The Influence of Depressive and Manic Symptoms on Suicidal Ideation in Mixed Mood States

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Ostacher, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6551903/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 14 Jun, 2025 Read the published version in International Journal of Bipolar Disorders → Version 1 posted 12 You are reading this latest preprint version Abstract Background: While bipolar disorder is strongly linked to an increased risk of suicide, recent evidence has challenged the assumption that mixed symptoms play a distinct role in suicidal ideation beyond depressive severity. This study examines how depressive, hypo/manic, and mixed features influence suicidal ideation in individuals with bipolar disorder. Data from 903 participants in the Stanley Foundation Bipolar Network (1995–2002) were analyzed to assess associations between mood states, classified by the Inventory of Depressive Symptomatology–Clinician-Rated (IDS-C) and the Young Mania Rating Scale (YMRS), and suicidal ideation, measured using IDS-C item 18, using generalized estimating equations. Results: Depressive symptoms were strongly associated with suicidal ideation (OR = 21.98, 95% CI: 15.31–31.54). Moderate hypo/manic symptoms also conferred risk (OR = 3.11, 95% CI: 1.51–6.49), and milder hypo/mania showed a weaker but significant association (OR = 1.74, 95% CI: 1.05–2.89). The highest suicidal ideation was observed in individuals with hypo/mania featuring mixed symptoms (OR = 29.43), exceeding that of depression or depression with mixed features (OR = 21.98). However, findings diverged based on modeling approach: in continuous predictor models, SI was driven solely by depressive symptom severity, with no significant association observed for hypo/mania or its interaction with depression. In contrast, when mood states were categorized using clinically meaningful thresholds, hypo/mania with mixed features emerged as a distinct contributor to suicidal ideation risk. Conclusion: These findings underscore the need for integrating both dimensional and categorical approaches to mood state classification in research on suicidality in bipolar disorder. Bipolar Disorder Mania Depression Mixed States Mixed features Mixity Suicidal Ideation Figures Figure 1 BACKGROUND Individuals with bipolar disorder (BD) face a markedly elevated risk of suicide, with estimates suggesting a 20–30-fold increase compared to the general population. 1 The International Society for Bipolar Disorder (ISBD) Task Force on Suicide in BD reported an annual suicide rate of 164 per 100,000 individuals. 2 While mixed symptoms have long been considered a key risk factor for suicidality in BD, recent evidence suggests that their association with suicidal ideation (SI) may primarily reflect the severity of underlying depressive symptoms rather than an independent effect. Mixed states are characterized by the co-occurrence of manic and depressive symptoms and are common among individuals with BD. 3 – 9 Historically, the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-4) defined mixed episodes narrowly, requiring patients to simultaneously meet full diagnostic criteria for both a major depressive episode and a manic episode. 10 This definition was restricted to individuals with bipolar I disorder (BD I) and excluded presentations with subthreshold symptoms. With the publication of the DSM-5 and the International Classification of Diseases, 11th Revision ( ICD-11), the classification of mixed episodes was revised. DSM-5 introduced the "with mixed features" specifier, allowing for the recognition of mixed symptoms even if full criteria for both mood states are not met. 11 Unlike the DSM-4 framework, this specifier accounts for subthreshold symptoms, potentially increasing the identification of individuals with mixed states. ICD-11, in contrast, classifies mixed episodes as a distinct entity, emphasizing the clinical prominence of mixed mood states rather than a strict symptom threshold. 12 There is some evidence indicating that mixed states may heighten suicide risk. For instance, individuals experiencing mania with mixed features report higher levels of suicidal ideation (SI) compared to those with pure mania. 13 – 15 Additionally, prior studies have found that mixed states were associated with a greater risk of SI, attempts, and completed suicide compared to pure hypo/mania. 16,17 However, it remains unclear whether mixed states confer a higher risk of suicide or if this is a higher risk due to more severe depression during a mixed state compared to pure depression 16 , 18 , 19 Recent research has raised key questions on this issue of mixed states and suicidal ideation or attempts. Some studies suggest that mixed states do not independently increase SI or behavior beyond the effects of depressive symptom severity. 20 – 22 For example, Persons and colleagues found that individuals with BD I and a history of mixed states were more likely to exhibit suicidal behavior when depressed compared to those without such a history. However, 71% of this excess risk was attributed to time spent in depressive episodes. 22 Similarly, Fiedorowicz et al. reported that SI and behavior were strongly associated with depressive symptoms, whereas manic or mixed symptoms, including hypo/mania with mixed features, did not show a significant independent relationship. 20 , 21 These findings challenge the notion that mixed symptoms confer unique suicide risk and instead suggest that depressive severity is the primary driver of SI in BD. Whether mixed mood states confer additional risk for SI beyond depression alone remains a subject of ongoing debate. Clarifying the relationship between mixed symptoms and SI is essential for improving risk assessment and informing targeted intervention strategies. This study aims to examine the association between SI and depressive, hypomanic/manic, and mixed mood states over time, while also exploring whether gender or bipolar subtype moderates this relationship. By comparing both categorical and continuous models, we seek to determine whether mixed symptoms independently predict SI or if their effects are accounted for by depressive severity only. METHODS Study Design and Procedures The methods and procedures for the Stanley Foundation Bipolar Treatment Outcome Network (SFBN) study (1995–2002) have been previously described in detail. 23 , 24 All participants provided written informed consent, approved by the respective local Institutional Review Boards (IRBs), prior to study enrollment. Study details are described in brief below. Participants A total of 935 adults were recruited from four U.S. and three European sites for this naturalistic, longitudinal study, which involved the prospective assessment of clinical mood states. All participants were diagnosed using the Structured Clinical Interview from the DSM-4. 10 Patients were evaluated at least monthly, with treatment adjustments made as clinically indicated. Patients met DSM-4 criteria for bipolar I disorder (BD-I), bipolar II disorder (BD-II), bipolar disorder not otherwise specified (BD-NOS), or schizoaffective disorder–bipolar type. Patient characteristics stratified by bipolar disorder subtype are presented in Table 1 . An interrater reliability was maintained between clinical sites (κ values: YMRS, 0.7 and IDS-C, 0.85). 4 Table 1 Distribution of bipolar subtypes, gender, and age among participants with and without suicidal ideation across all visits All subjects (N = 903 [100%]) Subjects with no visits with suicidal ideation (N = 352 [39.0%]) Subjects with one or more visits with suicidal ideation (N = 551 [61.0%]) Bipolar Type BDI BDII BD NOS SD – Bipolar type 677 (75.0%) 186 (20.6%) 18 (2.0%) 22 (2.4%) 260 (73.9%) 73 (20.7%) 10 (3.1%) 9 (2.8%) 417 (75.7%) 113 (20.5%) 8 (1.5%) 13 (2.4%) Gender Female Male 505 (55.9%) 398 (44.1%) 208 (59.1%) 145 (41.2%) 297 (53.9%) 253 (45.9%) Age 40.98 ± 11.53 40.63 ± 11.87 41.41 ± 11.32 Suicidal Ideation is here defined as a score ≥ 1 at the IDS-C - item 18; BDI: Bipolar Disorder, type I; BDII: Bipolar Disorder, type II; BD NOS: Bipolar Disorder, Not Otherwise Specified; SD – Bipolar type: Schizoaffective Disorder – Bipolar type. Individuals who participated in defined, open-label, or double-blind clinical trials were excluded from the cohort. 23 , 25 The current analyses focuses on patients who completed at least one visit with concurrent assessments of manic and depressive symptoms using the Young Mania Rating Scale (YMRS) 26 and the Inventory of Depressive Symptomatology–Clinician-Rated (IDS-C). 27 , 28 Mood State Assessment Mood states were classified using scores from the YMRS and the IDS-C, both of which are clinician-administered and have demonstrated strong reliability and validity. 26 – 28 These measures were completed during study visits, with symptoms assessed on the day of visit and for the preceding 3 and 7 days for YMRS and IDS-C, respectively. To identify mood states, we applied symptom-based cut-offs derived from prior work which used YMRS and IDS-C thresholds in a naturalistic study of SFBN data (see Table 2 ). 4 , 29 Depressive symptoms were defined as an IDS-C R score of 15 or higher, indicating at least mild depression. Depression with mixed features was defined as the co-occurrence of depressive symptoms (IDS-C R ≥ 15) alongside mild hypo/manic symptoms, as indicated by YMRS scores between 3 and 11. Hypo/mania with mixed features was defined as the presence of depressive symptoms (IDS-C R ≥ 15) with moderate hypo/manic symptoms, characterized by YMRS scores of 12 or greater. Table 2 Definitions of mood states by symptom scales IDS-C YMRS Symptom category Depressive symptoms ≥ 15 - Mild hypomanic symptoms - > 2 and 2 and < 12 Pure hypo/mania < 15 ≥ 12 Hypo/mania with mixed features ≥ 15 ≥ 12 Euthymia < 15 < 12 IDS-C: Inventory of Depressive Symptomatology-Clinician-Rated Version (assessed day of and prior 7 days); YMRS: Young Mania Rating Scale (assessed day of and prior 3 days). For depression symptom categorization, we used the full IDS-C score; however, for statistical analyses, we utilized a modified version of the IDS-C (IDS-C R) in which item 18 (suicidal ideation) was removed to avoid circularity, ensuring that the predictor (depression severity) does not include variance from the outcome variable. The IDS-C and IDS-C R scores were highly correlated (r = 0.99, p < 0.0001). The YMRS and IDS-C share several items that assess overlapping symptoms, including sleep disturbances, irritability, and psychomotor agitation. To determine whether the observed associations were driven by these overlapping symptoms rather than distinct mood state effects, we conducted a sensitivity analysis in which these items were removed. Specifically, we excluded items 4 (Sleep) and 5 (Irritability) from the YMRS, and items 1–3 (Insomnia), 6 (Irritability), and 24 (Psychomotor agitation) from the IDS-C in subsequent analyses. This allowed us to isolate the relationship of interest from potential artifact. Suicidal Ideation Assessment SI was assessed using item 18 of the IDS-C, which evaluates the presence and severity of suicidal thoughts. Item 18 is scored as follows: 0 indicates no thoughts of suicide or death; 1 indicates a sense of emptiness or the belief that life is not worth living; 2 indicates suicidal thoughts occurring several times per week for several minutes; and 3 indicates suicidal thoughts occurring daily, with or without a plan or past suicide attempt. For our analyses, we dichotomized suicidal ideation to IDS-C item 18 = 0 and IDS-C item 18 ≥ 1. Statistical Analysis Statistical analyses were conducted using SPSS version 28 (IBM Corp., Armonk, NY, USA). Generalized estimating equations (GEE) were used to examine the association between mood symptoms—specifically depressive, hypo/manic, and their co-occurrence—and SI assessing both the strength and direction of these relationships. The primary analyses utilized categorical models, with mood symptoms categorized based on predefined thresholds that capture distinct mood presentations. The GEE models were specified using binary logistic regression with a robust covariance estimator and an independent working correlation matrix to account for repeated observations within individuals. The dependent variable in all models was the IDS-C item 18 score, which reflects the presence and severity of SI. The primary predictor variables were the categorical indicators of depressive, moderate, and mild hypo/manic symptoms. An interaction term was included to capture the potential synergistic effect of co-occurring depressive and hypo/manic symptoms. The interpretation of the GEE model coefficients followed conventional guidelines for binary logistic regression. A positive β-value indicates an increased likelihood of suicidal ideation as symptom severity increases, whereas a negative β-value suggests a decreased likelihood. Odds ratios (OR) were derived from the β-coefficients using the standard transformation OR = e (β) providing a measure of odds for SI based on mood symptom severity. A statistically significant interaction term indicates that the relationship between mood symptoms SI differs from the additive contributions of depressive and hypo/manic symptoms. Age and study week were included as linear covariates in all models to control for potential time- and age-related effects. Additional covariates included gender, both as a main effect and in interaction with mood symptoms, and bipolar subtype. To assess the combined effect of depressive and hypo/manic symptoms, we calculated combined ORs by exponentiating the sum of the relevant β-coefficients (e.g., OR combined = exp (β_depression + β_hypomania + β_interaction) ). This allowed us to quantify how co-occurring depressive and hypo/manic symptoms modify SI beyond their individual contributions. For combined OR calculations, only statistically significant β-values were included to ensure that the resulting estimate reflected meaningful associations. If a β-coefficient was not significant (p > 0.05), its corresponding OR was not included in the combined calculation, as its contribution to the overall effect was uncertain. Similarly, if the revised scales (e.g., excluding overlapping items) altered statistical significance, the corresponding OR was excluded, ensuring that the final combined OR was based only on robust, validated effects. In addition to the primary categorical models, secondary analyses were conducted using continuous YMRS and IDS-C R scores as predictor variables to replicate methodology from prior research. 