Ellen Frank

Pet imaging of serotonin 1A receptor binding in depression

BACKGROUND The serotonin-1A (5HT1A) receptor system has been implicated in the pathophysiology of major depression by postmortem studies of suicide victims and depressed subjects dying of natural causes. This literature is in disagreement, however, regarding the brain regions where 5HT1A receptor binding differs between depressives and controls and the direction of such differences relative to the normal baseline, possibly reflecting the diagnostic heterogeneity inherent within suicide samples. PET imaging using the 5HT1A receptor radioligand, [11C]WAY-100635, may clarify the clinical conditions under which 5HT1A receptor binding potential (BP) is abnormal in depression. METHODS Regional 5HT1A receptor BP values were compared between 12 unmedicated depressives with primary, recurrent, familial mood disorders and 8 healthy controls using PET and [carbonyl-11C]WAY-100635. Regions-of-interest (ROI) assessed were the mesiotemporal cortex (hippocampus-amygdala) and midbrain raphe, where previous postmortem studies suggested 5HT1A receptor binding is abnormal in depression. RESULTS The mean 5HT1A receptor BP was reduced 41.5% in the raphe (p < .02) and 26.8% in the mesiotemporal cortex (p < .025) in the depressives relative to the controls. Post hoc comparisons showed the abnormal reduction in 5HT1A receptor BP was not limited to these regions, but extended to control ROI in the occipital cortex and postcentral gyrus as well. The magnitude of these abnormalities was most prominent in bipolar depressives (n = 4) and unipolar depressives with bipolar relatives (n = 4). CONCLUSIONS Serotonin-1A receptor BP is abnormally decreased in the depressed phase of familial mood disorders in multiple brain regions. Of the regions tested, the magnitude of this reduction was most prominent in the midbrain raphe. Converging evidence from postmortem studies of mood disorders suggests these reductions of 5HT1A receptor BP may be associated with histopathological changes involving the raphe.

Rationale, design, and methods of the systematic treatment enhancement program for bipolar disorder (STEP-BD)

The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) was conceived in response to a National Institute of Mental Health initiative seeking a public health intervention model that could generate externally valid answers to treatment effectiveness questions related to bipolar disorder. STEP-BD, like all effectiveness research, faces many design challenges, including how to do the following: recruit a representative sample of patients for studies of readily available treatments; implement a common intervention strategy across diverse settings; determine outcomes for patients in multiple phases of illness; make provisions for testing as yet undetermined new treatments; integrate adjunctive psychosocial interventions; and avoid biases due to subject drop-out and last-observation-carried-forward data analyses. To meet these challenges, STEP-BD uses a hybrid design to collect longitudinal data as patients make transitions between naturalistic studies and randomized clinical trials. Bipolar patients of every subtype with age >/= 15 years are accessioned into a study registry. All patients receive a systematic assessment battery at entry and are treated by a psychiatrist (trained to deliver care and measure outcomes in patients with bipolar disorder) using a series of model practice procedures consistent with expert recommendations. At every follow-up visit, the treating psychiatrist completes a standardized assessment and assigns an operationalized clinical status based on DSM-IV criteria. Patients have independent evaluations at regular intervals throughout the study and remain under the care of the same treating psychiatrist while making transitions between randomized care studies and the standard care treatment pathways. This article reviews the methodology used for the selection and certification of the clinical treatment centers, training study personnel, the general approach to clinical management, and the sequential treatment strategies offered in the STEP-BD standard and randomized care pathways for bipolar depression and relapse prevention.

Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk

We propose a model wherein chronic stress results in glucocorticoid receptor resistance (GCR) that, in turn, results in failure to down-regulate inflammatory response. Here we test the model in two viral-challenge studies. In study 1, we assessed stressful life events, GCR, and control variables including baseline antibody to the challenge virus, age, body mass index (BMI), season, race, sex, education, and virus type in 276 healthy adult volunteers. The volunteers were subsequently quarantined, exposed to one of two rhinoviruses, and followed for 5 d with nasal washes for viral isolation and assessment of signs/symptoms of a common cold. In study 2, we assessed the same control variables and GCR in 79 subjects who were subsequently exposed to a rhinovirus and monitored at baseline and for 5 d after viral challenge for the production of local (in nasal secretions) proinflammatory cytokines (IL-1β, TNF-α, and IL-6). Study 1: After covarying the control variables, those with recent exposure to a long-term threatening stressful experience demonstrated GCR; and those with GCR were at higher risk of subsequently developing a cold. Study 2: With the same controls used in study 1, greater GCR predicted the production of more local proinflammatory cytokines among infected subjects. These data provide support for a model suggesting that prolonged stressors result in GCR, which, in turn, interferes with appropriate regulation of inflammation. Because inflammation plays an important role in the onset and progression of a wide range of diseases, this model may have broad implications for understanding the role of stress in health.

