Jay C. Fournier

Antidepressant Drug effects and Depression Severity: A Patient-Level Meta-Analysis

CONTEXT Antidepressant medications represent the best established treatment for major depressive disorder, but there is little evidence that they have a specific pharmacological effect relative to pill placebo for patients with less severe depression. OBJECTIVE To estimate the relative benefit of medication vs placebo across a wide range of initial symptom severity in patients diagnosed with depression. DATA SOURCES PubMed, PsycINFO, and the Cochrane Library databases were searched from January 1980 through March 2009, along with references from meta-analyses and reviews. STUDY SELECTION Randomized placebo-controlled trials of antidepressants approved by the Food and Drug Administration in the treatment of major or minor depressive disorder were selected. Studies were included if their authors provided the requisite original data, they comprised adult outpatients, they included a medication vs placebo comparison for at least 6 weeks, they did not exclude patients on the basis of a placebo washout period, and they used the Hamilton Depression Rating Scale (HDRS). Data from 6 studies (718 patients) were included. DATA EXTRACTION Individual patient-level data were obtained from study authors. RESULTS Medication vs placebo differences varied substantially as a function of baseline severity. Among patients with HDRS scores below 23, Cohen d effect sizes for the difference between medication and placebo were estimated to be less than 0.20 (a standard definition of a small effect). Estimates of the magnitude of the superiority of medication over placebo increased with increases in baseline depression severity and crossed the threshold defined by the National Institute for Clinical Excellence for a clinically significant difference at a baseline HDRS score of 25. CONCLUSIONS The magnitude of benefit of antidepressant medication compared with placebo increases with severity of depression symptoms and may be minimal or nonexistent, on average, in patients with mild or moderate symptoms. For patients with very severe depression, the benefit of medications over placebo is substantial.

Prediction of Response to Medication and Cognitive Therapy in the Treatment of Moderate to Severe Depression

A recent randomized controlled trial found nearly equivalent response rates for antidepressant medications and cognitive therapy in a sample of moderate to severely depressed outpatients. In this article, the authors seek to identify the variables that were associated with response across both treatments as well as variables that predicted superior response in one treatment over the other. The sample consisted of 180 depressed outpatients: 60 of whom were randomly assigned to cognitive therapy; 120 were assigned to antidepressant medications. Treatment was provided for 16 weeks. Chronic depression, older age, and lower intelligence each predicted relatively poor response across both treatments. Three prescriptive variables-marriage, unemployment, and having experienced a greater number of recent life events-were identified, and each predicted superior response to cognitive therapy relative to antidepressant medications. Thus, 6 markers of treatment outcome were identified, each of which might be expected to carry considerable clinical utility. The 3 prognostic variables identify subgroups that might benefit from alternative treatment strategies; the 3 prescriptive variables identify groups who appear to respond particularly well to cognitive therapy.

The Personalized Advantage Index: translating research on prediction into individualized treatment recommendations. A demonstration.

Background Advances in personalized medicine require the identification of variables that predict differential response to treatments as well as the development and refinement of methods to transform predictive information into actionable recommendations. Objective To illustrate and test a new method for integrating predictive information to aid in treatment selection, using data from a randomized treatment comparison. Method Data from a trial of antidepressant medications (N = 104) versus cognitive behavioral therapy (N = 50) for Major Depressive Disorder were used to produce predictions of post-treatment scores on the Hamilton Rating Scale for Depression (HRSD) in each of the two treatments for each of the 154 patients. The patients own data were not used in the models that yielded these predictions. Five pre-randomization variables that predicted differential response (marital status, employment status, life events, comorbid personality disorder, and prior medication trials) were included in regression models, permitting the calculation of each patients Personalized Advantage Index (PAI), in HRSD units. Results For 60% of the sample a clinically meaningful advantage (PAI≥3) was predicted for one of the treatments, relative to the other. When these patients were divided into those randomly assigned to their “Optimal” treatment versus those assigned to their “Non-optimal” treatment, outcomes in the former group were superior (d = 0.58, 95% CI .17—1.01). Conclusions This approach to treatment selection, implemented in the context of two equally effective treatments, yielded effects that, if obtained prospectively, would rival those routinely observed in comparisons of active versus control treatments.

