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Cited by 5Suicide and Self-Harm StudiesTreatment of Major DepressionElectroconvulsive Therapy Studies

Clinical indicators of the suicide crisis and response to ketamine

Open access
Ballard, Elizabeth D., Neely, Lucinda, Waldman, Laura, Greenstein, Dede, Zarate, Carlos A.·2025·Journal of Affective Disorders
DOI 10.1016/j.jad.2024.11.080PMC PMC11729457
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Abstract

Background: This analysis sought to identify potential clinical targets for the suicide crisis. Characteristics of a useful clinical target include elevation at the time of suicide crisis and responsiveness to rapid-acting interventions. Suicidal ideation (SI), depression, and hopelessness were hypothesized to meet these criteria. Methods: Participants were 118 adults across the continuum of suicide risk, including 14 high-risk (HR) individuals who had attempted or seriously considered suicide within the last two weeks. Clinical characteristics were evaluated by: 1) comparing individuals with a recent crisis state to those whose suicide crises had resolved; 2) quantifying responses to a semi-structured interview about the time just before a suicide crisis; and 3) comparing symptomatology before and after an open-label ketamine infusion (0.5mg/kg) in a subset of the HR group (n=10). Results: As hypothesized, SI, depression, and hopelessness were elevated just after a suicide crisis and responded to ketamine, although findings were mixed depending on the assessment used. Psychological pain and traumatic stress symptoms were also associated with the suicide crisis and responded to ketamine. Participants reported high levels of SI, depression, and anxiety just before their suicide attempt. Limitations: Limitations include the small sample size, inconsistent assessments across analyses, and that ketamine was the only intervention examined. Conclusions: These results underscore the importance of SI, depression, hopelessness, psychological pain, and traumatic stress in this population, all of which were elevated during the suicide crisis and responded to ketamine. A multifactorial and longitudinal approach is indicated to assess and treat suicide risk.

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Written from the paper’s full text.

TL;DR

In 118 adults across a continuum of suicide risk, suicidal ideation, depression, hopelessness, psychological pain, and traumatic stress were elevated around a recent suicide crisis and generally declined after open-label ketamine in a high-risk subset. Findings varied by assessment, especially for suicidal ideation.

Key findings

  • The high-risk (HR) group (n=14) had higher scores than low-risk, clinical-control, and minimal-risk groups on global functioning, SI, psychological pain, hopelessness, interpersonal needs, traumatic stress, depression, borderline symptoms, and impulsivity; effect sizes were generally medium to large versus low-risk and clinical-control groups, though confidence intervals crossed 0 for BDI, HAM-D, C-SSRS, SHAPS, TEPS, HAM-A, and BPA.
  • In retrospective reports from HR participants (n=11), most reported severe depression, anxiety, and SI just before their suicide crisis (score ≥8); lower levels were reported for anger (9% at ≥8) and agitation (36% at ≥8).
  • After ketamine in 10 HR participants, predominantly large effect sizes were seen for total scores, Suicide Status Form item scores, and the combined MADRS/HAM-D SI item, with 95% confidence intervals consistently above zero; the C-SSRS effect size was small, and CGI/C-SSRS bootstrapped confidence intervals could not be calculated due to many zero differences.
  • Psychological pain and traumatic stress were associated with the suicide crisis and declined after ketamine; SI findings were inconsistent across measures.

Methods

  • Two-phase study: Phase 1 cross-sectional assessment of 118 adults (HR n=14, low-risk n=39, clinical controls n=38, minimal risk n=27), with group status assigned by C-SSRS; Phase 2 was an open-label trial of intravenous racemic ketamine (0.5 mg/kg, up to five administrations over three weeks) offered only to the HR group, with 10 of 14 consenting.
  • Measures included SSI, C-SSRS, BHS, MADRS, HAM-D, BDI-II, HAM-A, SHAPS, TEPS, MBPPAS, INQ, IES-R, YMRS, BSL, BIS, BPA, AUDIT, and CGI; a semi-structured retrospective interview (RRSA) asked HR participants (n=11) to rate symptoms just before their suicide attempt.
  • Analyses used Cohen’s d with 95% CIs for Phase 1 group differences, descriptive and Spearman correlations for RRSA, and Wilcoxon signed-rank tests with effect sizes r = z/√n and bootstrapped 95% CIs for pre-post ketamine differences; p-values were reported in the supplement.