20 – 22 , 30 The continuous models followed the same GEE specifications as the categorical models; however, instead of dichotomizing symptoms, mood symptoms were modeled as continuous variables to capture variability in symptom severity without the use of predefined clinical categories. The interaction between continuous depressive and hypo/manic symptom scores was included to identify potential nonlinear relationships and mixed symptom presentations. RESULTS Patients’ demographics and duration of follow-up Out of the original cohort of 935 adults, 903 patients had completed at least one visit with both YMRS and IDS-C assessments (mean age = 40.98 ± 11.53, 55.9% female; Table 1 ). Across 14,213 visits, patients had a median of 12 visits (mean = 16.6 ± 14.2) over a median follow-up of 15 months (mean = 22.7 ± 22.9 months). Suicidal ideation scores ≥ 1 were recorded in 17.2% (2,449 visits), scores ≥ 2 in 6.9% (977 visits), and scores = 3 in 1.1% (160 visits). Visits and mood states Among 14,213 visits, the majority (N = 8,281 [58.3%]) occurred during a euthymic phase (Fig. 1 ). Depressive symptoms (IDS-C score ≥ 15) were present in 4,907 visits (34.5%). Of these, 2,781 (19.6%) were characterized as pure depression and 2,126 (14.9%) as depression with mixed features (> 2 YMRS < 12 and IDS-C ≥ 15). Furthermore, 1,025 visits (7.2%) reported hypo/manic symptoms, of which 440 visits (3.1%) reached scores for pure hypo/mania (YMRS ≥ 12), while 585 visits (4.1%) were characterized as hypo/mania with mixed features (IDSC-C ≥ 15 and YMRS ≥ 12). Visits and Suicidal Ideation An IDS-C item 18 score of ≥ 1 was observed in 2,449 visits (17.2%), with 977 visits (6.9%) showing a score of ≥ 2 and 160 visits (1.1%) showing a score of 3. The distribution of SI across different mood states is shown in Fig. 1 . Relationship between suicidal ideation and categorical indicators of mood states Results from the GEE models using categorical variables for depressive symptoms, hypo/manic symptoms, and their interaction are summarized in Table 3 . Depressive symptoms were strongly related to SI (β = 3.09, 95% CI: 2.73–3.45). Moderate hypo/manic symptoms had a smaller but significant association with SI (β = 1.135, 95% CI 0.41–1.87) and mild hypo/mania demonstrated a modest contribution (β = 0.552, 95% CI: 0.05–1.06). There was a significant interaction effect between moderate hypo/mania and depression (β = -0.843, 95% CI: -1.59 – -0.10) Table 3 Associations of depressive and hypomanic symptoms on suicidal ideation Suicidal ideation ≥ 1 β 95% CI P value a Depressive symptoms 3.09 2.73–3.45 0.000 Moderate hypo/manic symptoms 1.135 0.41–1.87 0.002 Mild hypo/manic symptoms 0.552 0.05–1.06 0.032 Interaction between depressive and mild hypo/mania symptoms -0.43 -0.95–0.91 0.105 Interaction between depressive and moderate hypo/mania symptoms -0.843 -1.59 – -0.1 0.026 CI: Confidence Intervals See eTable 2 for full details, including additional predictors and reference categories. a GEE models used Bonferroni correction to adjust for multiple comparisons When using the revised YMRS scale with overlapping items removed, the findings for hypo/mania with mixed features remained consistent, with significant contributions from depression, hypo/mania, and their interaction. However, the previously observed association between mild hypo/mania and suicidal ideation was no longer significant (β = 0.308, 95% CI: -0.14 to 0.76) and was therefore excluded from the combined odds for depression with mixed features (see eTable 1 in the Supplement). Table 4 presents the odds of SI for each mood category relative to euthymia, calculated using beta coefficients from the GEE models. Depression was associated with significantly higher odds of SI (OR = 21.98, 95% CI: 15.31–31.54), while moderate and mild hypo/manic symptoms were associated with smaller but significant odds (OR = 3.11, 95% CI: 1.51–6.49; OR = 1.74, 95% CI: 1.05–2.89). Table 4 Effects of pure and mixed mood states on suicidal ideation relative to euthymia Symptom Category Odds Ratio 95% CI Depression 21.98 15.31–31.54 Moderate hypo/mania 3.11 1.51–6.49 Mild hypo/mania 1.74 1.05–2.89 Mixed Mood State Depression with mixed features 21.98 Hypo/mania with mixed features 29.43 CI: Confidence Intervals For mixed mood states, depression with mixed features had the same odds of SI as pure depression (OR = 21.98), as its calculation included only the depressive symptom component, with mild hypomania and its interaction with depression excluded. Hypo/mania with mixed features had the highest odds of SI (OR = 29.43), calculated from the individual effects of mania, depression, and their interaction term. Confidence intervals for the mixed mood states were not reported due to variance instability. Relationship between suicidal ideation and other predictors Gender significantly moderated the relationship between mood state and SI, with a protective effect for males in pure hypo/mania (β = -1.451, 95% CI: -2.58 – -0.32) while age and bipolar subtype did not demonstrate any significant relationship (eTable 2 in supplement). Relationship between suicidal ideation and continuous IDS-C R and YMRS scores A secondary GEE model was built using continuous variables as predictor variables. Results are shown in eTable 3 in the Supplement. In the continuous models, depressive symptom severity was significantly associated with increased suicidal ideation (β = 0.133, p < 0.001), while hypo/manic symptoms (β = 0.022, p = 0.115) and their interaction (β = -0.001, p = 0.252) were not significant predictors. DISCUSSION In this large well-characterized sample of patients with bipolar disorder 60.7% of participants had at least one visit where broadly defined SI was present (IDS-C item 18 score ≥ 1). When mood states were categorized by degree of severity, hypo/mania with mixed features emerged as a distinct risk factor for SI, suggesting that threshold effects captured by categorical models are not captured in previous continuous analyses. Using categorical mood states as predictors, hypo/mania with mixed features had the highest observed odds of SI (OR = 29.43), whereas depression with mixed features had the same odds as pure depression (OR = 21.98). The increased risk in hypo/mania with mixed features was driven by significant contributions from mania, depression, and their interaction term. In contrast, for depression with mixed features, the odds of SI were based solely on the depressive symptom contribution, as mild hypo/mania and its interaction with depression were not statistically significant or lacked robustness in sensitivity analyses, leading to their exclusion from the final calculation. In order to categorize and differentiate between mixed states, as used in earlier studies with this population, a lower YMRS cutoff (3–11) was used to define depression with mixed features, capturing concurrent hypo/manic symptoms, while a higher YMRS threshold (12 or greater) identified hypo/mania with mixed features. In the primary analyses using the full scales, both moderate and mild hypo/mania were significantly associated with an increased likelihood of SI, but in the sensitivity analyses where overlapping items between the YMRS and IDS-C were removed, the association between mild hypo/mania and SI was no longer significant, suggesting that SI in this context is driven by depressive symptoms alone. This pattern indicates that overlapping symptoms, such as irritability and sleep disturbances, may have contributed to the observed relationship between mild hypo/mania and SI when YMRS scores fell between 3 and 11. To replicate prior studies, we tested whether the association between mixed mood states and SI was primarily driven by the presence of depressive symptoms alone, or by the combination of depressive and hypomanic symptoms. Using continuous mood symptom scores, we found that depressive symptoms accounted for the observed association with SI, while hypomanic symptoms and their interaction with depression did not significantly contribute. These findings align with previous research indicating that SI in mixed states may largely reflect the influence of depressive symptoms. A summary of earlier work in this area includes three different populations of patients with bipolar disorder. Firstly, data from the National Network of Depression Centers (NNDC) Mood Outcomes Program showed that depressive symptoms assessed with the Patient Health Questionnaire (PHQ-8) were the strongest predictor of SI, while manic symptoms measured with the Altman Self-Rating Mania Scale (ASRM) were not associated with increased suicide risk in bipolar disorder and were inversely associated with SI in major depression. 20 An additional analysis of NNDC data found that neither manic nor anxiety symptoms independently contributed to SI. 30 Similarly, in an analysis of the NNDC Clinical Care Registry found that depressive symptoms assessed with the PHQ-9 strongly predicted SI and behavior, while manic symptoms and mixed states—whether modeled continuously or categorically—were not significantly associated with suicide risk. 21 These findings suggest that across different assessment methods, the relationship between depressive symptoms and SI remains consistent when mood symptoms are treated as continuous variables. Lastly, prospective data from the NIMH Collaborative Depression Study followed 429 individuals with bipolar disorder over an average of 18 years and similarly supports this pattern. Using the LIFE Psychiatric Status Rating (PSR) scale to characterize mood states, the study identified depression as a high-risk state for suicidal behavior, while mixed states did not confer additional risk beyond the depressive component. 22 A limitation of the NIMH study is that while prospective mood symptoms may only have been queried every 6 or 12 months making complete mixed mood descriptions limited. This body of work suggests that threshold effects captured by categorical models are not adequately reflected in continuous analyses. The categorical models in our study revealed an increased odds of SI associated with moderate hypo/mania with mixed features, which diverges from findings in studies using continuous analyses. Much of the prior research primarily relied on self-reported mood assessments such as PHQ-8, PHQ-9, or ASRM. In contrast, our study used monthly clinician-rated IDS-C and YMRS scores and predefined categorical thresholds for mood states. It should be noted the study of the NNDC registry analysis used the Columbia-Suicide Severity Rating Scale (C-SSRS) to assess SI and behavior, while our study relied on item 18 of the IDS-C. It is also important to note that our definition of mixed features differs from those used in the NNDC and NIMH studies due to differences in measurement tools and threshold scores required to define mood states. These methodological variations may contribute to the observed discrepancies in categorical findings. The divergence between the categorical and continuous models raises important considerations regarding how mixed symptoms are best characterized in relation to SI risk. One possible explanation is that categorical models, which define mood states using clinical thresholds, may better capture the episodic nature of bipolar disorder and its relevance to SI, whereas continuous measures assume a linear relationship that may not fully account for dynamic symptom interactions. The use of categorical models may allow for the identification of clinically meaningful subgroups at increased risk, while continuous models may fail to capture nonlinear relationships between symptom severity and SI risk. These differing analytic approaches highlight the complexity of assessing mood states in bipolar disorder and suggest that future studies should explore the potential advantages and limitations of each method. Prior research also found that women are more likely than men to meet DSM-5 criteria for mixed hypomania or mania. 29 Women also experience depressive symptoms more frequently during hypomania, whereas men’s depressive symptoms are primarily characterized by irritability and agitation. 4 While gender did not significantly impact suicidal ideation in mixed states in our study, it did interact with pure hypomania, reducing SI risk in men. This is consistent with prior research indicating that manic symptoms increase SI risk in women but not in men, as observed in NNDC findings. 