Multimodal brain-derived subtypes of Major depressive disorder differentiate patients for anergic symptoms, immune-inflammatory markers, history of childhood trauma and treatment-resistance.

An estimated 30 % of Major Depressive Disorder (MDD) patients exhibit resistance to conventional antidepressant treatments. Identifying reliable biomarkers of treatment-resistant depression (TRD) represents a major goal of precision psychiatry, which is hampered by the clinical and biological heterogeneity. To uncover biologically-driven subtypes of MDD, we applied an unsupervised data-driven framework to stratify 102 MDD patients on their neuroimaging signature, including extracted measures of cortical thickness, grey matter volumes, and white matter fractional anisotropy. Our novel analytical pipeline integrated different machine learning algorithms to harmonize data, perform data dimensionality reduction, and provide a stability-based relative clustering validation. The obtained clusters were characterized for immune-inflammatory peripheral biomarkers, TRD, history of childhood trauma and depressive symptoms. Our results indicated two different clusters of patients, differentiable with 67 % of accuracy: one cluster (n = 59) was associated with a higher proportion of TRD, and higher scores of energy-related depressive symptoms, history of childhood abuse and emotional neglect; this cluster showed a widespread reduction in cortical thickness (d = 0.43-1.80) and volumes (d = 0.45-1.05), along with fractional anisotropy in the fronto-occipital fasciculus, stria terminalis, and corpus callosum (d = 0.46-0.52); the second cluster (n = 43) was associated with cognitive and affective depressive symptoms, thicker cortices and wider volumes. Multivariate analyses revealed distinct brain-inflammation relationships between the two clusters, with increase in pro-inflammatory markers being associated with decreased cortical thickness and volumes. Our stratification of MDD patients based on structural neuroimaging identified clinically-relevant subgroups of MDD with specific symptomatic and immune-inflammatory profiles, which can contribute to the development of tailored personalized interventions for MDD.

Understanding and treating postpartum depression: a narrative review.

Postpartum depression (PPD) is an increasingly prevalent but still poorly characterized disorder. Causal and modulating factors include hormones fluctuations, such as estrogen, progesterone, and allopregnolone, pathways imbalances, such as oxytocin and kynurenine, chronobiological factors, and brain imaging alterations. Treatment may differ from the traditional major depression management, while selective serotonin reuptake inhibitors such as sertraline are commonly used and suggested by guidelines, neurosteroids such as brexanolone and the more convenient zuranolone have been recently approved. Newer neurosteroids such as ganaxolone, valaxanolone, and lysaxanolone are currently under development, but also esketamine and psychedelics are promising potential treatments. Other somatic treatments including brain stimulation techniques and light therapy also showed benefit. PPD is therefore increasingly understood as, at least partially, independent from major depressive disorder. Specific and individualized treatments including pharmacological and non-pharmacological therapies are progressively being introduced in the routine clinical practice.

The impact of menopause on antidepressant response: an explorative analysis from a real-world study.

This study endeavors to deepen our understanding of the subject matter by exploring, within a real-world sample, the impact of menopausal status on the antidepressant treatments response. The whole sample included a total of 447 patients, 156 male and 291 female, 110 pre-menopause and 181 post-menopause. In our sample post-menopause women showed a worse response to antidepressants than pre-menopause women (p = 0.006), and this difference seems to be unrelated to age or brain aging.

How different definition criteria may predict clinical outcome in treatment resistant depression: Results from a prospective real-world study.

Management of treatment-resistant depression (TRD) remains a major public health challenge, also due to the lack of a consensus around TRD definition. We investigated the impact of different definitions of TRD on identifying patients with distinct features in terms of baseline characteristics, treatment strategies, and clinical outcome. We conducted a prospective naturalistic study on 538 depressed inpatients. Patients were screened for treatment resistance by two TRD definitions: looser criteria (lTRD) and stricter criteria (sTRD). We compared baseline characteristics, treatment and clinical outcome between the TRD groups and their non-TRD counterparts. 52.97 % of patients were identified as lTRD, only 28.81 % met the criteria for sTRD. sTRD patients showed lower rates of remission and slower symptom reduction compared to non-TRD patients and received more challenging treatments. Surprisingly, patients identified as sTRD also exhibited lower rates of psychiatric comorbidities, including personality disorders, substance abuse, or alcohol misuse. Stricter TRD criteria identify patients with worse clinical outcomes. Looser criteria may lead to overdiagnosis and over treatment. Clinical features known to be possible risk factors for TRD, as psychiatric comorbidities, showed to be more suggestive of a "difficult to manage" depression rather than a proper TRD.

Low-dose interleukin 2 antidepressant potentiation in unipolar and bipolar depression: Safety, efficacy, and immunological biomarkers.

