Edward S. Friedman

Toward Clinically Useful Neuroimaging in Depression Treatment: Prognostic Utility of Subgenual Cingulate Activity for Determining Depression Outcome in Cognitive Therapy Across Studies, Scanners, and Patient Characteristics

CONTEXT Among depressed individuals not receiving medication in controlled trials, 40% to 60% respond to cognitive therapy (CT). Multiple previous studies suggest that activity in the subgenual anterior cingulate cortex (sgACC; Brodmann area 25) predicts outcome in CT for depression, but these results have not been prospectively replicated. OBJECTIVE To examine whether sgACC activity is a reliable and robust prognostic outcome marker of CT for depression and whether sgACC activity changes in treatment. DESIGN Two inception cohorts underwent assessment with functional magnetic resonance imaging using different scanners on a task sensitive to sustained emotional information processing before and after 16 to 20 sessions of CT, along with a sample of control participants who underwent testing at comparable intervals. SETTING A hospital outpatient clinic. PATIENTS Forty-nine unmedicated depressed adults and 35 healthy controls. MAIN OUTCOME MEASURES Pretreatment sgACC activity in an a priori region in response to negative words was correlated with residual severity and used to classify response and remission. RESULTS As expected, in both samples, participants with the lowest pretreatment sustained sgACC reactivity in response to negative words displayed the most improvement after CT (R2 = 0.29, >75% correct classification of response, >70% correct classification of remission). Other a priori regions explained additional variance. Response/remission in cohort 2 was predicted based on thresholds from cohort 1. Subgenual anterior cingulate activity remained low for patients in remission after treatment. CONCLUSIONS Neuroimaging provides a quick, valid, and clinically applicable way of assessing neural systems associated with treatment response/remission. Subgenual anterior cingulate activity, in particular, may reflect processes that interfere with treatment (eg, emotion generation) in addition to its putative regulatory role; alternately, its absence may facilitate treatment response.

Effect of concurrent anxiety on response to sertraline and imipramine in patients with chronic depression

Anxiety commonly complicates the clinical presentation of depression and has been associated with poorer long‐term outcome, but little information is available on the clinical correlates, and comparative effect on treatment response, of subsyndromic or secondary anxiety. Patients diagnosed with chronic major or double depression were randomized to 12 weeks of double‐blind treatment with either sertraline or imipramine in a 2:1 ratio. A high anxiety subgroup was operationally defined by a HAM‐D anxiety/somatization factor score ≥ 7. The effect of study treatment was measured utilizing the HAM‐D, CGI, HAM‐D anxiety/somatization factor, as well as a quality of life measure (Q‐LES‐Q) and a measure of psychosocial functioning (the MOS‐SF‐36). Two hundred nine patients were treated with imipramine and 426 patients were treated with sertraline. Thirty‐six percent of the total met criteria for the high anxiety subgroup. According to Kaplan‐Meier probability estimates, patients with significant concurrent anxiety symptoms were more likely to respond by 12 weeks (66.4%) than those without significant anxiety symptoms (54.2%). There was no significant difference in response rates for sertraline vs. imipramine. Both drugs were effective at treating high baseline levels of anxiety, with 60% of sertraline patients and 58% of imipramine patients having 50% or greater reduction from baseline in HAM‐D anxiety/somatization factor scores, and only 4.6% and 9.9%, respectively, reporting treatment‐emergent worsening in anxiety at study endpoint. Despite the chronicity of depressive illness, acute treatment with both sertraline and imipramine significantly improved psychosocial and quality of life measures. High baseline levels of anxiety did not reduce overall antidepressant response but did somewhat delay the onset of response to sertraline or imipramine in patients with chronic depression. Depression and Anxiety 13:18–27, 2001.

A prospective test of criteria for response, remission, relapse, recovery, and recurrence in depressed patients treated with cognitive behavior therapy

The definitions that are commonly employed to describe the outcome of the depressive disorders are often used in inconsistent ways and remain largely untested. The lack of a standard and valid set of outcome definitions hinders the study of the naturalistic course and treatment of depressive disorders. In the present study, we operationalized definitions for response, remission, relapse, recovery, and recurrence and examined their validity in a sample of depressed patients treated with cognitive behavior therapy. Validity was evaluated by the ability of the definitions to predict subsequent outcome in acute treatment and during a 3 year follow-up period. All five definitions demonstrated moderate to excellent validity. Moreover, we were able to empirically distinguish response from remission, and relapse from recurrence, despite the frequent confusion of these terms in the literature. Several of the findings suggest that continued refinement of the outcome definitions may enhance validity even further.

