Characterizing the cognitive subtype of depression with distinct symptoms, treatment response, and presentation
1. This prespecified secondary analysis of data from a randomized clinical trial (RCT) identified a potential cognitive subtype (or “biotype”) of depression, with a distinct symptom profile, differences in conductivity of the cognitive control circuit, and impaired responses to treatment (most pronounced with sertraline).
2. Results also indicated that for this cognitive biotype of depressed patients, the improvement of cognition during treatment more strongly mediated posttreatment outcomes, challenging the prevailing assumption that cognitive impairments resolve as a secondary effect of overall symptom severity improvement.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Major depressive disorder (MDD) is a condition known to disrupt interpersonal, psychosocial, and work-related function in individuals. One of the nine symptoms of MDD defined in the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition, Text Revision; DSM V-TR) includes decreased concentration and indecisiveness. The literature has also demonstrated that impaired cognitive function itself is a major contributor to poor functional outcomes and decreased responses to treatment. The current study sought to elucidate a possibly distinct, clinically actionable cognitive subgroup (“biotype”) of depression. In this prespecified secondary analysis of data from the International Study to Predict Optimized Treatment in Depression (iSPOT-D) RCT, cognitive testing, measures of depressive symptoms severity, psychosocial functioning, and functional neuroimaging were analyzed. Overall, analyses suggested that 27% of participants displayed what could be a “cognitive biotype positive” profile. Compared with the rest of the sample, there were distinct neural mechanistic processes observed in the cognitive biotype positive group related to the activation of the cognitive control circuit, unique cognitive deficits in the executive function and response inhibition domains of cognitive control, and distinct baseline symptom profiles identified. Posttreatment analyses reflected continued cognitive impairment and lower rates of symptom response and remission. Patients in the positive cognitive biotype subgroup had significantly lower rates of response and remission to antidepressants compared with the rest of the sample, especially when treated with sertraline. Overall, the results of this study should be further elucidated, and more specific biomarkers should be explored. The possibility of biotyping for other DSM specifiers of MDD could also be studied. The distinct symptom profile and potential benefits of tailoring treatments for this proposed subset of MDD could prove clinically useful.
Click to read the study in JAMA Open Network
Relevant Reading: International Study to Predict Optimized Treatment for Depression (iSPOT-D), a randomized clinical trial: rationale and protocol
In-Depth [randomized controlled trial]: The manifestations of MDD vary widely, and the literature supports a cognitive component to depression. However, impairments to cognition have not been explored previously as their own potential “biotype” of depression. This secondary analysis from the iSPOT-D RCT identified a group of outpatient individuals followed for moderate to severe MDD. A total of 1008 patients (571 [56.6%] female; mean [SD] age, 37.8 [12.6] years) were included in the analysis, and additional analyses of functional magnetic resonance imaging (fMRI) were conducted in a subset of 96 individuals (45 [46.7%] female; mean [SD] age, 34.5 [13.5] years). Pharmacological treatments were randomized in a 1:1:1 ratio with escitalopram, sertraline, or venlafaxine extended-release and assessed at both baseline and 8 weeks on multimodal outcomes. The main outcomes were pretreatment and posttreatment behavioural measures of cognitive performance across 9 domains, scores on two depressive symptom scales, scores for psychosocial function, and analysis of neural circuit function during a cognitive control task using fMRI.At baseline, those identified as the “cognitive biotype positive” subgroup via machine learning cluster analyses demonstrated significantly higher symptom severity (mean difference, 0.73; P = .01). Baseline data imply a distinct neural process and symptom profile for this proposed cognitive biotype. These participants also demonstrated a distinct symptom profile on the Hamilton Rating Scale for Depression (HRSD-17) and Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR-16), specifically on items related to slower information processing, less effortful thinking, increased psychomotor retardation, and increased insomnia, but significantly less self-blame. There was also significantly higher functional impairment pretreatment (scored using the Social and Occupational Functioning Assessment Scale, SOFAS) compared to the negative subgroup (P < .001). Cognitive task-evoked neural activation was reduced in the right dorsolateral prefrontal cortex (dLPFC; P = .003) and dorsal anterior cingulate (dACC; P = .04), both regions of the cognitive control circuit. Treatment outcomes at 8 weeks also reflected differences between the groups. The cognitive biotype positive subgroup had significantly lower rates of response to and remission to antidepressants compared to the rest of participants (HRSD-17 response, 54.8% vs 64.9%, P = .02; HRSD-17 remission, 38.8% vs 47.7%, P = .04). This difference was particularly pronounced for those being treated with sertraline (HRSD-17 response, P < .001; HRSD-17 remission, P = .04). Cognitive impairments persisted posttreatment in the cognitive biotype positive subgroup, remaining at least 0.2 standard deviations below the healthy mean, with effects most pronounced in the domains of executive function and response inhibition (executive function; P < .001; response inhibition; P < .001). The extent of cognitive control impairment also mediated the extent of symptom and psychosocial improvement posttreatment.
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