20 , 21 The study has significant limitations which limit the interpretability of the results. The presence of SI was assessed only through item 18 of the IDS-C, therefore it may not be generalized to other definitions of suicide. As such, the conclusions drawn from this analysis are more relevant to the odds of SI than to the odds of suicide attempt or completed suicide. The GEE models used in our analyses assume independence of observations across different study sites, which may not fully capture site-specific variations and could impact the robustness of our findings. The use of mood symptom rating scales involved empirical cut-offs for symptoms, and it was not possible to differentiate whether symptoms present at visits represented new or persistent mood symptoms, thus limiting our interpretation of the longitudinal trajectories and the casual effect of mixed symptoms. Finally, although the elevated SI risk observed in hypo/mania with mixed features compared to depression with mixed features appears clinically meaningful, confidence intervals were not reported for mixed mood states due to variance instability. As a result, formal statistical comparisons with pure mood states (e.g., depression) were not possible. Despite this, the present study has several strengths including a large sample of well-characterized patients with BD and a prospective design with standardized rating scales for the clinical assessments. The broad inclusion criteria enhanced the generalizability of our findings. CONCLUSIONS This study highlights individuals with hypo/mania with mixed features demonstrate an increased odd of SI, reflecting contributions from depression, hypo/mania and their interaction. These findings lay the groundwork for future research to better understand the relationship between mixed mood states and suicidality. Abbreviations Altman Self-Rating Mania Scale (ASRM), Bipolar Disorder (BD), Bipolar Disorder I (BD-I), Bipolar Disorder II (BD-II), Bipolar Disorder Not Otherwise Specified (BD-NOS), Columbia-Suicide Severity Rating Scale (C-SSRS), Confidence Interval (CI), Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-4), Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), Generalized Estimating Equations (GEE), International Classification of Diseases, Eleventh Revision (ICD-11), International Society for Bipolar Disorder (ISBD), Inventory of Depressive Symptomatology–Clinician-Rated (IDS-C), Inventory of Depressive Symptomatology–Clinician-Rated, Revised (IDS-C R), Institutional Review Board (IRB), National Institute of Mental Health (NIMH), National Network of Depression Centers (NNDC), Odds Ratio (OR), Patient Health Questionnaire-8 (PHQ-8), Patient Health Questionnaire-9 (PHQ-9), Psychiatric Status Rating (PSR), Structured Clinical Interview for DSM Disorders (SCID), Stanley Foundation Bipolar Network (SFBN), Suicidal Ideation (SI), Statistical Package for the Social Sciences (SPSS), Young Mania Rating Scale (YMRS) Declarations Ethics approval and consent to participate All participants provided written informed consent prior to enrollment in the Stanley Foundation Bipolar Treatment Outcome Network study, with study procedures approved by the Institutional Review Boards (IRBs) at each participating site. Consent for publication Not applicable. Availability of data and materials The datasets generated and/or analyzed during the current study are not publicly available due to privacy and confidentiality agreements with the original study participants but may be available from the corresponding author upon reasonable request and with appropriate Institutional Review Board approval. Competing interests T.S. reported research funding from Compass Pathways, the National Institute on Drug Abuse (NIDA), the National Institutes of Health (NIH), the VA Cooperative Studies Program, and the Steven & Alexandra Cohen Foundation. She has served as a consultant or advisory board member for Zylorion, MindMed, Intracellular Therapies, Sunovion Pharmaceuticals, Merck Research Laboratories, and Impel NeuroPharma Inc., and has financial interests with PsiloTec (stock options, terminated 8/2024). She also has stock ownership in Zylorion. Continuing medical education honoraria were received from Medscape (WebMD). She receives royalties from American Psychiatric Association Publishing, Hogrefe Publishing, Jones and Bartlett, and Wolters Kluwer Health (UpToDate). M.J.O. is currently serving as the Neurocrine Biosciences IDMC chair and has received research funding from Otsuka Pharmaceutical Development & Commercialization, Inc. B.D.O. has received lecture honoraria and grants from Angelini, Lundbeck, Janssen, Pfizer, Otsuka, Neuraxpharm, and Livanova. S.L.M. is employed by the University of Cincinnati College of Medicine, the University of Cincinnati Physicians, and the Lindner Center of HOPE. She serves as a consultant or advisory board member for Axsome, Idorsia, Levo, Novo Nordisk, and Otsuka, and has been a principal investigator or co-investigator on studies sponsored by Axsome, the Marriott Foundation, Novo Nordisk, and Otsuka. Dr. McElroy is also the inventor of United States Patent No. 6,323,236 B2 and receives royalties from Johnson & Johnson Pharmaceutical Research & Development, L.L.C. H.G. received honoraria for lectures, scientific expertise, or advisory board participation from Janssen-Cilag, Recordati, and Rovi. M.A.F. received grant support from Assurex Health, the Baszucki Group, Breakthrough Discoveries for Thriving with Bipolar Disorder (BD2), and the Mayo Foundation, serves as a consultant for Carnot Laboratories and the American Physician Institute, and has financial interests in Chymia LLC. R.C., M.M., C.M.K., R.W.K., P.E.K., J.L., W.A.N., and R.M.P. report no financial relationships with commercial interests. Funding The original Stanley Foundation Bipolar Network study was funded by the Stanley Medical Research Institute, Bethesda, Md. No additional external funding was used for the present secondary analysis. Authors' contributions M.M., R.C., and C.M.K. contributed equally to the conceptualization, data analysis, and drafting of the manuscript. M.J.O., B.D.O., and J.L. assisted with statistical analysis, interpretation of results, and critical revision of the manuscript. M.A.F., R.W.K., S.L.M., W.A.N., P.E.K., R.M.P., and H.G. contributed to the acquisition of clinical data and provided critical revisions. T.S. supervised the study design, data analysis, and manuscript preparation. T.S. and H.G. served as principal investigators and guarantors of the overall content. All authors read and approved the final manuscript. Acknowledgements In kind remembrance of our close colleagues who have passed, Lori Altshuler and Gabrielle S. Leverich. We are deeply grateful to Federico Ambrogi for his invaluable support in advancing the research approach. We also acknowledge the generous support of the Stanley Medical Research Institute for providing original funding between 1995 and 2002 for the Stanley Foundation Bipolar Network. References Pompili M, Gonda X, Serafini G, et al. Epidemiology of suicide in bipolar disorders: a systematic review of the literature. Bipolar Disord. 2013;15(5):457–90. 10.1111/bdi.12087 . Schaffer A, Isometsä ET, Tondo L, et al. Epidemiology, neurobiology and pharmacological interventions related to suicide deaths and suicide attempts in bipolar disorder: Part I of a report of the International Society for Bipolar Disorders Task Force on Suicide in Bipolar Disorder. Aust N Z J Psychiatry. 2015;49(9):785–802. 10.1177/0004867415594427 . Dilsaver SC, Benazzi F, Akiskal HS. Mixed states: the most common outpatient presentation of bipolar depressed adolescents? Psychopathology. 2005;38(5):268–72. 10.1159/000088443 . Suppes T, Mintz J, McElroy SL, et al. Mixed hypomania in 908 patients with bipolar disorder evaluated prospectively in the Stanley Foundation Bipolar Treatment Network: a sex-specific phenomenon. Arch Gen Psychiatry. 2005;62(10):1089–96. 10.1001/archpsyc.62.10.1089 . Swann AC, Steinberg JL, Lijffijt M, Moeller GF. Continuum of depressive and manic mixed states in patients with bipolar disorder: quantitative measurement and clinical features. World Psychiatry. 2009;8(3):166–72. 10.1002/j.2051-5545.2009.tb00245.x . Goldberg JF, McElroy SL. Bipolar mixed episodes: characteristics and comorbidities. J Clin Psychiatry. 2007;68(10):e25. 10.4088/jcp.1007e25 . Born C, Grunze H, Post RM, et al. Mania and bipolar depression: complementing not opposing poles-a post-hoc analysis of mixed features in manic and hypomanic episodes. Int J Bipolar Disord. 2021;9(1):36. 10.1186/s40345-021-00241-5 . González-Pinto A, Barbeito S, Alonso M, et al. Poor long-term prognosis in mixed bipolar patients: 10-year outcomes in the Vitoria prospective naturalistic study in Spain. J Clin Psychiatry. 2011;72(5):671–6. 10.4088/JCP.09m05483yel . Hantouche EG, Akiskal HS, Azorin JM, Châtenet-Duchêne L, Lancrenon S. Clinical and psychometric characterization of depression in mixed mania: a report from the French National Cohort of 1090 manic patients. J Affect Disord. 2006;96(3):225–32. 10.1016/j.jad.2005.01.005 . American Psychiatric Association. Diagnostic and statistical manual of mental disorders (4th ed., text rev.) . American Psychiatric Publishing; 2000. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. American Psychiatric Publishing; 2013. World Health Organization. Clinical descriptions and diagnostic requirements for ICD-11 mental, behavioural and neurodevelopmental disorders. World Health Organization. Accessed Mar 14, 2025. Goldberg JF, Garno JL, Leon AC, Kocsis JH, Portera L. Association of recurrent suicidal ideation with nonremission from acute mixed mania. Am J Psychiatry. 1998;155(12):1753–5. 10.1176/ajp.155.12.1753 . Reinares M, Bonnín Cdel M, Hidalgo-Mazzei D, et al. Making sense of DSM-5 mania with depressive features. Aust N Z J Psychiatry. 2015;49(6):540–9. 10.1177/0004867415585583 . Tondo L, Vazquez GH, Baldessarini RJ. Suicidal Behavior Associated with Mixed Features in Major Mood Disorders. Psychiatr Clin North Am. 2020;43(1):83–93. 10.1016/j.psc.2019.10.008 . Lage RR, Santana CMT, Nardi AE, Cheniaux E. Mixed states and suicidal behavior: a systematic review. Trends Psychiatry Psychother. 2019;41(2):191–200. 10.1590/2237-6089-2018-0042 . Bartoli F, Crocamo C, Carrà G. Clinical correlates of DSM-5 mixed features in bipolar disorder: A meta-analysis. J Affect Disord. 2020;276:234–40. 10.1016/j.jad.2020.07.035 . Swann AC, Lafer B, Perugi G, et al. Bipolar mixed states: an international society for bipolar disorders task force report of symptom structure, course of illness, and diagnosis. Am J Psychiatry. 2013;170(1):31–42. 10.1176/appi.ajp.2012.12030301 . Seo HJ, Wang HR, Jun TY, Woo YS, Bahk WM. Factors related to suicidal behavior in patients with bipolar disorder: the effect of mixed features on suicidality. Gen Hosp Psychiatry. 2016;39:91–6. 10.1016/j.genhosppsych.2015.12.005 . Fiedorowicz JG, Persons JE, Assari S, et al. Moderators of the association between depressive, manic, and mixed mood symptoms and suicidal ideation and behavior: An analysis of the National Network of Depression Centers Mood Outcomes Program. J Affect Disord. 2021;281:623–30. 10.1016/j.jad.2020.11.101 . Fiedorowicz JG, Persons JE, Assari S, et al. Depressive symptoms carry an increased risk for suicidal ideation and behavior in bipolar disorder without any additional contribution of mixed symptoms. J Affect Disord. 2019;246:775–82. 10.1016/j.jad.2018.12.057 . Persons JE, Coryell WH, Solomon DA, Keller MB, Endicott J, Fiedorowicz JG. Mixed state and suicide: Is the effect of mixed state on suicidal behavior more than the sum of its parts? Bipolar Disord. 2018;20(1):35–41. 10.1111/bdi.12538 . Leverich GS, Nolen WA, Rush AJ, et al. The Stanley Foundation Bipolar Treatment Outcome Network. I. Longitudinal methodology. J Affect Disord. 2001;67(1–3):33–44. 10.1016/s0165-0327(01)00430-x . Suppes T, Leverich GS, Keck PE, et al. The Stanley Foundation Bipolar Treatment Outcome Network. II. Demographics and illness characteristics of the first 261 patients. J Affect Disord. 2001;67(1–3):45–59. 10.1016/s0165-0327(01)00432-3 . Post RM, Leverich GS, Altshuler LL, et al. An overview of recent findings of the Stanley Foundation Bipolar Network (Part I). Bipolar Disord. 2003;5(5):310–9. 10.1034/j.1399-5618.2003.00051.x . Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry. 1978;133:429–35. 10.1192/bjp.133.5.429 . Rush AJ, Gullion CM, Basco MR, Jarrett RB, Trivedi MH. The Inventory of Depressive Symptomatology (IDS): psychometric properties. Psychol Med. 1996;26(3):477–86. 10.1017/s0033291700035558 . Trivedi MH, Rush AJ, Ibrahim HM, et al. The Inventory of Depressive Symptomatology, Clinician Rating (IDS-C) and Self-Report (IDS-SR), and the Quick Inventory of Depressive Symptomatology, Clinician Rating (QIDS-C) and Self-Report (QIDS-SR) in public sector patients with mood disorders: a psychometric evaluation. Psychol Med. 2004;34(1):73–82. 10.1017/s0033291703001107 . Miller S, Suppes T, Mintz J, et al. Mixed Depression in Bipolar Disorder: Prevalence Rate and Clinical Correlates During Naturalistic Follow-Up in the Stanley Bipolar Network. Am J Psychiatry. 2016;173(10):1015–23. 10.1176/appi.ajp.2016.15091119 . Persons JE, Lodder P, Coryell WH, Nurnberger JI, Fiedorowicz JG. Symptoms of mania and anxiety do not contribute to suicidal ideation or behavior in the presence of bipolar depression. Psychiatry Res. 2022;307:114296. 10.1016/j.psychres.2021.114296 . Ostacher MJ, Nierenberg AA, Rabideau D, et al. A clinical measure of suicidal ideation, suicidal behavior, and associated symptoms in bipolar disorder: Psychometric properties of the Concise Health Risk Tracking Self-Report (CHRT-SR). J Psychiatr Res. 2015;71:126–33. 