Limitations

  • The paper states limitations including the small sample size of recently suicidal individuals, inconsistent assessments across analyses (e.g., no hopelessness rating in the RRSA), and that ketamine was the only intervention examined.
  • The paper also states the RRSA was not validated as a formal timeline follow-back interview, participant groups were selected by recency of suicidal thoughts and behavior, and further analyses of sex, socioeconomic status, and diagnosis are needed.
  • Evident from the text: the ketamine phase was open-label with a small HR subset (n=10), no control intervention was described, and the statistical approach emphasized effect sizes without a priori power analyses.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.jad.2024.11.080

Cites

56 of 56 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 22 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    For depression (BDI and HAM-D), SI (C-SSRS), anhedonia (SHAPS and TEPS), anxiety (HAM-A), and aggression (BPA), confidence intervals for HR vs LR/CC effect sizes crossed zero.

    “While effect sizes were consistently positive and generally fell in the medium to large effect size range (HR group>LR and CC groups), some confidence intervals crossed 0 on measures of depression (BDI and HAM-D), SI (C-SSRS), anhedonia (SHAPS and TEPS), anxiety (HAM-A), and aggression (BPA).”
    Quote in the paperNot a substantial claim
  • Findingown data

    All measured symptoms declined after ketamine administration, including psychological pain and traumatic stress.

    “All of these measured symptoms declined after ketamine administration, including psychological pain and traumatic stress, highlighting their role as potential treatment targets for the suicide crisis.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Symptom improvements from before to after open-label ketamine administration reflect ketamine's effect rather than placebo, regression to the mean, or other time-related factors.
  • Findingown data

    Lower levels of anger and agitation were reported just before the suicide crisis (9% and 36% of participants reported ≥8, respectively).

    “In comparison, lower levels of anger and agitation were reported just before the suicide crisis (9% and 36% of participants reported 8 or more on this scale, respectively).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Participants' retrospective ratings on the RRSA accurately reflect the symptoms they experienced just before their suicide attempt.
  • Findingown data

    RRSA items were generally correlated with corresponding Phase 1 clinical ratings.

    “Overall, items from the RRSA were generally correlated with the corresponding Phase 1 rating.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Participants' retrospective ratings on the RRSA accurately reflect the symptoms they experienced just before their suicide attempt.
  • Findingown data

    Psychological pain and traumatic stress symptoms were linked to the suicide crisis.

    “Psychological pain and traumatic stress symptoms were also associated with the suicide crisis and responded to ketamine.”
    • Also stated in: § Discussion · plain
      “Unique findings from this analysis included the role of psychological pain and traumatic stress in the suicide crisis as well as the role of global functioning, interpersonal dysregulation, borderline symptoms, and impulsivity.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The high-risk group's clinical state at Phase 1 assessment represents the period just after a suicide crisis.
  • May combine two claims. 13
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 10

  • May combine two claims.

    Findingown data

    Reported SI on the RRSA was not correlated with SI at Phase 1, but was correlated with depression and traumatic stress.

    “Reported SI on the RRSA was not correlated with SI at the time of Phase 1 research participation, but it was correlated with depression and traumatic stress.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Participants' retrospective ratings on the RRSA accurately reflect the symptoms they experienced just before their suicide attempt.

  • May combine two claims.

    Findingown data

    In the high-risk group, scores exceeded each non-crisis group (LR, CC, MR) on global functioning (CGI), SI (SSI), psychological pain (MBPPAS), hopelessness (BHS), interpersonal needs (INQ), traumatic stress (IES-R), depression (MADRS), borderline symptoms (BSL), and impulsivity (BIS).

