Twenty-six years of psychosocial interventions to reduce suicide risk in adolescents: Systematic review and meta-analysis.

BACKGROUND: During adolescence, suicide risk increases; effective treatments are needed to reduce risk. METHODS: Databases were searched (1995-2020) for randomized controlled trials (RCTs) concerning psychosocial treatments for suicide prevention in adolescents (10-18 yrs). Data were extracted from the timepoint closest to 6 months. Cohen's ds were estimated for reducing suicidal ideation (SI), self-harming behaviors (SHB) excluding strictly non-suicidal self-injury, and suicide attempts (SA) and analyzed using generalized least square regression. Meta-analytic innovations included within-person correlations to reflect trait suicidality; annualization to control for exposure; estimated lifetime risk based on ages; and modeling inclusion/exclusion criteria. Alternate approaches included relative risk and comparison of intervention and control treatments to baseline. RESULTS: Of 30 RCTs, 6 assessing SHB (4 measuring SA), and 7 assessing SI demonstrated treatment effectiveness. Overall, interventions decreased SI (n = 25) with low effect size (d = 0.08, p = 0.01), non-significant after controlling for publication bias (d = 0.05, p = 0.1); interventions were non-significant for SHB (n = 25, d = 0.001, p = 0.97) or SA (n = 18, d = 0.03, p = 0.52). To prevent one SHB, the number needed to treat (NNT) was 45[26,156]; for SA, NNT=42[24,149]. Non-superiority may relate to effectiveness of control treatments. Thus, experimental and control treatments also were compared to baseline: both reduced SI (p < 0.0001), and effectiveness improved for SHB (NNT=12) and SA (NNT=11). LIMITATIONS: Study heterogeneity and inconsistent statistical reporting limited meta-analysis. CONCLUSIONS: Psychosocial interventions for suicide risk in adolescents showed little effectiveness compared with control treatments; suicide outcomes improved in both groups compared to baseline. Different approaches may be needed, including precision medicine methodologies and standardized statistical reporting criteria.

Relationships between inflammatory markers and suicide risk status in major depression.

Pro-inflammatory status has been implicated in depression and suicidal behaviors. Polyunsaturated fatty acids (PUFAs) and cytokines, two types of inflammatory biomarkers, have been associated with suicide, independent of depression severity. How these biomarkers relate to each other is less clear. We measured plasma phospholipid levels of arachidonic acid (AA%), docosahexaenoic acid (DHA%), and eicosapentaenoic acid (EPA%) as a percentage of total phospholipids, as well as serum interleukin-6 (IL-6), interleukin-1ß (IL-1ß) and tumor necrosis factor α (TNF-α), in 80 patients with major depressive disorder (MDD) and 24 healthy controls (HC). Individual PUFA and cytokine species were compared using ANOVA across four suicide risk-stratified groups: 1) highest-risk, recent (within 5 years) suicide attempters (n = 20); 2) high-risk, severe current suicidal ideators (having intent or plan) with no recent attempt history (n = 22); 3) low-risk, current non-ideators who were also lifetime non-attempters (n = 38); and 4) HC (n = 24). None of the participants were enrolled following an acute suicide attempt. Of biomarkers studied, only DHA% (p = 0.012) and IL-1ß (p = 0.002) differed between groups. In post-hoc testing, DHA% was lower in attempters than ideators (p = 0.018) or MDD non-ideators (trend level, p = 0.073). IL-1ß was lowest in attempters, differentiating them from ideators (p = 0.009) and HC (p = 0.004). Recent suicide attempt, one of the most powerful predictors of suicide risk, was also most closely tied to inflammatory indices in this study. Low DHA% as an indicator of suicide risk is consistent with previous reports; however, lower IL-1ß was unexpected and may relate to acuity/chronicity of inflammation. There is a need for prospective studies of immune status with respect to suicidal behaviors.

The role of cytokines in the pathophysiology of suicidal behavior.