10.1016/j.jpsychires.2015.10.004 . Additional Declarations Competing interest reported. T.S. reported research funding from Compass Pathways, the National Institute on Drug Abuse (NIDA), the National Institutes of Health (NIH), the VA Cooperative Studies Program, and the Steven & Alexandra Cohen Foundation. She has served as a consultant or advisory board member for Zylorion, MindMed, Intracellular Therapies, Sunovion Pharmaceuticals, Merck Research Laboratories, and Impel NeuroPharma Inc., and has financial interests with PsiloTec (stock options, terminated 8/2024). She also has stock ownership in Zylorion. Continuing medical education honoraria were received from Medscape (WebMD). She receives royalties from American Psychiatric Association Publishing, Hogrefe Publishing, Jones and Bartlett, and Wolters Kluwer Health (UpToDate). M.J.O. is currently serving as the Neurocrine Biosciences IDMC chair and has received research funding from Otsuka Pharmaceutical Development & Commercialization, Inc. B.D.O. has received lecture honoraria and grants from Angelini, Lundbeck, Janssen, Pfizer, Otsuka, Neuraxpharm, and Livanova. S.L.M. is employed by the University of Cincinnati College of Medicine, the University of Cincinnati Physicians, and the Lindner Center of HOPE. She serves as a consultant or advisory board member for Axsome, Idorsia, Levo, Novo Nordisk, and Otsuka, and has been a principal investigator or co-investigator on studies sponsored by Axsome, the Marriott Foundation, Novo Nordisk, and Otsuka. Dr. McElroy is also the inventor of United States Patent No. 6,323,236 B2 and receives royalties from Johnson & Johnson Pharmaceutical Research & Development, L.L.C. H.G. received honoraria for lectures, scientific expertise, or advisory board participation from Janssen-Cilag, Recordati, and Rovi. M.A.F. received grant support from Assurex Health, the Baszucki Group, Breakthrough Discoveries for Thriving with Bipolar Disorder (BD2), and the Mayo Foundation, serves as a consultant for Carnot Laboratories and the American Physician Institute, and has financial interests in Chymia LLC. R.C., M.M., C.M.K., R.W.K., P.E.K., J.L., W.A.N., and R.M.P. report no financial relationships with commercial interests. Supplementary Files IJBDMixitySUPPLEMENTAL.docx Cite Share Download PDF Status: Published Journal Publication published 14 Jun, 2025 Read the published version in International Journal of Bipolar Disorders → Version 1 posted Editorial decision: Revision requested 21 May, 2025 Reviews received at journal 13 May, 2025 Reviews received at journal 12 May, 2025 Reviewers agreed at journal 04 May, 2025 Reviewers agreed at journal 04 May, 2025 Reviewers agreed at journal 03 May, 2025 Reviewers agreed at journal 02 May, 2025 Reviewers agreed at journal 02 May, 2025 Reviewers invited by journal 02 May, 2025 Editor assigned by journal 30 Apr, 2025 Submission checks completed at journal 30 Apr, 2025 First submitted to journal 28 Apr, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6551903","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":451960022,"identity":"901c15d9-f567-45f0-a710-bf317dfa4c1a","order_by":0,"name":"Monica Macellaro","email":"","orcid":"","institution":"University of Milan","correspondingAuthor":false,"prefix":"","firstName":"Monica","middleName":"","lastName":"Macellaro","suffix":""},{"id":451960023,"identity":"5742822b-ac1c-4d2b-89bd-fd3ef3098c15","order_by":1,"name":"Rita Cafaro","email":"","orcid":"","institution":"University of Milan","correspondingAuthor":false,"prefix":"","firstName":"Rita","middleName":"","lastName":"Cafaro","suffix":""},{"id":451960025,"identity":"2c9efb34-a586-419b-88bc-87c85cdd9320","order_by":2,"name":"Carlton Max Kelly","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA60lEQVRIiWNgGAWjYFACNsYHEhU1cmB2BQMDYwMDgwEhLcwGFmeOGTOwAdlniNTCJlHZwpzYQLQW/mnHEiRuNrClz5/f/OzBgYp7sg3szdsk8GmRuJ12wHDmDpncDcfYzA0OnCk2buA5VoZXi4F0ekOy5Bm23A1sDGbSH9sSEhskcswIajn8t405Xb6N/ZvEQZAW+TeEtKQdbJBsY05gOMZjBtEiwYNfC9AvyQwSZ44ZbjiWUyZx4EyCcRtPWrEFPi38s9PMfwCjUl6++fg2iQMVCbL97Ic33sCnBROwkaZ8FIyCUTAKRgE2AAAVP0vghygqygAAAABJRU5ErkJggg==","orcid":"","institution":"Stanford University School of Medicine, Stanford University","correspondingAuthor":true,"prefix":"","firstName":"Carlton","middleName":"Max","lastName":"Kelly","suffix":""},{"id":451960026,"identity":"6070170e-865f-47fd-9fa4-601cb335b83f","order_by":3,"name":"Michael J. 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Nolen","email":"","orcid":"","institution":"University of Groningen","correspondingAuthor":false,"prefix":"","firstName":"Willem","middleName":"A.","lastName":"Nolen","suffix":""},{"id":451960042,"identity":"7daa1461-4c6c-44ea-b29f-679edc3b28ae","order_by":10,"name":"Paul E. Keck","email":"","orcid":"","institution":"Lindner Center of HOPE, University of Cincinnati","correspondingAuthor":false,"prefix":"","firstName":"Paul","middleName":"E.","lastName":"Keck","suffix":""},{"id":451960047,"identity":"91d11c1d-db3a-4210-9f39-8c8a7393ffd4","order_by":11,"name":"Robert M. Post","email":"","orcid":"","institution":"Clinical Professor of Psychiatry, George Washington School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Robert","middleName":"M.","lastName":"Post","suffix":""},{"id":451960049,"identity":"91ac6416-484b-4552-ae6d-668c7b3d5e5b","order_by":12,"name":"Heinz Grunze","email":"","orcid":"","institution":"Psychiatrie Schwäbisch Hall \u0026, Paracelsus Medical University","correspondingAuthor":false,"prefix":"","firstName":"Heinz","middleName":"","lastName":"Grunze","suffix":""},{"id":451960051,"identity":"bd51a496-3379-460c-b00b-3bdfecb909c7","order_by":13,"name":"Trisha Suppes","email":"","orcid":"","institution":"Stanford University School of Medicine, Stanford University","correspondingAuthor":false,"prefix":"","firstName":"Trisha","middleName":"","lastName":"Suppes","suffix":""}],"badges":[],"createdAt":"2025-04-29 03:08:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6551903/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6551903/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s40345-025-00390-x","type":"published","date":"2025-06-14T15:57:03+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":82350490,"identity":"02bac2e1-860d-4aa2-b355-cce51a1bebfb","added_by":"auto","created_at":"2025-05-09 10:52:24","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":32476,"visible":true,"origin":"","legend":"\u003cp\u003eNumber of visits in which suicidal ideation was detected by mood state\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eEuthymia is defined as an IDS-C score \u0026lt; 15 and a YMRS score \u0026lt; 12; pure hypo/mania is defined as an IDS-C score \u0026lt; 15 and a YMRS score ≥ 12; hypo/mania with mixed features is defined as an IDS-C score ≥ 15 while YMRS score ≥ 12; pure depression is defined as an IDS-C score ≥ 15 while YMRS score ≤ 2; depression with mixed features is defined as a concomitant IDS-C score ≥ 15 and a YMRS score \u0026gt; 2 and \u0026lt; 12. Suicidal ideation is here defined as a score ≥ 1 at the IDS-C – item 18.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6551903/v1/8381b8cca1558528b5e1aba5.png"},{"id":84726773,"identity":"49cab7dc-57dd-453a-ba88-91d6c31db764","added_by":"auto","created_at":"2025-06-16 16:08:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1010236,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6551903/v1/cbda8adf-ac1a-414f-a654-9a937843f7da.pdf"},{"id":82350491,"identity":"170d6bd0-a83c-4051-9226-769b8bd55cbe","added_by":"auto","created_at":"2025-05-09 10:52:24","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":28165,"visible":true,"origin":"","legend":"","description":"","filename":"IJBDMixitySUPPLEMENTAL.docx","url":"https://assets-eu.researchsquare.com/files/rs-6551903/v1/5b3da72e7cb92e0c06f3aca2.docx"}],"financialInterests":"Competing interest reported. T.S. reported research funding from Compass Pathways, the National Institute on Drug Abuse (NIDA), the National Institutes of Health (NIH), the VA Cooperative Studies Program, and the Steven \u0026 Alexandra Cohen Foundation. She has served as a consultant or advisory board member for Zylorion, MindMed, Intracellular Therapies, Sunovion Pharmaceuticals, Merck Research Laboratories, and Impel NeuroPharma Inc., and has financial interests with PsiloTec (stock options, terminated 8/2024). She also has stock ownership in Zylorion. Continuing medical education honoraria were received from Medscape (WebMD). She receives royalties from American Psychiatric Association Publishing, Hogrefe Publishing, Jones and Bartlett, and Wolters Kluwer Health (UpToDate).\nM.J.O. is currently serving as the Neurocrine Biosciences IDMC chair and has received research funding from Otsuka Pharmaceutical Development \u0026 Commercialization, Inc.\nB.D.O. has received lecture honoraria and grants from Angelini, Lundbeck, Janssen, Pfizer, Otsuka, Neuraxpharm, and Livanova.\nS.L.M. is employed by the University of Cincinnati College of Medicine, the University of Cincinnati Physicians, and the Lindner Center of HOPE. She serves as a consultant or advisory board member for Axsome, Idorsia, Levo, Novo Nordisk, and Otsuka, and has been a principal investigator or co-investigator on studies sponsored by Axsome, the Marriott Foundation, Novo Nordisk, and Otsuka. Dr. McElroy is also the inventor of United States Patent No. 6,323,236 B2 and receives royalties from Johnson \u0026 Johnson Pharmaceutical Research \u0026 Development, L.L.C.\nH.G. received honoraria for lectures, scientific expertise, or advisory board participation from Janssen-Cilag, Recordati, and Rovi.\nM.A.F. received grant support from Assurex Health, the Baszucki Group, Breakthrough Discoveries for Thriving with Bipolar Disorder (BD2), and the Mayo Foundation, serves as a consultant for Carnot Laboratories and the American Physician Institute, and has financial interests in Chymia LLC.\nR.C., M.M., C.M.K., R.W.K., P.E.K., J.L., W.A.N., and R.M.P. report no financial relationships with commercial interests.","formattedTitle":"The Influence of Depressive and Manic Symptoms on Suicidal Ideation in Mixed Mood States","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eIndividuals with bipolar disorder (BD) face a markedly elevated risk of suicide, with estimates suggesting a 20\u0026ndash;30-fold increase compared to the general population.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e The International Society for Bipolar Disorder (ISBD) Task Force on Suicide in BD reported an annual suicide rate of 164 per 100,000 individuals.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e While mixed symptoms have long been considered a key risk factor for suicidality in BD, recent evidence suggests that their association with suicidal ideation (SI) may primarily reflect the severity of underlying depressive symptoms rather than an independent effect.\u003c/p\u003e \u003cp\u003eMixed states are characterized by the co-occurrence of manic and depressive symptoms and are common among individuals with BD.\u003csup\u003e\u003cspan additionalcitationids=\"CR4 CR5 CR6 CR7 CR8\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e Historically, the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-4) defined mixed episodes narrowly, requiring patients to simultaneously meet full diagnostic criteria for both a major depressive episode and a manic episode.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e This definition was restricted to individuals with bipolar I disorder (BD I) and excluded presentations with subthreshold symptoms.\u003c/p\u003e \u003cp\u003eWith the publication of the DSM-5 and the International Classification of Diseases, 11th Revision \u003cb\u003e(\u003c/b\u003eICD-11), the classification of mixed episodes was revised. DSM-5 introduced the \"with mixed features\" specifier, allowing for the recognition of mixed symptoms even if full criteria for both mood states are not met.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e Unlike the DSM-4 framework, this specifier accounts for subthreshold symptoms, potentially increasing the identification of individuals with mixed states. ICD-11, in contrast, classifies mixed episodes as a distinct entity, emphasizing the clinical prominence of mixed mood states rather than a strict symptom threshold.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThere is some evidence indicating that mixed states may heighten suicide risk. For instance, individuals experiencing mania with mixed features report higher levels of suicidal ideation (SI) compared to those with pure mania.\u003csup\u003e\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e Additionally, prior studies have found that mixed states were associated with a greater risk of SI, attempts, and completed suicide compared to pure hypo/mania.\u003csup\u003e16,17\u003c/sup\u003e However, it remains unclear whether mixed states confer a higher risk of suicide or if this is a higher risk due to more severe depression during a mixed state compared to pure depression \u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eRecent research has raised key questions on this issue of mixed states and suicidal ideation or attempts. Some studies suggest that mixed states do not independently increase SI or behavior beyond the effects of depressive symptom severity.\u003csup\u003e\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e For example, Persons and colleagues found that individuals with BD I and a history of mixed states were more likely to exhibit suicidal behavior when depressed compared to those without such a history. However, 71% of this excess risk was attributed to time spent in depressive episodes.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e Similarly, Fiedorowicz et al. reported that SI and behavior were strongly associated with depressive symptoms, whereas manic or mixed symptoms, including hypo/mania with mixed features, did not show a significant independent relationship.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e These findings challenge the notion that mixed symptoms confer unique suicide risk and instead suggest that depressive severity is the primary driver of SI in BD. Whether mixed mood states confer additional risk for SI beyond depression alone remains a subject of ongoing debate.