Achieving a Brighter Future: A Career-Focused Mentoring Program Designed for Adolescents and Young Adults with Cancer.

Despite high survival rates for many adolescent or young adult (AYA) cancer diagnoses, the psychosocial, academic, and vocational repercussions for survivors are profound and enduring. Hospital systems are able to address many AYA needs, but the ability to provide the human connectedness and knowledge that drive long-term school and career planning is lacking. This study assessed a group of AYAs who have or had cancer (n = 108, 54% female, 71% white, mean age 20.6 ± 4.4) to determine the school, career, medical, emotional, and psychosocial needs that are not currently being met by hospital staff and support networks. We identified the most common unmet needs of AYAs, differences between needs of AYAs in active treatment and survivorship, and the role of a career-focused mentoring program developed by the nonprofit organization Connecting Champions (CC) to address the array of unmet AYA needs. We found that the most commonly reported needs were all related to career and school, and that the top needs did not differ significantly throughout the cancer journey. These findings suggest that career and school-based needs are a high priority for AYAs, yet social isolation can make the necessary people or resources inaccessible. The CC mentoring program was reported as effective in attending to unmet needs (with an average score of 95.1/100) and can be a valuable resource for hospital systems, nonprofit organizations, and health insurers to provide personalized, career-focused support to AYAs during cancer treatment and survivorship.

Neural connectivity moderators and mechanisms of ketamine treatment among treatment-resistant depressed patients: a randomized controlled trial.

BACKGROUND: Intravenous (IV) ketamine has emerged as a rapid and effective treatment for TRD. However, the specific neural mechanisms of ketamine's effects in humans remains unclear. Although neuroplasticity is implicated as a mechanism of action in animal models, relatively few randomized controlled trials (RCTs) in TRD patients have examined ketamine's impact on functional connectivity, a posited functional marker of neuroplasticity-particularly in the context of a mood-induction paradigm (termed miFC). METHODS: 152 adults with TRD (63% female; 37% male) were randomly allocated to receive a single infusion of ketamine or saline in a 2:1 ratio. We examined changes in connectivity (from baseline to 24-h post-infusion) that differed by treatment, and whether clinical treatment response at 24-h post-infusion was uniquely related (among patients allocated to ketamine relative to saline) to (1) pre-treatment connectivity and (2) changes in connectivity. We examined both miFC and rsFC, using prefrontal cortex and limbic seed regions. We also conducted a multiverse analysis to examine findings most robust against analytic decisions. FINDINGS: Across both miFC and rsFC, ketamine was associated with greater in prefrontal/limbic connectivity compared to saline, and lower baseline connectivity of limbic and prefrontal regions predicted greater treatment response in patients receiving ketamine. Greater connectivity increases in participants receiving ketamine was uniquely related to greater treatment response. In addition, certain findings were identified as being reproducible against different analytic decisions in multiverse analyses. INTERPRETATION: Our findings identify specific neural connectivity patterns impacted by ketamine and were uniquely related to outcomes following ketamine (relative to saline). These findings generally support prominent neuroplasticity models of ketamine's therapeutic efficacy. These findings lay new groundwork for understanding how to enhance and optimize ketamine treatments and develop novel rapid-acting treatments for depression. FUNDING: This research was supported by NIH grant R01MH113857 and by the Clinical and Translational Sciences Institute at the University of Pittsburgh (UL1-TR-001857).

Risk Factors and Clinical Correlates of Pediatric Serotonin Syndrome in Hospitalized Suicide Attempters.

