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.

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.

Insulin resistance disrupts white matter microstructure and amplitude of functional spontaneous activity in bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is linked to several structural and functional brain alterations. In addition, BD patients have a three-fold increased risk of developing insulin resistance, which is associated with neural changes and poorer BD outcomes. Therefore, we investigated the effects of insulin and two derived measures (insulin resistance and sensitivity) on white matter (WM) microstructure, resting-state (rs) functional connectivity (FC), and fractional amplitude of low-frequency fluctuation (fALFF). METHODS: BD patients (n = 92) underwent DTI acquisition, and a subsample (n = 22) underwent rs-fMRI. Blood samples were collected to determine insulin and glucose levels. The Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI) were computed. DTI data were analyzed via tract-based spatial statistics and threshold-free cluster enhancement. From rs-fMRI data, both ROI-to-ROI FC matrices and fALFF maps were extracted. RESULTS: Insulin showed a widespread negative association with fractional anisotropy (FA) and a positive effect on radial diffusivity (RD) and mean diffusivity (MD). HOMA-IR exerted a significant effect on RD in the right superior longitudinal fasciculus, whereas QUICKI was positively associated with FA and negatively with RD and MD in the left superior longitudinal fasciculus, left anterior corona radiata, and forceps minor. fALFF was negatively modulated by insulin and HOMA-IR and positively associated with QUICKI in the precuneus. No significant results were found in the ROI-to-ROI analysis. CONCLUSION: Our findings suggest that WM microstructure and functional alterations might underlie the effect of IR on BD pathophysiology, even if the causal mechanisms need to be further investigated.

Treating bipolar depression with esketamine: Safety and effectiveness data from a naturalistic multicentric study on esketamine in bipolar versus unipolar treatment-resistant depression.

BACKGROUND: Bipolar depression accounts for most of the disease duration in type I and type II bipolar disorder (BD), with few treatment options, often poorly tolerated. Many individuals do not respond to first-line therapeutic options, resulting in treatment-resistant bipolar depression (B-TRD). Esketamine, the S-enantiomer of ketamine, has recently been approved for treatment-resistant depression (TRD), but no data are available on its use in B-TRD. OBJECTIVES: To compare the efficacy of esketamine in two samples of unipolar and bipolar TRD, providing preliminary indications of its effectiveness in B-TRD. Secondary outcomes included the evaluation of the safety and tolerability of esketamine in B-TRD, focusing on the average risk of an affective switch. METHODS: Thirty-five B-TRD subjects treated with esketamine nasal spray were enrolled and compared with 35 TRD patients. Anamnestic data and psychometric assessments (Montgomery-Asberg Depression Rating Scale/MADRS, Hamilton-depression scale/HAM-D, Hamilton-anxiety scale/HAM-A) were collected at baseline (T0), at one month (T1), and three months (T2) follow up. RESULTS: A significant reduction in depressive symptoms was found at T1 and T2 compared to T0, with no significant differences in response or remission rates between subjects with B-TRD and TRD. Esketamine showed a greater anxiolytic action in subjects with B-TRD than in those with TRD. Improvement in depressive symptoms was not associated with treatment-emergent affective switch. CONCLUSIONS: Our results supported the effectiveness and tolerability of esketamine in a real-world population of subjects with B-TRD. The low risk of manic switch in B-TRD patients confirmed the safety of this treatment.

Investigating the Effectiveness and Tolerability of Intranasal Esketamine Among Older Adults With Treatment-Resistant Depression (TRD): A Post-hoc Analysis from the REAL-ESK Study Group.

