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Translating Interventional Neuroscience to Suicide: It’s About Time

  • Author Footnotes
    1 JB and MB contributed equally to this work.
    Jennifer Barredo
    Correspondence
    Address correspondence to Jennifer Barredo, Ph.D.
    Footnotes
    1 JB and MB contributed equally to this work.
    Affiliations
    VA RR&D Center for Neurorestoration and Neurotechnology, Providence VA Medical Center, Providence, Rhode Island

    Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, Rhode Island

    COBRE Center for Neuromodulation and Neuroimaging, Providence, Rhode Island
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  • Author Footnotes
    1 JB and MB contributed equally to this work.
    Melanie L. Bozzay
    Footnotes
    1 JB and MB contributed equally to this work.
    Affiliations
    VA RR&D Center for Neurorestoration and Neurotechnology, Providence VA Medical Center, Providence, Rhode Island

    Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, Rhode Island
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  • Jennifer M. Primack
    Affiliations
    Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, Rhode Island

    Psychosocial Research Program, Butler Hospital, Providence, Rhode Island

    Providence VA Medical Center, Providence, Rhode Island
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  • Heather T. Schatten
    Affiliations
    Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, Rhode Island

    Psychosocial Research Program, Butler Hospital, Providence, Rhode Island
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  • Michael F. Armey
    Affiliations
    Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, Rhode Island

    Psychosocial Research Program, Butler Hospital, Providence, Rhode Island
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  • Linda L. Carpenter
    Affiliations
    VA RR&D Center for Neurorestoration and Neurotechnology, Providence VA Medical Center, Providence, Rhode Island

    Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, Rhode Island

    COBRE Center for Neuromodulation and Neuroimaging, Providence, Rhode Island
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  • Noah S. Philip
    Affiliations
    VA RR&D Center for Neurorestoration and Neurotechnology, Providence VA Medical Center, Providence, Rhode Island

    Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, Rhode Island

    COBRE Center for Neuromodulation and Neuroimaging, Providence, Rhode Island
    Search for articles by this author
  • Author Footnotes
    1 JB and MB contributed equally to this work.
Open AccessPublished:February 01, 2021DOI:https://doi.org/10.1016/j.biopsych.2021.01.013

      Abstract

      Despite significant advances in psychiatric and psychological treatment over the last 30 years, suicide deaths have increased. Unfortunately, neuroscience insights have yielded few translational interventions that specifically target suicidal thoughts and behaviors. In our view, this is attributable to two factors. The first factor is our limited integration of neurocircuitry models with contemporary suicide theory. The second challenge is inherent to the variable nature of suicide risk over time. Few interventional neuroscience studies evaluate how temporal fluctuations in risk affect treatment, despite evidence that temporality is a key component distinguishing suicide phenotypes. To wit, individual variability in risk trajectories may provide different treatment targets to engage as a patient moves between suicidal ideation and attempt. Here, we first review contemporary ideation-to-action theories of suicide from a neurobiological perspective, focusing on valence and executive function circuits and the key role of state-induced (e.g., within stressful contexts) functional modulation on longitudinal risk trajectories. We then describe neural correlates of suicide reduction following various interventions, ranging from circuit specific (i.e., transcranial magnetic stimulation) to broader pharmacological (i.e., ketamine, lithium) to psychological (i.e., brief cognitive therapy). We then introduce novel strategies for tracking risk in naturalistic settings and real time using ecological momentary interventions. We provide a critical integration of the literature focusing on the intersection between targets and temporality, and we conclude by proposing novel research designs integrating real-time and biologically based interventions to generate novel strategies for future suicide reduction research.

      Keywords

      Since 1999, suicide deaths in the United States have increased by 35% (
      • Hedegaard H.
      • Curtin S.C.
      • Warner M.
      Increase in suicide mortality in the United States, 1999-2018.
      ). In response, investment in research has increased significantly. The U.S. National Institutes of Health’s increased spending on suicide research paralleled the rise in mortality, growing approximately 13% from 2011 to 2019 after adjusting for inflation. Despite increased investment, few novel, neuroscience-based suicide interventions have been developed. Although recent psychosocial research has promoted wider appreciation for the important temporal aspects of suicide, spurring development of more complex, biopsychosocial models (
      • Oquendo M.A.
      • Sullivan G.M.
      • Sudol K.
      • Baca-Garcia E.
      • Stanley B.H.
      • Sublette M.E.
      • Mann J.J.
      Toward a biosignature for suicide.
      ,
      • Rizk M.M.
      • Galfalvy H.
      • Singh T.
      • Keilp J.G.
      • Sublette M.E.
      • Oquendo M.A.
      • et al.
      Toward subtyping of suicidality: Brief suicidal ideation is associated with greater stress response.
      ,
      • Jollant F.
      • Wagner G.
      • Richard-Devantoy S.
      • Köhler S.
      • Bär K.J.
      • Turecki G.
      • Pereira F.
      Neuroimaging-informed phenotypes of suicidal behavior: A family history of suicide and the use of a violent suicidal means.
      ), these models are not fully integrated into clinical research.
      Here, we argue that greater incorporation of critical psychosocial perspectives into clinical neuroscience will accelerate suicide treatment innovation. Toward this goal, we first introduce contemporary models of suicide emphasizing temporality—a key aspect of phenotypic variance. Next, we provide a focused review of the neuroimaging of suicide and summarize the state of the science of suicide treatment. We conclude with recommendations for improving research designs emphasizing interdisciplinary approaches and real-time risk tracking.

      Contemporary Psychosocial Models of Suicide

      Early psychosocial models posited that particular distal factors [e.g., sociological (
      • Durkheim E.
      Le Suicide; Étude de Sociologie.
      ), psychache (
      • Shneidman E.S.
      Suicide as psychache.
      ), emotional dysregulation (
      • Linehan M.M.
      Cognitive-Behavioral Treatment of Borderline Personality Disorder.
      ), diathesis–stress (
      • Wenzel A.
      • Beck A.T.
      A cognitive model of suicidal behavior: Theory and treatment.
      )] drove periods of heightened suicide risk and were influential in guiding the development of assessments and interventions. However, recent evidence recommends these models’ refinement, demonstrating that common distal risk factors are, at best, modest predictors of behavior (
      • Franklin J.C.
      • Ribeiro J.D.
      • Fox K.R.
      • Bentley K.H.
      • Kleiman E.M.
      • Huang X.
      • et al.
      Risk factors for suicidal thoughts and behaviors: A meta-analysis of 50 years of research.
      ), failing to identify who will make future attempts (
      • Klonsky E.D.
      • May A.M.
      Differentiating suicide attempters from suicide ideators: A critical frontier for suicidology research.
      ). This is critical because most who contemplate suicide never attempt (
      • Nock M.K.
      • Borges G.
      • Bromet E.J.
      • Alonso J.
      • Angermeyer M.
      • Beautrais A.
      • et al.
      Cross-national prevalence and risk factors for suicidal ideation, plans and attempts.
      ,
      • ten Have M.
      • de Graaf R.
      • van Dorsselaer S.
      • Verdurmen J.
      • van ’t Land H.
      • Vollebergh W.
      • Beekman A.
      Incidence and course of suicidal ideation and suicide attempts in the general population.
      ).
      Contemporary ideation-to-action models of suicide explicitly address this shortcoming, taking the perspective that suicide comprises stages of variable risk. These models seek to identify who is at risk of attempt and when their risk is greatest [e.g., three-step theory (
      • Klonsky E.D.
      • Saffer B.Y.
      • Bryan C.J.
      Ideation-to-action theories of suicide: A conceptual and empirical update.
      ), interpersonal-psychological theory (
      • Van Orden K.A.
      • Witte T.K.
      • Cukrowicz K.C.
      • Braithwaite S.R.
      • Selby E.A.
      • Joiner Jr., T.E.
      The interpersonal theory of suicide.
      ), integrated motivational-volitional model (
      • Rudd M.D.
      Fluid vulnerability theory: A cognitive approach to understanding the process of acute and chronic suicide risk.
      ), fluid vulnerability theory (FVT) (
      • O’Connor R.C.
      Towards an integrated motivational-volitional model of suicidal behavior.
      )]. These models treat ideation and attempt as distinct stages, and each variant defines a suicidogenic pathway wherein key factors [e.g., belongingness and burdensomeness (
      • Van Orden K.A.
      • Witte T.K.
      • Cukrowicz K.C.
      • Braithwaite S.R.
      • Selby E.A.
      • Joiner Jr., T.E.
      The interpersonal theory of suicide.
      ), defeat and entrapment (
      • Rudd M.D.
      Fluid vulnerability theory: A cognitive approach to understanding the process of acute and chronic suicide risk.
      ), pain and hopelessness (
      • Klonsky E.D.
      • Saffer B.Y.
      • Bryan C.J.
      Ideation-to-action theories of suicide: A conceptual and empirical update.
      )] govern transitions from ideation to behavior. Ideation-to-action models have identified several factors demarcating which individuals may attempt suicide (
      • Klonsky E.D.
      • Saffer B.Y.
      • Bryan C.J.
      Ideation-to-action theories of suicide: A conceptual and empirical update.
      ). However, because they largely treat suicidogenic pathways as static, most struggle to account for recent evidence that risk processes are heterogeneous (
      • Kleiman E.M.
      • Turner B.J.
      • Fedor S.
      • Beale E.E.
      • Huffman J.C.
      • Nock M.K.
      Examination of real-time fluctuations in suicidal ideation and its risk factors: Results from two ecological momentary assessment studies.
      ) and vary substantively over time (
      • Kleiman E.M.
      • Turner B.J.
      • Fedor S.
      • Beale E.E.
      • Huffman J.C.
      • Nock M.K.
      Examination of real-time fluctuations in suicidal ideation and its risk factors: Results from two ecological momentary assessment studies.
      ,
      • Bryan C.J.
      • Rozek D.C.
      • Butner J.
      • Rudd M.D.
      Patterns of change in suicide ideation signal the recurrence of suicide attempts among high-risk psychiatric outpatients.
      ,
      • Bryan C.J.
      • Rudd M.D.
      Nonlinear change processes during psychotherapy characterize patients who have made multiple suicide attempts.
      ,
      • Bryan C.J.
      • Rudd M.D.
      • Peterson A.L.
      • Young-McCaughan S.
      • Wertenberger E.G.
      The ebb and flow of the wish to live and the wish to die among suicidal military personnel.
      ).
      FVT (
      • O’Connor R.C.
      Towards an integrated motivational-volitional model of suicidal behavior.
      ) is distinguished from its ideation-to-action counterparts by its focus on suicide risk as a temporally dynamic process and its consideration of multiple interacting risk pathways. FVT posits that stable, preexisting vulnerabilities to suicide (e.g., genetics, stress responsiveness, neurocognitive function) are exacerbated or triggered by life stressors, intensifying risk states (e.g., hopelessness, anger, isolation, sleep deprivation), thereby driving immediate fluctuations and longer-term patterns of risk over time (
      • O’Connor R.C.
      Towards an integrated motivational-volitional model of suicidal behavior.
      ,
      • Bryan C.J.
      • Rudd M.D.
      • Peterson A.L.
      • Young-McCaughan S.
      • Wertenberger E.G.
      The ebb and flow of the wish to live and the wish to die among suicidal military personnel.
      ). Thus, FVT accounts for evidence that suicide attempt risk is a moving, nonlinear target fluctuating rapidly over brief periods [i.e., hours to days (
      • Kleiman E.M.
      • Turner B.J.
      • Fedor S.
      • Beale E.E.
      • Huffman J.C.
      • Nock M.K.
      Examination of real-time fluctuations in suicidal ideation and its risk factors: Results from two ecological momentary assessment studies.
      ,
      • Bryan C.J.
      • Rudd M.D.
      Nonlinear change processes during psychotherapy characterize patients who have made multiple suicide attempts.
      ,
      • Bryan C.J.
      • Rudd M.D.
      • Peterson A.L.
      • Young-McCaughan S.
      • Wertenberger E.G.
      The ebb and flow of the wish to live and the wish to die among suicidal military personnel.
      )]. FVT’s interactionist perspective also aligns with naturalistic suicidal behavior and machine learning insights underscoring the complex, interacting nature of risk factors (
      • Walsh C.G.
      • Ribeiro J.D.
      • Franklin J.C.
      Predicting risk of suicide attempts over time through machine learning.
      ,
      • Kessler R.C.
      • Warner C.H.
      • Ivany C.
      • Petukhova M.V.
      • Rose S.
      • Bromet E.J.
      • et al.
      Predicting suicides after psychiatric hospitalization in US Army soldiers: The Army Study to Assess Risk and rEsilience in Servicemembers (Army STARRS).
      ). In essence, FVT conceptualizes risk escalation as a perfect storm of stable and dynamic factors in time and space whose emergence is influenced by longer-term vulnerabilities (e.g., phenotypic factors).