Objective: To evaluate the risk factors and clinical correlates of pediatric serotonin syndrome (SS) given that research on SS in adults exists, there is a dearth of literature on pediatric SS. Study design: We conducted a retrospective chart review of 183 pediatric patients who were medically hospitalized after a suicide attempt. We investigated associations between SS and several of its risk factors and clinical correlates. We also assessed the sensitivity/specificity of Hunter's criteria and criterion symptoms in predicting SS. Results: SS occurred in 21.7% of patients with a serotonergic overdose. Recent marijuana use and overdose on a selective serotonin reuptake inhibitor were significantly associated with SS. Individuals with SS required a greater number of days to be medically stabilized and had a greater likelihood of being placed on a ventilator during treatment. Hunter's criteria had 66.7% sensitivity and 92.3% specificity in diagnosing SS. Conclusions: Our study reveals both novel risk factors associated with SS (eg, recent marijuana use) and clinical correlates for patients with pediatric SS. In children, Hunter's criteria appeared to have good specificity but poor sensitivity in identifying SS. Our results set the stage for future work aimed at enhancing clinicians' ability to more rapidly identify and treat pediatric SS.

Exploring the multiverse: the impact of researchers' analytic decisions on relationships between depression and inflammatory markers.

In recent years, a replication crisis in psychiatry has led to a growing focus on the impact of researchers' analytic decisions on the results from studies. Multiverse analyses involve examining results across a wide array of possible analytic decisions (e.g., log-transforming variables, number of covariates, or treatment of outliers) and identifying if study results are robust to researchers' analytic decisions. Studies have begun to use multiverse analysis for well-studied relationships that have some heterogeneity in results/conclusions across studies.We examine the well-studied relationship between peripheral inflammatory markers (PIMs; e.g., white blood cell count (WBC) and C-reactive protein (CRP)) and depression severity in the large NHANES dataset (n = 25,962). Specification curve analyses tested the impact of 9 common analytic decisions (comprising of 58,000+ possible combinations) on the association of PIMs and depression severity. Relationships of PIMs and total depression severity are robust to analytic decisions (based on tests of inference jointly examining effect sizes and p-values). However, moderate/large differences are noted in effect sizes based on analytic decisions and the majority of analyses do not result in significant findings, with the percentage of analyses with statistically significant results being 46.1% for WBC and 43.8% for CRP. For associations of PIMs with specific symptoms of depression, some associations (e.g., sleep, appetite) in males (but not females) were robust to analytic decisions. We discuss how multiverse analyses can be used to guide research and also the need for authors, reviewers, and editors to incorporate multiverse analyses to enhance replicability of research findings.

Resting-State Functional Connectivity Differences Following Experimental Manipulation of the Orbitofrontal Cortex in Two Directions via Theta-Burst Stimulation.

Compulsive behaviors (CBs) have been linked to orbitofrontal cortex (OFC) function in animal and human studies. However, brain regions function not in isolation but as components of widely distributed brain networks-such as those indexed via resting-state functional connectivity (RSFC). Sixty-nine individuals with CB disorders were randomized to receive a single session of neuromodulation targeting the left OFC-intermittent theta-burst stimulation (iTBS) or continuous TBS (cTBS)-followed immediately by computer-based behavioral "habit override" training. OFC seeds were used to quantify RSFC following iTBS and following cTBS. Relative to cTBS, iTBS showed increased RSFC between right OFC (Brodmann's area 47) and other areas, including dorsomedial prefrontal cortex (dmPFC), occipital cortex, and a priori dorsal and ventral striatal regions. RSFC connectivity effects were correlated with OFC/frontopolar target engagement and with subjective difficulty during habit-override training. Findings help reveal neural network-level impacts of neuromodulation paired with a specific behavioral context, informing mechanistic intervention development.

Splitting the reward: Differences in inflammatory marker associations with neural connectivity between reward anticipation and reward outcome in adolescents at high risk for depression.