Types of Stressors That Increase Susceptibility to the Common Cold in Healthy Adults

Two-hundred seventy-six volunteers completed a life stressor interview and psychological questionnaires and provided blood and urine samples. They were then inoculated with common cold viruses and monitored for the onset of disease. Although severe acute stressful life events (less than 1 month long) were not associated with developing colds, severe chronic stressors (1 month or longer) were associated with a substantial increase in risk of disease. This relation was attributable primarily to under- or unemployment and to enduring interpersonal difficulties with family or friends. The association between chronic stressors and susceptibility to colds could not be fully explained by differences among stressed and nonstressed persons in social network characteristics, personality, health practices, or prechallenge endocrine or immune measures.

Report by the ACNP Task Force on Response and Remission in Major Depressive Disorder

This report summarizes recommendations from the ACNP Task Force on the conceptualization of remission and its implications for defining recovery, relapse, recurrence, and response for clinical investigators and practicing clinicians. Given the strong implications of remission for better function and a better prognosis, remission is a valid, clinically relevant end point for both practitioners and investigators. Not all depressed patients, however, will reach remission. Response is a less desirable primary outcome in trials because it depends highly on the initial (often single) baseline measure of symptom severity. It is recommended that remission be ascribed after 3 consecutive weeks during which minimal symptom status (absence of both sadness and reduced interest/pleasure along with the presence of fewer than three of the remaining seven DSM-IV-TR diagnostic criterion symptoms) is maintained. Once achieved, remission can only be lost if followed by a relapse. Recovery is ascribed after at least 4 months following the onset of remission, during which a relapse has not occurred. Recovery, once achieved, can only be lost if followed by a recurrence. Day-to-day functioning and quality of life are important secondary end points, but they were not included in the proposed definitions of response, remission, recovery, relapse, or recurrence. These recommendations suggest that symptom ratings that measure all nine criterion symptom domains to define a major depressive episode are preferred as they provide a more certain ascertainment of remission. These recommendations were based largely on logic, the need for internal consistency, and clinical experience owing to the lack of empirical evidence to test these concepts. Research to evaluate these recommendations empirically is needed.

Major depressive disorder: new clinical, neurobiological, and treatment perspectives

In this Seminar we discuss developments from the past 5 years in the diagnosis, neurobiology, and treatment of major depressive disorder. For diagnosis, psychiatric and medical comorbidity have been emphasised as important factors in improving the appropriate assessment and management of depression. Advances in neurobiology have also increased, and we aim to indicate genetic, molecular, and neuroimaging studies that are relevant for assessment and treatment selection of this disorder. Further studies of depression-specific psychotherapies, the continued application of antidepressants, the development of new treatment compounds, and the status of new somatic treatments are also discussed. We address two treatment-related issues: suicide risk with selective serotonin reuptake inhibitors, and the safety of antidepressants in pregnancy. Although clear advances have been made, no fully satisfactory treatments for major depression are available.

The International Society for Bipolar Disorders (ISBD) Task Force report on the nomenclature of course and outcome in bipolar disorders.

OBJECTIVES Via an international panel of experts, this paper attempts to document, review, interpret, and propose operational definitions used to describe the course of bipolar disorders for worldwide use, and to disseminate consensus opinion, supported by the existing literature, in order to better predict course and treatment outcomes. METHODS Under the auspices of the International Society for Bipolar Disorders, a task force was convened to examine, report, discuss, and integrate findings from the scientific literature related to observational and clinical trial studies in order to reach consensus and propose terminology describing course and outcome in bipolar disorders. RESULTS Consensus opinion was reached regarding the definition of nine terms (response, remission, recovery, relapse, recurrence, subsyndromal states, predominant polarity, switch, and functional outcome) commonly used to describe course and outcomes in bipolar disorders. Further studies are needed to validate the proposed definitions. CONCLUSION Determination and dissemination of a consensus nomenclature serve as the first step toward producing a validated and standardized system to define course and outcome in bipolar disorders in order to identify predictors of outcome and effects of treatment. The task force acknowledges that there is limited validity to the proposed terms, as for the most part they represent a consensus opinion. These definitions need to be validated in existing databases and in future studies, and the primary goals of the task force are to stimulate research on the validity of proposed concepts and further standardize the technical nomenclature.