\u003c/p\u003e \u003cp\u003eClarifying the relationship between mixed symptoms and SI is essential for improving risk assessment and informing targeted intervention strategies. This study aims to examine the association between SI and depressive, hypomanic/manic, and mixed mood states over time, while also exploring whether gender or bipolar subtype moderates this relationship. By comparing both categorical and continuous models, we seek to determine whether mixed symptoms independently predict SI or if their effects are accounted for by depressive severity only.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eStudy Design and Procedures\u003c/h2\u003e\n \u003cp\u003eThe methods and procedures for the Stanley Foundation Bipolar Treatment Outcome Network (SFBN) study (1995\u0026ndash;2002) have been previously described in detail.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e All participants provided written informed consent, approved by the respective local Institutional Review Boards (IRBs), prior to study enrollment. Study details are described in brief below.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eParticipants\u003c/h3\u003e\n\u003cp\u003eA total of 935 adults were recruited from four U.S. and three European sites for this naturalistic, longitudinal study, which involved the prospective assessment of clinical mood states. All participants were diagnosed using the Structured Clinical Interview from the DSM-4.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e Patients were evaluated at least monthly, with treatment adjustments made as clinically indicated. Patients met DSM-4 criteria for bipolar I disorder (BD-I), bipolar II disorder (BD-II), bipolar disorder not otherwise specified (BD-NOS), or schizoaffective disorder\u0026ndash;bipolar type. Patient characteristics stratified by bipolar disorder subtype are presented in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. An interrater reliability was maintained between clinical sites (\u0026kappa; values: YMRS, 0.7 and IDS-C, 0.85).\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003c/p\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eDistribution of bipolar subtypes, gender, and age among participants with and without suicidal ideation across all visits\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAll subjects\u003c/p\u003e\n \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;903 [100%])\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSubjects with no visits with suicidal ideation\u003c/p\u003e\n \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;352 [39.0%])\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSubjects with one or more visits with suicidal ideation\u003c/p\u003e\n \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;551 [61.0%])\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBipolar Type\u003c/p\u003e\n \u003cp\u003eBDI\u003c/p\u003e\n \u003cp\u003eBDII\u003c/p\u003e\n \u003cp\u003eBD NOS\u003c/p\u003e\n \u003cp\u003eSD \u0026ndash; Bipolar type\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e677 (75.0%)\u003c/p\u003e\n \u003cp\u003e186 (20.6%)\u003c/p\u003e\n \u003cp\u003e18 (2.0%)\u003c/p\u003e\n \u003cp\u003e22 (2.4%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e260 (73.9%)\u003c/p\u003e\n \u003cp\u003e73 (20.7%)\u003c/p\u003e\n \u003cp\u003e10 (3.1%)\u003c/p\u003e\n \u003cp\u003e9 (2.8%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e417 (75.7%)\u003c/p\u003e\n \u003cp\u003e113 (20.5%)\u003c/p\u003e\n \u003cp\u003e8 (1.5%)\u003c/p\u003e\n \u003cp\u003e13 (2.4%)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e505 (55.9%)\u003c/p\u003e\n \u003cp\u003e398 (44.1%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e208 (59.1%)\u003c/p\u003e\n \u003cp\u003e145 (41.2%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e297 (53.9%)\u003c/p\u003e\n \u003cp\u003e253 (45.9%)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e40.98\u0026thinsp;\u0026plusmn;\u0026thinsp;11.53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e40.63\u0026thinsp;\u0026plusmn;\u0026thinsp;11.87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e41.41\u0026thinsp;\u0026plusmn;\u0026thinsp;11.32\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003e\u003cem\u003eSuicidal Ideation is here defined as a score\u0026thinsp;\u0026ge;\u0026thinsp;1 at the IDS-C - item 18; BDI: Bipolar Disorder, type I; BDII: Bipolar Disorder, type II; BD NOS: Bipolar Disorder, Not Otherwise Specified; SD \u0026ndash; Bipolar type: Schizoaffective Disorder \u0026ndash; Bipolar type.\u003c/em\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cp\u003eIndividuals who participated in defined, open-label, or double-blind clinical trials were excluded from the cohort.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e The current analyses focuses on patients who completed at least one visit with concurrent assessments of manic and depressive symptoms using the Young Mania Rating Scale (YMRS)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e and the Inventory of Depressive Symptomatology\u0026ndash;Clinician-Rated (IDS-C).\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003ch3\u003eMood State Assessment\u003c/h3\u003e\n\u003cp\u003eMood states were classified using scores from the YMRS and the IDS-C, both of which are clinician-administered and have demonstrated strong reliability and validity.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e These measures were completed during study visits, with symptoms assessed on the day of visit and for the preceding 3 and 7 days for YMRS and IDS-C, respectively.\u003c/p\u003e\n\u003cp\u003eTo identify mood states, we applied symptom-based cut-offs derived from prior work which used YMRS and IDS-C thresholds in a naturalistic study of SFBN data (see Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e Depressive symptoms were defined as an IDS-C R score of 15 or higher, indicating at least mild depression. Depression with mixed features was defined as the co-occurrence of depressive symptoms (IDS-C R\u0026thinsp;\u0026ge;\u0026thinsp;15) alongside mild hypo/manic symptoms, as indicated by YMRS scores between 3 and 11. Hypo/mania with mixed features was defined as the presence of depressive symptoms (IDS-C R\u0026thinsp;\u0026ge;\u0026thinsp;15) with moderate hypo/manic symptoms, characterized by YMRS scores of 12 or greater.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eDefinitions of mood states by symptom scales\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"3\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIDS-C\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eYMRS\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003e\u003cem\u003eSymptom category\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDepressive symptoms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ge;\u0026thinsp;15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMild hypomanic symptoms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;2 and \u0026lt;\u0026thinsp;12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eModerate hypo/manic symptoms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ge;\u0026thinsp;12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003eMood state\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePure depression\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ge;\u0026thinsp;15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026le;\u0026thinsp;2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDepression with mixed features\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ge;\u0026thinsp;15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;2 and \u0026lt;\u0026thinsp;12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePure hypo/mania\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ge;\u0026thinsp;12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHypo/mania with mixed features\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ge;\u0026thinsp;15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ge;\u0026thinsp;12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEuthymia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\"\u003e\u003cem\u003eIDS-C: Inventory of Depressive Symptomatology-Clinician-Rated Version (assessed day of and prior 7 days); YMRS: Young Mania Rating Scale (assessed day of and prior 3 days).\u003c/em\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eFor depression symptom categorization, we used the full IDS-C score; however, for statistical analyses, we utilized a modified version of the IDS-C (IDS-C R) in which item 18 (suicidal ideation) was removed to avoid circularity, ensuring that the predictor (depression severity) does not include variance from the outcome variable. The IDS-C and IDS-C R scores were highly correlated (r\u0026thinsp;=\u0026thinsp;0.99, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001).\u003c/p\u003e\n\u003cp\u003eThe YMRS and IDS-C share several items that assess overlapping symptoms, including sleep disturbances, irritability, and psychomotor agitation. To determine whether the observed associations were driven by these overlapping symptoms rather than distinct mood state effects, we conducted a sensitivity analysis in which these items were removed. Specifically, we excluded items 4 (Sleep) and 5 (Irritability) from the YMRS, and items 1\u0026ndash;3 (Insomnia), 6 (Irritability), and 24 (Psychomotor agitation) from the IDS-C in subsequent analyses. This allowed us to isolate the relationship of interest from potential artifact.\u003c/p\u003e\n\u003ch3\u003eSuicidal Ideation Assessment\u003c/h3\u003e\n\u003cp\u003eSI was assessed using item 18 of the IDS-C, which evaluates the presence and severity of suicidal thoughts. Item 18 is scored as follows: 0 indicates no thoughts of suicide or death; 1 indicates a sense of emptiness or the belief that life is not worth living; 2 indicates suicidal thoughts occurring several times per week for several minutes; and 3 indicates suicidal thoughts occurring daily, with or without a plan or past suicide attempt. For our analyses, we dichotomized suicidal ideation to IDS-C item 18\u0026thinsp;=\u0026thinsp;0 and IDS-C item 18\u0026thinsp;\u0026ge;\u0026thinsp;1.\u003c/p\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003eStatistical Analysis\u003c/h2\u003e\n \u003cp\u003eStatistical analyses were conducted using SPSS version 28 (IBM Corp., Armonk, NY, USA). Generalized estimating equations (GEE) were used to examine the association between mood symptoms\u0026mdash;specifically depressive, hypo/manic, and their co-occurrence\u0026mdash;and SI assessing both the strength and direction of these relationships. The primary analyses utilized categorical models, with mood symptoms categorized based on predefined thresholds that capture distinct mood presentations.\u003c/p\u003e\n \u003cp\u003eThe GEE models were specified using binary logistic regression with a robust covariance estimator and an independent working correlation matrix to account for repeated observations within individuals. The dependent variable in all models was the IDS-C item 18 score, which reflects the presence and severity of SI. The primary predictor variables were the categorical indicators of depressive, moderate, and mild hypo/manic symptoms. An interaction term was included to capture the potential synergistic effect of co-occurring depressive and hypo/manic symptoms.\u003c/p\u003e\n \u003cp\u003eThe interpretation of the GEE model coefficients followed conventional guidelines for binary logistic regression. A positive \u0026beta;-value indicates an increased likelihood of suicidal ideation as symptom severity increases, whereas a negative \u0026beta;-value suggests a decreased likelihood. Odds ratios (OR) were derived from the \u0026beta;-coefficients using the standard transformation OR\u0026thinsp;=\u0026thinsp;e\u003csup\u003e(\u0026beta;)\u003c/sup\u003e providing a measure of odds for SI based on mood symptom severity. A statistically significant interaction term indicates that the relationship between mood symptoms SI differs from the additive contributions of depressive and hypo/manic symptoms. Age and study week were included as linear covariates in all models to control for potential time- and age-related effects. Additional covariates included gender, both as a main effect and in interaction with mood symptoms, and bipolar subtype.\u003c/p\u003e\n \u003cp\u003eTo assess the combined effect of depressive and hypo/manic symptoms, we calculated combined ORs by exponentiating the sum of the relevant \u0026beta;-coefficients (e.g., OR\u003csub\u003ecombined\u003c/sub\u003e = exp\u003csup\u003e(\u0026beta;_depression + \u0026beta;_hypomania + \u0026beta;_interaction)\u003c/sup\u003e). This allowed us to quantify how co-occurring depressive and hypo/manic symptoms modify SI beyond their individual contributions. For combined OR calculations, only statistically significant \u0026beta;-values were included to ensure that the resulting estimate reflected meaningful associations. If a \u0026beta;-coefficient was not significant (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05), its corresponding OR was not included in the combined calculation, as its contribution to the overall effect was uncertain. Similarly, if the revised scales (e.g., excluding overlapping items) altered statistical significance, the corresponding OR was excluded, ensuring that the final combined OR was based only on robust, validated effects.\u003c/p\u003e\n \u003cp\u003eIn addition to the primary categorical models, secondary analyses were conducted using continuous YMRS and IDS-C R scores as predictor variables to replicate methodology from prior research.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e The continuous models followed the same GEE specifications as the categorical models; however, instead of dichotomizing symptoms, mood symptoms were modeled as continuous variables to capture variability in symptom severity without the use of predefined clinical categories. The interaction between continuous depressive and hypo/manic symptom scores was included to identify potential nonlinear relationships and mixed symptom presentations.