BACKGROUND: Adolescent depression is associated with both dysfunction in neural reward processing and peripheral inflammatory markers (PIMs), such as interleukin-6 (IL-6), C-reactive-protein (CRP), and tumor-necrosis factor alpha (TNFα). Few adolescent studies have examined neural-inflammatory marker associations and associated behavioral correlates, which would contribute to a better understanding of developmental processes linked to depression. METHODS: 36 adolescents at high risk of depression completed an fMRI reward task (during anticipation and outcome), blood draw for PIMs (IL-6, CRP, and TNFα), and a behavioral task assessing motivation to expend effort. Analyses examined associations of task-dependent functional connectivity (FC; ventral striatum to frontal and default mode network brain regions), and if the interaction of PIMs and task-dependent FC predicted motivation to expend effort. RESULTS: For anticipation contrast, TNFα was associated with increased task-dependent FC between the LVS and PCC/vmPFC. In moderation analyses, for anticipation contrasts, the combination of higher IL-6 and stronger FC (LVS-precuneus/PCC) was associated with lower motivation to expend effort, while for outcome contrasts, the combination of higher IL-6 and stronger FC (VS-precuneus/PCC) was associated with greater motivation to expend effort. CONCLUSIONS: Our findings in adolescents during an important developmental time period suggest that PIMs are directly linked to greater FC between the VS and DMN brain regions during win anticipation, consistent with prior studies. Effects of PIMs on motivation to expend effort may vary the strength/type of neural reward processing (anticipation or outcome), which could guide better understanding how inflammatory markers and neural reward substrates contribute to development of depression in high-risk adolescents.

A Pilot Study of Ketamine Infusion after Suicide Attempt: New Frontiers in Treating Acute Suicidality in a Real-World Medical Setting.

Ketamine, in research settings, rapidly reduces suicidal thoughts 2-24 h after a single infusion in patients with high suicidal ideation. In this study, the authors investigate ketamine's effects on suicidality in a real-world sample of recent suicide attempters on a tertiary-care Consultation-Liaison (CL) psychiatry service. Using an open-label design, 16 transdiagnostic CL patients were recruited, 18-65 years old, to receive a single dose of intravenous ketamine (0.5 mg/kg) in the acute medical setting. All were psychiatrically hospitalized post-infusion. Baseline suicidality and depression measures were compared to ratings taken at 24 h, 5 days, 12 days, and 1, 3 and 6 months post-infusion using paired t-tests. Across all measures, rapid, statistically significant decreases (p's < 0.001) were observed with large to very large effect sizes (Cohen's d's: 1.7-8.8) at acute timepoints (24 h; 5 days). These gains were uniformly maintained to 6 months post-infusion. Open-label ketamine appeared to rapidly and robustly reduced suicidal symptoms in an ultra-high-risk, heterogeneous, real-world sample. Ketamine infusion may therefore be a safe, feasible, viable method to rapidly reduce suicidality among medically hospitalized patients after a suicide attempt, with potentially enduring benefits. The current pilot findings suggest ketamine could be readily integrated into the settings where high-risk CL patients already receive healthcare, with the potential to become an important and novel tool in the treatment of suicidality.

Does the moderator matter? Identification of multiple moderators of the association between peripheral inflammatory markers and depression severity in a large racially diverse community cohort.

Depressive symptomology has been linked to low-grade peripheral inflammatory markers (PIMs), specifically C-reactive protein (CRP) and white blood cell count (WBC). However, such associations may be affected by multiple moderators (including race/ethnicity), though few well-powered and racially diverse studies have examined this. We examined 31 moderators of PIM-depression relationships in a large racially diverse cohort (n = 21,570). We also examined if associations between PIM and depression severity were dependent on clinical cutpoints for moderate depressive symptoms and elevated CRP. We found several positive moderators of PIM-depression relationships for both WBC and CRP: ongoing medication use (antidepressant, statin, or any prescription drug), presence of sleep concerns, and poor health status (ß's = 0.06-0.21, p's < 0.05). For both WBC and CRP, individuals of non-Hispanic White race/ethnicity were found to have stronger PIM-depression associations overall relative to minoritized groups (B's = 0.14 to 1.01, p's < 0.05). For CRP, stronger PIM-depression relationships existed for individuals with moderate (or greater) depression severity or elevated CRP (B's = 0.27 to 0.49, p's < 0.05). Thus, a wide range of moderators appears to affect PIM-depression associations. These results could help identify participants with strong coupling of PIM-depression severity, to guide future research and personalized treatments for depression and to indicate gaps in the applicability of widely referenced theoretical models among racial/ethnic minoritized groups.