OBJECTIVE: Immune dysregulation has been implicated in depression and other psychiatric disorders. What is less clear is how immune dysregulation can affect risk of suicidal behavior. We reviewed the scientific literature concerning cytokines related to suicidal ideation, suicidal behavior and suicide, and surveyed clinical and neurobiological factors associated with cytokine levels that may modulate effects of inflammation on suicide risk. METHODS: We searched PubMed, Embase, Scopus and PsycINFO for relevant studies published from 1980 through February, 2015. Papers were included if they were written in English and focused on cytokine measurements in patients with suicidal behaviors. RESULTS: The literature search yielded 22 studies concerning cytokines and suicidal ideation, suicide attempts or suicide completion. The most consistent finding was elevated interleukin (IL)-6, found in 8 out of 14 studies, in CSF, blood, and postmortem brain. In one study, IL-6 in CSF was also found to be higher in violent than nonviolent attempters and to correlate with future suicide completion. Low plasma IL-2 was observed in 2 studies of suicide attempters, while divergent results were seen for tumor necrosis factor (TNF)-α, interferon (IFN)-γ, transforming growth factor (TGF)-ß, IL-4, and soluble Il-2 receptors. CONCLUSIONS: Given the complexity suggested by the heterogenous cytokine findings, putative mediators and moderators of inflammation on suicidal behavior merit further study. Elevated IL-6 was the most robust cytokine finding, associated with suicidal ideation and both nonfatal suicide attempts and suicides. Future studies should evaluate the predictive value of high IL-6, consider how this may alter brain function to impact suicidal behavior, and explore the potential beneficial effects of reducing IL-6 on suicide risk.

Positron Emission Tomographic Imaging of the Serotonergic System and Prediction of Risk and Lethality of Future Suicidal Behavior.

IMPORTANCE: Biomarkers that predict suicidal behavior, especially highly lethal behavior, are urgently needed. In cross-sectional studies, individuals with depression who attempt suicide have lower midbrain serotonin transporter binding potential compared with those who do not attempt suicide, and higher serotonin1A binding potential in the raphe nuclei (RN) is associated with greater lethality of past suicide attempts and suicidal intent and ideation. OBJECTIVES: To determine whether serotonin transporter binding potential in the lower midbrain predicts future suicide attempts and whether higher RN serotonin1A binding potential predicts future suicidal ideation and intent and lethality of future suicide attempts. DESIGN, SETTING, AND PARTICIPANTS: In this prospective 2-year observational study, a well-characterized cohort of 100 patients presenting for treatment of a major depressive episode of at least moderate severity underwent positron emission tomography using carbon 11-labeled N-(2-(1-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl))-N-(2-pyridyl)-cyclohexanecarboxamide ([11C]WAY-100635), a serotonin1A antagonist; a subset of 50 patients also underwent imaging with carbon 11-labeled 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)- benzonitrile ([11C]DASB), a serotonin transporter radioligand. Imaging was performed at Columbia University Medical Center from May 3, 1999, to March 11, 2008. Follow-up was completed on May 28, 2010, and data were analyzed from August 1, 2013, to March 1, 2016. EXPOSURES: Patients were treated naturalistically in the community and followed up for 2 years with documentation of suicidal behavior, its lethality, and suicidal ideation and intent. MAIN OUTCOMES AND MEASURES: Suicide attempt or suicide. RESULTS: Of the 100 patients undergoing follow-up for more than 2 years (39 men; 61 women; mean [SD] age, 40.2 [11.2] years), 15 made suicide attempts, including 2 who died by suicide. Higher RN serotonin1A binding potential predicted more suicidal ideation at 3 (b = 0.02; t = 3.45; P = .001) and 12 (b = 0.02; t = 3.63; P = .001) months and greater lethality of subsequent suicidal behavior (b = 0.08; t = 2.89; P = .01). Exploratory analyses suggest that the serotonin1A binding potential of the insula (t = 2.41; P = .04), anterior cingulate (t = 2.27; P = .04), and dorsolateral prefrontal cortex (t = 2.44; P = .03) were also predictive of lethality. Contrary to our hypotheses, suicidal intent was not predicted by serotonin1A binding potential in any brain region (F1,10 = 0.83; P = .38), and midbrain serotonin transporter binding potential did not predict future attempts (log-rank χ21 = 0.4; P = .54), possibly owing to low power. CONCLUSIONS AND RELEVANCE: Greater RN serotonin1A binding potential predicted higher suicidal ideation and more lethal suicidal behavior during a 2-year period. This effect may be mediated through less serotonin neuron firing and release, which affects mood and suicidal ideation and thereby decision making.