      The Neurocircuitry of Suicide

      Progress requires a temporally sensitive theoretical framework of suicide, integrating knowledge of risk processes across clinical presentations. Distinct pathophysiologies may underlie suicide phenotypes, defined in part by temporal trends in individuals’ risk (
      • Jollant F.
      • Wagner G.
      • Richard-Devantoy S.
      • Köhler S.
      • Bär K.J.
      • Turecki G.
      • Pereira F.
      Neuroimaging-informed phenotypes of suicidal behavior: A family history of suicide and the use of a violent suicidal means.
      ,
      • Bernanke J.A.
      • Stanley B.H.
      • Oquendo M.A.
      Toward fine-grained phenotyping of suicidal behavior: The role of suicidal subtypes.
      ,
      • Oquendo M.A.
      • Galfalvy H.C.
      • Choo T.-H.
      • Kandlur R.
      • Burke A.K.
      • Sublette M.E.
      • et al.
      Highly variable suicidal ideation: A phenotypic marker for stress induced suicide risk.
      ). Because neuroimaging investigations primarily use cross-sectional designs for practical reasons, this hypothesis is largely untested. Moreover, because structure-function is typically compared between suicidal and nonsuicidal individuals within diagnoses, the generalizability of relevant neuroimaging to phenotypes and temporality remains unclear. These caveats notwithstanding, we now highlight findings potentially localizing key pathways and affective and behavioral traits to specific brain networks. In keeping with FVT’s interactionist perspective, we highlight how state factors (e.g., sleep, substance use, stress) and accelerating/decelerating phenotypic tendencies influence circuits.

      Functional Brain Networks and Suicide

      Functional networks are constellations of brain regions serving common functional domains (e.g., vision, language). Prior neuroimaging implicates the valence (or reward), default, and cognitive control networks in suicide (
      • Schmaal L.
      • van Harmelen A.L.
      • Chatzi V.
      • Lippard E.T.C.
      • Toenders Y.J.
      • Averill L.A.
      • et al.
      Imaging suicidal thoughts and behaviors: A comprehensive review of 2 decades of neuroimaging studies.
      ). The valence network processes feedback signals appraising the rewarding value of current or anticipated events that are central to emotion and learning (Figure 1). The default mode network (DMN) (Figure 1) is involved in autobiographical memory, prospection, and social cognition (
      • Andrews-Hanna J.R.
      • Reidler J.S.
      • Sepulcre J.
      • Poulin R.
      • Buckner R.L.
      Functional-anatomic fractionation of the brain’s default network.
      ,
      • Buckner R.L.
      • Andrews-Hanna J.R.
      • Schacter D.L.
      The brain’s default network: Anatomy, function, and relevance to disease.
      ,
      • Spreng R.N.
      • Stevens W.D.
      • Viviano J.D.
      • Schacter D.L.
      Attenuated anticorrelation between the default and dorsal attention networks with aging: Evidence from task and rest.
      ,
      • Buckner R.L.
      • Carroll D.C.
      Self-projection and the brain.
      ,
      • Schacter D.L.
      • Addis D.R.
      • Buckner R.L.
      Remembering the past to imagine the future: The prospective brain.
      ). Cognitive control, i.e., the adaptive control of thought and behavior (Figure 1), modulates processing in other brain networks toward goal-directed thought and action (
      • Miller E.K.
      • Cohen J.D.
      An integrative theory of prefrontal cortex function.
      ). Functional decrements in these networks map to suicidal processes in FVT [e.g., impaired future orientation, attentional biases, emotional dysregulation, problem-solving deficits (
      • Allen K.J.D.
      • Bozzay M.L.
      • Edenbaum E.R.
      Neurocognition and suicide risk in adults.
      )] differing between phenotypic presentations and map to specific circuits. Because these networks interact functionally via the cortico-striatal-thalamocortical loops (
      • Haber S.N.
      Corticostriatal circuitry.
      ), impairment in one has repercussions in other networks. Moreover, this detail of brain architecture facilitates recursive interactions between stable and dynamic factors underlying the “perfect storm.” Unless stated otherwise, imaging studies below compare individuals with suicidal thoughts and behaviors (STBs) to diagnostic controls.
      Figure thumbnail gr1
      Figure 1Target engagement along suicide risk trajectories. The valence (yellow), default (fuchsia), and cognitive control (blue) networks hold special relevance for suicide phenotypes. The cortico-striatal-thalamocortical loops integrate information across these distributed networks; thus, alterations in one network may impact functioning in other networks. Arousal and salience regions also interact with these networks, both directly and via the anatomical loop system. The development of suicidal ideation is influenced by the valence network’s sensitivity to positive and negative stimuli, including high-stress triggers, and the impact of valence bias on prospection and social cognition in the default network. Although cognitive control does influence longer-term patterns of risk, e.g., potential impulsive phenotypes, its most significant impact may be on momentary stress responses and transitions between risk states. Notably, cognitive control deteriorates in the aftermath of changes in cognition, behavior, emotion, and physiology that may occur secondary to triggers—this is the fluid vulnerability theory’s “perfect storm,” the confluence of stable and dynamic factors in time and space that rapidly escalate risk. Thus, it may be more efficient for treatments for longer-term factors to target valence and default networks, whereas targeting the control network may be a better strategy for rapid symptom reduction and improved regulation.