Immune-inflammatory mechanisms are promising targets for antidepressant pharmacology. Immune cell abnormalities have been reported in mood disorders showing a partial T cell defect. Following this line of reasoning we defined an antidepressant potentiation treatment with add-on low-dose interleukin 2 (IL-2). IL-2 is a T-cell growth factor which has proven anti-inflammatory efficacy in autoimmune conditions, increasing thymic production of naïve CD4 + T cells, and possibly correcting the partial T cell defect observed in mood disorders. We performed a single-center, randomised, double-blind, placebo-controlled phase II trial evaluating the safety, clinical efficacy and biological responses of low-dose IL-2 in depressed patients with major depressive (MDD) or bipolar disorder (BD). 36 consecutively recruited inpatients at the Mood Disorder Unit were randomised in a 2:1 ratio to receive either aldesleukin (12 MDD and 12 BD) or placebo (6 MDD and 6 BD). Active treatment significantly potentiated antidepressant response to ongoing SSRI/SNRI treatment in both diagnostic groups, and expanded the population of T regulatory, T helper 2, and percentage of Naive CD4+/CD8 + immune cells. Changes in cell frequences were rapidly induced in the first five days of treatment, and predicted the later improvement of depression severity. No serious adverse effect was observed. This is the first randomised control trial (RCT) evidence supporting the hypothesis that treatment to strengthen the T cell system could be a successful way to correct the immuno-inflammatory abnormalities associated with mood disorders, and potentiate antidepressant response.

Hippocampal and parahippocampal volume and function predict antidepressant response in patients with major depression: A multimodal neuroimaging study.

BACKGROUND: For many patients with major depressive disorder (MDD) adequate treatment remains elusive. Neuroimaging techniques received attention for their potential use in guiding and predicting response, but were rarely investigated in real-world psychiatric settings. AIMS: To identify structural and functional Magnetic Resonance Imaging (MRI) biomarkers associated with antidepressant response in a real-world clinical sample. METHODS: We studied 100 MDD inpatients admitted to our psychiatric ward, treated with various antidepressants upon clinical need. Hamilton Depression Rating Scale percentage decrease from admission to discharge was used as a measure of response. All patients underwent 3.0 T MRI scanning. Grey matter (GM) volumes were investigated both in a voxel-based morphometry (VBM), and in a regions of interest (ROI) analysis. In a subsample of patients, functional resting-state connectivity patterns were also explored. RESULTS: In the VBM analysis, worse response was associated to lower GM volumes in two clusters, encompassing the left hippocampus and parahippocampal gyrus, and the right superior and middle temporal gyrus. Investigating ROIs, lower bilateral hippocampi and amygdalae volumes predicted worse treatment outcomes. Functional connectivity in the right temporal and parahippocampal gyrus was also associated to response. CONCLUSION: Our results expand existing literature on the relationship between the structure and function of several brain regions and treatment response in MDD. While we are still far from routine use of MRI biomarkers in clinical practice, we confirm a possible role of these techniques in guiding treatment choices and predicting their efficacy.

Add-On Treatment with Passiflora incarnata L., herba, during Benzodiazepine Tapering in Patients with Depression and Anxiety: A Real-World Study.

Chronic and inappropriate benzodiazepine intake represents an important health and social concern worldwide. The aim of our study was to investigate the effectiveness of P. incarnata L., herba, in reducing benzodiazepine misuse in a real-world population of depressed and anxious patients in a long-term treatment with benzodiazepines. We conducted a retrospective naturalistic study on 186 patients undergoing benzodiazepine downtitration, 93 with the addition of a dry extract of P. incarnata L., herba (Group A), and 93 without any add-on treatment (Group B). Regarding the benzodiazepine dosage variation in the two groups, a repeated measure ANOVA showed a significant effect of time (p < 0.001), group (p = 0.018), and time x group interaction (p = 0.011). We found a significantly higher rate, i.e., of 50%, reduction in Group A vs. Group B at 1 month (p < 0.001) and at 3 months (p < 0.001) and complete benzodiazepine discontinuation at 1 month (p = 0.002) and at 3 months (p = 0.016). Our findings suggest the role of P. incarnata as an effective add-on treatment during benzodiazepine tapering. These findings highlight the need for further studies to better investigate the promising properties of P. incarnata in the management of such a relevant clinical and social issue.

Genetics of nonpharmacological treatments of depression.

Nonpharmacological antidepressant treatments are effective and well tolerated in selected patients. However, response is heterogeneous and validated biomarkers would be precious to aid treatment choice. We searched Pubmed, Scopus, and Google Scholar until May 2022 for original articles evaluating the association of genetic variables with the efficacy of nonpharmacological treatments for major depressive episodes. Most studies analyzed small sample sizes using the candidate gene approach, leading to poorly replicated findings that need to be interpreted cautiously. The few available methylome-wide and genome-wide association studies (GWASs) considered only electroconvulsive therapy (ECT) and cognitive-behavioral therapy in small samples, providing interesting findings by using polygenic risk scores. A deeper knowledge of the genetic factors implicated in treatment response may lead to a better understanding of the neurobiological mechanisms of nonpharmacological therapies for depression, and depression itself. Future GWAS are going to expand their sample size, thanks to consortia such as the gen-ECT-ic consortium.