The association of physical illness and low-grade inflammatory markers with depressive symptoms in a large NHANES community sample: Dissecting mediating and moderating effects.

BACKGROUND: Both low-grade elevation in peripheral inflammatory markers (e.g., white blood count (WBC) and C-reactive protein (CRP)) and physical illness (both chronic and acute) have been associated with depressive symptomology. However, it is unclear if low-grade elevation in inflammatory markers mediates relationships between physical illness and depression or if physical illness positively moderates relationships between inflammatory markers and depression. METHODS: In a well-powered, racially diverse cohort (n = 21,525) from NHANES datasets, we examined if inflammatory markers (CRP and WBC) and physical illnesses (acute and chronic) were independently associated with depression severity. We also examined if associations between physical illness and depression severity were mediated by inflammatory markers and if physical illness moderated associations between inflammatory markers and depression. RESULTS: We found that both inflammatory markers and physical illness were associated with depression severity, even after considering a wide range of potential confounders (e.g., age, gender, body mass index). Inflammatory markers mediated a marginal portion (<5%; p < 0.001) of potential effects of physical illness on depression severity. In moderation analyses, associations between inflammatory markers and depression severity were significantly stronger in participants with chronic physical illness than those without. This moderating effect was not present for acute physical illness. CONCLUSIONS: Inflammatory markers and physical illness appear independently linked to depression severity and, in individuals with chronic physical illness, inflammatory markers are more tightly connected to depressive symptomology. Such findings could help guide future individualized treatment research for depression based on both inflammatory marker level and physical illness burden.

Cytokine and Reward Circuitry Relationships in Treatment-Resistant Depression.

BACKGROUND: Depressive disorders are linked to dysfunction in reward-related behaviors and corticostriatal reward circuitry. Low-grade dysregulation of the immune system, e.g., elevations in plasma interleukin 6 (IL-6) and tumor necrosis factor α, have been thought to affect corticostriatal reward circuitry. Little is presently known about the degree to which these relationships generalize to patients with treatment-resistant depression (TRD) and/or childhood trauma history. METHODS: Resting-state functional connectivity between the ventral striatum (VS) and ventromedial prefrontal cortex (vmPFC) regions and plasma inflammatory marker levels (IL-6, tumor necrosis factor α) were measured in 74 adults with TRD. Regression analyses examined associations of inflammatory markers with VS-vmPFC connectivity and the moderating effects of self-reported childhood trauma on these associations, with exploratory analyses examining trauma subtypes. RESULTS: IL-6 was negatively associated with VS-vmPFC connectivity (specifically for the left VS). Childhood trauma moderated the relationships between tumor necrosis factor α and VS-vmPFC connectivity (specifically for the right VS) such that greater childhood trauma severity (particularly emotional neglect) was associated with stronger cytokine-connectivity associations. CONCLUSIONS: This study independently extends previously reported associations between IL-6 and reductions in corticostriatal connectivity to a high-priority clinical population of treatment-seeking patients with TRD and further suggests that childhood trauma moderates specific associations between cytokines and corticostriatal connectivity. These findings suggest that associations between elevated plasma cytokine levels and reduced corticostriatal connectivity are a potential pathophysiological mechanism generalizable to patients with TRD and that such associations may be affected by trauma severity.

Linking childhood trauma and cytokine levels in depressed adolescents.

