Immune-Targeted Therapies for Depression: Current Evidence for Antidepressant Effects of Monoclonal Antibodies.

Importance: Increasing evidence suggests a potential role of immune-modulatory drugs for treatment-resistant depression. This scoping review explores the emerging evidence regarding the antidepressant effects of monoclonal antibodies (mAbs), a relatively newer class of immune therapeutics with favorable safety profile.Observations: PubMed was searched up to November 2023 for English publications addressing the antidepressant effects of mAbs, including meta-analyses, randomized controlled trials, open-label, single-arm studies, and case series. Several mAbs have shown potential antidepressant effects, but most studies in primary inflammatory disorders included patients with mild depression. Only infliximab and sirukumab were directly examined in individuals with primary depression. mAbs that do not require laboratory monitoring, such as ixekizumab and dupilumab, could hold potential promise if future studies establish their safety profile regarding suicide risk.Conclusions and Relevance: The use of several mAbs for the treatment of primary inflammatory disorders has been associated with improvement of comorbid depressive symptoms. Given their unique mechanisms of action, mAbs may offer a new hope for depressed patients who do not respond to currently available antidepressants. Further research addressing individuals with more severe depressive symptoms is essential. Direct examination of antidepressant effects of mAbs in people with primary depressive disorders is also crucial to refine their clinical use in the treatment of depression.

Immune-related biomarkers and suicidal behaviors: A meta-analysis.

Biomarkers that can differentiate between psychiatric disorders with and without suicidal behavior history from each other and from healthy volunteers may explain part of the pathogenesis of suicidal behavior. We conducted the hitherto largest meta-analysis comparing immune biomarkers between subjects with and without suicide attempt history or death by suicide. The study protocol was registered with PROSPERO, CRD42020212841. Standardized mean differences (SMD) were pooled with random-effects models. Heterogeneity between studies was assessed with the I2-statistic and publication bias was evaluated by the Egger test and funnel plots. Data were based on 36 studies including 2679 persons with suicidal behaviors and 6839 comparison subjects, and four immune-related biomarkers (CRP, IL-6, TNF-α and IL-1ß). Suicidal behavior was associated with higher CRP blood levels compared with: healthy controls (SMD [95%CI] = 1.42[0.85-1.98]); patients with depression alone (SMD [95%CI] = 1.23[0.20-2.26]); and patients with any psychiatric disorders (SMD [95%CI] = 0.39[0.22-0.55]). IL-6 blood level was higher in patients with suicidal behaviors compared with healthy controls (SMD [95%CI] = 1.13[0.45-1.82]) and when compared with psychiatric patients without suicidal behaviors (SMD [95%CI] = 0.22 [0.11-0.33]). Meta-regression and subgroup analyses revealed that increased CRP in suicidal behavior is primarily driven by recent suicidal behavior. These results implicate the immune system and inflammatory response in suicidal behavior independent of a relationship to major psychiatric disorders, and that these biological measures are predominantly state-dependent markers. Future studies are needed to determine the cause-and-effect relationship of these immune system biomarkers with suicidal behavior, and their potential predictive properties.

Rethinking the medication management of major depression.

INTRODUCTION: Current treatment of major depressive disorder (MDD) warrants critical reexamination. Initial treatment response rates are modest and drop dramatically after 3 months. Meanwhile, MDD is emerging as the leading cause of disease burden worldwide. AREAS COVERED: We searched PubMed (up to June 2021) for randomized controlled trials comparing antidepressant combinations versus monotherapy. We discuss findings from these studies in light of current treatment guidelines for MDD. These recommend a sequence of single, six-week-long, medication trials, before trying antidepressant combinations. The result leaves one third of patients still depressed after six months of treatment. EXPERT OPINION: Optimizing the first three months of MDD treatment is crucial because response rates during this period are five times better than in the second three months. We propose a new, evidence-based algorithm of sequential antidepressant treatment steps, termed Accelerated Sequential Antidepressant Protocol (ASAP), that may offer better response rates than current guidelines. ASAP involves shorter duration medication trials (2-4 weeks) and earlier use of antidepressant combinations, seeking additive antidepressant effects without worsening side effects. Future research should compare ASAP to current treatment guidelines. Research is also needed on the role of rapidly acting antidepressants like ketamine for acutely ill and suicidal depressed patients.

