Determinants and Outcomes of Suicidal Behavior Among Patients With Major Depressive Disorder

Key Points Question What are the clinical and societal outcomes, including all-cause mortality, associated with suicidal behavior in patients with major depressive disorder (MDD)? Findings In this cohort study of 158 169 unipolar MDD episodes, 1.4% involved records of suicidal behavior. The all-cause mortality among patients with suicidal behavior was 2.6 times higher than among matched patients with MDD without records of suicidal behavior. Meaning These findings show an association between suicidal behavior and all-cause mortality in patients with MDD and warrant additional interventional studies in health care practice.

This supplemental material has been provided by the authors to give readers additional information about their work.

eAppendix. Definition of Major Depressive Disorder (MDD) Episode
Since we do not have clinical depression ratings scales recorded at regular timepoints for all patients, we invented a definition in order to get a proxy for the length of an MDD-episode (or rather, the duration of healthcare contacts related to MDD).This was operationally defined based on recorded activities related to depression: (1) We identified each patient's first recorded MDD-diagnosis (ICD10: F32-Depressive episode and F33-Recurrent depressive episode), which marked the start of the first documented depressive episode (i.e., the MDD-baseline).
(2) For each patient we further analyzed the time from first recorded MDD-diagnosis to subsequent depressive events.If the time-interval between the two records of depressive events was ≤365 days the episode was categorized as ongoing, while if the time interval was >365 days the episode was categorized as closed at the date of the last depressive event.Depressive events were defined as: (1) records of depression diagnoses, (2) filled prescriptions of antidepressants (AD; ATC: N06A) and addon medication for depression (lithium, risperidone, olanzapine, aripiprazole, and quetiapine (>100 mg)), electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), or treatment with psychotherapy.If the last depressive event was a dispensation of either AD or add-on medication, we extended the episode with the number of dispensed tablets (i.e., a maximum of 100 days was added).( 3) When an episode is categorized as closed, a subsequent record of a depression diagnosis code would mark the start of a new episode.
A filled prescription of an antidepressant Each major depressive disorder (MDD) episode a with at least one record of suicidal behavior (SB) b (MDD-SB) within the episode was matched to an MDD-episode without a record of SB (MDD-non-SB).The episodes were matched by patients' age, sex, and socioeconomic status.The matched MDD-episodes in MDD-non-SB group also had to have an MDD-duration at least as long as the time from start of MDD until record of first SB for the episodes to which they were matched within the MDD-SB group.Matched controls were given the same index date as the matched case (see figure below).This means that if an MDD-episode has a record of SB 100 days after start of the MDD-episode, the index date was start of the MDD-episode + 100 days.The five matched MDD-episodes (with no records of SB) were given the same index, i.e., start of depressive episode + 100 days.a Definition of a major depressive disorder (MDD) episode is displayed in Supplement A. b Suicidal behavior (SB) was defined by the ICD10 codes X60-X84 (intentional self-harm) recorded in any diagnosis position and in both outpatient and inpatient healthcare settings.See methods section for more information.This binary variable indicates if the patient within the past three years before start of current MDD-episode either has been diagnosed with mental and behavioral disorders due to psychoactive substance use (ICD10:F10-F19).

Personality disorder
This binary variable indicates if the patient within the past three years before start of current MDD-episode been diagnosed with personality disorder (ICD10:F60) Hyperkinetic disorders This binary variable indicates if the patient within the past three years before start of current MDD-episode been diagnosed for hyperkinetic disorders (ICD10:F90) Autism spectrum disorder -ASD This binary variable indicates if the patient within the past three years before start of current MDD-episode been diagnosed with autism spectrum disorder (ICD10:F840, F841, F845) Intentional self-harm This binary variable indicates if the patient within the past three years before start of current MDD-episode has a recording of intentional self-harm (ICD10:X60-X84).We included diagnosis of intentional self-harm recorded both in outpatient and inpatient care.