BACKGROUND: Evidence supports raised circulating levels of inflammatory mediators, such as interleukin-6 (IL-6) and tumor necrosis factor (TNFα), among clinically depressed adults, although preliminary findings in adolescents are mixed. Independently, meta-analyses identify correlations between childhood trauma and elevated cytokine levels in adulthood. Here, we examine the possible role of individual differences in exposure to childhood trauma in contributing to variability in cytokine levels in depressed adolescents. METHODS: 52 depressed adolescents and 20 healthy adolescents completed measures of childhood trauma and provided blood for the assessment of plasma IL-6 and TNFα. Cross-sectional associations of childhood trauma and cytokine measures were assessed in both depressed and healthy adolescents, along with exploratory analysis of childhood trauma subtypes. Longitudinal relationships between childhood trauma and cytokine measures were also studied in an exploratory fashion within a subset of depressed participants (n = 36). RESULTS: Higher childhood trauma (particularly emotional abuse) was positively associated with TNFα in depressed adolescents. Childhood trauma was not linked to longitudinal changes in cytokine levels. DISCUSSION: In depressed adolescents, childhood trauma may relate to higher levels of the proinflammatory cytokine TNFα and contribute to heterogeneity in cytokine elevation among depressed adolescents. Such findings may ultimately help guide more effective individualized treatments for adolescents with depression.

What's in a Face? Amygdalar Sensitivity to an Emotional Threatening Faces Task and Transdiagnostic Internalizing Disorder Symptoms in Participants Receiving Attention Bias Modification Training.

BACKGROUND: Altered amygdala activation in response to the emotional matching faces (EMF) task, a task thought to reflect implicit emotion detection and reactivity, has been found in some patients with internalizing disorders; mixed findings from the EMF suggest individual differences (within and/or across diagnoses) that may be important to consider. Attention Bias Modification (ABM), a mechanistic attention-targeting intervention, has demonstrated efficacy in treatment of internalizing disorders. Individual differences in neural activation to a relatively attention-independent task, such as the EMF, could reveal novel neural substrates relevant in ABM's transdiagnostic effects, such as the brain's generalized threat reactivity capacity. METHODS: In a sample of clinically anxious patients randomized to ABM (n = 43) or sham training (n = 18), we measured fMRI activation patterns during the EMF and related them to measures of transdiagnostic internalizing symptoms (i.e., anxious arousal, general distress, anhedonic depression, and general depressive symptoms). RESULTS: Lower baseline right amygdala activation to negative (fearful/angry) faces, relative to shapes, predicted greater pre-to-post reduction in general depression symptoms in ABM-randomized patients. Greater increases in bilateral amygdalae activation from pre-to-post ABM were associated with greater reductions in general distress, anhedonic depression, and general depression symptoms. CONCLUSIONS: ABM may lead to greater improvement in depressive symptoms in individuals exhibiting blunted baseline amygdalar responses to the EMF task, potentially by enhancing neural-level discrimination between negative and unambiguously neutral stimuli. Convergently, longitudinal increases in amygdala reactivity from pre-to-post-ABM may be associated with greater improvement in depression, possibly secondary to improved neural discrimination of threat and/or decreased neurophysiological threat avoidance in these specific patients.

A chicken and egg scenario in psychoneuroimmunology: Bidirectional mechanisms linking cytokines and depression.

Background: Cytokines are an important part of the immune system. Certain cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα), have well-described associations with depression. Various mechanisms exist that may explain bidirectional effects of cytokines on depression and vice versa. No recent reviews to our knowledge have comprehensively characterized both these mechanisms and the interaction of these mechanisms using evidence from the molecular level to the clinical level. The goal of this review is to both evaluate the present knowledge base and identify knowledge gaps to help guide future research. Methods: We conducted an extensive bibliographic search across multiple databases, using both general (e.g. "cytokine") and topic-specific (e.g. "kynurenine") keywords. Results: We describe the most recent evidence outlining these mechanisms, including the role of the hypothalamic pituitary axis, the kynurenine pathway, and neural circuitry. For relevant topics, we outline the pathways by which cytokine activation may lead to depressive symptoms, and how depressive symptomology may lead to elevations in cytokines. We also identify key areas for future research, including the need for longitudinal clinical studies to examine causality in pertinent mechanisms and modulating factors in the cytokine-depression interaction. Limitations: Given the numerous potential mechanisms associating cytokines and depressions, this review paper solely focuses on the most commonly described mechanisms at a basic level. Conclusions: Bidirectional evidence exists for several mechanisms in the relationship between cytokines and depression. However, more work is required to further elucidate the role of these mechanisms in specific clinical populations.