Latent Toxoplasmosis is Associated with Depression and Suicidal Behavior.

OBJECTIVE: Neuroinflammation is implicated in the pathophysiology of depression. Toxoplasma gondii (T. gondii) causes chronic brain inflammatory process and may thus contribute to both depression and its most serious complication, suicidal behavior. In this study, we hypothesized that latent toxoplasmosis may underlie current depression and/or suicidal behavior. METHOD: Currently depressed individuals (N = 384) and age, sex, and residence-matched healthy controls (HC) (N = 400) were tested for latent toxoplasmosis (i.e., positive serum T. gondii IgG antibodies). Exclusions included positive IgM and negative IgG antibodies indicating acute T. gondii infection and history of cognitive problems. Depression severity and history of lifetime suicide attempts were assessed using Beck Depression Inventory (BDI) and Columbia Suicide Severity Rating Scale, respectively. RESULTS: Participants with seropositive anti-T. gondii IgG antibody had a significantly higher odds of being depressed compared with seronegative participants (OR = 2.9, 95% CI: 1.9-4.3; p < 0.001). BDI score was significantly different between depressed seropositive and depressed seronegative individuals (IgG＋: mean (SD)= 39.65 (11.83) vs. IgG-: mean (SD)= 33.44(9.80); t = 5.03, p < 0.001). Further, seropositive depressed participants were more likely to have prior history of actual suicide attempts compared with seronegative participants (OR= 6.2, 95% CI: 3.4-11.2, p < 0.001). CONCLUSIONS: Latent toxoplasmosis may represent be a risk factor for depression and suicidal behavior. Screening for, and treatment of, underlying T. gondii infection may help improve depression and curb the increasing suicide rates. Future studies should prospectively test these hypotheses to be adequately implemented.HIGHLIGHTSLatent toxoplasmosis has been linked to history of psychiatric disorders.Depressed individuals have higher positivity rate of T. gondii IgG antibody than healthy controls.Depressed T. gondii seropositive individuals have increased likelihood to have history of suicidal behavior.

Suicide Risk and Addiction: The Impact of Alcohol and Opioid Use Disorders.

Purpose of Review: Suicide is a major public health concern and a leading cause of death in the US. Alcohol and opioid use disorders (AUD/OUD) significantly increase risk for suicidal ideation, attempts, and death, and are the two most frequently implicated substances in suicide risk. We provide a brief overview of shared risk factors and pathways in the pathogenesis of AUD/OUD and suicidal thoughts and behaviors. We also review clinical recommendations on inpatient care, pharmacotherapy, and psychotherapeutic interventions for people with AUD/OUD and co-occurring suicidal ideation and behavior. Recent Findings: Among people with an underlying vulnerability to risk-taking and impulsive behaviors, chronic alcohol intoxication can increase maladaptive coping behaviors and hinder self-regulation, thereby increasing the risk of suicide. Additionally, chronic opioid use can result in neurobiological changes that lead to increases in negative affective states, jointly contributing to suicide risk and continued opioid use. Despite significantly elevated suicide risk in individuals with AUD/OUD, there is a dearth of research on pharmacological and psychosocial interventions for co-occurring AUD/OUD and suicidal ideation and behavior. Summary: Further research is needed to understand the effects of alcohol and opioid use on suicide risk, as well as address notable gaps in the literature on psychosocial and pharmacological interventions to lower risk for suicide among individuals with AUD/OUD.

Characteristics of depressed suicide attempters with remitted substance use disorders.