      The Valence Network: Emotion, Learning, and Decision-Making Biases

      Valence and arousal signals are central to emotion (
      • Lindquist K.A.
      • Barrett L.F.
      A functional architecture of the human brain: Emerging insights from the science of emotion.
      ) (Figure 1). Functional magnetic resonance imaging (fMRI) activation in the pars orbitalis/orbitofrontal cortex is attuned to negative affect in those with mood disorders and STBs. In adults with depression, orbitofrontal cortex activation is more robust during passive viewing of negative emotional faces (
      • Jollant F.
      • Lawrence N.S.
      • Giampietro V.
      • Brammer M.J.
      • Fullana M.A.
      • Drapier D.
      • et al.
      Orbitofrontal cortex response to angry faces in men with histories of suicide attempts.
      ,
      • Olié E.
      • Ding Y.
      • Le Bars E.
      • de Champfleur N.M.
      • Mura T.
      • Bonafé A.
      • et al.
      Processing of decision-making and social threat in patients with history of suicidal attempt: A neuroimaging replication study.
      ). Valence and arousal functional connectivity is also affectively biased in adolescents with bipolar disorder and attempt(s), who exhibit hyperconnectivity while viewing negative faces, but hypoconnectivity for positive emotion (
      • Johnston J.A.Y.
      • Wang F.
      • Liu J.
      • Blond B.N.
      • Wallace A.
      • Liu J.
      • et al.
      Multimodal neuroimaging of frontolimbic structure and function associated with suicide attempts in adolescents and young adults with bipolar disorder.
      ). Privileged negative emotional processing may confer stable vulnerability underlying depressive suicide phenotypes (
      • Bernanke J.A.
      • Stanley B.H.
      • Oquendo M.A.
      Toward fine-grained phenotyping of suicidal behavior: The role of suicidal subtypes.
      ). These biases may influence interpersonal interactions, strong drivers of momentary risk (
      • Bryan C.J.
      • Butner J.E.
      • May A.M.
      • Rugo K.F.
      • Harris J.
      • Oakey D.N.
      • et al.
      Nonlinear change processes and the emergence of suicidal behavior: A conceptual model based on the fluid vulnerability theory of suicide.
      ).
      Valence biases may also broadly influence feedback learning and decision making in STBs. Attempt history is associated with sunk cost bias (
      • Baek K.
      • Kwon J.
      • Chae J.H.
      • Chung Y.A.
      • Kralik J.D.
      • Min J.A.
      • et al.
      Heightened aversion to risk and loss in depressed patients with a suicide attempt history.
      ,
      • Szanto K.
      • Bruine de Bruin W.
      • Parker A.M.
      • Hallquist M.N.
      • Vanyukov P.M.
      • Dombrovski A.Y.
      Decision-making competence and attempted suicide.
      ), excessive loss aversion (
      • Baek K.
      • Kwon J.
      • Chae J.H.
      • Chung Y.A.
      • Kralik J.D.
      • Min J.A.
      • et al.
      Heightened aversion to risk and loss in depressed patients with a suicide attempt history.
      ,
      • Hadlaczky G.
      • Hökby S.
      • Mkrtchian A.
      • Wasserman D.
      • Balazs J.
      • Machín N.
      • et al.
      Decision-making in suicidal behavior: The protective role of loss aversion.
      ), short-term reward preference (
      • Dombrovski A.Y.
      • Szanto K.
      • Siegle G.J.
      • Wallace M.L.
      • Forman S.D.
      • Sahakian B.
      • et al.
      Lethal forethought: Delayed reward discounting differentiates high- and low-lethality suicide attempts in old age.
      ,
      • Dombrovski A.Y.
      • Siegle G.J.
      • Szanto K.
      • Clark L.
      • Reynolds C.F.
      • Aizenstein H.
      The temptation of suicide: Striatal gray matter, discounting of delayed rewards, and suicide attempts in late-life depression.
      ,
      • Dombrovski A.Y.
      • Szanto K.
      • Clark L.
      • Reynolds C.F.
      • Siegle G.J.
      Reward signals, attempted suicide, and impulsivity in late-life depression.
      ), and decision-making patterns reflecting inadequate feedback and/or anticipatory processing (
      • Dombrovski A.Y.
      • Hallquist M.N.
      The decision neuroscience perspective on suicidal behavior: Evidence and hypotheses.
      ). fMRI evidence links the valence network to feedback bias (orbitofrontal cortex, win > loss bias) [(
      • Jollant F.
      • Lawrence N.S.
      • Olie E.
      • O’Daly O.
      • Malafosse A.
      • Courtet P.
      • Phillips M.L.
      Decreased activation of lateral orbitofrontal cortex during risky choices under uncertainty is associated with disadvantageous decision-making and suicidal behavior.
      ), but see (
      • Olié E.
      • Ding Y.
      • Le Bars E.
      • de Champfleur N.M.
      • Mura T.
      • Bonafé A.
      • et al.
      Processing of decision-making and social threat in patients with history of suicidal attempt: A neuroimaging replication study.
      )] and blunted anticipatory signaling [ventromedial prefrontal cortex (PFC) (
      • Dombrovski A.Y.
      • Szanto K.
      • Clark L.
      • Reynolds C.F.
      • Siegle G.J.
      Reward signals, attempted suicide, and impulsivity in late-life depression.
      )] in older adults with depression and prior attempt (
      • Dombrovski A.Y.
      • Szanto K.
      • Clark L.
      • Reynolds C.F.
      • Siegle G.J.
      Reward signals, attempted suicide, and impulsivity in late-life depression.
      ) and to risk processing abnormalities in youths with attention deficits and ideation (
      • Dir A.L.
      • Allebach C.L.
      • Hummer T.A.
      • Adams Z.W.
      • Aalsma M.C.
      • Finn P.R.
      • et al.
      Atypical cortical activation during risky decision making in disruptive behavior disordered youths with histories of suicidal ideation.
      ). These deficits promote riskier, short-term–focused decision making, trait impulsivity, and perhaps, under proximal stress, suicide (
      • Dombrovski A.Y.
      • Hallquist M.N.
      The decision neuroscience perspective on suicidal behavior: Evidence and hypotheses.
      ).
      These findings highlight valence network emotion and feedback learning pathways that influence stable risk, proximal risk, and phenotypic expression. Other valence correlates of ideation (
      • Barredo J.
      • Aiken E.
      • van ’t Wout-Frank M.
      • Greenberg B.D.
      • Carpenter L.L.
      • Philip N.S.
      Neuroimaging correlates of suicidality in decision-making circuits in posttraumatic stress disorder.
      ,
      • Quevedo K.
      • Ng R.
      • Scott H.
      • Kodavaganti S.
      • Smyda G.
      • Diwadkar V.
      • Phillips M.
      Ventral striatum functional connectivity during rewards and losses and symptomatology in depressed patients.
      ), attempt (
      • Wagner G.
      • Koch K.
      • Schachtzabel C.
      • Schultz C.C.
      • Sauer H.
      • Schlösser R.G.
      Structural brain alterations in patients with major depressive disorder and high risk for suicide: Evidence for a distinct neurobiological entity?.
      ,
      • Soloff P.H.
      • Pruitt P.
      • Sharma M.
      • Radwan J.
      • White R.
      • Diwadkar V.A.
      Structural brain abnormalities and suicidal behavior in borderline personality disorder.
      ,
      • Lopez-Larson M.
      • King J.B.
      • McGlade E.
      • Bueler E.
      • Stoeckel A.
      • Epstein D.J.
      • Yurgelun-Todd D.
      Enlarged thalamic volumes and increased fractional anisotropy in the thalamic radiations in veterans with suicide behaviors.
      ,
      • Jia Z.
      • Wang Y.
      • Huang X.
      • Kuang W.
      • Wu Q.
      • Lui S.
      • et al.
      Impaired frontothalamic circuitry in suicidal patients with depression revealed by diffusion tensor imaging at 3.0 T.
      ,
      • Ding Y.
      • Lawrence N.
      • Olié E.
      • Cyprien F.
      • le Bars E.
      • Bonafé A.
      • et al.
      Prefrontal cortex markers of suicidal vulnerability in mood disorders: A model-based structural neuroimaging study with a translational perspective.
      ,
      • Aguilar E.J.
      • García-Martí G.
      • Martí-Bonmatí L.
      • Lull J.J.
      • Moratal D.
      • Escartí M.J.
      • et al.
      Left orbitofrontal and superior temporal gyrus structural changes associated to suicidal behavior in patients with schizophrenia.
      ), and attempt lethality (
      • Dombrovski A.Y.
      • Siegle G.J.
      • Szanto K.
      • Clark L.
      • Reynolds C.F.
      • Aizenstein H.
      The temptation of suicide: Striatal gray matter, discounting of delayed rewards, and suicide attempts in late-life depression.
      ,
      • Gifuni A.J.
      • Ding Y.
      • Olié E.
      • Lawrence N.
      • Cyprien F.
      • Le Bars E.
      • et al.
      Subcortical nuclei volumes in suicidal behavior: Nucleus accumbens may modulate the lethality of acts.
      ,
      • Soloff P.H.
      • Chowdury A.
      • Diwadkar V.A.
      Affective interference in borderline personality disorder: The lethality of suicidal behavior predicts functional brain profiles.
      ) have also been reported. Research is needed to address biases associated with nondepressive phenotypes (e.g., reward hypersensitivity in bipolar disorder or borderline personality disorder [BPD]). The circuitry underlying phenotypic interactions with proximal factors or how they amplify the impact of stress/trauma is also poorly understood. Examining how valence phenotypes influence attention in STBs (
      • Keilp J.G.
      • Gorlyn M.
      • Russell M.
      • Oquendo M.A.
      • Burke A.K.
      • Harkavy-Friedman J.
      • Mann J.J.
      Neuropsychological function and suicidal behavior: Attention control, memory and executive dysfunction in suicide attempt.
      ) will be important for understanding suicide in posttraumatic stress disorder (
      • Krysinska K.
      • Lester D.
      Post-traumatic stress disorder and suicide risk: A systematic review.
      ).

