previous studies. Here we extend these results to the amygdala. We raise the possibility that neuroplastic changes in the amygdala associated with BD are moderated by some mood stabilizing medications.

A comparison of cognitive functioning in medicated and unmedicated subjects with bipolar depression

OBJECTIVE Neuropsychological studies of bipolar disorder reveal deficits in a variety of domains, including affective processing, memory, and sustained attention. These findings are difficult to interpret due to the potential confounding effects of mood-stabilizing medications. The present study aims to compare the cognitive performance of medicated and unmedicated subjects with bipolar depression to healthy control subjects. METHOD Unmedicated subjects with bipolar depression (UBD, n = 32), subjects with bipolar depression on therapeutic doses of lithium or valproic acid (MBD, n = 33), and healthy control subjects (HC, n = 52) performed neuropsychological tasks measuring affective processing, visual memory, and sustained attention. Performance measures were covaried with age and mood ratings, where applicable. RESULTS With regard to affective processing, the MBD group exhibited greater response latency than the UBD and HC groups. For the same task, the MBD group made more omission errors during the happy condition than in the sad condition. On a task of sustained attention, the MBD group made more errors than the HC group. There were no significant group differences on measures of visual memory. CONCLUSIONS Deficits in affective processing were found in the medicated group, while unmedicated subjects appear to be unaffected. In particular, the MBD group made more errors during happy conditions, indicating a potential attentional bias in subjects with bipolar depression on mood-stabilizing medications. The present study also implicates impairment in sustained attention for medicated subjects with bipolar disorder, particularly those with the type II variety.

A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study of α4β2 Agonist ABT-894 in Adults with ADHD

Dysregulation of the neuronal nicotinic acetylcholine receptor (NNR) system has been implicated in attention-deficit/hyperactivity disorder (ADHD), and nicotinic agonists improve attention across preclinical species and humans. Hence, a randomized, double-blind, placebo-controlled, crossover study was designed to determine the safety and efficacy of a novel α4β2 NNR agonist (ABT-894 (3-(5,6-dichloro-pyridin-3-yl)-1(S),5 (S)-3,6-diazabicyclo[3.2.0]heptane)) in adults with ADHD. Participants (N=243) were randomized to one of four dose regimens of ABT-894 (1, 2, and 4 mg once daily (QD)) or 4 mg twice daily (BID) or the active comparator atomoxetine (40 mg BID) vs placebo for 28 days. Following a 2-week washout period, participants crossed over to the alternative treatment condition (active or placebo) for an additional 28 days. Primary efficacy was based on an investigator-rated Conners’ Adult ADHD Rating Scale (CAARS:Inv) Total score at the end of each 4-week treatment period. Additional secondary outcome measures were assessed. A total of 238 patients were assessed for safety end points, 236 patients were included in the intent-to-treat data set, and 196 were included in the completers data set, which was the prespecified, primary data set for efficacy. Both the 4 mg BID ABT-894 and atomoxetine groups demonstrated significant improvement on the primary outcome compared with placebo. Several secondary outcome measures were also significantly improved with 4 mg BID ABT-894. Overall, ABT-894 was well tolerated at all dose levels. These results provide initial proof of concept for the use of α4β2 agonists in the treatment of adults with ADHD. Further investigation of ABT-894, including higher doses, is therefore warranted.

Sex differences in the neural correlates of autonomic arousal: a pilot PET study.