Substance use disorder (SUD) comorbidity in mood disorders increases suicide risk. Suicide attempters with active SUD appear to have distinct characteristics but little is known whether these characteristics persist during remission and if they are related to different aspects of suicidal behavior. In this study, suicide attempters with a DSM mood disorder and remitted SUD (AT+SUD) (N = 135) were compared to those without lifetime SUD (AT-SUD) (N = 219) in terms of demographic, clinical and suicidal behavioral characteristics. Factor analyses were conducted to generate subjective distress and impulsivity/aggression factors - previously identified by our group to predict suicide risk in mood disorders. Associations between these traits and SUD history and suicidal behavior characteristics were then tested. Compared with AT-SUD, AT+SUD were more likely to be male, less educated and to have a Cluster B personality disorder. AT+SUD individuals had greater impulsivity/aggression factor scores, but comparable subjective distress scores. AT+SUD made a greater number of suicide attempts, with higher lethality, despite comparable suicide intent and degree of planning with AT-SUD. Impulsivity/aggression was higher in multiple versus single attempters, but did not correlate with suicide attempt lethality. Among suicide attempters with mood disorders, a history of lifetime SUD was associated with more frequent and more lethal suicide attempts. Among other correlates of lifetime SUD in this sample, impulsive/aggressive traits may explain greater frequency of suicide attempts. The results underscore that persons with mood disorders and lifetime SUD are at particularly high risk of frequent and lethal suicide attempts where more intensive prevention efforts are warranted.

Smaller left hippocampal subfield CA1 volume is associated with reported childhood physical and/or sexual abuse in major depression: A pilot study.

BACKGROUND: Smaller hippocampal volumes are reported in adults with major depressive disorder (MDD) and in reported childhood abuse. The hippocampus is a complex structure with distinct functional subfields. We sought to examine the effect of MDD diagnosis and childhood abuse on hippocampal subfields. METHODS: Forty-one MDD participants (17 reported abuse and 24 did not) and 46 healthy volunteers (HV) (2 reported abuse) underwent T1- weighted structural magnetic resonance imaging (MRI) and clinical characterization in a retrospective design. A subfield segmentation program was used to measure the whole and subfield hippocampal volumes. Linear mixed-effects models were fitted for group comparisons. RESULTS: No main effect of diagnosis interaction effect between diagnosis and subfield region was observed. However, a comparison of abused MDD vs. HVs showed a group by region interaction. A significant interaction between childhood abuse and region was observed. Effects were confined to the left side of the brain, and post hoc, exploratory region-specific tests indicated smaller left CA1 volume in abused MDD compared with non-abused MDD. In addition, smaller amygdala volume was found in all MDD compared with HVs. LIMITATIONS: We did not have a sample of healthy volunteers with reported childhood abuse. CONCLUSIONS: The diagnosis of pure MDD may not be sufficient to exert effects on hippocampal volumes, indicating the importance of taking into account childhood trauma in studies on psychopathological mechanisms. Left CA1 might be the hippocampal subfield most relevant to reported childhood abuse. Smaller amygdala volume may be related to MDD diagnosis independent of childhood abuse.

Suicidal subtypes, stress responsivity and impulsive aggression.

While prominent models of suicidal behavior emphasize the hypothalamic- pituitary-adrenal (HPA) axis dysregulation, studies examining its role have yielded contradictory results. One possible explanation is that suicide attempters are a heterogeneous group and HPA axis dysregulation plays a more important role only in a subset of suicidal individuals. HPA axis dysregulation also plays a role in impulsivity and aggression. We hypothesize subgroups of attempters, based on levels of impulsivity and aggression, will differ in HPA axis dysregulation. We examined baseline cortisol, total cortisol output, and cortisol reactivity in mood disordered suicide attempters (N = 35) and non-attempters (N = 37) during the Trier Social Stress Test. Suicide attempters were divided into four subgroups: low aggression/low impulsivity, high aggression/low impulsivity, low aggression/high impulsivity, and high aggression/high impulsivity. As hypothesized, attempters and non-attempters did not differ in any cortisol measures while stress response differed based on impulsivity/aggression levels in suicide attempters, and when compared to non-attempters. Specifically, attempters with high impulsive aggression had a more pronounced cortisol response compared with other groups. This is the first study to examine the relationship between cortisol response and suicidal behavior in impulsive aggressive subgroups of attempters. These findings may help to identify a stress responsive suicidal subtype of individuals.