      The Default Network: Prospection and Social Cognition

      Midsagittal DMN regions integrate episodic memories [posterior cingulate cortex and precuneus (
      • Andrews-Hanna J.R.
      • Reidler J.S.
      • Sepulcre J.
      • Poulin R.
      • Buckner R.L.
      Functional-anatomic fractionation of the brain’s default network.
      )] with context and affect (medial PFC) into a self-referential framework (
      • Hamilton J.P.
      • Farmer M.
      • Fogelman P.
      • Gotlib I.H.
      Depressive rumination, the default-mode network, and the dark matter of clinical neuroscience.
      ). This is the foundation of our personal narratives and, to an extent, our future because experience guides prospection (
      • Schacter D.L.
      • Addis D.R.
      • Buckner R.L.
      Remembering the past to imagine the future: The prospective brain.
      ). Negative reinforcements are more readily recalled [reviewed in (
      • Vaish A.
      • Grossmann T.
      • Woodward A.
      Not all emotions are created equal: The negativity bias in social-emotional development.
      )], amplifying valence biases’ sway over prospection. Several studies of attempt in depression illustrate valence’s influence over DMN and memory prioritization. Posterior cingulate cortex activation while viewing positive self-referential images is attenuated in adolescents (
      • Quevedo K.
      • Ng R.
      • Scott H.
      • Martin J.
      • Smyda G.
      • Keener M.
      • Oppenheimer C.W.
      The neurobiology of self-face recognition in depressed adolescents with low or high suicidality.
      ). By contrast, the posterior cingulate cortex is hyperactive in adults viewing pictures of suicidal means (
      • Kim Y.J.
      • Park H.J.
      • Jahng G.H.
      • Lee S.M.
      • Kang W.S.
      • Kim S.K.
      • et al.
      A pilot study of differential brain activation to suicidal means and DNA methylation of CACNA1C gene in suicidal attempt patients.
      ). Such biases may reinforce maladaptive cognitive patterns [e.g., rumination and self-conceptual distortions (
      • Wenzel A.
      • Beck A.T.
      A cognitive model of suicidal behavior: Theory and treatment.
      ,
      • Van Orden K.A.
      • Witte T.K.
      • Cukrowicz K.C.
      • Braithwaite S.R.
      • Selby E.A.
      • Joiner Jr., T.E.
      The interpersonal theory of suicide.
      ), prospective impairments (
      • Williams J.M.
      • Ellis N.C.
      • Tyers C.
      • Healy H.
      • Rose G.
      • MacLeod A.K.
      The specificity of autobiographical memory and imageability of the future.
      )] long associated with suicidality.
      Function in the theory of mind (ToM) subnetwork (
      • Saxe R.
      • Kanwisher N.
      People thinking about thinking people. The role of the temporo-parietal junction in ”theory of mind”.
      ) (Figure 1) may contribute to social-cognitive suicide risk factors [e.g., hypermentalization (
      • Sharp C.
      • Ha C.
      • Carbone C.
      • Kim S.
      • Perry K.
      • Williams L.
      • Fonagy P.
      Hypermentalizing in adolescent inpatients: Treatment effects and association with borderline traits.
      ), perceived burdensomeness (
      • Van Orden K.A.
      • Witte T.K.
      • Cukrowicz K.C.
      • Braithwaite S.R.
      • Selby E.A.
      • Joiner Jr., T.E.
      The interpersonal theory of suicide.
      )]. ToM network fMRI activation during social exclusion is elevated in women with depression and attempt history (
      • Olié E.
      • Jollant F.
      • Deverdun J.
      • de Champfleur N.M.
      • Cyprien F.
      • Le Bars E.
      • et al.
      The experience of social exclusion in women with a history of suicidal acts: A neuroimaging study.
      ). Vulnerabilities rooted in ToM dysfunction may enhance stress responses, accelerating risk. Indeed, ToM coactivation with arousal/stress regions during exclusion scales with perceived burdensomeness (
      • Le T.M.
      • Zhornitsky S.
      • Wang W.
      • Li C.R.
      Perceived burdensomeness and neural responses to ostracism in the Cyberball task.
      ). Differences in network volume are common in disorders/symptoms associated with attempts [BPD (
      • Soloff P.H.
      • Pruitt P.
      • Sharma M.
      • Radwan J.
      • White R.
      • Diwadkar V.A.
      Structural brain abnormalities and suicidal behavior in borderline personality disorder.
      ,
      • Soloff P.
      • White R.
      • Diwadkar V.A.
      Impulsivity, aggression and brain structure in high and low lethality suicide attempters with borderline personality disorder.
      ), psychosis (
      • Giakoumatos C.I.
      • Tandon N.
      • Shah J.
      • Mathew I.T.
      • Brady R.O.
      • Clementz B.A.
      • et al.
      Are structural brain abnormalities associated with suicidal behavior in patients with psychotic disorders?.
      ), schizophrenia (
      • Aguilar E.J.
      • García-Martí G.
      • Martí-Bonmatí L.
      • Lull J.J.
      • Moratal D.
      • Escartí M.J.
      • et al.
      Left orbitofrontal and superior temporal gyrus structural changes associated to suicidal behavior in patients with schizophrenia.
      )]. Although understudied, the transdiagnostic nature of ToM observations is aligned with interpersonal difficulty as a universal driver of intensifying proximal risk (
      • Bryan C.J.
      • Butner J.E.
      • May A.M.
      • Rugo K.F.
      • Harris J.
      • Oakey D.N.
      • et al.
      Nonlinear change processes and the emergence of suicidal behavior: A conceptual model based on the fluid vulnerability theory of suicide.
      ).
      Despite the clear relevance of the DMN’s function to the phenomenon of suicide, it is comparatively understudied. Future work should investigate how broad DMN disruptions (e.g., resting hyperactivity) associated with general psychopathology (
      • Anticevic A.
      • Cole M.W.
      • Murray J.D.
      • Corlett P.R.
      • Wang X.J.
      • Krystal J.H.
      The role of default network deactivation in cognition and disease.
      ), such as rumination (
      • Hamilton J.P.
      • Farmer M.
      • Fogelman P.
      • Gotlib I.H.
      Depressive rumination, the default-mode network, and the dark matter of clinical neuroscience.
      ) and intrusions, specifically contribute to suicide. The plasticity of the DMN in chronic stress (
      • Soares J.M.
      • Sampaio A.
      • Marques P.
      • Ferreira L.M.
      • Santos N.C.
      • Marques F.
      • et al.
      Plasticity of resting state brain networks in recovery from stress.
      ) also merits attention given its potential to undermine encoding of positive memories while preserving negative ones, entrenching hopelessness.