    “The HR group had higher scores across a range of clinical symptoms relative to each of the other non-crisis groups (LR, CC, and MR), including global functioning (CGI), SI (SSI), psychological pain (MBPPAS), hopelessness (BHS), interpersonal needs (INQ), traumatic stress (IES-R), depression (MADRS), borderline symptoms (BSL), and impulsivity (BIS).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The high-risk group's clinical state at Phase 1 assessment represents the period just after a suicide crisis.

  • May combine two claims.

    Findingown data

    In Phase 2, predominantly large effect sizes were seen for total scores, SSF item scores, and the combined MADRS/HAM-D SI item, indicating general symptom improvement after ketamine.

    “Predominantly large effect sizes were seen for total scores, SSF item scores, and the combined MADRS/HAM-D SI item, representing a general pattern of symptom improvement in response to ketamine, as hypothesized; one exception was the small C-SSRS effect size.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Symptom improvements from before to after open-label ketamine administration reflect ketamine's effect rather than placebo, regression to the mean, or other time-related factors.

  • The quote only partly states this claim.

    Findingown data

    Ninety-five percent confidence intervals for Phase 2 effect sizes consistently fell above zero.

    “Ninety-five percent confidence intervals consistently fell above zero.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Suicidal ideation, depression, and hopelessness improved after ketamine, though results differed by assessment.

    “As hypothesized, SI, depression, and hopelessness were elevated just after a suicide crisis and responded to ketamine, although findings were mixed depending on the assessment used.”
    • Also stated in: § Phase 2 Post-Ketamine: Clinical Assessments · plain
      “Predominantly large effect sizes were seen for total scores, SSF item scores, and the combined MADRS/HAM-D SI item, representing a general pattern of symptom improvement in response to ketamine, as hypothesized; one exception was the small C-SSRS effect size.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Symptom improvements from before to after open-label ketamine administration reflect ketamine's effect rather than placebo, regression to the mean, or other time-related factors.

  • May combine two claims.

    Findingown data

    Psychological pain and traumatic stress symptoms improved after ketamine.

    “Psychological pain and traumatic stress symptoms were also associated with the suicide crisis and responded to ketamine.”
    • Also stated in: § Discussion · plain
      “All of these measured symptoms declined after ketamine administration, including psychological pain and traumatic stress, highlighting their role as potential treatment targets for the suicide crisis.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Symptom improvements from before to after open-label ketamine administration reflect ketamine's effect rather than placebo, regression to the mean, or other time-related factors.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    CGI and C-SSRS bootstrapped confidence intervals could not be calculated because of a high rate of zero differences; the C-SSRS lower confidence bound could extend below zero.

    “Although the CGI and the C-SSRS bootstrapped confidence intervals could not be calculated because of a high rate of zero differences (resulting in all zeros in bootstrapped samples), it is possible that the C-SSRS lower confidence bound could extend below zero (Figure 4).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Previous studies suggest SI is variable across the day and may be particularly reactive to the placebo effect.

    “Indeed, previous studies suggest that SI is variable across the day (Kleiman et al., 2017) and may be particularly reactive to the placebo effect (Bloomfield-Clagett et al., 2022).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Kleiman et al., 2017 source

      Not checked in the free run.

    • cites Bloomfield-Clagett et al., 2022 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Newer theories suggest a subtype of individuals with highly variable SI may be at particular risk for suicidal behavior in times of stress.

    “newer theories of suicide risk suggest that a subtype of individuals who report highly variable SI may be at particular risk for suicidal behavior in times of stress (Oquendo et al., 2021).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Oquendo et al., 2021 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Ketamine is just one potential rapid intervention; other rapid-acting interventions are likely associated with different patterns of symptom improvement.

    “Finally, ketamine is just one potential rapid intervention for depression and suicidal thoughts; other rapid-acting interventions are likely associated with different patterns of symptom improvement (Bryan et al., 2018; Croarkin et al., 2018).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Bryan et al., 2018 source

      Not checked in the free run.