Antidepressant medications v. cognitive therapy in people with depression with or without personality disorder

BACKGROUND There is conflicting evidence about comorbid personality pathology in depression treatments. AIMS To test the effects of antidepressant drugs and cognitive therapy in people with depression distinguished by the presence or absence of personality disorder. METHOD Random assignment of 180 out-patients with depression to 16 weeks of antidepressant medication or cognitive therapy. Random assignment of medication responders to continued medication or placebo, and comparison with cognitive therapy responders over a 12-month period. RESULTS Personality disorder status led to differential response at 16 weeks; 66% v. 44% (antidepressants v. cognitive therapy respectively) for people with personality disorder, and 49% v. 70% (antidepressants v. cognitive therapy respectively) for people without personality disorder. For people with personality disorder, sustained response rates over the 12-month follow-up were nearly identical (38%) in the prior cognitive therapy and continuation-medication treatment arms. People with personality disorder withdrawn from medication evidenced the lowest sustained response rate (6%). Despite the poor response of people with personality disorder to cognitive therapy, nearly all those who did respond sustained their response. CONCLUSIONS Comorbid personality disorder was associated with differential initial response rates and sustained response rates for two well-validated treatments for depression.

Elevated serum measures of lipid peroxidation and abnormal prefrontal white matter in euthymic bipolar adults: toward peripheral biomarkers of bipolar disorder

Diffusion tensor imaging (DTI) studies consistently reported abnormalities in fractional anisotropy (FA) and radial diffusivity (RD), measures of the integrity of white matter (WM), in bipolar disorder (BD), that may reflect underlying pathophysiologic processes. There is, however, a pressing need to identify peripheral measures that are related to these WM measures, to help identify easily obtainable peripheral biomarkers of BD. Given the high lipid content of axonal membranes and myelin sheaths, and that elevated serum levels of lipid peroxidation are reported in BD, these serum measures may be promising peripheral biomarkers of underlying WM abnormalities in BD. We used DTI and probabilistic tractography to compare FA and RD in ten prefrontal-centered WM tracts, 8 of which are consistently shown to have abnormal FA (and/or RD) in BD, and also examined serum lipid peroxidation (lipid hydroperoxides, LPH and 4-hydroxy-2-nonenal, 4-HNE), in 24 currently euthymic BD adults (BDE) and 19 age- and gender-matched healthy adults (CONT). There was a significant effect of group upon FA in these a priori WM tracts (BDE<CONT: F[1,41]=6.8; P=0.013) and RD (BDE>CONT: F[1,41]=10.3; P=0.003), and a significant between-group difference in LPH (BDE>CONT: t[40]=2.4; P=0.022), but not in 4-HNE. Multivariate multiple regression analyses revealed that LPH variance explained, respectively, 59 and 51% of the variance of FA and RD across all study participants. This is the first study to examine relationships between measures of WM integrity and peripheral measures of lipid peroxidation. Our findings suggest that serum LPH may be useful in the development of a clinically relevant, yet easily obtainable and inexpensive, peripheral biomarkers of BD.

The Clinical Effectiveness of Cognitive Therapy for Depression in an Outpatient Clinic

BACKGROUND Cognitive therapy (CT) has been shown to be efficacious in the treatment of depression in numerous randomized controlled trials (RCTs). However, little evidence is available that speaks to the effectiveness of this treatment under routine clinical conditions. METHOD This paper examines outcomes of depressed individuals seeking cognitive therapy at an outpatient clinic (N=217, Center for Cognitive Therapy; CCT). Outcomes were then compared to those of participants in a large NIMH-funded RCT of cognitive therapy and medications as treatments for depression. RESULTS The CCT is shown to be a clinically representative setting, and 61% of participants experienced reliable change in symptoms over the course of treatment; of those, 45% (36% of the total sample) met criteria for recovery by the end of treatment. Participants at CCT had similar outcomes to participants treated in the RCT, but there was some evidence that those with more severe symptoms at intake demonstrated greater improvement in the RCT than their counterparts at CCT. LIMITATIONS The CCT may not be representative of all outpatient settings, and the structure of treatment there was considerably different from that in the RCT. Treatment fidelity was not assessed at CCT. CONCLUSIONS Depressed individuals treated with cognitive therapy in a routine clinical care setting showed a significant improvement in symptoms. When compared with outcomes evidenced in RCTs, there was little evidence of superior outcomes in either setting. However, for more severe participants, outcomes were found to be superior when treatment was delivered within an RCT than in an outpatient setting. Clinicians treating such patients in non-research settings may thus benefit from making modifications to treatment protocols to more closely resemble research settings.