Longitudinal relationships of cytokines, depression and anhedonia in depressed adolescents.

BACKGROUND: Depression has been associated with low-grade elevation of plasma cytokines (e.g. interleukin-6, IL-6; tumor necrosis factor alpha, TNFα) in both cross-sectional and longitudinal studies in adults. Preclinical and clinical studies also suggest that IL-6 and TNFα elevation are associated with anhedonia. However, few studies have examined longitudinal relationships between cytokines and depression/anhedonia in clinically depressed samples, particularly adolescents. METHODS: Thirty-six adolescents with a depressive disorder receiving standard-of-care community treatment were assessed at a baseline and a follow-up timepoint. Self-report and clinical measures of depression and anhedonia, along with plasma IL-6 and TNFα levels, were obtained at both timepoints. Baseline cytokine measures were examined in association with baseline and follow-up clinical measures. On an exploratory basis, change in clinical measures over time was examined in relation to change in cytokine levels over time. RESULTS: Higher baseline TNFα levels predicted higher follow-up depression severity after approximately four months (controlling for baseline depression). Higher baseline TNFα levels also associated positively with baseline anhedonia and predicted higher anhedonia at follow-up (controlling for baseline anhedonia). No association was found between change in clinical measures and change in cytokine levels over time. CONCLUSIONS: Among adolescents receiving standard-of-care community treatment for depression, higher levels of TNFα predicted greater depressive symptoms at 4-month follow-up, suggesting this cytokine may be used to help identify patients in need of more intensive treatment. Elevated TNFα levels were also associated with concurrent and future anhedonia symptoms, suggesting a specific mechanism in which TNFα affects depression trajectories. Future studies should examine the relationships between cytokine levels and depression/anhedonia symptoms at multiple timepoints in larger cohorts of depressed adolescents.

Rare variants and biological pathways identified in treatment-refractory depression.

Individuals diagnosed with major depressive disorder not responding to at least two adequate treatments are defined as treatment-refractory major depressive disorder (TR-MDD). Some TR-MDD patients have altered metabolic phenotypes that may be pharmacologically reversed. The characterization of these phenotypes and their underlying etiologies is paramount, particularly their genetic components. In this study, TR-MDD patients (n = 124) were recruited and metabolites were quantified in their cerebrospinal fluid (CSF) and peripheral blood. Three sub-categories of deficiencies were examined, namely 5-methyltetrahydrofolte (in CSF; n = 13), tetrahydrobiopterin (in CSF; n = 11), and abnormal acylcarnitine profiles (in peripheral blood; n = 8). Whole exome sequencing was performed on genomic DNA from the entire TR-MDD cohort and exonic variant allele frequencies for cases were compared to a control cohort (1:5 matching on ancestry). Low frequency, damaging alleles were identified and used for in silico pathway analyses. Three association signals for TR-MDD approached genome-wide significance on chromosomes 22, 7, and 3. Three risk-associated variants from a prior depression study were replicated. Relevant biological pathways were identified that contained an enrichment of rare, damaging variants in central nervous system (CNS)-specific pathways, including neurotransmitter receptors, potassium channels, and synapse transmission. Some TR-MDD patients had rare variants in genes that were previously associated with other psychiatric disorders, psychiatric endophenotypes, CNS structural defects, and CNS-related cellular and molecular functions. Exome analysis of metabolically phenotyped TR-MDD patients has identified potentially functional gene pathways and low frequency, deleterious gene variants for further investigation. Further studies in larger cohorts of biochemically phenotyped TR-MDD patients are desirable to extend and confirm these findings.

Contemporary Characteristics and Lethality Correlates of Serious Suicide Attempts in Children and Adolescents.