      Cognitive Control: Transitions From Ideation to Attempt

      Although cognitive control influences suicide, its role is unclear, with the strength of its association varying substantially between clinical populations [reviewed in (
      • Bredemeier K.
      • Miller I.W.
      Executive function and suicidality: A systematic qualitative review.
      )]. Still, despite these discrepancies and because of its modulatory nature, cognitive control is a likely determinant of the acceleration/deceleration of risk processes and transitions to suicidal behaviors. Here, we consider cognitive control’s contributions to three elements critical for weathering the perfect storm: decision processes, emotional regulation, and inhibitory control.
      One recent perspective on suicide casts it as a disorder of aberrant decision making (
      • Dombrovski A.Y.
      • Hallquist M.N.
      The decision neuroscience perspective on suicidal behavior: Evidence and hypotheses.
      ). Although it emphasizes the neurobiology of valence, paradoxical findings on the delay-discounting task supporting this model suggest a role for cognitive control. There is a robust association between histories of more/less lethal or planned attempts and the exaggerated/limited ability to delay gratification in older adults with depression (
      • Dombrovski A.Y.
      • Szanto K.
      • Siegle G.J.
      • Wallace M.L.
      • Forman S.D.
      • Sahakian B.
      • et al.
      Lethal forethought: Delayed reward discounting differentiates high- and low-lethality suicide attempts in old age.
      ,
      • Dombrovski A.Y.
      • Siegle G.J.
      • Szanto K.
      • Clark L.
      • Reynolds C.F.
      • Aizenstein H.
      The temptation of suicide: Striatal gray matter, discounting of delayed rewards, and suicide attempts in late-life depression.
      ,
      • Vanyukov P.M.
      • Szanto K.
      • Hallquist M.N.
      • Siegle G.J.
      • Reynolds 3rd, C.F.
      • Forman S.D.
      • et al.
      Paralimbic and lateral prefrontal encoding of reward value during intertemporal choice in attempted suicide.
      ). Subjective value comparison during delay-discounting evokes fMRI activation in the dorsolateral PFC (DLPFC) (
      • Frost R.
      • McNaughton N.
      The neural basis of delay discounting: A review and preliminary model.
      ), a central cognitive control hub. This activation is reduced in older adults with histories of more planned attempts during delay discounting (
      • Vanyukov P.M.
      • Szanto K.
      • Hallquist M.N.
      • Siegle G.J.
      • Reynolds 3rd, C.F.
      • Forman S.D.
      • et al.
      Paralimbic and lateral prefrontal encoding of reward value during intertemporal choice in attempted suicide.
      ). Reduced engagement of the DLPFC in attempters during performance of other risk evaluation tasks (
      • Olié E.
      • Ding Y.
      • Le Bars E.
      • de Champfleur N.M.
      • Mura T.
      • Bonafé A.
      • et al.
      Processing of decision-making and social threat in patients with history of suicidal attempt: A neuroimaging replication study.
      ) reinforces linkage of decision making, cognitive control, and suicidal behavior (
      • Dombrovski A.Y.
      • Hallquist M.N.
      The decision neuroscience perspective on suicidal behavior: Evidence and hypotheses.
      ). Superior cognitive control may, paradoxically, be a stable vulnerability associated with a high-risk phenotype (
      • Bernanke J.A.
      • Stanley B.H.
      • Oquendo M.A.
      Toward fine-grained phenotyping of suicidal behavior: The role of suicidal subtypes.
      ,
      • Schmaal L.
      • van Harmelen A.L.
      • Chatzi V.
      • Lippard E.T.C.
      • Toenders Y.J.
      • Averill L.A.
      • et al.
      Imaging suicidal thoughts and behaviors: A comprehensive review of 2 decades of neuroimaging studies.
      ,
      • Dombrovski A.Y.
      • Hallquist M.N.
      The decision neuroscience perspective on suicidal behavior: Evidence and hypotheses.
      ). Because higher control function is typically associated with better coping skills and psychiatric health, it will be important to fully specify when superior control is a liability.
      Our allusion to the interplay between traits and naturalistic state factors is relevant to the DLPFC’s role in emotional regulation and suicide. Poor regulation is a transdiagnostic risk factor for self-injurious behaviors (
      • Cha C.B.
      • Wilson K.M.
      • Tezanos K.M.
      • DiVasto K.A.
      • Tolchin G.K.
      Cognition and self-injurious thoughts and behaviors: A systematic review of longitudinal studies.
      ). Emotional regulation is the control-dependent modification of reactions to emotionally evocative events (
      • Ochsner K.N.
      • Gross J.J.
      The cognitive control of emotion.
      ); this regulation evokes DLPFC activation [reviewed in (
      • Braunstein L.M.
      • Gross J.J.
      • Ochsner K.N.
      Explicit and implicit emotion regulation: A multi-level framework.
      )]. The inclusion of emotional feedback in decision-making tasks generally alters prefrontal dynamics, but more so in adult suicide attempters than clinical control subjects (
      • Alacreu-Crespo A.
      • Olié E.
      • Le Bars E.
      • Cyprien F.
      • Deverdun J.
      • Courtet P.
      Prefrontal activation in suicide attempters during decision making with emotional feedback.
      ). DLPFC recruitment also distinguishes depressed adolescents with/without STBs during explicit regulation (
      • Miller A.B.
      • McLaughlin K.A.
      • Busso D.S.
      • Brueck S.
      • Peverill M.
      • Sheridan M.A.
      Neural correlates of emotion regulation and adolescent suicidal ideation.
      ), but not passive tasks (
      • Miller A.B.
      • McLaughlin K.A.
      • Busso D.S.
      • Brueck S.
      • Peverill M.
      • Sheridan M.A.
      Neural correlates of emotion regulation and adolescent suicidal ideation.
      ,
      • Pan L.A.
      • Phillips M.L.
      Toward identification of neural markers of suicide risk in adolescents.
      ). Individuals for whom regulation is more biologically costly may be more vulnerable under “perfect storm” scenarios conducive to rapid temporal escalation of proximal risk. One can imagine higher-risk scenarios where situational factors, such as weeks of impaired sleep, reduce capacity for reactive control during immediate stressors.
      Ventrolateral PFC (VLPFC) inhibition may also shape STB manifestation, especially under proximal stress. The VLPFC facilitates the suppression/countermanding of thoughts and actions (
      • Aron A.R.
      • Fletcher P.C.
      • Bullmore E.T.
      • Sahakian B.J.
      • Robbins T.W.
      Stop-signal inhibition disrupted by damage to right inferior frontal gyrus in humans.
      ,
      • Aron A.R.
      • Robbins T.W.
      • Poldrack R.A.
      Inhibition and the right inferior frontal cortex: One decade on.
      ), often in response to conflict signals from arousal or salience circuits (
      • Seeley W.W.
      • Menon V.
      • Schatzberg A.F.
      • Keller J.
      • Glover G.H.
      • Kenna H.
      • et al.
      Dissociable intrinsic connectivity networks for salience processing and executive control.
      ,
      • Botvinick M.M.
      • Cohen J.D.
      • Carter C.S.
      Conflict monitoring and anterior cingulate cortex: An update.
      ). Although speculative, stronger functional connectivity between these circuits may enable conflict detection, driving fluctuations in ideation and negative affect and rumination. Indeed, functional connectivity between the VLPFC and salience circuits is elevated in young adults with mood disorders and ideation (
      • Stange J.P.
      • Jenkins L.M.
      • Pocius S.
      • Kreutzer K.
      • Bessette K.L.
      • DelDonno S.R.
      • et al.
      Using resting-state intrinsic network connectivity to identify suicide risk in mood disorders.
      ). Two antecedents of risk escalation, hypomania and negative urgency, are associated with differential VLPFC activity in more impulsive individuals (
      • Edmiston E.K.
      • Fournier J.C.
      • Chase H.W.
      • Bertocci M.A.
      • Greenberg T.
      • Aslam H.A.
      • et al.
      Assessing relationships among impulsive sensation seeking, reward circuitry activity, and risk for psychopathology: A functional magnetic resonance imaging replication and extension study.
      ) at a greater lifetime risk for STBs. Aberrant VLPFC suppression activation has also been noted in STBs with psychosis (
      • Minzenberg M.J.
      • Lesh T.A.
      • Niendam T.A.
      • Yoon J.H.
      • Rhoades R.N.
      • Carter C.S.
      Frontal cortex control dysfunction related to long-term suicide risk in recent-onset schizophrenia.
      ,
      • Minzenberg M.J.
      • Lesh T.A.
      • Niendam T.A.
      • Yoon J.H.
      • Cheng Y.
      • Rhoades R.N.
      • Carter C.S.
      Control-related frontal-striatal function is associated with past suicidal ideation and behavior in patients with recent-onset psychotic major mood disorders.
      ).
      The hypothesis that cognitive control modulates the acceleration/deceleration of risk state transitions awaits further evaluation. Unfortunately, control function is often treated as a static resource in neuroimaging, limiting insight into risk’s naturalistic, nonlinear evolution, escalating as a function of multiple suicide pathways. This missed opportunity is important given control’s central role in regulation, and because indicators of increased proximal risk [i.e., sleep (
      • Britton P.C.
      • McKinney J.M.
      • Bishop T.M.
      • Pigeon W.R.
      • Hirsch J.K.
      Insomnia and risk for suicidal behavior: A test of a mechanistic transdiagnostic model in veterans.
      ), substance abuse (
      • Rizk M.M.
      • Galfalvy H.
      • Miller J.M.
      • Milak M.
      • Parsey R.
      • Grunebaum M.
      • et al.
      Characteristics of depressed suicide attempters with remitted substance use disorders.
      ), mood/energy shifts (
      • Armey M.F.
      • Brick L.
      • Schatten H.T.
      • Nugent N.R.
      • Miller I.W.
      Ecologically assessed affect and suicidal ideation following psychiatric inpatient hospitalization.
      )] reduce control capacity [e.g., in depression (
      • Levens S.M.
      • Gotlib I.H.
      Impaired selection of relevant positive information in depression.
      ,
      • Levens S.M.
      • Muhtadie L.
      • Gotlib I.H.
      Rumination and impaired resource allocation in depression.
      ), anxiety (
      • Ford T.C.
      • Simpson T.
      • McPhee G.
      • Stough C.
      • Downey L.A.
      Trait and state anxiety is marked by increased working memory-related parietal BOLD signal.
      )]. Within-subjects examination of circuit function under varying levels of stress or control demand will be essential to revealing its role in suicide and relationship to impulsivity-related phenotypes and temporal risk trends (
      • Bernanke J.A.
      • Stanley B.H.
      • Oquendo M.A.
      Toward fine-grained phenotyping of suicidal behavior: The role of suicidal subtypes.
      ,
      • Dombrovski A.Y.
      • Hallquist M.N.
      The decision neuroscience perspective on suicidal behavior: Evidence and hypotheses.
      ). Although we advocate for the employ of state-trait interaction logic, we would be remiss not to acknowledge its limitations—within-subjects test-retest reliability and the potential for practice-related performance change.

      Neuroimaging Summary

      These findings highlight the valence, default, and cognitive control circuits’ significance to suicide, phenotypes, and risk temporal dynamics. Contradictory conclusions, however, indicate that much work remains. Transdiagnostic approaches that can identify both irrelevant variance and universal commonalities across clinical presentations will be essential for progress. Integrating high temporal resolution methodologies with imaging (see Opportunities in Suicide Research) may illuminate temporally delineated phenotypes. Other limitations include overemphasis on depression, modest delineation between ideation and attempt, and reliance on cross-sectional designs.

      Interventional Approaches to Suicide Reduction

      Several treatments developed primarily for depression have efficacy for suicide reduction. Here, we consider interventions for rapid reduction of suicidality and longer-term chronic risk factors, including treatments that have nonspecific impacts on function (i.e., medications) and those aimed at specific circuits or processes (i.e., neurostimulation, cognitive training). A few important caveats to this literature warrant attention. A number of studies consisted of secondary analyses utilizing single items extracted from various depression rating scales, limiting dimensionality and knowledge about the nature of the suicidal ideation or behavior. Moreover, the paucity of robust clinical trial effects may reflect their measurement over broad temporal windows aliasing rapid fluctuations in suicidality during high-risk periods.