Lost workdays
This continuous variable includes the number of lost workdays during the past 12 months before start of current MDD-episode.We included both sick-leave days and days with disability pension.a Suicidal behavior (SB) was defined by the ICD10 codes X60-X84 (intentional self-harm) recorded in any diagnosis position and in both outpatient and inpatient healthcare settings.See methods section for more information.b Definition of a major depressive disorder (MDD) episode is displayed in Supplement A.

ICD10-code N (%)
Intentional     non-linearities were handled by transforming the continuous variables using restricted cubic splines, each with three knots placed at the respective 10th, 50th, and 90th sample percentiles.We approximated the full model by using a fast backward algorithm on an ordinary least squares model in which the estimated linear predictor from the full model was the outcome and all variables were entered in exactly the same manner as in the full model.Thus, in the first step R 2 = 1.0 by design and by removing variables in a stepwise manner, the full model could be approximated to an arbitrary level.The model was internally validated using 300 bootstrap samples.In validation of the final model, we accounted for non-independence (i.e., that one individual could have had more than one SB/MDD-episode).Discrimination was assessed by Harrell's c-index and calibration was assessed graphically by comparing observed event rates with the predicted risk at one year after index.b Instructions on how to interpret the nomogram using an example: The risk for SB within one year after start of MDD-episode for a 40-year-old patient with no history of SB, but with a history of substance use and sleep disorders, who was diagnosed in non-psychiatric care, with a history of AD-therapy but no history of anxiety, is arrived at as follows.Start with the line "age and no history of SB" and mark "40".This mark is compared to the first row, by drawing a straight vertical line, to get the risk point of approximately 10.The row "history of substance use" is "yes" for the patient, which corresponds to around 32 risk points (first row) and "history of sleep disorders" is "yes" which corresponds to about 15 risk points."History of antidepressant therapy" was "yes" for the patient, which corresponds to approximately 8 risk points, and the rows "healthcare level where depression was diagnosed" and "history of anxiety disorders" both correspond to 0 risk points (as the patient had "no" on these two variables).Finally, all risk points are summed-up (i.e., 10+32+15+0+8+0 in this example) rendering in a total risk score (the row "total points") of 65.This sum is compared to the lowest row "predicted value", which is equivalent to a risk for SB just above 0.015 (1.5%).c Suicidal behavior (SB) was defined by the ICD10 codes X60-X84 (intentional self-harm) recorded in any diagnosis position and in both outpatient and inpatient healthcare settings.See methods section for more information.d Definition of a major depressive disorder (MDD) episode is displayed in Supplement A. e All covariates used in the development of the model are based on data during a time period of three years before start of the MDD-episode and defined in Supplement D.

eTable 4 .
Characteristics at Start of the Major Depressive Disorder (MDD) Episodes (MDD-Baseline) Among Patients With Records of Suicidal Behavior (SB) Within the Current MDD Episode Compared With All MDD Episodes (With and Without Records of SB) eFigure 4. Prevalence of Psychiatric Comorbid Conditions 12 Months Before and 12 Months After Index (Time of First Suicidal Behavior [SB] Within the Major Depressive Disorder [MDD] Episode) eFigure 5. Mean Monthly Health Care Resource Utilization (HCRU) and Work Loss 12 Months Before and 12 Months After Index (Time of First Suicidal Behavior [SB] Within the Major Depressive Disorder [MDD] Episode) eFigure 6. Nonogram for the Cox Proportional Hazards Model on Determinants for Suicidal Behavior Within 1 Year After Start of a Major Depressive Disorder (MDD) Episode, Based on Patients With MDD Episodes Between 2015 and 2017 Residing in Stockholm for at Least 3 Years Prior to Start of MDD eFigure 7. Calibration of the Cox Proportional Hazards Model on Determinants for Suicidal Behavior (SB) Within 1 Year After Start of a Major Depressive Disorder (MDD) Episode Figure 1.Definition of depressive episode

eFigure 2 .
Cumulative Proportion of Major Depressive Disorder (MDD) Episodes a With Records of Suicidal Behavior (SB) b After Start of an MDD Episode, by Age Strata a Definition of a major depressive disorder (MDD) episode is displayed in Supplement A. b Suicidal behavior (SB) was defined by the ICD10 codes X60-X84 (intentional self-harm) recorded in any diagnosis position and in both outpatient and inpatient healthcare settings.See methods section for more information.eTable 3. Specification of Type of Suicidal Behavior (SB) Events a in Descending Order Among the 2,240 Patients With Major Depressive Disorder (MDD) b and SB.Note that patients may have had more than one type of SB-event.