INTRODUCTION: Treatment-resistant depression (TRD) is a serious and debilitating psychiatric disorder that frequently affects older patients. Esketamine nasal spray (ESK-NS) has recently been approved as a treatment for TRD, with multiple studies establishing its efficacy and tolerability. However, the real-world effectiveness, tolerability, and safety of this treatment in older adults is still unclear. OBJECTIVES: To evaluate the efficacy and tolerability of ESK-NS in older subjects with TRD. METHODS: This is a post-hoc analysis of the REAL-ESK study, a multicenter, retrospective, observational study. Participants here selected were 65 years or older at baseline. The Montgomery-Åsberg Depression Rating Scale (MADRS) and the Hamilton Anxiety Rating Scale (HAM-A) were used to assess depressive and anxiety symptoms, respectively. Data were collected at three-time points: baseline, 1 month after the start of treatment (T1), and 3 months after treatment (T2). RESULTS: The sample included older adults with TRD (n = 30). MADRS and HAM-A values decreased significantly at T1 (T0 versus T1: pholm <0.001, Cohen's d = 0.840) and T2 follow-ups (T0 versus T2: pholm <0.001, Cohen's d = 1.419). At T2, 53.3% of subjects were responders (MADRS score reduced ≥50%), while 33.33% were in remission (MADRS<10). ESK-NS-related adverse effects were in order of frequency dizziness (50%), followed by dissociation (33.3%), sedation (30%), and hypertension (13.33%). Six out of 30 participants (20%) discontinued treatment. CONCLUSIONS: Our findings provide preliminary evidence of ESK-NS effectiveness in older adults with TRD, a highly debilitating depressive presentation. Furthermore, we observe high levels of treatment-emergent adverse events, which, in the majority of instances, did not require treatment suspension.

Adiponectin predicts poor response to antidepressant drugs in major depressive disorder.

OBJECTIVE: Produced by adipocytes, adiponectin crosses the blood-brain barrier to bind with specific receptors in the hypothalamus, brainstem, hippocampus, and cortex. In patients with major depressive disorder (MDD), circulating levels of adiponectin inversely related with antidepressant response to ketamine, and predicted a better response to multi-target drug combinations than to escitalopram. We investigated the effect of adiponectin on response to antidepressants in a naturalistic setting. METHODS: We assessed baseline plasma levels of adiponectin in 121 MDD inpatients, treated with antidepressant drug monotherapy based on clinical need (selective serotonin reuptake inhibitors, venlafaxine, duloxetine) in a specialized hospital setting. Severity of depression was weekly assessed with Hamilton scale ratings. RESULTS: Adiponectin plasma levels were higher in patients with MDD compared with healthy controls, and negatively influenced the pattern of antidepressant response (higher baseline levels, worse response) independent of the drug class and of the baseline severity of depression, and of age, sex, and body mass index. CONCLUSIONS: The identification of adiponectin as a predictor of antidepressant response to drugs of different mechanism of action, such as ketamine, SSRIs, and SNRIs, and both in experimental and in clinical settings, warrants interest for further study of its pathways to search for novel biomarkers and therapeutic targets.

Precision psychiatry in clinical practice.

The treatment of depression represents a major challenge for healthcare systems and choosing among the many available drugs without objective guidance criteria is an error-prone process. Recently, pharmacogenetic biomarkers entered in prescribing guidelines, giving clinicians the possibility to use this additional tool to guide prescription and improve therapeutic outcomes. This marked an important step towards precision psychiatry, which aim is to integrate biological and environmental information to personalise treatments. Only genetic variants in cytochrome enzymes are endorsed by prescribing guidelines, but in the future polygenic predictors of treatment outcomes may be translated into the clinic. The integration of genetics with other relevant information (e.g., concomitant diseases and treatments, drug plasma levels) could be managed in a standardised way through ad hoc software. The overcoming of the current obstacles (e.g., staff training, genotyping and informatics facilities) can lead to a broad implementation of precision psychiatry and represent a revolution for psychiatric care.Key pointsPrecision psychiatry aims to integrate biological and environmental information to personalise treatments and complement clinical judgementPharmacogenetic biomarkers in cytochrome genes were included in prescribing guidelines and represented an important step towards precision psychiatryTherapeutic drug monitoring is an important and cost-effective tool which should be integrated with genetic testing and clinical evaluation in order to optimise pharmacotherapyOther individual factors relevant to pharmacotherapy response (e.g., individual's symptom profile, concomitant diseases) can be integrated with genetic information through artificial intelligence to provide treatment recommendationsThe creation of pharmacogenetic services within healthcare systems is a challenging and multi-step process, education of health professionals, promotion by institutions and regulatory bodies, economic and ethical barriers are the main issues.

Bright light therapy accelerates the antidepressant effect of repetitive transcranial magnetic stimulation in treatment resistant depression: a pilot study.

