Alan F. Schatzberg

Dissociable Intrinsic Connectivity Networks for Salience Processing and Executive Control

Variations in neural circuitry, inherited or acquired, may underlie important individual differences in thought, feeling, and action patterns. Here, we used task-free connectivity analyses to isolate and characterize two distinct networks typically coactivated during functional MRI tasks. We identified a “salience network,” anchored by dorsal anterior cingulate (dACC) and orbital frontoinsular cortices with robust connectivity to subcortical and limbic structures, and an “executive-control network” that links dorsolateral frontal and parietal neocortices. These intrinsic connectivity networks showed dissociable correlations with functions measured outside the scanner. Prescan anxiety ratings correlated with intrinsic functional connectivity of the dACC node of the salience network, but with no region in the executive-control network, whereas executive task performance correlated with lateral parietal nodes of the executive-control network, but with no region in the salience network. Our findings suggest that task-free analysis of intrinsic connectivity networks may help elucidate the neural architectures that support fundamental aspects of human behavior.

Resting-State Functional Connectivity in Major Depression: Abnormally Increased Contributions from Subgenual Cingulate Cortex and Thalamus

BACKGROUND Positron emission tomography (PET) studies of major depression have revealed resting-state abnormalities in the prefrontal and cingulate cortices. Recently, fMRI has been adapted to examine connectivity within a specific resting-state neural network--the default-mode network--that includes medial prefrontal and anterior cingulate cortices. The goal of this study was to examine resting-state, default-mode network functional connectivity in subjects with major depression and in healthy controls. METHODS Twenty-eight subjects with major depression and 20 healthy controls underwent 5-min fMRI scans while resting quietly. Independent component analysis was used to isolate the default-mode network in each subject. Group maps of the default-mode network were compared. A within-group analysis was performed in the depressed group to explore effects of depression refractoriness on functional connectivity. RESULTS Resting-state subgenual cingulate and thalamic functional connectivity with the default-mode network were significantly greater in the depressed subjects. Within the depressed group, the length of the current depressive episode correlated positively with functional connectivity in the subgenual cingulate. CONCLUSIONS This is the first study to explore default-mode functional connectivity in major depression. The findings provide cross-modality confirmation of PET studies demonstrating increased thalamic and subgenual cingulate activity in major depression. Further, the within-subject connectivity analysis employed here brings these previously isolated regions of hypermetabolism into the context of a disordered neural network. The correlation between refractoriness and subgenual cingulate functional connectivity within the network suggests that a quantitative, resting-state fMRI measure could be used to guide therapy in individual subjects.

Differential responses to psychotherapy versus pharmacotherapy in patients with chronic forms of major depression and childhood trauma

Major depressive disorder is associated with considerable morbidity, disability, and risk for suicide. Treatments for depression most commonly include antidepressants, psychotherapy, or the combination. Little is known about predictors of treatment response for depression. In this study, 681 patients with chronic forms of major depression were treated with an antidepressant (nefazodone), Cognitive Behavioral Analysis System of Psychotherapy (CBASP), or the combination. Overall, the effects of the antidepressant alone and psychotherapy alone were equal and significantly less effective than combination treatment. Among those with a history of early childhood trauma (loss of parents at an early age, physical or sexual abuse, or neglect), psychotherapy alone was superior to antidepressant monotherapy. Moreover, the combination of psychotherapy and pharmacotherapy was only marginally superior to psychotherapy alone among the childhood abuse cohort. Our results suggest that psychotherapy may be an essential element in the treatment of patients with chronic forms of major depression and a history of childhood trauma.

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.

Disrupted Amygdalar Subregion Functional Connectivity and Evidence of a Compensatory Network in Generalized Anxiety Disorder

CONTEXT Little is known about the neural abnormalities underlying generalized anxiety disorder (GAD). Studies in other anxiety disorders have implicated the amygdala, but work in GAD has yielded conflicting results. The amygdala is composed of distinct subregions that interact with dissociable brain networks, which have been studied only in experimental animals. A functional connectivity approach at the subregional level may therefore yield novel insights into GAD. OBJECTIVES To determine whether distinct connectivity patterns can be reliably identified for the basolateral (BLA) and centromedial (CMA) subregions of the human amygdala, and to examine subregional connectivity patterns and potential compensatory amygdalar connectivity in GAD. DESIGN Cross-sectional study. SETTING Academic medical center. PARTICIPANTS Two cohorts of healthy control subjects (consisting of 17 and 31 subjects) and 16 patients with GAD. MAIN OUTCOME MEASURES Functional connectivity with cytoarchitectonically determined BLA and CMA regions of interest, measured during functional magnetic resonance imaging performed while subjects were resting quietly in the scanner. Amygdalar gray matter volume was also investigated with voxel-based morphometry. RESULTS Reproducible subregional differences in large-scale connectivity were identified in both cohorts of healthy controls. The BLA was differentially connected with primary and higher-order sensory and medial prefrontal cortices. The CMA was connected with the midbrain, thalamus, and cerebellum. In GAD patients, BLA and CMA connectivity patterns were significantly less distinct, and increased gray matter volume was noted primarily in the CMA. Across the subregions, GAD patients had increased connectivity with a previously characterized frontoparietal executive control network and decreased connectivity with an insula- and cingulate-based salience network. CONCLUSIONS Our findings provide new insights into the functional neuroanatomy of the human amygdala and converge with connectivity studies in experimental animals. In GAD, we find evidence of an intra-amygdalar abnormality and engagement of a compensatory frontoparietal executive control network, consistent with cognitive theories of GAD.

