NeuroPharm study: EEG wakefulness regulation as a biomarker in MDD

While several electroencephalogram (EEG)-based biomarkers have been proposed as diagnostic or predictive tools in major depressive disorder (MDD), there is a clear lack of replication studies in this field. Markers that link clinical features such as disturbed wakefulness regulation in MDD with neurophysiological patterns are particularly promising candidates for e.g., EEG-informed choices of antidepressive treatment. We investigate if we in an independent MDD sample can replicate abnormal findings of EEG-vigilance regulation during rest and as a predictor for antidepressive treatment response. EEG-resting state was recorded in 91 patients and 35 healthy controls from the NeuroPharm trial. EEG-vigilance was assessed using the Vigilance Algorithm Leipzig (VIGALL). We compared the vigilance regulation during rest between patients and healthy controls and between remitters/responders and non-remitters/non-responders after eight weeks of SSRI/SNRI treatment using two different sets of response criteria (NeuroPharm and iSPOT-D). We replicated previous findings showing hyperstable EEG-wakefulness regulation in patients in comparison to healthy subjects. Responders defined by the iSPOT-D criteria showed a higher propensity toward low vigilance stages in comparison to patients with no response at pretreatment, however, this did not apply when using the NeuroPharm criteria. EEG-wakefulness regulation patterns normalized toward patterns of healthy controls after 8 weeks of treatment. This replication study supports the diagnostic value of EEG-vigilance regulation and its usefulness as a biomarker for the choice of treatment in MDD

Evaluating cognitive disturbances as treatment target and predictor of antidepressant action in major depressive disorder: A NeuroPharm study.

Cognitive disturbances in major depressive disorder (MDD) constitute a critical treatment target and hold promise as an early predictor of antidepressant treatment response; yet their clinical relevance is not fully established. Therefore, we here investigate if (1) cognitive performance improves over the course of antidepressant treatment and (2) cognitive performance at baseline is predictive of antidepressant treatment response. In the NeuroPharm study (clinical trial id: NCT02869035), 92 antidepressant-free patients with a moderate to severe depressive episode were assessed with a comprehensive cognitive test battery including both cold (emotion-independent) and hot (emotion-dependent) tasks. Patients were tested before and after 12 weeks of standard antidepressant treatment with escitalopram in flexible doses of 10-20 mg. Performance improved across most cognitive domains over the course of antidepressant treatment. Notably, these improvements were independent of improvement in mood symptoms, emphasizing that cognitive disturbances are a distinct symptom and therefore treatment target in MDD. Results did not suggest that performance on any single cognitive measure at baseline was associated with later clinical response to antidepressant treatment. However, a small cluster of patients (N = 28) with globally disturbed cognition at baseline exhibited poorer clinical response after 8 but not 12 weeks of antidepressant treatment, suggesting that severe cognitive disturbances may delay treatment response. Thus, while pretreatment cognitive performance on individual tests may not be useful as clinical markers of treatment response, profiles capturing performance across different cognitive domains may be useful for stratification of patients with MDD and could be helpful in future intervention trials

Pretreatment qEEG biomarkers for predicting pharmacological treatment outcome in major depressive disorder: Independent validation from the NeuroPharm study

Several electroencephalogram (EEG) biomarkers for prediction of drug response in major depressive disorder (MDD) have been proposed, but validations in larger independent datasets are missing. In the current study, we investigated the prognostic value of previously suggested EEG biomarkers. We gathered data that matched prior studies in terms of EEG methodology, clinical criteria for MDD, and statistical approach as closely as possible. The NeuroPharm study is a non-randomized and open label prospective clinical trial. One hundred antidepressant free patients with MDD were enrolled in the study and 79 (57 female) were included in the per-protocol analysis. The biomarkers candidates for cross-validation were derived from prior studies such as iSPOT-D and EMBARC and include frontal and occipital alpha power and asymmetry and delta and theta activity at anterior cingulate cortex (ACC). The alpha asymmetry, reported in two out of six prior studies, could be partially validated. We found that in female patients, larger right than left frontal alpha power prior to drug treatment was associated with better clinical outcome 8 weeks later. Moreover, female non-responder had higher central left alpha power relative to the right. In contrast to prior reports, we found that lower theta activity at ACC was present in remitters and was associated with greater improvement at week 8. We provide evidence that in women with MDD, alpha asymmetry seems to be the most promising EEG biomarker for prediction of treatment response

Concurrent anxiety in patients with major depression and cerebral serotonin 4 receptor binding. A NeuroPharm-1 study

Abstract Concurrent anxiety is frequent in major depressive disorder and a shared pathophysiological mechanism between anxiety and other depressive symptoms is plausible. The serotonin 4 receptor (5-HT4R) has been implicated in both depression and anxiety. This is the first study to investigate the association between the cerebral 5-HT4R binding and anxiety in patients with depression before and after antidepressant treatment and the association to treatment response. Ninety-one drug-free patients with depression were positron emission tomography scanned with the 5-HT4R ligand [11C]-SB207145. Depression severity and concurrent anxiety was measured at baseline and throughout 8 weeks of antidepressant treatment. Anxiety measures included four domains: anxiety/somatization factor score; Generalized Anxiety Disorder 10-items (GAD-10) score; anxiety/somatization factor score ≥7 (anxious depression) and syndromal anxious depression. Forty patients were rescanned at week 8. At baseline, we found a negative association between global 5-HT4R binding and both GAD-10 score (p < 0.01) and anxiety/somatization factor score (p = 0.06). Further, remitters had a higher baseline anxiety/somatization factor score compared with non-responders (p = 0.04). At rescan, patients with syndromal anxious depression had a greater change in binding relative to patients with non-syndromal depression (p = 0.04). Concurrent anxiety in patients with depression measured by GAD-10 score and anxiety/somatization factor score is negatively associated with cerebral 5-HT4R binding. A lower binding may represent a subtype with reduced natural resilience against anxiety in a depressed state, and concurrent anxiety may influence the effect on the 5-HT4R from serotonergic antidepressants. The 5-HT4R is a promising neuroreceptor for further understanding the underpinnings of concurrent anxiety in patients with depression