Objectives: We performed a randomized single-blinded study to assess the superiority of the combination strategy of repetitive Transcranial Magnetic Stimulation (rTMS) and Bright Light Therapy (BLT) over rTMS treatment alone in reducing depressive symptoms in treatment-resistant depression (TRD).Methods: We enrolled 80 inpatients with a diagnosis of TRD. All patients were randomly assigned into two groups: group A was treated with rTMS, compared to group B treated with a combination of rTMS and BLT. Depressive symptoms were weekly assessed (T0, T1, T2, T3) through the 17-item Hamilton depression rating scale (HDRS-17).Results: rANOVA (F=2.766, p=0.043) and post-hoc in HDRS-17 showed significant better scores in favour of group B every week (p<0.025, T1: 22.075 vs 17.200; T2: 16.100 vs 12.775; T3: 12.225 vs 8.900).Conclusions: The antidepressant effect of rTMS was enhanced and accelerated by its combination with BLT in treating resistant depression.KEYPOINTSAlmost one third of depressed patients does not respond to antidepressants; emerging neuromodulation and chronobiological techniques are effective antidepressant augmentation treatments.The aim of this study was to assess the superiority of the combination strategy of Light Therapy and TMS over TMS treatment alone in a group of treatment resistant depressed patients.The implication of this study in clinical practice is that a safe, low risk and cost-effective treatment, as Light Therapy, improves and accelerates the antidepressant effect of TMS.

Passiflora incarnata L., herba, in benzodiazepine tapering: long-term safety and efficacy in a real-world setting.

Introduction: Chronic and inappropriate benzodiazepine (BDZ) prescription and intake represent an important health and social concern worldwide. The aim of our study was to investigate the safety and efficacy of P. incarnata L., herba in reducing BDZ misuse in a real-world population of depressed and anxious patients in a long-term treatment with BDZs. Methods: Over an 18-month period (from July 2021 to December 2022), we previously conducted a retrospective and naturalistic study on euthymic outpatients with a diagnosis of anxiety or depression and chronically taking BDZs. In this study we contacted patients 12 months after their enrollment in the previous study to assess their disease status and their BDZs and P. incarnata intake. Results: Our findings support the effectiveness of a dry extract of P. incarnata L., herba, as an add-on treatment during BDZ tapering in patients with anxiety or depression. We confirmed this effect to be sustained over time, and P. incarnata showed to be easily discontinued with no rebound, withdrawal or psychological dependence effect. The absence of side effects and adverse events confirmed the safety of P. incarnata in a real-world population. Personality disorders confirmed to be a relevant risk factor for maintaining addictive behavior, even when symptoms associated to withdrawal seem to be not particularly relevant. Discussion: We confirmed the possible effectiveness of P. incarnata as an add-on treatment in BDZ reduction. Further studies may be helpful to better investigate the promising properties of P. incarnata in the management of relevant clinical issues, such as anxiety disorders and addiction, that are classically known to benefit from GABAergic treatments.

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.

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.

History of Peripartum Depression Moderates the Association Between Estradiol Polygenic Risk Scores and Basal Ganglia Volumes in Major Depressive Disorder.

BACKGROUND: The neurobiological differences between women who have experienced a peripartum episode and those who have only had episodes outside of this period are not well understood. METHODS: 64 parous female patients with major depressive disorder that have either a positive (n=30) or negative (n=34) history of peripartum depression (PPD) underwent MRI acquisition to obtain structural brain images. An independent two-sample t-test comparing patients with and without a history of PPD was performed using voxel-based morphometry analysis (VBM). Additionally, polygenic risk scores (PRSs) for estradiol were calculated and a moderation analysis was conducted between 3 estradiol PRSs and PPD history status on extracted cluster volumes using IBM SPSS PROCESS macro. RESULTS: The VBM analysis identified larger grey matter volumes in bilateral clusters encompassing the putamen, pallidum, caudate, and thalamus in patients with PPD history compared to patients without a history. The moderation analysis identified a significant interaction of 2 estradiol PRSs and PPD history on grey matter cluster volumes with a positive effect in PPD women and a negative effect in women with no history of PPD. CONCLUSIONS: Our findings demonstrate that women who have experienced a peripartum episode are neurobiologically distinct from women who have no history of PPD in a cluster within the basal ganglia, an area important for motivation, decision-making, and emotional processing. Furthermore, we show that the genetic load for estradiol has a differing effect in this area based on PPD status which supports the claim that PPD is associated with sensitivity to sex steroid hormones.