Remission Prognosis for Cognitive Therapy for Recurrent Depression Using the Pupil: Utility and Neural Correlates

BACKGROUND Although up to 60% of people with major depressive disorder respond to cognitive therapy (CT) in controlled trials, clinicians do not routinely use standardized assessments to inform which patients should receive this treatment. Inexpensive, noninvasive prognostic indicators could aid in matching patients with appropriate treatments. Pupillary response to emotional information is an excellent candidate, reflecting limbic reactivity and executive control. This study examined 1) whether pretreatment assessment of pupillary responses to negative information were associated with remission in CT and 2) their associated brain mechanisms. METHODS We examined whether pretreatment pupillary responses to emotional stimuli were prognostic for remission in an inception cohort of 32 unipolar depressed adults to 16 to 20 sessions of CT. Twenty patients were then assessed on the same task using functional magnetic resonance imaging. Pupillary responses were assessed in 51 never-depressed controls for reference. RESULTS Remission was associated with either low initial severity or the combination of higher initial severity and low sustained pupillary responses to negative words (87% correct classification of remitters and nonremitters, 93% sensitivity, 80% specificity; 88% correct classification of high-severity participants, p < .01, 90% sensitivity, 92% specificity). Increased pupillary responses were associated with increased activity in dorsolateral prefrontal regions associated with executive control and emotion regulation. CONCLUSIONS For patients with higher severity, disruptions of executive control mechanisms responsible for initiating emotion regulation, which are indexed by low sustained pupil responses and targeted in therapy, may be key to remitting in this intervention. These mechanisms can be measured using inexpensive noninvasive psychophysiological assessments.

Electroencephalographic sleep profiles in single-episode and recurrent unipolar forms of major depression: II. comparison during remission

BACKGROUND Previous studies indicate that recurrent forms of depression are associated with greater biological disturbances as compared to single-episode cases. This study examines whether the observed differences in the sleep patterns during recurrent and single-episode depression persist into remission following nonpharmacologic treatment. METHODS Two groups of patients (27 single episode [SE] and 53 recurrent unipolar [RU]) with major depression underwent sleep studies before and after nonpharmacologic treatment. Groups were equated for age, severity, and proportion of men and women. Groups were compared using multivariate analyses of covariance and/or analyses of covariance to examine six sets of sleep measures. RESULTS The differences observed between the SE and RU groups during the index episode persisted into early remission. The findings of greater disturbances of sleep continuity, rapid eye movement sleep and diminished slow wave sleep in the RU group supports the hypothesis that recurrent depression is associated with a more severe neurophysiological substrate than clinically comparable SE cases. CONCLUSIONS Although these observations are consistent with an illness progression model, the possibility that recurrent affective illness is associated with a more virulent, stable phenotype cannot be ruled out. Resolution of this issue requires longitudinal and family studies.

Transition to Mania During Treatment of Bipolar Depression

Some individuals with bipolar disorder transition directly from major depressive episodes to manic, hypomanic, or mixed states during treatment, even in the absence of antidepressant treatment. Prevalence and risk factors associated with such transitions in clinical populations are not well established, and were examined in the Systematic Treatment Enhancement Program for Bipolar Disorder study, a longitudinal cohort study. Survival analysis was used to examine time to transition to mania, hypomania, or mixed state among 2166 bipolar I and II individuals in a major depressive episode. Cox regression was used to examine baseline clinical and sociodemographic features associated with hazard for such a direct transition. These features were also examined for interactive effects with antidepressant treatment. In total, 461/2166 subjects in a major depressive episode (21.3%) transitioned to a manic/hypomanic or mixed state before remission, including 289/1475 (19.6%) of those treated with antidepressants during the episode. Among the clinical features associated with greatest transition hazard were greater number of past depressive episodes, recent or lifetime rapid cycling, alcohol use disorder, previous suicide attempt, and history of switch while treated with antidepressants. Greater manic symptom severity was also associated with risk for manic transition among both antidepressant-treated and antidepressant-untreated individuals. Three features, history of suicide attempt, younger onset age, and bipolar subtype, exhibited differential effects between individuals treated with antidepressants and those who were not. These results indicate that certain clinical features may be associated with greater risk of transition from depression to manic or mixed states, but the majority of them are not specific to antidepressant-treated patients.

General Medical Burden in Bipolar Disorder: Findings from the LiTMUS Comparative Effectiveness Trial

This study examined general medical illnesses and their association with clinical features of bipolar disorder.

Effects of sertraline on sleep architecture in patients with depression.