      Longer-term Nonspecific Interventions

      Clozapine

      Clozapine is approved by the United States Food and Drug Administration for reduction of attempts in schizophrenia or schizoaffective disorder (
      • Editorial
      Practice guideline for the assessment and treatment of patients with suicidal behaviors.
      ). An early, unblinded study of clozapine in treatment-resistant patients found an 88% reduction in attempts (
      • Meltzer H.Y.
      • Okayli G.
      Reduction of suicidality during clozapine treatment of neuroleptic-resistant schizophrenia: Impact on risk-benefit assessment.
      ). Another small study found superior reductions in self-directed aggression and suicide risk after clozapine over haloperidol (
      • Spivak B.
      • Shabash E.
      • Sheitman B.
      • Weizman A.
      • Mester R.
      The effects of clozapine versus haloperidol on measures of impulsive aggression and suicidality in chronic schizophrenia patients: An open, nonrandomized, 6-month study.
      ). The largest trial to date, comparing clozapine (n = 479) to olanzapine (n = 477), found superior reductions in suicidal behavior favoring clozapine (
      • Meltzer H.Y.
      • Alphs L.
      • Green A.I.
      • Altamura A.C.
      • Anand R.
      • Bertoldi A.
      • et al.
      Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT).
      ). Despite clear efficacy, the prominent side effect burden associated with clozapine (e.g., anticholinergic side effects, weight gain, leukopenia, cardiotoxicity, and increased suicide risk after discontinuation) has limited its use (
      • Walker A.M.
      • Lanza L.L.
      • Arellano F.
      • Rothman K.J.
      Mortality in current and former users of clozapine.
      ,
      • Patchan K.M.
      • Richardson C.
      • Vyas G.
      • Kelly D.L.
      The risk of suicide after clozapine discontinuation: Cause for concern.
      ).

      Lithium

      Lithium is a mood stabilizer and augmentation agent used to treat bipolar disorder and major depressive disorder (MDD). Long-term lithium (>18 mo) reduces suicidality (
      • Schwartz-Lifshitz M.
      • Zalsman G.
      • Giner L.
      • Oquendo M.A.
      Can we really prevent suicide?.
      ). A meta-analysis associated lithium with reduced suicide risk versus placebo and was generally better than other pharmacotherapies, although statistically superior only to carbamazepine (
      • Cipriani A.
      • Hawton K.
      • Stockton S.
      • Geddes J.R.
      Lithium in the prevention of suicide in mood disorders: Updated systematic review and meta-analysis.
      ). Partial randomized controlled trial (RCT) data suggest that lithium does not reduce deliberate self-harm in depression (
      • Girlanda F.
      • Cipriani A.
      • Agrimi E.
      • Appino M.G.
      • Barichello A.
      • Beneduce R.
      • et al.
      Effectiveness of lithium in subjects with treatment-resistant depression and suicide risk: Results and lessons of an underpowered randomised clinical trial.
      ) or attempts during a 1-year controlled trial (
      • Lauterbach E.
      • Felber W.
      • Müller-Oerlinghausen B.
      • Ahrens B.
      • Bronisch T.
      • Meyer T.
      • et al.
      Adjunctive lithium treatment in the prevention of suicidal behaviour in depressive disorders: A randomised, placebo-controlled, 1-year trial.
      ). A cohort study of patients with bipolar disorder found that lithium and valproic acid were the only specific agents associated with reduced suicide; lithium’s lower mortality risk led to its recommendation for patients with bipolar disorder at risk for suicide (
      • Antolín-Concha D.
      • Lähteenvuo M.
      • Vattulainen P.
      • Tanskanen A.
      • Taipale H.
      • Vieta E.
      • Tiihonen J.
      Suicide mortality and use of psychotropic drugs in patients hospitalized due to bipolar disorder: A Finnish nationwide cohort study.
      ). Lithium concentrations in drinking water have also been linked to reduced suicide rates and psychiatric hospital admissions (
      • Eyre-Watt B.
      • Mahendran E.
      • Suetani S.
      • Firth J.
      • Kisely S.
      • Siskind D.
      The association between lithium in drinking water and neuropsychiatric outcomes: A systematic review and meta-analysis from across 2678 regions containing 113 million people.
      ). Lithium’s larger antisuicidal than mood episode effect in a meta-analysis (
      • Cipriani A.
      • Hawton K.
      • Stockton S.
      • Geddes J.R.
      Lithium in the prevention of suicide in mood disorders: Updated systematic review and meta-analysis.
      ) suggests that independent, unidentified mechanisms could be at play. fMRI in healthy subjects showed that lithium modulated striatal reward anticipation and prediction error coding (
      • Volman I.
      • Pringle A.
      • Verhagen L.
      • Browning M.
      • Cowen P.J.
      • Harmer C.J.J.N.
      Lithium modulates striatal reward anticipation and prediction error coding in healthy volunteers.
      ). However, lithium’s inconsistent benefits across diagnoses and side effects (e.g., tremor, dizziness, sedation) limit its role as a suicide treatment.

      Rapid Nonspecific Interventions

      Electroconvulsive Therapy

      Electroconvulsive therapy (ECT) has been used for decades for the rapid relief of ideation in individuals with refractory symptoms of depression, mania, and psychosis (
      • Fink M.
      • Kellner C.H.
      • McCall W.V.
      The role of ECT in suicide prevention.
      ). ECT is an inpatient procedure administered under anesthesia, involving the application of electrical current to the scalp in a dose sufficient to induce a generalized tonic-clonic seizure. Two studies of depression, one using bilateral ECT and the other right unilateral, found that it reduced ideation (
      • Kellner C.H.
      • Fink M.
      • Knapp R.
      • Petrides G.
      • Husain M.
      • Rummans T.
      • et al.
      Relief of expressed suicidal intent by ECT: A consortium for research in ECT study.
      ,
      • Sackeim H.A.
      • Haskett R.F.
      • Mulsant B.H.
      • Thase M.E.
      • Mann J.J.
      • Pettinati H.M.
      • et al.
      Continuation pharmacotherapy in the prevention of relapse following electroconvulsive therapy: A randomized controlled trial.
      ), with effects persisting up to 12 weeks after completion. These clinical studies cannot address neural mechanisms of suicidality reductions, but they likely involve networks implicated in ECT response [e.g., visual, limbic, default networks (
      • Moreno-Ortega M.
      • Prudic J.
      • Rowny S.
      • Patel G.H.
      • Kangarlu A.
      • Lee S.
      • et al.
      Resting state functional connectivity predictors of treatment response to electroconvulsive therapy in depression.
      )], also implicated in the broader neurobiology reviewed above.

      Ketamine and Esketamine

      Ketamine (delivered intravenously) and esketamine (delivered as a nasal spray) are emerging rapid pharmacotherapies acting primarily as NMDA receptor antagonists. Both are fast-acting antidepressants for treatment-resistant symptoms (
      • Papakostas G.I.
      • Salloum N.C.
      • Hock R.S.
      • Jha M.K.
      • Murrough J.W.
      • Mathew S.J.
      • et al.
      Efficacy of esketamine augmentation in major depressive disorder: A meta-analysis.
      ,
      • Ballard E.D.
      • Yarrington J.S.
      • Farmer C.A.
      • Richards E.
      • Machado-Vieira R.
      • Kadriu B.
      • et al.
      Characterizing the course of suicidal ideation response to ketamine.
      ) and promising antisuicidal treatments (
      • Ionescu D.F.
      • Swee M.B.
      • Pavone K.J.
      • Taylor N.
      • Akeju O.
      • Baer L.
      • et al.
      Rapid and sustained reductions in current suicidal ideation following repeated doses of intravenous ketamine: Secondary analysis of an open-label study.
      ). RCTs in patients with depression at imminent risk have demonstrated efficacy for reducing ideation within 24 hours of drug initiation [i.e., ketamine vs. midazolam in bipolar disorder with ideation (
      • Grunebaum M.F.
      • Ellis S.P.
      • Keilp J.G.
      • Moitra V.K.
      • Cooper T.B.
      • Marver J.E.
      • et al.
      Ketamine versus midazolam in bipolar depression with suicidal thoughts: A pilot midazolam-controlled randomized clinical trial.
      ), ketamine vs. midazolam for MDD with ideation (
      • Grunebaum M.F.
      • Galfalvy H.C.
      • Choo T.H.
      • Keilp J.G.
      • Moitra V.K.
      • Parris M.S.
      • et al.
      Ketamine for rapid reduction of suicidal thoughts in major depression: A midazolam-controlled randomized clinical trial.
      ), adjunctive esketamine vs. placebo for MDD with ideation (
      • Canuso C.M.
      • Singh J.B.
      • Fedgchin M.
      • Alphs L.
      • Lane R.
      • Lim P.
      • et al.
      Efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: Results of a double-blind, randomized, placebo-controlled study.
      ,
      • Fu D.J.
      • Ionescu D.F.
      • Li X.
      • Lane R.
      • Lim P.
      • Sanacora G.
      • et al.
      Esketamine nasal spray for rapid reduction of major depressive disorder symptoms in patients who have active suicidal ideation with intent: Double-blind, randomized study (ASPIRE I).
      )]. Small sample sizes, sample heterogeneity, and inadequate control for nonspecific effects [e.g., effect sizes for midazolam- vs. saline-controlled studies (
      • Wilkinson S.T.
      • Farmer C.
      • Ballard E.D.
      • Mathew S.J.
      • Grunebaum M.F.
      • Murrough J.W.
      • et al.
      Impact of midazolam vs. saline on effect size estimates in controlled trials of ketamine as a rapid-acting antidepressant.
      )] contribute to inconsistencies across trials [e.g., (
      • Fu D.J.
      • Ionescu D.F.
      • Li X.
      • Lane R.
      • Lim P.
      • Sanacora G.
      • et al.
      Esketamine nasal spray for rapid reduction of major depressive disorder symptoms in patients who have active suicidal ideation with intent: Double-blind, randomized study (ASPIRE I).
      ,
      • Ionescu D.F.
      • Bentley K.H.
      • Eikermann M.
      • Taylor N.
      • Akeju O.
      • Swee M.B.
      • et al.
      Repeat-dose ketamine augmentation for treatment-resistant depression with chronic suicidal ideation: A randomized, double blind, placebo controlled trial.
      )], but aggregated evidence was sufficiently compelling for the Food and Drug Administration’s approval of esketamine for MDD with acute STBs. Ketamine/esketamine’s acute side effects, including dizziness, sedation, nausea, and dissociation, have posed challenges to blinding in trials; side effects and the need for intensive vital signs monitoring limit broad applicability for treating STBs (
      • Schatzberg A.F.
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      ,
      • Drevets W.C.
      • Singh J.B.
      • Hough D.
      • Daly E.J.
      • Popova V.
      • Manji H.
      Comment on a word to the wise about intranasal esketamine.
      ,
      • Popova V.
      • Daly E.J.
      • Trivedi M.
      • Cooper K.
      • Lane R.
      • Lim P.
      • et al.
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      ). Connectome fingerprinting following ketamine administration found evidence of weakening functional connectivity within the control network but enhanced connectivity to external networks (
      • Abdallah C.G.
      • Ahn K.H.
      • Averill L.A.
      • Nemati S.
      • Averill C.L.
      • Fouda S.
      • et al.
      A robust and reproducible connectome fingerprint of ketamine is highly associated with the connectomic signature of antidepressants.
      ).