OBJECTIVE: Adolescent suicide rates have increased in the past decade. Few studies have examined contemporary pediatric suicide attempters with medically serious suicide attempts, particularly among younger pediatric suicide attempters. METHOD: This preliminary chart review study examined 200 adolescents with medically serious suicide attempts and sought to identify general cohort characteristics, differences in cohort characteristics based on age, correlates of lethality, and correlates of rescue (likelihood of prompt medical attention). RESULTS: Our study found that younger adolescents specifically endorsed increased cyberbullying (ß = 1.1, p = .046) and less hopelessness (ß = -0.83, p = .02) compared to older adolescents. Suicide attempt lethality was negatively associated with female gender (ß = -0.59, p = .041), rescue (ß = -0.19, p = .005), an anxiety diagnosis (ß = -0.81, p = .0003), and history of consensual sexual activity (ß = -0.79, p = .002). Rescue was positively associated with an ADHD diagnosis (ß = 0.73, p = .018) and less attempt planning (ß = 0.96, p = .01), while a history of previous suicide attempt (ß = -0.54, p = .04) and more proximal suicide attempt (ß = -0.045, p = .008) were associated with a lower rescue score. CONCLUSION: Our preliminary findings suggest clinicians and future researchers may need to assess certain social and diagnostic factors in children and adolescents at particularly high risk for death by suicide.

Signaling networks in inflammatory pathways and risk for suicidal behavior.

BACKGROUND: Suicide is a leading cause of death in the young adult population, with few biological markers identified thus far to be associated with suicidality. Cytokines (including IL-6 and TNFα) may contribute to increased risk for depression and suicidality. Few studies have examined the associations of cytokine mRNA expression with depression and suicidal ideation and behavior. This study examines these associations and whether cytokine signaling networks differentiate suicide attempters (SA), suicide ideators (SI), and healthy controls (HC). METHODS: Cytokine pathway marker (CPM; e.g. cytokines and proteins in cytokine signaling pathways) mRNA gene expression in whole blood was examined in suicide attempters (n = 38), suicide ideators (n = 38), and healthy controls (n = 36). Between-group differences in CPM gene expression were examined. We also examined association of the mRNA of these genes with the severity of depression and suicidal ideation. Novel Gaussian Graphical Model (GGM) techniques were utilized to examine between-network partial correlation differences in cytokine signaling networks relevant to IL-6 and TNFα signaling pathways. RESULTS: The severity of depression symptoms was positively associated with TNFα mRNA levels and negatively associated with IL-10 mRNA levels, but CPM expression was not associated with suicidal ideation severity. There were no between-group differences in CPM markers among healthy controls, SI and SA groups after correcting for multiple comparisons. In network analyses, we found suggestive results of between-group network differences between SI and control groups in gene pairs with IL-6R and STAT3 as common nodes. DISCUSSION: In a cohort of suicide attempters and ideators, TNFα and IL-10 mRNA levels appear to be associated with depressive symptomology, consistent with elevation of pro-inflammatory cytokine production and reduction of anti-inflammatory cytokine production. Additionally, cytokine signaling networks may differentiate suicide ideators from healthy controls based on between-network differences, with differences possibly related to relationships of IL6R or STAT3 with other components of cytokine signaling networks.

Reduction of Postdischarge Suicidal Behavior Among Adolescents Through a Telephone-Based Intervention.