Variability in Suicidal Ideation is Associated with Affective Instability in Suicide Attempters with Borderline Personality Disorder.

Objective: Suicidal ideation (SI) is heterogeneous with different patterns and risk factors. SI can be persistent with stable severity, but may also fluctuate rapidly over a short period of time. The latter pattern is likely associated with affective instability and may consist of activation of SI at times of stress, that then subside. Although affective instability is a hallmark of borderline personality disorder (BPD), little is known about SI variability in BPD. We hypothesized that SI variability would be associated with affective instability in BPD suicide attempters. Method: Sample included 38 females with BPD and history of suicidal behavior. SI was assessed over 1 week using ecological momentary assessment (EMA) at six epochs daily. The relationship between SI variability (i.e., change of SI from one epoch to another) and SI severity (i.e., average scores across epochs), and affective instability, assessed using the Affective Lability Scale (ALS), were examined. Possible confounding effects of depression severity and impulsiveness were tested. Results: Participants demonstrated high ALS scores and wide range of SI variability. ALS scores predicted SI variability, even after controlling for depression severity. Although ALS also predicted SI severity, this association was driven by depression severity. ALS did not correlate with impulsiveness score. Conclusions: Affective instability may predict SI variability in BPD suicide attempters independent of depression severity. This supports our model of suicidal subgroups with different constellations of clinical aspects and risk factors. Future studies could examine these associations in larger samples and different populations to determine implications for suicide prevention.

Resting-state amplitude of low-frequency fluctuation is associated with suicidal ideation.

BACKGROUND: Identifying brain activity patterns that are associated with suicidal ideation (SI) may help to elucidate its pathogenesis and etiology. Suicide poses a significant public health problem, and SI is a risk factor for suicidal behavior. METHODS: Forty-one unmedicated adult participants in a major depressive episode (MDE), 26 with SI on the Beck Scale for Suicidal Ideation and 15 without SI, underwent resting-state functional magnetic resonance imaging scanning. Twenty-one healthy volunteers (HVs) were scanned for secondary analyses. Whole brain analysis of both amplitude of low-frequency fluctuations (ALFFs) and fractional ALFF was performed in MDE subjects to identify regions where activity was associated with SI. RESULTS: Subjects with SI had greater ALFF than those without SI in two clusters: one in the right hippocampus and one in the thalamus and caudate, bilaterally. Multi-voxel pattern analysis distinguished between those with and without SI. Post hoc analysis of the mean ALFF in the hippocampus cluster found it to be associated with a delayed recall on the Buschke memory task. Mean ALFF from the significant clusters was not associated with depression severity and did not differ between MDE and HV groups. DISCUSSION: These results indicate that SI is associated with altered resting-state brain activity. The pattern of elevated activity in the hippocampus may be related to how memories are processed.

Gray matter volumetric study of major depression and suicidal behavior.

Structural brain deficits are linked to risk for suicidal behavior. However, there is disagreement about the nature of these deficits, probably due to the heterogeneity of suicidal behavior in terms of the suicidal act's lethality. We hypothesized that individuals with major depressive disorder (MDD) and history of more lethal suicide attempts would have lower gray matter volume (GMV) of the prefrontal regions and insula compared with MDD lower-lethality attempters and MDD non-attempters. We collected structural MRI scans on 91 individuals with MDD; 11 with history of higher-lethality suicide attempts, 14 with lower-lethality attempts, and 66 were non-attempters. Differences in GMV between these three groups were examined using both regions-of-interest (ROI) and brain-wide voxel-based morphometry (VBM) analyses. Both ROI and VBM analyses showed that higher-lethality suicide attempters have greater GMV of the prefrontal cortical regions and insula, compared with the other two groups. Although this contrasts with our hypothesis, the observed larger prefrontal cortex GMV in higher-lethality suicide attempters may underlie the set of attributes observed previously in this suicidal subgroup, including enhanced suicide attempt planning, greater response inhibition, and delayed reward capabilities. Future studies should further examine the role of these brain regions in relation to suicidal intent and planning.