      Longer-term Circuit-Specific Interventions

      Psychotherapies

      There is a wide body of literature that describes neurobiological changes associated with psychotherapy [e.g., reviewed in (
      • Linden D.E.
      How psychotherapy changes the brain—The contribution of functional neuroimaging.
      )]. Different psychotherapy paradigms target—and modify—brain regions and circuits involved in impulse control, cognitive reappraisal, and emotion regulation. Co-occurring pharmacological treatment may augment these neurobiological changes. There remains a paucity of neuroimaging studies providing insight into mechanisms underlying psychotherapy’s antisuicidal effects.

      Psychotherapies: Cognitive Behavioral Therapy

      Cognitive behavioral therapy (CBT) for suicide has reduced suicide attempts (
      • Brown G.K.
      • Karlin B.E.
      • Trockel M.
      • Gordienko M.
      • Yesavage J.
      • Taylor C.B.
      Effectiveness of cognitive behavioral therapy for veterans with depression and suicidal ideation.
      ). In brief CBT for suicide (BCBT), a time-limited version of CBT, patients complete training in three control-dependent skills—cognitive reappraisal, problem solving, and emotional regulation—and develop and rehearse a relapse prevention plan. RCTs in patients with a wide range of psychiatric diagnoses found that those receiving CBT/BCBT were 50% to 60% less likely to attempt suicide and more likely to remain in treatment (
      • Rudd M.D.
      • Bryan C.J.
      • Wertenberger E.G.
      • Peterson A.L.
      • Young-McCaughan S.
      • Mintz J.
      • et al.
      Brief cognitive-behavioral therapy effects on post-treatment suicide attempts in a military sample: Results of a randomized clinical trial with 2-year follow-up.
      ); however, there is still room for improvement.

      Psychotherapies: Dialectical Behavior Therapy

      Dialectical behavior therapy was initially designed to treat patients with suicidal behavior and BPD and has demonstrated efficacy for reducing attempt (
      • Linehan M.M.
      • Comtois K.A.
      • Murray A.M.
      • Brown M.Z.
      • Gallop R.J.
      • Heard H.L.
      • et al.
      Two-year randomized controlled trial and follow-up of dialectical behavior therapy vs therapy by experts for suicidal behaviors and borderline personality disorder.
      ). Patients focus on developing skills in mindfulness (including cognitive reappraisal), distress tolerance, emotion regulation, and interpersonal effectiveness, with STBs targeted in an individualized hierarchy (
      • Lynch T.R.
      • Chapman A.L.
      • Rosenthal M.Z.
      • Kuo J.R.
      • Linehan M.M.
      Mechanisms of change in dialectical behavior therapy: Theoretical and empirical observations.
      ). RCTs indicate that patients receiving dialectical behavior therapy are less likely to engage in self-directed violence, are more likely to remain in therapy, and have fewer hospitalizations versus treatment as usual (
      • Linehan M.M.
      • Comtois K.A.
      • Murray A.M.
      • Brown M.Z.
      • Gallop R.J.
      • Heard H.L.
      • et al.
      Two-year randomized controlled trial and follow-up of dialectical behavior therapy vs therapy by experts for suicidal behaviors and borderline personality disorder.
      ) or psychoanalysis (
      • Lynch T.R.
      • Chapman A.L.
      • Rosenthal M.Z.
      • Kuo J.R.
      • Linehan M.M.
      Mechanisms of change in dialectical behavior therapy: Theoretical and empirical observations.
      ). Dialectical behavior therapy skills depend on cognitive control, but with greater emphasis on emotional regulation. Despite its effectiveness, its time- and resource-intensive nature hinders wider implementation.

      Transcranial Magnetic Stimulation

      Recently, transcranial magnetic stimulation (TMS), a noninvasive form of therapeutic brain stimulation, has received attention as an antisuicidal treatment. TMS uses rapidly fluctuating magnetic fields to induce electrical activity in targeted brain regions (
      • Rowny S.
      • Lisanby S.H.
      Brain stimulation in psychiatry.
      ). When efficacious, several weeks of daily TMS leads to downstream changes in neural networks (
      • Philip N.S.
      • Barredo J.
      • Aiken E.
      • Carpenter L.L.
      Neuroimaging mechanisms of therapeutic transcranial magnetic stimulation for major depressive disorder.
      ). TMS is cleared for pharmacoresistant MDD and has demonstrated efficacy in other disorders associated with suicide risk.
      In suicide research, stimulation is commonly applied over the DLPFC to target cognitive and affective control regions (
      • Davidson R.J.
      • Lewis D.A.
      • Alloy L.B.
      • Amaral D.G.
      • Bush G.
      • Cohen J.D.
      • et al.
      Neural and behavioral substrates of mood and mood regulation.
      ). Clinical trials of TMS for suicide have been conducted in more than 500 patients, and TMS consistently reduces depressive symptoms [reviewed in (
      • Bozzay M.L.
      • Primack J.
      • Barredo J.
      • Philip N.S.
      Transcranial magnetic stimulation to reduce suicidality - A review and naturalistic outcomes.
      )]. Reductions in suicidality were promising, albeit less robust. Studies’ limitations included unblinded designs, modest samples, reliance on single-item measures, and frequent exclusion of higher-risk participants. Newer forms of stimulation such as theta burst TMS demonstrated fewer suicide attempts and hospitalizations 1 year following stimulation (
      • Petrosino N.J.
      • Wout-Frank M.V.'
      • Aiken E.
      • Swearingen H.R.
      • Barredo J.
      • Zandvakili A.
      • Philip N.S.
      One-year clinical outcomes following theta burst stimulation for post-traumatic stress disorder.
      ).

      Rapid Circuit-Specific Interventions

      Multiple daily applications (accelerated TMS) have reported rapid reductions in suicidal thoughts (
      • Desmyter S.
      • Duprat R.
      • Baeken C.
      • Bijttebier S.
      • van Heeringen K.
      The acute effects of accelerated repetitive transcranial magnetic stimulation on suicide risk in unipolar depression: Preliminary results.
      ), although RCT findings were less robust (
      • George M.S.
      • Raman R.
      • Benedek D.M.
      • Pelic C.G.
      • Grammer G.G.
      • Stokes K.T.
      • et al.
      A two-site pilot randomized 3 day trial of high dose left prefrontal repetitive transcranial magnetic stimulation (rTMS) for suicidal inpatients.
      ). Most recently, an unblinded study demonstrated that accelerated theta burst TMS had a rapid antisuicidal effect (
      • Cole E.J.
      • Stimpson K.H.
      • Bentzley B.S.
      • Gulser M.
      • Cherian K.
      • Tischler C.
      • et al.
      Stanford accelerated intelligent neuromodulation therapy for treatment-resistant depression.
      ). Questions remain, such as whether it is best used as a rapid stabilizing agent or longer-term intervention (or both), but TMS shows promise as a rapid circuit-based suicide intervention.

      Opportunities in Suicide Research

      Recent methodological advances permit increasingly novel approaches to suicide research. Here, we highlight advances in temporal sampling, transdiagnostic analyses, biological components of suicide reduction, and individualized treatment. Broader integration of the following approaches with neuroimaging may advance the development of more efficacious intervention and prevention strategies.