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u0026rsquo; demographics and duration of follow-up\u003c/h2\u003e \u003cp\u003eOut of the original cohort of 935 adults, 903 patients had completed at least one visit with both YMRS and IDS-C assessments (mean age\u0026thinsp;=\u0026thinsp;40.98\u0026thinsp;\u0026plusmn;\u0026thinsp;11.53, 55.9% female; Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Across 14,213 visits, patients had a median of 12 visits (mean\u0026thinsp;=\u0026thinsp;16.6\u0026thinsp;\u0026plusmn;\u0026thinsp;14.2) over a median follow-up of 15 months (mean\u0026thinsp;=\u0026thinsp;22.7\u0026thinsp;\u0026plusmn;\u0026thinsp;22.9 months). Suicidal ideation scores\u0026thinsp;\u0026ge;\u0026thinsp;1 were recorded in 17.2% (2,449 visits), scores\u0026thinsp;\u0026ge;\u0026thinsp;2 in 6.9% (977 visits), and scores\u0026thinsp;=\u0026thinsp;3 in 1.1% (160 visits).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eVisits and mood states\u003c/h3\u003e\n\u003cp\u003eAmong 14,213 visits, the majority (N\u0026thinsp;=\u0026thinsp;8,281 [58.3%]) occurred during a euthymic phase (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Depressive symptoms (IDS-C score\u0026thinsp;\u0026ge;\u0026thinsp;15) were present in 4,907 visits (34.5%). Of these, 2,781 (19.6%) were characterized as pure depression and 2,126 (14.9%) as depression with mixed features (\u0026gt;\u0026thinsp;2 YMRS\u0026thinsp;\u0026lt;\u0026thinsp;12 and IDS-C\u0026thinsp;\u0026ge;\u0026thinsp;15). Furthermore, 1,025 visits (7.2%) reported hypo/manic symptoms, of which 440 visits (3.1%) reached scores for pure hypo/mania (YMRS\u0026thinsp;\u0026ge;\u0026thinsp;12), while 585 visits (4.1%) were characterized as hypo/mania with mixed features (IDSC-C\u0026thinsp;\u0026ge;\u0026thinsp;15 and YMRS\u0026thinsp;\u0026ge;\u0026thinsp;12).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eVisits and Suicidal Ideation\u003c/h2\u003e \u003cp\u003eAn IDS-C item 18 score of \u0026ge;\u0026thinsp;1 was observed in 2,449 visits (17.2%), with 977 visits (6.9%) showing a score of \u0026ge;\u0026thinsp;2 and 160 visits (1.1%) showing a score of 3. The distribution of SI across different mood states is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eRelationship between suicidal ideation and categorical indicators of mood states\u003c/h2\u003e \u003cp\u003eResults from the GEE models using categorical variables for depressive symptoms, hypo/manic symptoms, and their interaction are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Depressive symptoms were strongly related to SI (β\u0026thinsp;=\u0026thinsp;3.09, 95% CI: 2.73\u0026ndash;3.45). Moderate hypo/manic symptoms had a smaller but significant association with SI (β\u0026thinsp;=\u0026thinsp;1.135, 95% CI 0.41\u0026ndash;1.87) and mild hypo/mania demonstrated a modest contribution (β\u0026thinsp;=\u0026thinsp;0.552, 95% CI: 0.05\u0026ndash;1.06). There was a significant interaction effect between moderate hypo/mania and depression (β = -0.843, 95% CI: -1.59 \u0026ndash; -0.10)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAssociations of depressive and hypomanic symptoms on suicidal ideation\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eSuicidal ideation\u0026thinsp;\u0026ge;\u0026thinsp;1\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eβ\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDepressive symptoms\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.73\u0026ndash;3.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eModerate hypo/manic symptoms\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.135\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.41\u0026ndash;1.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMild hypo/manic symptoms\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.552\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.05\u0026ndash;1.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.032\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInteraction between depressive and mild hypo/mania symptoms\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-0.95\u0026ndash;0.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.105\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInteraction between depressive and moderate hypo/mania symptoms\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.843\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-1.59 \u0026ndash; -0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.026\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003cem\u003eCI: Confidence Intervals\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003cem\u003eSee eTable 2 for full details, including additional predictors and reference categories.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003csup\u003e\u003cem\u003ea\u003c/em\u003e\u003c/sup\u003e \u003cem\u003eGEE models used Bonferroni correction to adjust for multiple comparisons\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eWhen using the revised YMRS scale with overlapping items removed, the findings for hypo/mania with mixed features remained consistent, with significant contributions from depression, hypo/mania, and their interaction. However, the previously observed association between mild hypo/mania and suicidal ideation was no longer significant (β\u0026thinsp;=\u0026thinsp;0.308, 95% CI: -0.14 to 0.76) and was therefore excluded from the combined odds for depression with mixed features (see eTable 1 in the Supplement).\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e presents the odds of SI for each mood category relative to euthymia, calculated using beta coefficients from the GEE models. Depression was associated with significantly higher odds of SI (OR\u0026thinsp;=\u0026thinsp;21.98, 95% CI: 15.31\u0026ndash;31.54), while moderate and mild hypo/manic symptoms were associated with smaller but significant odds (OR\u0026thinsp;=\u0026thinsp;3.11, 95% CI: 1.51\u0026ndash;6.49; OR\u0026thinsp;=\u0026thinsp;1.74, 95% CI: 1.05\u0026ndash;2.89).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eEffects of pure and mixed mood states on suicidal ideation relative to euthymia\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSymptom Category\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOdds Ratio\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDepression\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e21.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15.31\u0026ndash;31.54\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eModerate hypo/mania\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.51\u0026ndash;6.49\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMild hypo/mania\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.05\u0026ndash;2.89\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMixed Mood State\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDepression with mixed features\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e21.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypo/mania with mixed features\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e29.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003cem\u003eCI: Confidence Intervals\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eFor mixed mood states, depression with mixed features had the same odds of SI as pure depression (OR\u0026thinsp;=\u0026thinsp;21.98), as its calculation included only the depressive symptom component, with mild hypomania and its interaction with depression excluded. Hypo/mania with mixed features had the highest odds of SI (OR\u0026thinsp;=\u0026thinsp;29.43), calculated from the individual effects of mania, depression, and their interaction term. Confidence intervals for the mixed mood states were not reported due to variance instability.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eRelationship between suicidal ideation and other predictors\u003c/h2\u003e \u003cp\u003eGender significantly moderated the relationship between mood state and SI, with a protective effect for males in pure hypo/mania (β = -1.451, 95% CI: -2.58 \u0026ndash; -0.32) while age and bipolar subtype did not demonstrate any significant relationship (eTable 2 in supplement).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eRelationship between suicidal ideation and continuous IDS-C R and YMRS scores\u003c/h2\u003e \u003cp\u003eA secondary GEE model was built using continuous variables as predictor variables. Results are shown in eTable 3 in the Supplement. In the continuous models, depressive symptom severity was significantly associated with increased suicidal ideation (β\u0026thinsp;=\u0026thinsp;0.133, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), while hypo/manic symptoms (β\u0026thinsp;=\u0026thinsp;0.022, p\u0026thinsp;=\u0026thinsp;0.115) and their interaction (β = -0.001, p\u0026thinsp;=\u0026thinsp;0.252) were not significant predictors.\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this large well-characterized sample of patients with bipolar disorder 60.7% of participants had at least one visit where broadly defined SI was present (IDS-C item 18 score\u0026thinsp;\u0026ge;\u0026thinsp;1). When mood states were categorized by degree of severity, hypo/mania with mixed features emerged as a distinct risk factor for SI, suggesting that threshold effects captured by categorical models are not captured in previous continuous analyses. Using categorical mood states as predictors, hypo/mania with mixed features had the highest observed odds of SI (OR\u0026thinsp;=\u0026thinsp;29.43), whereas depression with mixed features had the same odds as pure depression (OR\u0026thinsp;=\u0026thinsp;21.98). The increased risk in hypo/mania with mixed features was driven by significant contributions from mania, depression, and their interaction term. In contrast, for depression with mixed features, the odds of SI were based solely on the depressive symptom contribution, as mild hypo/mania and its interaction with depression were not statistically significant or lacked robustness in sensitivity analyses, leading to their exclusion from the final calculation.\u003c/p\u003e \u003cp\u003eIn order to categorize and differentiate between mixed states, as used in earlier studies with this population, a lower YMRS cutoff (3\u0026ndash;11) was used to define depression with mixed features, capturing concurrent hypo/manic symptoms, while a higher YMRS threshold (12 or greater) identified hypo/mania with mixed features. In the primary analyses using the full scales, both moderate and mild hypo/mania were significantly associated with an increased likelihood of SI, but in the sensitivity analyses where overlapping items between the YMRS and IDS-C were removed, the association between mild hypo/mania and SI was no longer significant, suggesting that SI in this context is driven by depressive symptoms alone. This pattern indicates that overlapping symptoms, such as irritability and sleep disturbances, may have contributed to the observed relationship between mild hypo/mania and SI when YMRS scores fell between 3 and 11.\u003c/p\u003e \u003cp\u003eTo replicate prior studies, we tested whether the association between mixed mood states and SI was primarily driven by the presence of depressive symptoms alone, or by the combination of depressive and hypomanic symptoms. Using continuous mood symptom scores, we found that depressive symptoms accounted for the observed association with SI, while hypomanic symptoms and their interaction with depression did not significantly contribute. These findings align with previous research indicating that SI in mixed states may largely reflect the influence of depressive symptoms.\u003c/p\u003e \u003cp\u003eA summary of earlier work in this area includes three different populations of patients with bipolar disorder. Firstly, data from the National Network of Depression Centers (NNDC) Mood Outcomes Program showed that depressive symptoms assessed with the Patient Health Questionnaire (PHQ-8) were the strongest predictor of SI, while manic symptoms measured with the Altman Self-Rating Mania Scale (ASRM) were not associated with increased suicide risk in bipolar disorder and were inversely associated with SI in major depression.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e An additional analysis of NNDC data found that neither manic nor anxiety symptoms independently contributed to SI.\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e Similarly, in an analysis of the NNDC Clinical Care Registry found that depressive symptoms assessed with the PHQ-9 strongly predicted SI and behavior, while manic symptoms and mixed states\u0026mdash;whether modeled continuously or categorically\u0026mdash;were not significantly associated with suicide risk.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e These findings suggest that across different assessment methods, the relationship between depressive symptoms and SI remains consistent when mood symptoms are treated as continuous variables.\u003c/p\u003e \u003cp\u003eLastly, prospective data from the NIMH Collaborative Depression Study followed 429 individuals with bipolar disorder over an average of 18 years and similarly supports this pattern. Using the LIFE Psychiatric Status Rating (PSR) scale to characterize mood states, the study identified depression as a high-risk state for suicidal behavior, while mixed states did not confer additional risk beyond the depressive component.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e A limitation of the NIMH study is that while prospective mood symptoms may only have been queried every 6 or 12 months making complete mixed mood descriptions limited.