eFigure 3 .
Cumulative Probability of All-Cause Mortality in Patients With Major Depressive Disorder (MDD) a , With and Without Suicidal Behavior (MDD-SB) b Compared With MDD-Non-SB, c Sensitivity Analysis In this sensitivity analysis, MDD-episodes were censored at the end of the MDD-episode.a Definition of a major depressive disorder (MDD) episode is displayed in Supplement A. b Suicidal behavior (SB) was defined by the ICD10 codes X60-X84 (intentional self-harm) recorded in any diagnosis position and in both outpatient and inpatient healthcare settings.See methods section for more information.c For MDD-SB, index is the date of first SB within the MDD-episode.The matched controls (MDD-non-SB) aregiven the same index date as their matched case.The matching procedure is explained in Supplement B.
7) a Definition of a major depressive disorder (MDD) episode is displayed in Supplement A. b Suicidal behavior (SB) was defined by the ICD10 codes X60-X84 (intentional self-harm) recorded in any diagnosis position and in both outpatient and inpatient healthcare settings.See methods section for more information.c Psychiatric and non-psychiatric comorbid conditions recorded five years prior to the start of the MDD-episode.Definitions are displayed in Supplement C. d Treatments recorded at any time prior to the start of the MDD-episode.Definitions are displayed in Supplement C. e HCRU recorded within one year prior to the start of the MDD-episode.See methods section for more information.f Work-loss recorded within one year prior to the start of the MDD-episode.See methods section for more information.eFigure 4. Prevalence of Psychiatric Comorbid Conditions a 12 Months Before and 12 Months After Index (Time of First Suicidal Behavior [SB] b Within the Major Depressive Disorder [MDD] Episode c ) a Psychiatric comorbid conditions are defined in Supplement C. b Suicidal behavior (SB) was defined by the ICD10 codes X60-X84 (intentional self-harm) recorded in any diagnosis position and in both outpatient and inpatient healthcare settings.See methods section for more information.c Definition of a major depressive disorder (MDD) episode is displayed in Supplement A. eFigure 5. Mean Monthly Health Care Resource Utilization (HCRU) and Work Loss 12 Months Before and 12 Months After Index (Time of First Suicidal Behavior [SB] a Within the Major Depressive Disorder [MDD] Episode b )a Suicidal behavior (SB) was defined by the ICD10 codes X60-X84 (intentional self-harm) recorded in any diagnosis position and in both outpatient and inpatient healthcare settings.See methods section for more information.b Definition of a major depressive disorder (MDD) episode is displayed in Supplement A.

eFigure 6 .
Nomogram a,b for the Cox Proportional Hazards Model on Determinants for Suicidal Behavior (SB) c Within 1 Year After Start of a Major Depressive Disorder (MDD) Episode d , Based on Patients With MDD Episodes Between 2015 and 2017 Residing in Stockholm for at Least 3 Years Prior to Start of MDD e a A Cox's proportional hazard model including all variables (see Supplement D) was fitted to the data.Possible

Definition of Variables Included in the Development of the Cox Proportional Hazards Model on Determinants for Suicidal Behavior (SB) a Within 1 Year After Start of a Major Depressive Disorder (MDD) Episode b
AnxietyThis binary variable indicates if the patient within the past three years before start of current MDD-episode either has been diagnosed for anxiety (ICD10:F41) Substance use Definition of a major depressive disorder (MDD) episode is displayed in Supplement A. b