Greater cortical gray matter density in lithium-treated patients with bipolar disorder.

BACKGROUND The neurobiological underpinnings of bipolar disorder are not well understood. Previous neuroimaging findings have been inconsistent; however, new methods for three-dimensional (3-D) computational image analysis may better characterize neuroanatomic changes than standard volumetric measures. METHODS We used high-resolution magnetic resonance imaging and cortical pattern matching methods to map gray matter differences in 28 adults with bipolar disorder, 70% of whom were lithium-treated (mean age = 36.1 +/- 10.5; 13 female subject), and 28 healthy control subjects (mean age = 35.9 +/- 8.5; 11 female subjects). Detailed spatial analyses of gray matter density (GMD) were conducted by measuring local proportions of gray matter at thousands of homologous cortical locations. RESULTS Gray matter density was significantly greater in bipolar patients relative to control subjects in diffuse cortical regions. Greatest differences were found in bilateral cingulate and paralimbic cortices, brain regions critical for attentional, motivational, and emotional modulation. Secondary region of interest (ROI) analyses indicated significantly greater GMD in the right anterior cingulate among lithium-treated bipolar patients (n = 20) relative to those not taking lithium (n = 8). CONCLUSIONS These brain maps are consistent with previous voxel-based morphometry reports of greater GMD in portions of the anterior limbic network in bipolar patients and suggest neurotrophic effects of lithium as a possible etiology of these neuroanatomic differences.

MRI investigation of temporal lobe structures in bipolar patients

Previous anatomical MRI studies have suggested abnormalities in amygdala volumes in bipolar disorder, whereas hippocampus, temporal lobe (TL), and superior temporal gyri (STG) measures have been reported to be normal. This study further investigated the existence of anatomical abnormalities in these brain structures in bipolar subjects, to attempt to replicate previously reported findings. Twenty-four DSM-IV bipolar patients (mean age+/-S.D.=35+/-10 years) and 36 healthy controls (mean age+/-S.D.=37+/-10 years) were studied. 3D SPGR images were obtained with a 1.5T-GE Signa magnet (TR=25 ms, TE=5 ms, FOV=24 cm, slice-thickness=1.5 mm, matrix-size=256 x 192). Volumetric measurements of TL, hippocampus, amygdala, and STG were performed blindly, with a semi-automated software. Bipolar patients had significantly larger left amygdala volumes compared with controls (mean volumes+/-S.D.=2.57+/-0.69 vs. 2.17+/-0.58 ml, respectively; ANCOVA, age, gender, ICV as covariates; F=4.42, df=1/55, P=0.04). The volumes of the other temporal lobe structures did not differ significantly between the two groups (ANCOVA, age, gender, and ICV as covariates, P>0.05). Our findings of enlarged left amygdala in bipolar patients are in agreement with prior MRI studies, suggesting that abnormalities in this brain structure may be implicated in pathophysiology of the illness. Longitudinal studies in high-risk offspring and first-episode patients will be needed to examine whether such abnormalities precede the appearance of symptoms, or whether they may appear subsequently as a result of illness course.

Increased gray matter volume in lithium-treated bipolar disorder patients

Lithiums neurotrophic effects have been reported in several in vitro and ex vivo studies. Preliminary human studies with magnetic resonance imaging (MRI) and spectroscopy have recently provided evidence of lithium-induced increases in gray matter volumes and N-acetyl-aspartate levels. In order to further examine the hypothesis that lithium treatment would relate to detectable increases in gray matter brain content, we blindly measured gray and white matter volumes in MRI images of 12 untreated and 17 lithium-treated bipolar patients and 46 healthy controls. Using multivariate analysis of covariance with age and gender as covariates, we found that total gray matter volumes were significantly increased in lithium-treated (747.9 +/- 69.8 cm(3)) compared with untreated patients (639.2 +/- 91.2 cm(3); F = 10.6; d.f. = 1, 25; P = 0.003) and healthy individuals (675.8 +/- 61.8 cm(3); F = 17.4; d.f. = 1, 59; P < 0.001), suggesting in vivo effects of lithium on gray matter, which could possibly reflect lithiums neurotrophic effects.