OBJECTIVE: Brief telephone follow-up for a patient with suicidal tendencies after he or she has been discharged from an emergency room or hospital has been shown to decrease subsequent suicide attempts. However, despite the high rate of suicidal behavior in adolescents, this intervention has not been examined in this population. As part of a quality improvement intervention, postdischarge telephone contacts were used to attempt to reduce suicidal behavior and inpatient rehospitalizations among adolescents. METHODS: Adolescents who were hospitalized for suicidal ideation or attempt (N=142) were randomly assigned to one of two telephone interventions delivered over a 90-day period: either a single call intervention (SCI) or a multiple calls intervention (MCI). The intervention consisted of assessment of suicidality, review of safety plan, and discussion of medication and weapon safety, with up to six telephone contacts in the MCI and up to one contact in the SCI. Primary outcome measures included suicidal behavior and inpatient rehospitalizations; secondary outcome measures included adolescents' confidence in their safety plan. RESULTS: Adolescents receiving the MCI had a significantly lower rate of suicidal behavior (6%) compared with adolescents receiving SCI (17%; odds ratio [OR]=0.28, p=0.037); results persisted while the analysis controlled for relevant covariates (OR=0.25, p=0.032). Similarly, adolescents receiving the MCI reported significantly greater confidence in their safety plan at 90 days (95%vs. 74%; p=0.001), which, in turn, was associated with a lower rate of suicidal behavior (OR=0.95, p=0.019). CONCLUSIONS: A telephone-based intervention for providing recurrent follow-up soon after discharge is feasible in the adolescent population and may be effective in reducing postdischarge suicidal behavior.

Infusing hope into the treatment of suicidality: A review of ketamine's effects on suicidality.

PURPOSE OF REVIEW: Given recent increases in rates of suicide and lack of rapid treatments for suicidality, ketamine has been identified as a potential fast-acting anti-suicidal treatment. Our review seeks to describe the effects of ketamine on suicidality, given the growing literature on the use of ketamine in reducing suicidality. We examine open-label studies and randomized controlled trials evaluating treatment of suicidality with ketamine. Furthermore, our manuscript identifies potential mechanisms of ketamine's effects on suicidality. RECENT FINDINGS: Based on existing RCTs, ketamine appears to have rapid anti-suicidal effects, with most literature studying such effects in timeframes less than one week. Although still in the early stages of research, mechanisms of ketamine include modulation of molecular, inflammatory, neural, cognitive, and behavioral processes. SUMMARY: Thus, ketamine appears to be a promising treatment for suicidality, but requires larger scale and more robust RCTs to confirm the potential use of this agent in clinical settings.

Neurometabolic Disorders: Potentially Treatable Abnormalities in Patients With Treatment-Refractory Depression and Suicidal Behavior.

OBJECTIVE: Treatment-refractory depression is a devastating condition with significant morbidity, mortality, and societal cost. At least 15% of cases of major depressive disorder remain refractory to treatment. The authors previously identified a young adult with treatment-refractory depression and multiple suicide attempts with an associated severe deficiency of CSF tetrahydrobiopterin, a critical cofactor for monoamine neurotransmitter synthesis. Treatment with sapropterin, a tetrahydrobiopterin analogue, led to dramatic and long-lasting remission of depression. This sentinel case led the authors to hypothesize that the incidence of metabolic abnormalities contributing to treatment-refractory depression is underrecognized. METHOD: The authors conducted a case-control, targeted, metabolomic evaluation of 33 adolescent and young adult patients with well-characterized histories of treatment-refractory depression (at least three maximum-dose, adequate-duration medication treatments), and 16 healthy comparison subjects. Plasma, urine, and CSF metabolic profiling were performed by coupled gas chromatography/mass spectrometry and high-performance liquid chromatography electrospray ionization tandem mass spectrometry. RESULTS: CSF metabolite abnormalities were identified in 21 of the 33 participants with treatment-refractory depression. Cerebral folate deficiency (N=12) was most common, with normal serum folate levels and low CSF 5-methyltetrahydrofolate (5-MTHF) levels. All patients with cerebral folate deficiency, including one with low CSF levels of 5-MTHF and tetrahydrobiopterin intermediates, showed improvement in depression symptom inventories after treatment with folinic acid; the patient with low tetrahydrobiopterin also received sapropterin. None of the healthy comparison subjects had a metabolite abnormality. CONCLUSIONS: Examination of metabolic disorders in treatment-refractory depression identified an unexpectedly large proportion of patients with potentially treatable abnormalities. The etiology of these abnormalities remains to be determined.