    • cites Croarkin et al., 2018 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    The RRSA was not validated as a formal timeline follow-back interview, which requires in-depth assessment of the crisis and a control time period.

    “The RRSA provided supplemental information on the time of the actual suicide crisis, but it was not validated as a formal timeline follow-back interview, which requires in-depth assessment of the crisis and a control time period for comparison purposes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Assessments were not consistent across analyses (e.g., no hopelessness rating in the RRSA), limiting direct comparisons across measures.

    “Second, the assessments were not consistent across analyses (e.g., there was no hopelessness rating in the RRSA), which limits direct comparisons across measures.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    The findings support a multifactorial and longitudinal approach to both suicide risk assessment and treatment.

    “The findings support a multifactorial and longitudinal approach to both suicide risk assessment and treatment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Ketamine's therapeutic effects occur within hours, with the strongest effect sizes observed at one day post-administration.

    “Ketamine’s therapeutic effects occur within hours, with the strongest effect sizes observed at one day post-administration (Zarate et al., 2006).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Zarate et al., 2006 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    These results are in line with current models of Suicide Crisis Syndrome and Acute Suicidal Affective Disturbance.

    “These results are in line with current models of the Suicide Crisis Syndrome and Acute Suicidal Affective Disturbance, in which a host of interrelated affective symptoms are believed to co-occur at the time of the crisis (Rogers et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rogers et al., 2017 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Psychological pain has long been described as a critical component of the suicide crisis.

    “Psychological pain, often termed ‘psychache’, has long been described as a critical component of the suicide crisis (Ducasse et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ducasse et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Few effective treatments exist for suicide risk and even fewer target the suicide crisis state.

    “Few effective treatments exist for suicide risk and even fewer target the suicide crisis state (Mann et al., 2021).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Mann et al., 2021 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    A priori power analyses were not performed.

    “A priori power analyses were not performed and, relatedly, our statistical approach emphasized effect sizes rather than p-values.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Previous estimates suggest the time between deciding to act on suicidal thoughts and initiating the attempt is often less than 30 minutes.

    “For example, previous estimates suggest that the time between deciding to act on suicidal thoughts and initiating the attempt is often less than 30 minutes (Deisenhammer et al., 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Deisenhammer et al., 2009 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Traumatic stress has been linked to short and long-term suicide risk and has been shown to decrease in relation to ketamine administration.

    “Traumatic stress has also been linked to short and long-term suicide risk (Rugo-Cook et al., 2021) and has been shown to decrease in relation to ketamine administration (Feder et al., 2014).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Rugo-Cook et al., 2021 source

      Not checked in the free run.

    • cites Feder et al., 2014 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In the three-step theory of suicide, suicidal thoughts are hypothesized to emerge at the intersection of psychological pain and hopelessness.

    “In the three-step theory of suicide, suicidal thoughts are hypothesized to emerge at the intersection of psychological pain and hopelessness (Klonsky and May, 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Klonsky and May, 2015 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Intravenous racemic ketamine has rapid antidepressant and anti-suicidal ideation effects.

    “Intravenous racemic ketamine, a glutamatergic modulator with rapid antidepressant and anti-suicidal ideation effects, has emerged in the past decade as a potential intervention for individuals at risk for suicide (Wilkinson et al., 2018).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Wilkinson et al., 2018 source

      Not checked in the free run.

22 of 22

  • The paper relies on this without support.

    Participants' retrospective ratings on the RRSA accurately reflect the symptoms they experienced just before their suicide attempt.

    “Participants in the HR group were asked to think back to the time before their suicide attempt and rate the symptoms they experienced on a scale from 1–10, including depressive symptoms, anxiety, anger, agitation, joy, physical symptoms, and SI (see Supplement).”
    “The RRSA provided supplemental information on the time of the actual suicide crisis, but it was not validated as a formal timeline follow-back interview, which requires in-depth assessment of the crisis and a control time period for comparison purposes.”