Toward subtyping of suicidality: Brief suicidal ideation is associated with greater stress response.

BACKGROUND: Suicide is a heterogeneous phenomenon, and thus defining more homogeneous subgroups may help in understanding its underlying biology and ultimately in its prevention. Suicidal ideation is far more common than suicidal behavior and predicts future suicide attempts. Hypothalamic-pituitary-adrenal (HPA)-axis reactivity has been implicated in individuals with suicidal ideation but findings are mixed with some studies showing increased and others demonstrating decreased reactivity. This suggests that dysregulation of HPA-axis is related to a specific character of suicidal ideation. We hypothesized that individuals with brief suicidal ideation are more stress responsive than those with longer/continuous ideation. METHODS: Thirty-five individuals with major depressive disorder (MDD) and 23 healthy volunteers (HVs), aged 18-65 years, underwent the Trier Social Stress Test (TSST). Salivary cortisol was measured at 6 time-points before and during TSST. Total severity and duration of current suicidal ideation were assessed using the Beck Scale for Suicidal Ideation (SSI). Brief suicidal ideators (N = 18), longer/continuous ideators (N = 17) and HVs were compared regarding cortisol response, baseline cortisol and total output. RESULTS: Participants with brief suicidal ideation had greater cortisol response compared to those with longer/continuous ideation and HVs, even after controlling for relevant covariates. However, total SSI score was not associated with cortisol response. Baseline cortisol and total output were not related to overall severity or duration of suicidal ideation. LIMITATIONS: The cross-sectional design and modest sample limit generalizability of the results. CONCLUSIONS: Hyper-responsiveness of HPA-axis to social stress is associated with brief suicidal ideation, possibly defining a pathway for exploring the biological subtyping of suicidal individuals.

White matter correlates of impaired attention control in major depressive disorder and healthy volunteers.

BACKGROUND: Major depressive disorder (MDD) is associated with impaired attention control and alterations in frontal-subcortical connectivity. We hypothesized that attention control as assessed by Stroop task interference depends on white matter integrity in fronto-cingulate regions and assessed this relationship using diffusion tensor imaging (DTI) in MDD and healthy volunteers (HV). METHODS: DTI images and Stroop task were acquired in 29 unmedicated MDD patients and 16 HVs, aged 18-65 years. The relationship between Stroop interference and fractional anisotropy (FA) was examined using region-of-interest (ROI) and tract-based spatial statistics (TBSS) analyses. RESULTS: ROI analysis revealed that Stroop interference correlated positively with FA in left caudal anterior cingulate cortex (cACC) in HVs (r = 0.62, p = 0.01), but not in MDD (r = -0.05, p= 0.79) even after controlling for depression severity. The left cACC was among 4 ROIs in fronto-cingulate network where FA was lower in MDD relative to HVs (F(1,41) = 8.87, p = 0.005). Additionally, TBSS showed the same group interaction of differences and correlations, although only at a statistical trend level. LIMITATIONS: The modest sample size limits the generalizability of the findings. CONCLUSIONS: Structural connectivity of white matter network of cACC correlated with magnitude of Stroop interference in HVs, but not MDD. The cACC-frontal network, sub-serving attention control, may be disrupted in MDD. Less cognitive control may include enhanced effects of salience in HVs, or less effective response inhibition in MDD. Further studies of salience and inhibition components of executive function may better elucidate the relationship between brain white matter changes and executive dysfunction in MDD.