Neuroendocrine aspects of hypercortisolism in major depression

A consistent finding in biological psychiatry is that hypothalamic-pituitary-adrenal (HPA) axis physiology is altered in humans with major depression. These findings include hypersecretion of cortisol at baseline and on the dexamethasone suppression test. In this review, we present a process-oriented model for HPA axis regulation in major depression. Specifically, we suggest that acute depressions are characterized by hypersecretion of hypothalamic corticotropin-releasing factor, pituitary adrenocorticotropic hormone (ACTH), and adrenal cortisol. In chronic depressions, however, enhanced adrenal responsiveness to ACTH and glucocorticoid negative feedback work in complementary fashion so that cortisol levels remain elevated while ACTH levels are reduced. In considering the evidence for hypercortisolism in humans, studies of nonhuman primates are presented and their utility and limitations as comparative models of human depression are discussed.

Gender differences in chronic major and double depression.

BACKGROUND While the sex difference in prevalence rates of unipolar depression is well established, few studies have examined gender differences in clinical features of depression. Even less is known about gender differences in chronic forms of depression. METHODS 235 male and 400 female outpatients with DSM-III-R chronic major depression or double depression (i.e., major depression superimposed on dysthymia) were administered an extensive battery of clinician-rated and self-report measures. RESULTS Women were less likely to be married and had a younger age at onset and greater family history of affective disorder compared to men. Symptom profile was similar in men and women, with the exception of more sleep changes, psychomotor retardation and anxiety/somatization in women. Women reported greater severity of illness and were more likely to have received previous treatment for depression with medications and/or psychotherapy. Greater functional impairment was noted by women in the area of marital adjustment, while men showed more work impairment. LIMITATIONS Since our population consisted of patients enrolling in a clinical trial, study exclusion criteria may have affected gender-related differences found. CONCLUSIONS Chronicity of depression appears to affect women more seriously than men, as manifested by an earlier age of onset, greater family history of affective disorders, greater symptom reporting, poorer social adjustment and poorer quality of life. These findings represent the largest study to date of gender differences in a population with chronic depressive conditions.

Failure of anterior cingulate activation and connectivity with the amygdala during implicit regulation of emotional processing in generalized anxiety disorder.

OBJECTIVE Clinical data suggest that abnormalities in the regulation of emotional processing contribute to the pathophysiology of generalized anxiety disorder, yet these abnormalities remain poorly understood at the neurobiological level. The authors recently reported that in healthy volunteers the pregenual anterior cingulate regulates emotional conflict on a trial-by-trial basis by dampening activity in the amygdala. The authors also showed that this process is specific to the regulation of emotional, compared to nonemotional, conflict. Here the authors examined whether this form of noninstructed emotion regulation is perturbed in generalized anxiety disorder. METHOD Seventeen patients with generalized anxiety disorder and 24 healthy comparison subjects underwent functional MRI while performing an emotional conflict task that involved categorizing facial affect while ignoring overlaid affect label words. Behavioral and neural measures were used to compare trial-by-trial changes in conflict regulation. RESULTS Comparison subjects effectively regulated emotional conflict from trial to trial, even though they were unaware of having done so. By contrast, patients with generalized anxiety disorder were completely unable to regulate emotional conflict and failed to engage the pregenual anterior cingulate in ways that would dampen amygdalar activity. Moreover, performance and brain activation were correlated with symptoms and could be used to accurately classify the two groups. CONCLUSIONS These data demonstrate that patients with generalized anxiety disorder show significant deficits in the noninstructed and spontaneous regulation of emotional processing. Conceptualization of anxiety as importantly involving abnormalities in emotion regulation, particularly a type occurring outside of awareness, may open up avenues for novel treatments, such as by targeting the medial prefrontal cortex.

An open label trial of C-1073 (mifepristone) for psychotic major depression*

BACKGROUND The rationale for treating patients with psychotic major depression (PMD) with glucocorticosteroid receptor (GR) antagonists is explained. METHODS Thirty patients with PMD, with Hamilton Rating Scale for Depression (HAMD-21) scores of 18 or greater, were assigned in an open label trial to receive 50 mg, 600 mg, or 1200 mg of mifepristone for 7 days. RESULTS All the subjects completed the protocol; there were no dropouts. Side effects were mild and sporadic. Of 19 subjects in the combined 600- and 1200-mg group, 13 had a 30% or greater decline in their Brief Psychiatric Rating Scale (BPRS) scores, compared with 4 of 11 in the 50-mg group. In the 600- and 1200-mg group, 12 of 19 subjects showed a 50% decline in the BPRS positive symptom subscale, a more sensitive index for the symptoms seen in PMD, compared with 3 of 11 in the 50-mg group; 8 of 19 subjects in the 600- and 1200-mg group had a 50% decline in the HAMD-21, compared with 2 of 11 in the 50-mg group. CONCLUSIONS These results suggest that short term use of GR antagonists may be effective in the treatment of psychotic major depression and that further blinded studies are warranted.

Rapid reversal of psychotic depression using mifepristone

The rationale for treating psychotic major depression with glucocorticoid receptor (GR) antagonists is reviewed. Five patients with psychotic major depression were given 600 mg of mifepristone in a 4-day, double-blind, placebo-controlled crossover study. All the patients completed the protocol and adverse effects were not observed or reported. All of the five patients showed substantial improvements in their Hamilton Rating Scale for Depression scores while they were receiving mifepristone, and four of the five patients showed substantial improvement in their Brief Psychiatric Rating Scale scores. Little, if any, improvement was seen with placebo. These preliminary results suggest that short-term use of GR antagonists may be effective in the treatment of psychotic major depression and that additional study, perhaps using higher doses or more treatment days, seems warranted.