  • The paper relies on this without support.

    Symptom improvements from before to after open-label ketamine administration reflect ketamine's effect rather than placebo, regression to the mean, or other time-related factors.

    “Phase 2 was an open-label trial of intravenous racemic ketamine (0.5 mg/kg, up to five administrations over three weeks) that was offered to the HR group only.”
    “representing a general pattern of symptom improvement in response to ketamine”

  • The paper relies on this without support.

    The high-risk group's clinical state at Phase 1 assessment represents the period just after a suicide crisis.

    “High-Risk (HR; individuals who had attempted or seriously considered suicide in the last two weeks) (n=14)”
    “As hypothesized, SI, depression, and hopelessness were elevated just after a suicide crisis and responded to ketamine, although findings were mixed depending on the assessment used.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Traumatic stress symptoms also improved after ketamine infusion, underscoring the multifactorial nature of acute suicidality and the value of targeting psychological pain alongside traditional mood symptoms.

    “Importantly, traumatic stress symptoms also improved, underscoring the multifactorial nature of acute suicidality and highlighting the value of targeting psychological pain alongside traditional mood symptoms.”

    From Targeting Psychological Pain After a Suicide Attempt: Scoping Review and Intervention Protocol (2026) · cites this paper as [50]

  • These findings suggest potential short-term benefits of ketamine, although long-term sustainability remains uncertain.

    “These findings suggest potential short-term benefits, although long-term sustainability remains uncertain.”

    From Targeting Psychological Pain After a Suicide Attempt: Scoping Review and Intervention Protocol (2026) · cites this paper as [50]

  • In high-risk individuals, suicidal ideation, depression, hopelessness, and psychological pain were heightened during acute suicidal states and decreased after ketamine infusion.

    “Ballard et al. [50] examined clinical indicators of the suicide crisis and the response to ketamine in a cohort of high-risk individuals. Their findings indicated that suicidal ideation, depression, hopelessness, and psychological pain were heightened during acute suicidal states and decreased after ketamine infusion”

    From Targeting Psychological Pain After a Suicide Attempt: Scoping Review and Intervention Protocol (2026) · cites this paper as [50]

  • The reviewed studies show that both psychological pain and suicidal ideation were reduced after intervention.

    “The reviewed studies show that both psychological pain and suicidal ideation were reduced after intervention [38,39,40,43,50,52].”

    From Targeting Psychological Pain After a Suicide Attempt: Scoping Review and Intervention Protocol (2026) · cites this paper as [50]

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Related

Authors
Ballard, E. D., Neely, L., Waldman, L., Greenstein, D., & Zarate, C. A.
Affiliations
National Institutes of Health (US)
Corresponding author
Ballard, Elizabeth D.
ORCID
Venue
Journal of Affective Disorders
Publisher
Elsevier BV
Published
2025-03
Volume
372
Pages
126-133
ISSN
0165-0327 (ISSN-L)
DOI
10.1016/j.jad.2024.11.080
PMC
PMC11729457
OpenAlex
W4404851667
Semantic Scholar
f88bc31c848195f225e0d01adf85fd3c3e880dc3
Cited by
5
References
57
Citations by year
2026: 2 · 2025: 3
FWCI
2.51
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Affective Disorders (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion)
Funders
  • National Institutes of Health (Z99 MH999999)
  • National Institute of Mental Health (ZIAMH002927)
Topics
  • Social Sciences › Psychology › Clinical Psychology › Suicide and Self-Harm Studies
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
Keywords
suicidal crisis, suicidal ideation, depression, hopelessness, ketamine, suicide risk, suicide attempts, psychological suffering, traumatic stress, anxiety, suicide prevention
MeSH terms
Adult, Anxiety, Depression, Female, Humans, Ketamine, Male, Middle Aged, Suicide, Suicide, Attempted, Young Adult, Suicidal Ideation, Hope

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