Electrophysiology, behavioral, and neuroimaging studies have revealed sex-related differences in autonomic cardiac control, as reflected in measurements of heart rate variability (HRV). Imaging studies indicate that the neurobiological correlates of autonomic nervous system (ANS) function can be investigated by measuring indices of HRV during the performance of mildly strenuous motor tasks or mildly stressful cognitive tasks. In this preliminary study, fifteen male and seven female healthy subjects underwent H(2)(15)O-positron emission tomography (PET) and electrocardiograph (ECG) recording while performing a handgrip motor task and an n-back task. Indices of HRV were calculated and correlated with regional cerebral blood flow (rCBF). We hypothesized that sex differences would be evident in brain regions known to participate in autonomic regulation: the anterior insula, the anterior cingulate cortex, the orbitofrontal cortex, and the amygdala. Our study found that associations between rCBF and parasympathetic indices differed significantly between female and male subjects in the amygdala. Females showed a positive correlation between rCBF and parasympathetic indices while males exhibited negative correlations. This differential correlation of amygdala rCBF and parasympathetic activity between males and females may reflect differences in parasympathetic/sympathetic balance between sexes, consistent with known sexual dimorphism in the amygdala and closely related structures such as the hypothalamus. These preliminary imaging results are consistent with earlier reports of significant correlation between brain activity and HRV, and extend these findings by demonstrating prominent sex differences in the neural control of the ANS. While the generalizability of our results was limited by the small size of the study samples, the relatively robust effect size of the differences found between groups encourages further work in larger samples to characterize sex differences in the neural correlates of autonomic arousal.

Heart rate variability during motor and cognitive tasks in females with major depressive disorder

Research indicates that major depressive disorder (MDD) is associated with alterations in autonomic control, particularly cardiac control as measured by heart rate variability (HRV). In this preliminary study, we investigated the neural correlates of autonomic control by measuring both HRV and associated brain activity during the performance of mildly stressful tasks. Medically healthy female subjects with MDD (N=10) and healthy controls (N=7) underwent H(2)(15)O-positron emission tomography (PET) and electrocardiographic ECG recording while performing a handgrip motor task and an n-back task. Indices of HRV were calculated and correlated with regional cerebral blood flow (rCBF). Differences in the rCBF and HRV correlations between depressed and healthy subjects were evident in both the medial and lateral orbital cortices. In addition, these areas appeared to be involved in different facets of autonomic control with regard to sympathetic or parasympathetic dominance of cardiac control. These results are consistent with the known roles of networks within the orbital cortex in both autonomic control and the pathophysiology of MDD.

A Randomized Trial to Assess the Efficacy and Safety of ABT-126, a Selective α7 Nicotinic Acetylcholine Receptor Agonist, in the Treatment of Cognitive Impairment in Schizophrenia

OBJECTIVE The authors sought to evaluate the efficacy and safety of ABT-126, a selective α7 nicotinic receptor partial agonist, in stable patients with schizophrenia. METHOD A 12-week, double-blind, placebo-controlled, parallel-group phase 2 study was conducted in 22 centers in the United States. Clinically stable patients with schizophrenia were randomly assigned to receive once-daily dosing with 10 mg of ABT-126, 25 mg of ABT-126, or placebo. The primary efficacy measure was change from baseline to week 12 on the MATRICS Consensus Cognitive Battery (MCCB) composite score compared with placebo, tested by a one-sided t test. Secondary measures included MCCB domain scores and UCSD Performance-Based Skills Assessment total score, each tested by two-sided t tests. RESULTS A total of 207 subjects were randomized, of whom 165 (81%) completed the study. ABT-126 showed an improvement that fell short of significance on the MCCB composite score at week 12 (least squares mean difference from placebo, 1.3 and 1.5 for the 10 mg and 25 mg groups, respectively). A significant treatment-by-smoking status interaction was observed on the mean change from baseline to final MCCB composite score: nonsmokers (N=69) demonstrated a difference from placebo of 2.9 (SE=1.4) in the 10 mg group and 5.2 (SE=1.6) in the 25 mg group, whereas no differences were observed in smokers (N=113). Among the nonsmokers in the ABT-126 25 mg group (N=19), significant improvements compared with placebo occurred at final assessment for verbal learning (least squares mean difference=5.5, SE=1.9), working memory (least squares mean difference=5.4, SE=2.0), and attention/vigilance (least squares mean difference=8.7, SE=2.5). The most frequently reported adverse events for ABT-126 were dizziness, diarrhea, and fatigue (all <8% incidence). CONCLUSIONS ABT-126 demonstrated a procognitive effect in nonsmoking subjects, particularly in verbal learning, working memory, and attention.