Previous studies indicate that selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, fluvoxamine, citalopram and paroxetine, suppress rapid eye movement sleep, and increased nocturnal arousals. There has been no published report of the impact of sertraline on the sleep of depressed patients. This study examines such effects. Forty-seven patients with major depressive disorder, randomized to double-blind treatment with sertraline or placebo, completed sleep studies before and after 12 weeks of pharmacotherapy. Groups were compared using multivariate analyses of covariance and/or analyses of covariance to examine 4 empirically defined sets of sleep measures. Compared to the placebo-treated group, patients who received sertraline experienced an increase in delta wave sleep in the first sleep cycle and prolonged rapid eye movement (REM) sleep latency. Although, sertraline therapy decreased the average number of REM periods (from 3.86 to 2.40), the activity of both REM period 1 and REM period 2 was significantly increased. Aside from an increase in sleep latency, sertraline therapy was not associated with a worsening of measures of sleep continuity. There was also no significant difference between the groups on a measure of subjective sleepiness. These findings are both similar and different from those observed in previous studies of other SSRIs. The increase in delta sleep ratio and consolidation of REM sleep may have some other clinical implications. However, the generalizability of these findings is limited because of a number of reasons. Further studies are needed to examine the effects of SSRIs in acute treatment of depressed patients with severe insomnia, and the relationship of acute changes and relapse prevention of recurrent depression.

Is psychotherapy an effective treatment for melancholia and other severe depressive states

The treatment of severe depression with psychotherapy, alone, is controversial. In this paper, we review the historical, conceptual, and empirical contexts of this controversy. In addition to work by others, we review recent work from our institute which has examined the psychobiological substrates of response to treatment in depressive subtypes. We examine the traditional categories that describe severe depressions. The features and psychobiological correlates of melancholia are discussed, as is the relationship between melancholia and aging. Research on treatment of melancholia and other severe depressive states with psychotherapies such as cognitive behavior therapy (CBT) and interpersonal psychotherapy (IPT) is reviewed in detail. We conclude that although some melancholic patients are responsive to IPT or CBT, there is not yet compelling evidence that melancholic patients respond to psychotherapy as well as they do to medications. The potentially mediating effects of hypercortisolism, alterations of sleep neurophysiology, and disturbances of information processing and regional cerebral metabolism represent fertile grounds for future investigation. We discuss the practical implications of the literature reviewed.

Preventing Depressive Relapse and Recurrence in Higher-Risk Cognitive Therapy Responders: A Randomized Trial of Continuation Phase Cognitive Therapy, Fluoxetine, or Matched Pill Placebo

IMPORTANCE Strategies to improve the course of recurrent major depressive disorder have great public health relevance. To reduce the risk of relapse/recurrence after acute phase cognitive therapy (CT), a continuation phase model of therapy may improve outcomes. OBJECTIVES To test the efficacy of continuation phase CT (C-CT) and fluoxetine for relapse prevention in a pill placebo (PBO)-controlled randomized trial and compare the durability of prophylaxis after discontinuation of treatments. DESIGN A sequential, 3-stage design with an acute phase (all patients received 12 weeks of CT); 8-month experimental phase (responders at higher risk were randomized to C-CT, fluoxetine, or PBO); and 24 months of longitudinal, posttreatment follow-up. SETTING Two university-based specialty clinics. PATIENTS A total of 523 adults with recurrent major depressive disorder began acute phase CT, of which 241 higher-risk responders were randomized and 181 subsequently entered the follow-up. INTERVENTIONS Cognitive therapy responders at higher risk for relapse were randomized to receive 8 months of C-CT (n = 86), fluoxetine (n = 86), or PBO (n = 69). MAIN OUTCOMES AND MEASURES Survival analyses of relapse/recurrence rates, as determined by blinded evaluators using DSM-IV criteria and the Longitudinal Interval Follow-up Evaluation. RESULTS As predicted, the C-CT or fluoxetine groups were significantly less likely to relapse than the PBO group across 8 months. Relapse/recurrence rates for C-CT and fluoxetine were nearly identical during the 8 months of treatment, although C-CT patients were more likely to accept randomization, stayed in treatment longer, and attended more sessions than those in the fluoxetine and PBO groups. Contrary to prediction, relapse/recurrence rates following the discontinuation of C-CT and fluoxetine did not differ. CONCLUSIONS AND RELEVANCE Relapse risk was reduced by both C-CT and fluoxetine in an enriched randomization sampling only CT responders. The preventive effects of C-CT were not significantly more durable than those of fluoxetine after treatment was stopped, suggesting that some higher-risk patients may require alternate longer-term interventions. TRIAL REGISTRATION clinicaltrials.gov Identifiers: NCT00118404, NCT00183664, and NCT00218764.