      Intensive Proximal Risk Sampling

      Proximal predictors influencing risk in the weeks, days, and hours before suicide are not well understood. Longitudinal methodologies (
      • Bolger N.
      • Laurenceau J.P.
      Intensive Longitudinal Methods: An Introduction to Diary and Experience Sampling Research.
      ) involving intensive daily samplings such as ecological momentary assessment (EMA) can address this gap. EMA enables the naturalistic investigation of risk processes at high temporal resolutions. This capacity permits the characterization of suicidal phenotypes (
      • Bryan C.J.
      • Rozek D.C.
      • Butner J.
      • Rudd M.D.
      Patterns of change in suicide ideation signal the recurrence of suicide attempts among high-risk psychiatric outpatients.
      ) distinguished by temporal variability [e.g., ideation chronicity vs. lability, cyclicity (
      • Mousavi S.G.
      • Bateni S.
      • Maracy M.R.
      • Mardanian F.
      • Mousavi S.H.
      Recurrent suicide attempt and female hormones.
      )]. Moreover, its naturalistic administration facilitates examination of the complex interplay between proximal factors as suicidality evolves (
      • Armey M.F.
      • Brick L.
      • Schatten H.T.
      • Nugent N.R.
      • Miller I.W.
      Ecologically assessed affect and suicidal ideation following psychiatric inpatient hospitalization.
      ,
      • Kleiman E.M.
      • Coppersmith D.D.L.
      • Millner A.J.
      • Franz P.J.
      • Fox K.R.
      • Nock M.K.
      Are suicidal thoughts reinforcing? A preliminary real-time monitoring study on the potential affect regulation function of suicidal thinking.
      ). Integrating EMA with neuroimaging research is one strategy for overcoming MRI constraints precluding examination of temporality. Mapping EMA-based suicide typologies to circuits will ground temporal phenotypes in neurobiological circuits.
      Digital phenotyping [e.g., smartphones, wearables; reviewed in (
      • Brietzke E.
      • Hawken E.R.
      • Idzikowski M.
      • Pong J.
      • Kennedy S.H.
      • Soares C.N.
      Integrating digital phenotyping in clinical characterization of individuals with mood disorders.
      ,
      • Stange J.P.
      • Kleiman E.M.
      • Mermelstein R.J.
      • Trull T.J.
      Using ambulatory assessment to measure dynamic risk processes in affective disorders.
      )] permits intensive sampling of potential objective suicide risk indicators (e.g., sleep, speech). Mapping finer-grained sensor data to EMA-derived phenotypes is an avenue toward personalized, real-time intervention. Ecological momentary interventions or just-in-time adaptive interventions use short-term indices of risk to trigger the delivery of suicide interventions, creating opportunities for intervention outside of provider interactions, when attempts are most likely to occur. Integrating with neuroimaging would allow even greater personalization, e.g., individualized targeting and neuromodulation of valence circuits triggered by reduction in the nature or frequency of patients’ typical social media use.

      Understanding Transdiagnostic Risk

      Suicide is a transdiagnostic behavior, often occurring in individuals with complex symptomatology and at higher rates in patients with symptom clusters crossing categorical diagnosis [e.g., mixed depressive episodes (
      • Balázs J.
      • Benazzi F.
      • Rihmer Z.
      • Rihmer A.
      • Akiskal K.K.
      • Akiskal H.S.
      The close link between suicide attempts and mixed (bipolar) depression: Implications for suicide prevention.
      )]. Prior work heavily focuses on diagnostic samples with high rates of ideation [e.g., depression (
      • Bozzay M.L.
      • Primack J.
      • Barredo J.
      • Philip N.S.
      Transcranial magnetic stimulation to reduce suicidality - A review and naturalistic outcomes.
      )], limiting generalizability to varied symptom profiles (e.g., depression comorbid with trauma, BPD). Deploying the integrated strategies discussed above (see Intensive Proximal Risk Sampling) across a broader range of symptom profiles will enable transdiagnostic characterization of suicide risk. This inclusive approach paves the way for the definition of phenotypes emerging from transdiagnostic symptom clusters and the characterization of related circuit-level vulnerabilities. We note, however, that adopting this enriched modeling approach will necessitate appropriate penalization for model complexity to ensure broad generalizability.

      Predictors and Mechanisms of Phenotypic Response

      A significant portion of patients respond inadequately to treatment, experiencing continued high ideation and subsequent reattempts (

      Nelson HD, Denneson L, Low A, Bauer BW, O’Neil M, Kansagara D, Teo AR (2015): Systematic review of suicide prevention in veterans. In: Health Services Research & Development Service (HSR&D) Evidence Synthesis Program, editor. VA Evidence Synthesis Program Reports. Washington, DC: Department of Veterans Affairs.

      ). Interdisciplinary treatment designs providing mechanistic data are critical for addressing this problem. Integrating measures of distal risk processes (e.g., neuroimaging, electrophysiology) and variation in risk processes over time (e.g., EMA, sensors) with intervention studies creates an opportunity to define predictors of treatment responsiveness associated with distinct phenotypes. These designs will be critical for improving outcomes via personalized prescription and target engagement guided by individuals’ EMA-derived risk phenotype.

      Interdisciplinary Personalized Interventions

      Developing personalized interventions is essential for improving treatment outcomes. Combining interdisciplinary treatments targeting different aspects of suicidal risk (e.g., augmenting CBT with circuit neuromodulation, modifying dosage/delivery by real-time indicators) may improve intervention outcomes. Combining brain stimulation with psychotherapy has been developed in other areas [e.g., (
      • Sathappan A.V.
      • Luber B.M.
      • Lisanby S.H.
      The dynamic duo: Combining noninvasive brain stimulation with cognitive interventions.
      ,
      • Nord C.L.
      • Halahakoon D.C.
      • Limbachya T.
      • Charpentier C.
      • Lally N.
      • Walsh V.
      • et al.
      Neural predictors of treatment response to brain stimulation and psychological therapy in depression: A double-blind randomized controlled trial.
      )] and is under investigation for suicide (
      • Bozzay M.L.
      • Primack J.M.
      • Swearingen H.R.
      • Barredo J.
      • Philip N.S.
      Combined transcranial magnetic stimulation and brief cognitive behavioral therapy for suicide: Study protocol for a randomized controlled trial in veterans.
      ). Optimizing implementation by phenotype (e.g., fMRI-guided circuit targeting for neurostimulation) (Figure 2) is another path forward. A preliminarily exemplar from depression (
      • Huckins J.F.
      • daSilva A.W.
      • Wang R.
      • Wang W.
      • Hedlund E.L.
      • Murphy E.I.
      • et al.
      Fusing mobile phone sensing and brain imaging to assess depression in college students.
      ) demonstrates localization of temporal risk patterns to circuits, although not to an intervention.
      Figure thumbnail gr2
      Figure 2Incorporating longitudinal methods into suicide intervention research. Integration of methods providing insight into biological mechanisms and temporality is critical for the advancement of neuroscience-based interventions for suicide. (A) One approach is to measure participants’ brain activity via neuroimaging or electrophysiological methods before and following the administration of intervention procedures (B) while concurrently and/or subsequently monitoring risk with devices providing real-time information (e.g., actigraphy, smartphone applications). More intensive designs may include collection of serial mechanistic data from multiple time points across the course of the intervention and follow-up period, especially during high-risk periods such as the 2 weeks immediately after an inpatient hospitalization. (C) Mapping temporal phenotypes derived from digital phenotyping to neuroimaging is one approach toward bridging magnetic resonance imaging’s temporal limitations. Matching treatment outcomes to digital phenotypes and biotypes can advance efforts toward personalized medicine approaches to suicide prevention and intervention; for example, phenotypic data could inform the selection of treatments or implementation parameters (e.g., functional magnetic resonance imaging to guide which circuits are targeted via transcranial magnetic stimulation). A, anterior; P, posterior.

      Conclusions

      Quelling the rise in suicide requires the refinement of existing treatments and the development of novel intervention strategies that are optimized for its complex, multidetermined nature. Integrating approaches capturing critical temporal elements of suicide risk with circuit-focused methodologies is essential for progress. Mapping temporality to circuits can guide personalized treatment tailored to individual biological vulnerabilities and indicators of near-term risk.

      Acknowledgments and Disclosures

      This work was supported by grants from VA Clinical Science Research and Development (Grant No. IK2 CX001824 [to JB]), the Brain Behavior Research Foundation (NARSAD) Young Investigator Award (to JB), VA Health Services Research and Development (Grant No. I01 HX002572 [to NSP and JMP] and Grant No. HX002972 [to JMP and HTS]), National Institute of Mental Health (Grant Nos. R01MH112674 and R01MH110379 [to MFA] and R01MH108610 [to HTS and MFA]), National Institute of General Medical Sciences (Grant No. P20 GM130452 [to JB, NSP, and LLC] and P20GM125507 [to HTS]), and VA Rehabilitation Research and Development (Grant No. I01 RX002450 [to NSP]). HTS was supported in part by the American Foundation for Suicide Prevention (Grant No. SRG-1-119-18), and MLB was supported by the VA RR&D Center for Neurorestoration and Neurotechnology (Grant No. RX002864) .
      The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the U.S. Department of Veterans Affairs or National Institutes of Health. The funders had no role in the conduct of the study, article preparation, or the decision to submit for publication.
      LLC reports grant/research support from Neuronetics, NeoSync, AffectNeuro, Nexstim, and Janssen, and she has been a consultant for Neuronetics, Nexstim, Janssen, AffectNeuro, Sage Therapeutics, and Otsuka. All other authors report no biomedical financial interests or potential conflicts of interest.

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