Hypomanic symptoms in major depressive disorder: Prognostic impact and treatment issues.

BACKGROUND: Mixed depression (MXD), defined as (hypo)manic symptoms occurring within major depressive episodes, is common in both bipolar and unipolar disorders, but its prognostic and treatment implications remain unclear. This study aimed to examine the relationship between hypomanic symptoms, treatment response and remission of suicidal thoughts. METHODS: We analyzed 1243 adults with major depressive disorder (MDD), recruited for a naturalistic study on treatment-resistant depression. Data were gathered cross-sectionally and retrospectively through structured interviews and clinical rating scales including the Young Mania Rating Scale (YMRS) and Montgomery-Asberg Depression Rating Scale (MADRS); statistical analyses were performed using univariate and multivariate methods. RESULTS: Hypomanic symptoms were present in 651 patients (45 %), while 307 patients (25 %) responded to treatment. Both treatment responders (p < 0.0001) and those who achieved remission from suicide ideation (p = 0.0085) showed lower hypomanic (YMRS) scores. Multivariate analysis showed that hypomanic symptoms were negatively linked to treatment response (O.R. 0.71-0.87), while bipolar spectrum markers such as age at illness onset (O.R. 1.00-1.03) and MDD recurrence (O.R. 0.47-0.89) predicted remission from suicidal thoughts. Medications commonly used to treat bipolar disorder showed some benefits, with dopamine/serotonin antagonists improving suicide ideation (p < 0.0001) and mood stabilizers being associated with reduced hypomanic symptoms (p = 0.0003). LIMITATIONS: The study lacked prospective clinical assessments and treatment randomization. CONCLUSION: Hypomanic symptoms are common in unipolar depression; their assessment is essential to identify challenging-to-treat cases and select the best pharmacological options.

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.

The clinical perspective on late-onset depression in European real-world treatment settings.

The clinical phenotype of the so-called late-onset depression (LOD) affecting up to 30% of older adults and yielding heterogeneous manifestations concerning symptoms, severity and course has not been fully elucidated yet. This European, cross-sectional, non-interventional, naturalistic multicenter study systematically investigated socio-demographic and clinical correlates of early-onset depression (EOD) and LOD (age of onset ≥ 50 years) in 1410 adult in- and outpatients of both sexes receiving adequate psychopharmacotherapy. In a total of 1329 patients (94.3%) with known age of disease onset, LOD was identified in 23.2% and was associated with unemployment, an ongoing relationship, single major depressive episodes, lower current suicidal risk and higher occurrence of comorbid hypertension. In contrast, EOD was related to higher rates of comorbid migraine and additional psychotherapy. Although the applied study design does not allow to draw any causal conclusions, the present results reflect broad clinical settings and emphasize easily obtainable features which might be characteristic for EOD and LOD. A thoughtful consideration of age of onset might, hence, contribute to optimized diagnostic and therapeutic processes in terms of the globally intended precision medicine, ideally enabling early and adequate treatment allocations and implementation of respective prevention programs.

The rapid antidepressant effectiveness of repeated dose of intravenous ketamine and intranasal esketamine: A post-hoc analysis of pooled real-world data.