Parsing Dimensional vs Diagnostic Category–Related Patterns of Reward Circuitry Function in Behaviorally and Emotionally Dysregulated Youth in the Longitudinal Assessment of Manic Symptoms Study

IMPORTANCE Pediatric disorders characterized by behavioral and emotional dysregulation pose diagnostic and treatment challenges because of high comorbidity, suggesting that they may be better conceptualized dimensionally rather than categorically. Identifying neuroimaging measures associated with behavioral and emotional dysregulation in youth may inform understanding of underlying dimensional vs disorder-specific pathophysiologic features. OBJECTIVE To identify, in a large cohort of behaviorally and emotionally dysregulated youth, neuroimaging measures that (1) are associated with behavioral and emotional dysregulation pathologic dimensions (behavioral and emotional dysregulation measured with the Parent General Behavior Inventory 10-Item Mania Scale [PGBI-10M], mania, depression, and anxiety) or (2) differentiate diagnostic categories (bipolar spectrum disorders, attention-deficit/hyperactivity disorder, anxiety, and disruptive behavior disorders). DESIGN, SETTING, AND PARTICIPANTS A multisite neuroimaging study was conducted from February 1, 2011, to April 15, 2012, at 3 academic medical centers: University Hospitals Case Medical Center, Cincinnati Childrens Hospital Medical Center, and University of Pittsburgh Medical Center. Participants included a referred sample of behaviorally and emotionally dysregulated youth from the Longitudinal Assessment of Manic Symptoms (LAMS) study (n = 85) and healthy youth (n = 20). MAIN OUTCOMES AND MEASURES Region-of-interest analyses examined relationships among prefrontal-ventral striatal reward circuitry during a reward paradigm (win, loss, and control conditions), symptom dimensions, and diagnostic categories. RESULTS Regardless of diagnosis, higher PGBI-10M scores were associated with greater left middle prefrontal cortical activity (r = 0.28) and anxiety with greater right dorsal anterior cingulate cortical (r = 0.27) activity to win. The 20 highest (t = 2.75) and 20 lowest (t = 2.42) PGBI-10M-scoring youth showed significantly greater left middle prefrontal cortical activity to win compared with 20 healthy youth. Disruptive behavior disorders were associated with lower left ventrolateral prefrontal cortex activity to win (t = 2.68) (all P < .05, corrected). CONCLUSIONS AND RELEVANCE Greater PGBI-10M-related left middle prefrontal cortical activity and anxiety-related right dorsal anterior cingulate cortical activity to win may reflect heightened reward sensitivity and greater attention to reward in behaviorally and emotionally dysregulated youth regardless of diagnosis. Reduced left ventrolateral prefrontal cortex activity to win may reflect reward insensitivity in youth with disruptive behavior disorders. Despite a distinct reward-related neurophysiologic feature in disruptive behavior disorders, findings generally support a dimensional approach to studying neural mechanisms in behaviorally and emotionally dysregulated youth.

Understanding processes of change: How some patients reveal more than others – and some groups of therapists less – about what matters in psychotherapy

Abstract Objective: We identify difficulties researchers encounter in psychotherapy process-outcome investigations, and we describe several limitations of the popular “variance accounted for” approach to understanding the effects of psychotherapy. Methods & Results: Using data simulations, we show how the expected correlation between an excellent measure of therapy quality and outcome would be surprisingly small (approximately .25) under conditions likely to be common in psychotherapy research. Even when we modeled conditions designed to increase the likelihood that strong process-outcome relationships would be observed, we found that the expected correlations were still only in the modest range (.38–.51). Conclusions: We discuss the implications of our analysis for the interpretation of process-outcome findings as well as for design considerations in future investigations.

Amygdala and whole‐brain activity to emotional faces distinguishes major depressive disorder and bipolar disorder

It can be clinically difficult to distinguish depressed individuals with bipolar disorder (BD) and major depressive disorder (MDD). To examine potential biomarkers of difference between the two disorders, the current study examined differences in the functioning of emotion‐processing neural regions during a dynamic emotional faces task.

Emotional Face Processing in Pediatric Bipolar Disorder: Evidence for Functional Impairments in the Fusiform Gyrus

OBJECTIVE Pediatric bipolar disorder involves poor social functioning, but the neural mechanisms underlying these deficits are not well understood. Previous neuroimaging studies have found deficits in emotional face processing localized to emotional brain regions. However, few studies have examined dysfunction in other regions of the face processing circuit. This study assessed hypoactivation in key face processing regions of the brain in pediatric bipolar disorder. METHOD Youth with a bipolar spectrum diagnosis (n = 20) were matched to a nonbipolar clinical group (n = 20), with similar demographics and comorbid diagnoses, and a healthy control group (n = 20). Youth participated in a functional magnetic resonance imaging (fMRI) scanning which employed a task-irrelevant emotion processing design in which processing of facial emotions was not germane to task performance. RESULTS Hypoactivation, isolated to the fusiform gyrus, was found when viewing animated, emerging facial expressions of happiness, sadness, fearfulness, and especially anger in pediatric bipolar participants relative to matched clinical and healthy control groups. CONCLUSIONS The results of the study imply that differences exist in visual regions of the brains face processing system and are not solely isolated to emotional brain regions such as the amygdala. Findings are discussed in relation to facial emotion recognition and fusiform gyrus deficits previously reported in the autism literature. Behavioral interventions targeting attention to facial stimuli might be explored as possible treatments for bipolar disorder in youth.