\u003c/p\u003e \u003cp\u003eThis body of work suggests that threshold effects captured by categorical models are not adequately reflected in continuous analyses. The categorical models in our study revealed an increased odds of SI associated with moderate hypo/mania with mixed features, which diverges from findings in studies using continuous analyses.\u003c/p\u003e \u003cp\u003eMuch of the prior research primarily relied on self-reported mood assessments such as PHQ-8, PHQ-9, or ASRM. In contrast, our study used monthly clinician-rated IDS-C and YMRS scores and predefined categorical thresholds for mood states. It should be noted the study of the NNDC registry analysis used the Columbia-Suicide Severity Rating Scale (C-SSRS) to assess SI and behavior, while our study relied on item 18 of the IDS-C. It is also important to note that our definition of mixed features differs from those used in the NNDC and NIMH studies due to differences in measurement tools and threshold scores required to define mood states. These methodological variations may contribute to the observed discrepancies in categorical findings.\u003c/p\u003e \u003cp\u003eThe divergence between the categorical and continuous models raises important considerations regarding how mixed symptoms are best characterized in relation to SI risk. One possible explanation is that categorical models, which define mood states using clinical thresholds, may better capture the episodic nature of bipolar disorder and its relevance to SI, whereas continuous measures assume a linear relationship that may not fully account for dynamic symptom interactions. The use of categorical models may allow for the identification of clinically meaningful subgroups at increased risk, while continuous models may fail to capture nonlinear relationships between symptom severity and SI risk. These differing analytic approaches highlight the complexity of assessing mood states in bipolar disorder and suggest that future studies should explore the potential advantages and limitations of each method.\u003c/p\u003e \u003cp\u003ePrior research also found that women are more likely than men to meet DSM-5 criteria for mixed hypomania or mania.\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e Women also experience depressive symptoms more frequently during hypomania, whereas men\u0026rsquo;s depressive symptoms are primarily characterized by irritability and agitation.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e While gender did not significantly impact suicidal ideation in mixed states in our study, it did interact with pure hypomania, reducing SI risk in men. This is consistent with prior research indicating that manic symptoms increase SI risk in women but not in men, as observed in NNDC findings.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe study has significant limitations which limit the interpretability of the results. The presence of SI was assessed only through item 18 of the IDS-C, therefore it may not be generalized to other definitions of suicide. As such, the conclusions drawn from this analysis are more relevant to the odds of SI than to the odds of suicide attempt or completed suicide. The GEE models used in our analyses assume independence of observations across different study sites, which may not fully capture site-specific variations and could impact the robustness of our findings. The use of mood symptom rating scales involved empirical cut-offs for symptoms, and it was not possible to differentiate whether symptoms present at visits represented new or persistent mood symptoms, thus limiting our interpretation of the longitudinal trajectories and the casual effect of mixed symptoms. Finally, although the elevated SI risk observed in hypo/mania with mixed features compared to depression with mixed features appears clinically meaningful, confidence intervals were not reported for mixed mood states due to variance instability. As a result, formal statistical comparisons with pure mood states (e.g., depression) were not possible. Despite this, the present study has several strengths including a large sample of well-characterized patients with BD and a prospective design with standardized rating scales for the clinical assessments. The broad inclusion criteria enhanced the generalizability of our findings.\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eThis study highlights individuals with hypo/mania with mixed features demonstrate an increased odd of SI, reflecting contributions from depression, hypo/mania and their interaction. These findings lay the groundwork for future research to better understand the relationship between mixed mood states and suicidality.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAltman Self-Rating Mania Scale (ASRM), Bipolar Disorder (BD), Bipolar Disorder I (BD-I), Bipolar Disorder II (BD-II), Bipolar Disorder Not Otherwise Specified (BD-NOS), Columbia-Suicide Severity Rating Scale (C-SSRS), Confidence Interval (CI), Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-4), Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), Generalized Estimating Equations (GEE), International Classification of Diseases, Eleventh Revision (ICD-11), International Society for Bipolar Disorder (ISBD), Inventory of Depressive Symptomatology–Clinician-Rated (IDS-C), Inventory of Depressive Symptomatology–Clinician-Rated, Revised (IDS-C R), Institutional Review Board (IRB), National Institute of Mental Health (NIMH), National Network of Depression Centers (NNDC), Odds Ratio (OR), Patient Health Questionnaire-8 (PHQ-8), Patient Health Questionnaire-9 (PHQ-9), Psychiatric Status Rating (PSR), Structured Clinical Interview for DSM Disorders (SCID), Stanley Foundation Bipolar Network (SFBN), Suicidal Ideation (SI), Statistical Package for the Social Sciences (SPSS), Young Mania Rating Scale (YMRS)\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cem\u003eEthics approval and consent to participate\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAll participants provided written informed consent prior to enrollment in the Stanley Foundation Bipolar Treatment Outcome Network study, with study procedures approved by the Institutional Review Boards (IRBs) at each participating site.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConsent for publication\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAvailability of data and materials\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analyzed during the current study are not publicly available due to privacy and confidentiality agreements with the original study participants but may be available from the corresponding author upon reasonable request and with appropriate Institutional Review Board approval.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCompeting interests\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eT.S. reported research funding from Compass Pathways, the National Institute on Drug Abuse (NIDA), the National Institutes of Health (NIH), the VA Cooperative Studies Program, and the Steven \u0026amp; Alexandra Cohen Foundation. She has served as a consultant or advisory board member for Zylorion, MindMed, Intracellular Therapies, Sunovion Pharmaceuticals, Merck Research Laboratories, and Impel NeuroPharma Inc., and has financial interests with PsiloTec (stock options, terminated 8/2024). She also has stock ownership in Zylorion. Continuing medical education honoraria were received from Medscape (WebMD). She receives royalties from American Psychiatric Association Publishing, Hogrefe Publishing, Jones and Bartlett, and Wolters Kluwer Health (UpToDate).\u003c/p\u003e\n\u003cp\u003eM.J.O. is currently serving as the Neurocrine Biosciences IDMC chair and has received research funding from Otsuka Pharmaceutical Development \u0026amp; Commercialization, Inc.\u003c/p\u003e\n\u003cp\u003eB.D.O. has received lecture honoraria and grants from Angelini, Lundbeck, Janssen, Pfizer, Otsuka, Neuraxpharm, and Livanova.\u003c/p\u003e\n\u003cp\u003eS.L.M. is employed by the University of Cincinnati College of Medicine, the University of Cincinnati Physicians, and the Lindner Center of HOPE. She serves as a consultant or advisory board member for Axsome, Idorsia, Levo, Novo Nordisk, and Otsuka, and has been a principal investigator or co-investigator on studies sponsored by Axsome, the Marriott Foundation, Novo Nordisk, and Otsuka. Dr. McElroy is also the inventor of United States Patent No. 6,323,236 B2 and receives royalties from Johnson \u0026amp; Johnson Pharmaceutical Research \u0026amp; Development, L.L.C.\u003c/p\u003e\n\u003cp\u003eH.G. received honoraria for lectures, scientific expertise, or advisory board participation from Janssen-Cilag, Recordati, and Rovi.\u003c/p\u003e\n\u003cp\u003eM.A.F. received grant support from Assurex Health, the Baszucki Group, Breakthrough Discoveries for Thriving with Bipolar Disorder (BD2), and the Mayo Foundation, serves as a consultant for Carnot Laboratories and the American Physician Institute, and has financial interests in Chymia LLC.\u003c/p\u003e\n\u003cp\u003eR.C., M.M., C.M.K., R.W.K., P.E.K., J.L., W.A.N., and R.M.P. report no financial relationships with commercial interests.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe original Stanley Foundation Bipolar Network study was funded by the Stanley Medical Research Institute, Bethesda, Md. No additional external funding was used for the present secondary analysis.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAuthors' contributions\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eM.M., R.C., and C.M.K. contributed equally to the conceptualization, data analysis, and drafting of the manuscript. M.J.O., B.D.O., and J.L. assisted with statistical analysis, interpretation of results, and critical revision of the manuscript. M.A.F., R.W.K., S.L.M., W.A.N., P.E.K., R.M.P., and H.G. contributed to the acquisition of clinical data and provided critical revisions. T.S. supervised the study design, data analysis, and manuscript preparation. T.S. and H.G. served as principal investigators and guarantors of the overall content. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAcknowledgements\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eIn kind remembrance of our close colleagues who have passed, Lori Altshuler and Gabrielle S. Leverich. We are deeply grateful to Federico Ambrogi for his invaluable support in advancing the research approach. We also acknowledge the generous support of the Stanley Medical Research Institute for providing original funding between 1995 and 2002 for the Stanley Foundation Bipolar Network.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ePompili M, Gonda X, Serafini G, et al. Epidemiology of suicide in bipolar disorders: a systematic review of the literature. Bipolar Disord. 2013;15(5):457\u0026ndash;90. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/bdi.12087\u003c/span\u003e\u003cspan address=\"10.1111/bdi.12087\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchaffer A, Isomets\u0026auml; ET, Tondo L, et al. Epidemiology, neurobiology and pharmacological interventions related to suicide deaths and suicide attempts in bipolar disorder: Part I of a report of the International Society for Bipolar Disorders Task Force on Suicide in Bipolar Disorder. Aust N Z J Psychiatry. 2015;49(9):785\u0026ndash;802. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1177/0004867415594427\u003c/span\u003e\u003cspan address=\"10.1177/0004867415594427\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDilsaver SC, Benazzi F, Akiskal HS. Mixed states: the most common outpatient presentation of bipolar depressed adolescents? Psychopathology. 2005;38(5):268\u0026ndash;72. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1159/000088443\u003c/span\u003e\u003cspan address=\"10.1159/000088443\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSuppes T, Mintz J, McElroy SL, et al. Mixed hypomania in 908 patients with bipolar disorder evaluated prospectively in the Stanley Foundation Bipolar Treatment Network: a sex-specific phenomenon. Arch Gen Psychiatry. 2005;62(10):1089\u0026ndash;96. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1001/archpsyc.62.10.1089\u003c/span\u003e\u003cspan address=\"10.1001/archpsyc.62.10.1089\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSwann AC, Steinberg JL, Lijffijt M, Moeller GF. Continuum of depressive and manic mixed states in patients with bipolar disorder: quantitative measurement and clinical features. World Psychiatry. 2009;8(3):166\u0026ndash;72. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/j.2051-5545.2009.tb00245.x\u003c/span\u003e\u003cspan address=\"10.1002/j.2051-5545.2009.tb00245.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGoldberg JF, McElroy SL. Bipolar mixed episodes: characteristics and comorbidities. J Clin Psychiatry. 2007;68(10):e25. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.4088/jcp.1007e25\u003c/span\u003e\u003cspan address=\"10.4088/jcp.1007e25\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBorn C, Grunze H, Post RM, et al. Mania and bipolar depression: complementing not opposing poles-a post-hoc analysis of mixed features in manic and hypomanic episodes. Int J Bipolar Disord. 2021;9(1):36. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s40345-021-00241-5\u003c/span\u003e\u003cspan address=\"10.1186/s40345-021-00241-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGonz\u0026aacute;lez-Pinto A, Barbeito S, Alonso M, et al. Poor long-term prognosis in mixed bipolar patients: 10-year outcomes in the Vitoria prospective naturalistic study in Spain. J Clin Psychiatry. 2011;72(5):671\u0026ndash;6. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.4088/JCP.09m05483yel\u003c/span\u003e\u003cspan address=\"10.4088/JCP.09m05483yel\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHantouche EG, Akiskal HS, Azorin JM, Ch\u0026acirc;tenet-Duch\u0026ecirc;ne L, Lancrenon S. Clinical and psychometric characterization of depression in mixed mania: a report from the French National Cohort of 1090 manic patients. J Affect Disord. 2006;96(3):225\u0026ndash;32. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jad.2005.01.005\u003c/span\u003e\u003cspan address=\"10.1016/j.jad.2005.01.005\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAmerican Psychiatric Association. \u003cem\u003eDiagnostic and statistical manual of mental disorders (4th ed., text rev.)\u003c/em\u003e. American Psychiatric Publishing; 2000.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAmerican Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. American Psychiatric Publishing; 2013.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWorld Health Organization. Clinical descriptions and diagnostic requirements for ICD-11 mental, behavioural and neurodevelopmental disorders. World Health Organization. Accessed Mar 14, 2025.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGoldberg JF, Garno JL, Leon AC, Kocsis JH, Portera L. Association of recurrent suicidal ideation with nonremission from acute mixed mania. Am J Psychiatry. 1998;155(12):1753\u0026ndash;5. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1176/ajp.155.12.1753\u003c/span\u003e\u003cspan address=\"10.1176/ajp.155.12.1753\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eReinares M, Bonn\u0026iacute;n Cdel M, Hidalgo-Mazzei D, et al. Making sense of DSM-5 mania with depressive features. Aust N Z J Psychiatry. 2015;49(6):540\u0026ndash;9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1177/0004867415585583\u003c/span\u003e\u003cspan address=\"10.1177/0004867415585583\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTondo L, Vazquez GH, Baldessarini RJ. Suicidal Behavior Associated with Mixed Features in Major Mood Disorders. Psychiatr Clin North Am. 2020;43(1):83\u0026ndash;93. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.psc.2019.10.008\u003c/span\u003e\u003cspan address=\"10.1016/j.psc.2019.10.008\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLage RR, Santana CMT, Nardi AE, Cheniaux E. Mixed states and suicidal behavior: a systematic review. Trends Psychiatry Psychother. 2019;41(2):191\u0026ndash;200. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1590/2237-6089-2018-0042\u003c/span\u003e\u003cspan address=\"10.1590/2237-6089-2018-0042\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBartoli F, Crocamo C, Carr\u0026agrave; G. Clinical correlates of DSM-5 mixed features in bipolar disorder: A meta-analysis. J Affect Disord. 2020;276:234\u0026ndash;40. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jad.2020.07.035\u003c/span\u003e\u003cspan address=\"10.1016/j.jad.2020.07.035\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSwann AC, Lafer B, Perugi G, et al. Bipolar mixed states: an international society for bipolar disorders task force report of symptom structure, course of illness, and diagnosis. Am J Psychiatry. 2013;170(1):31\u0026ndash;42. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1176/appi.ajp.2012.12030301\u003c/span\u003e\u003cspan address=\"10.1176/appi.ajp.2012.12030301\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSeo HJ, Wang HR, Jun TY, Woo YS, Bahk WM. Factors related to suicidal behavior in patients with bipolar disorder: the effect of mixed features on suicidality. Gen Hosp Psychiatry. 2016;39:91\u0026ndash;6. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.genhosppsych.2015.12.005\u003c/span\u003e\u003cspan address=\"10.1016/j.genhosppsych.2015.12.005\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFiedorowicz JG, Persons JE, Assari S, et al. Moderators of the association between depressive, manic, and mixed mood symptoms and suicidal ideation and behavior: An analysis of the National Network of Depression Centers Mood Outcomes Program. J Affect Disord. 2021;281:623\u0026ndash;30. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jad.2020.11.101\u003c/span\u003e\u003cspan address=\"10.1016/j.jad.2020.11.101\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFiedorowicz JG, Persons JE, Assari S, et al. Depressive symptoms carry an increased risk for suicidal ideation and behavior in bipolar disorder without any additional contribution of mixed symptoms. J Affect Disord. 2019;246:775\u0026ndash;82. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jad.2018.12.057\u003c/span\u003e\u003cspan address=\"10.1016/j.jad.2018.12.057\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePersons JE, Coryell WH, Solomon DA, Keller MB, Endicott J, Fiedorowicz JG. Mixed state and suicide: Is the effect of mixed state on suicidal behavior more than the sum of its parts? Bipolar Disord. 2018;20(1):35\u0026ndash;41. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/bdi.12538\u003c/span\u003e\u003cspan address=\"10.1111/bdi.12538\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLeverich GS, Nolen WA, Rush AJ, et al. The Stanley Foundation Bipolar Treatment Outcome Network. I. Longitudinal methodology. J Affect Disord. 2001;67(1\u0026ndash;3):33\u0026ndash;44. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/s0165-0327(01)00430-x\u003c/span\u003e\u003cspan address=\"10.1016/s0165-0327(01)00430-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSuppes T, Leverich GS, Keck PE, et al. The Stanley Foundation Bipolar Treatment Outcome Network. II. Demographics and illness characteristics of the first 261 patients. J Affect Disord. 2001;67(1\u0026ndash;3):45\u0026ndash;59. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/s0165-0327(01)00432-3\u003c/span\u003e\u003cspan address=\"10.1016/s0165-0327(01)00432-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePost RM, Leverich GS, Altshuler LL, et al. An overview of recent findings of the Stanley Foundation Bipolar Network (Part I). Bipolar Disord. 2003;5(5):310\u0026ndash;9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1034/j.1399-5618.2003.00051.x\u003c/span\u003e\u003cspan address=\"10.1034/j.1399-5618.2003.00051.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYoung RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry. 1978;133:429\u0026ndash;35. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1192/bjp.133.5.429\u003c/span\u003e\u003cspan address=\"10.1192/bjp.133.5.429\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRush AJ, Gullion CM, Basco MR, Jarrett RB, Trivedi MH. The Inventory of Depressive Symptomatology (IDS): psychometric properties. Psychol Med. 1996;26(3):477\u0026ndash;86. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1017/s0033291700035558\u003c/span\u003e\u003cspan address=\"10.1017/s0033291700035558\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTrivedi MH, Rush AJ, Ibrahim HM, et al. The Inventory of Depressive Symptomatology, Clinician Rating (IDS-C) and Self-Report (IDS-SR), and the Quick Inventory of Depressive Symptomatology, Clinician Rating (QIDS-C) and Self-Report (QIDS-SR) in public sector patients with mood disorders: a psychometric evaluation. Psychol Med. 2004;34(1):73\u0026ndash;82. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1017/s0033291703001107\u003c/span\u003e\u003cspan address=\"10.1017/s0033291703001107\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMiller S, Suppes T, Mintz J, et al. Mixed Depression in Bipolar Disorder: Prevalence Rate and Clinical Correlates During Naturalistic Follow-Up in the Stanley Bipolar Network. Am J Psychiatry. 2016;173(10):1015\u0026ndash;23. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1176/appi.ajp.2016.15091119\u003c/span\u003e\u003cspan address=\"10.1176/appi.ajp.2016.15091119\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePersons JE, Lodder P, Coryell WH, Nurnberger JI, Fiedorowicz JG. Symptoms of mania and anxiety do not contribute to suicidal ideation or behavior in the presence of bipolar depression. Psychiatry Res. 2022;307:114296. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.psychres.2021.114296\u003c/span\u003e\u003cspan address=\"10.1016/j.psychres.2021.114296\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOstacher MJ, Nierenberg AA, Rabideau D, et al. A clinical measure of suicidal ideation, suicidal behavior, and associated symptoms in bipolar disorder: Psychometric properties of the Concise Health Risk Tracking Self-Report (CHRT-SR). J Psychiatr Res. 2015;71:126\u0026ndash;33. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jpsychires.2015.10.004\u003c/span\u003e\u003cspan address=\"10.1016/j.jpsychires.2015.10.004\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-bipolar-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijbd","sideBox":"Learn more about [International Journal of Bipolar Disorders](http://journalbipolardisorders.springeropen.com/)","snPcode":"40345","submissionUrl":"https://submission.nature.com/new-submission/40345/3","title":"International Journal of Bipolar Disorders","twitterHandle":"@SpringerOpen","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Bipolar Disorder, Mania, Depression, Mixed States, Mixed features, Mixity, Suicidal Ideation","lastPublishedDoi":"10.21203/rs.3.rs-6551903/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6551903/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e While bipolar disorder is strongly linked to an increased risk of suicide, recent evidence has challenged the assumption that mixed symptoms play a distinct role in suicidal ideation beyond depressive severity. This study examines how depressive, hypo/manic, and mixed features influence suicidal ideation in individuals with bipolar disorder. Data from 903 participants in the Stanley Foundation Bipolar Network (1995–2002) were analyzed to assess associations between mood states, classified by the Inventory of Depressive Symptomatology–Clinician-Rated (IDS-C) and the Young Mania Rating Scale (YMRS), and suicidal ideation, measured using IDS-C item 18, using generalized estimating equations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Depressive symptoms were strongly associated with suicidal ideation (OR = 21.98, 95% CI: 15.31–31.54). Moderate hypo/manic symptoms also conferred risk (OR = 3.11, 95% CI: 1.51–6.49), and milder hypo/mania showed a weaker but significant association (OR = 1.74, 95% CI: 1.05–2.89). The highest suicidal ideation was observed in individuals with hypo/mania featuring mixed symptoms (OR = 29.43), exceeding that of depression or depression with mixed features (OR = 21.98). However, findings diverged based on modeling approach: in continuous predictor models, SI was driven solely by depressive symptom severity, with no significant association observed for hypo/mania or its interaction with depression. In contrast, when mood states were categorized using clinically meaningful thresholds, hypo/mania with mixed features emerged as a distinct contributor to suicidal ideation risk.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e These findings underscore the need for integrating both dimensional and categorical approaches to mood state classification in research on suicidality in bipolar disorder.\u003c/p\u003e","manuscriptTitle":"The Influence of Depressive and Manic Symptoms on Suicidal Ideation in Mixed Mood States","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-09 10:52:19","doi":"10.21203/rs.3.rs-6551903/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-05-21T14:49:47+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-13T11:54:02+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-12T20:05:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"128461004901881160906461741476350792155","date":"2025-05-04T13:46:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"233812766531491005912980344669051823252","date":"2025-05-04T10:02:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"245372538970023232059960927207207599914","date":"2025-05-03T08:18:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"281310299077657752950772118563685246292","date":"2025-05-02T13:48:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"123185326944635482690781482683044608526","date":"2025-05-02T13:40:05+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-05-02T13:24:42+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-30T06:51:16+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-04-30T06:48:12+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Bipolar Disorders","date":"2025-04-29T02:53:52+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-bipolar-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijbd","sideBox":"Learn more about [International Journal of Bipolar Disorders](http://journalbipolardisorders.springeropen.com/)","snPcode":"40345","submissionUrl":"https://submission.nature.com/new-submission/40345/3","title":"International Journal of Bipolar Disorders","twitterHandle":"@SpringerOpen","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"260beea4-ce20-4d6f-a638-c14d1f7636c3","owner":[],"postedDate":"May 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-06-16T16:06:01+00:00","versionOfRecord":{"articleIdentity":"rs-6551903","link":"https://doi.org/10.1186/s40345-025-00390-x","journal":{"identity":"international-journal-of-bipolar-disorders","isVorOnly":false,"title":"International Journal of Bipolar Disorders"},"publishedOn":"2025-06-14 15:57:03","publishedOnDateReadable":"June 14th, 2025"},"versionCreatedAt":"2025-05-09 10:52:19","video":"","vorDoi":"10.1186/s40345-025-00390-x","vorDoiUrl":"https://doi.org/10.1186/s40345-025-00390-x","workflowStages":[]},"version":"v1","identity":"rs-6551903","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6551903","identity":"rs-6551903","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}