INTRODUCTION: Intravenous ketamine (KET-IV) and intranasal esketamine (ESK-NS) are effective in the acute treatment of Treatment-Resistant Depression (TRD). Studies comparing KET-IV and ESK-NS concerning their action, safety, and tolerability are currently lacking. MATERIALS AND METHODS: We combined patients' data from two unipolar TRD cohorts that received KET-IV (n = 171) at the Canadian Rapid Treatment Center of Excellence in Toronto, Canada, or ESK-NS (n = 140) at several TRD clinics in Italy. The Quick Inventory for Depression Symptomatology-Self-Report-16/QIDS-SR16 in the KET-IV group and Montgomery-Åsberg Depression Rating Scale/MADRS in the ESK-NS group measured depressive symptoms at baseline (T0) and after the acute treatment phase (T1) (i.e., four infusions of KET-IV and eight administrations of ESK-NS). As different scales were used, the primary outcome was to compare the improvement in depression severity in the two cohorts by measuring effect sizes, response and remission rates. Finally, we compare side effects and discontinuation rates. RESULTS: At T1, KET-IV and ESK-NS significantly reduced depressive symptoms (respectively: QIDS-SR16 mean reduction = 5.65, p < 0.001; MADRS mean reduction = 11.41, p = 0.025). KET-IV showed larger effect sizes compared to ESK-NS (1.666 vs. 1.244). KET-IV had higher response rates (36 % vs. 25 %; p = 0.042) but not superior remission rates (13 % vs. 12 %; p = 0.845) than ESK-NS at T1. Despite more reported side effects, KET-IV did not cause more discontinuations for adverse events (4.6 % vs. 2.12 %; p = 0.228) than ESK-NS. CONCLUSION: KET-IV showed a higher short-term antidepressant effect, whereas ESK-NS exhibited lower side effects. Both were generally well tolerated. Future head-to-head studies should consider the long-term efficacy of these treatments.

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.

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.

Neutrophil to lymphocyte ratio and antidepressant treatment response in patients with major depressive disorder: Effect of sex and hippocampal volume.

Several factors may affect response to treatment in Major Depressive Disorder (MDD) including immune/inflammatory alterations and regional brain volumes, particularly in hippocampal regions which have shown to be influenced by inflammatory status. Neutrophil-to-lymphocyte ratio (NLR) is an inflammatory marker found to be elevated in depressed women in large population studies. Here we investigate the effect of NLR on treatment response in MDD patients, and the role of sex and hippocampal volume on influencing this relationship. A sample of 124 MDD depressed inpatients (F = 80) underwent MRI acquisition, admission NLR was calculated by dividing absolute neutrophil by absolute lymphocyte counts and depression severity was assessed at admission and discharge via the Hamilton Depression Rating Scale (HDRS). As a measure of treatment response, delta HDRS was calculated. We found a significant moderation effect of sex on the relationship between NLR and Delta HDRS: a negative relation was found in females and a positive one in males. NLR was found to negatively affect hippocampal volumes in females. Both left and right hippocampal volume positively associated with Delta HDRS. Finally, left hippocampal volume mediated the effect of NLR on Delta HDRS in females. Sex moderated the relation between inflammation and treatment response in line with previous reports linking inflammation to hampered antidepressant effect in females. Further, this effect is partially mediated by hippocampal volume, suggesting that antidepressant response may be hampered by the detrimental effect of inflammation on the brain.

Reduced corticolimbic habituation to negative stimuli characterizes bipolar depressed suicide attempters.

Suicide attempts in Bipolar Disorder are characterized by high levels of lethality and impulsivity. Reduced rates of amygdala and cortico-limbic habituation can identify a fMRI phenotype of suicidality in the disorder related to internal over-arousing states. Hence, we investigated if reduced amygdala and whole-brain habituation may differentiate bipolar suicide attempters (SA, n = 17) from non-suicide attempters (nSA, n = 57), and healthy controls (HC, n = 32). Habituation was assessed during a fMRI task including facial expressions of anger and fear and a control condition. Associations with suicidality and current depressive symptomatology were assessed, including machine learning procedure to estimate the potentiality of habituation as biomarker for suicidality. SA showed lower habituation compared to HC and nSA in several cortico-limbic areas, including amygdalae, cingulate and parietal cortex, insula, hippocampus, para-hippocampus, cerebellar vermis, thalamus, and striatum, while nSA displayed intermediate rates between SA and HC. Lower habituation rates in the amygdalae were also associated with higher depressive and suicidal current symptomatology. Machine learning on whole-brain and amygdala habituation differentiated SA vs. nSA with 94% and 69% of accuracy, respectively. Reduced habituation in cortico-limbic system can identify a candidate biomarker for attempting suicide, helping in detecting at-risk bipolar patients, and in developing new therapeutic interventions.