case study 142 depressed patient with suicidal thoughts

• Introduction
• Conclusions
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Flowchart describing the derivation of the study sample of patients with major depressive disorder (MDD) episodes (as defined in the eAppendix in Supplement 1 ), including the matched study sample of patients with MDD with and without suicidal behavior (SB). Suicidal behavior was defined using International Classification of Diseases, Tenth Revision codes X60 to X84 (intentional self-harm) recorded in any diagnosis position and in both outpatient and inpatient health care settings. The Methods section provides more information. For MDD with SB, the index is the date of first SB within the MDD episode. The matched controls (patients with MDD without SB) are given the same index date as their matched case. The matching procedure is explained in eFigure 1 in Supplement 1 .

Definition of an MDD episode is provided in the eAppendix in Supplement 1 . Suicidal behavior was defined using International Classification of Diseases, Tenth Revision codes X60 to X84 (intentional self-harm) recorded in any diagnosis position and in both outpatient and inpatient health care settings. The Methods section provides more information. For MDD with SB, index is the date of first SB within the MDD episode. The matched controls (MDD without SB) are given the same index date as their matched case. The matching procedure is explained in eFigure 1 in Supplement 1 .

Ongoing treatment with antidepressant therapy at 12 months before and 12 months after index.

eAppendix. Definition of Major Depressive Disorder (MDD) Episode

eFigure 1. Matching Procedure for Patients With Major Depressive Disorder (MDD) With and Without Suicidal Behavior (SB)

eTable 1. Definitions of Inclusion and Exclusion Criteria, Treatments, and Comorbid Conditions

eTable 2. Definition of Variables Included in the Development of the Cox Proportional Hazards Model on Determinants for Suicidal Behavior (SB) Within 1 Year After Start of a Major Depressive Disorder (MDD) Episode

eFigure 2. Cumulative Proportion of Major Depressive Disorder (MDD) Episodes With Records of Suicidal Behavior (SB) After Start of an MDD Episode, by Age Strata

eTable 3. Specification of Type of Suicidal Behavior (SB) Events in Descending Order Among the 2,240 Patients With Major Depressive Disorder (MDD) and SB

eFigure 3. Cumulative Probability of All-Cause Mortality in Patients With Major Depressive Disorder (MDD) With and Without Suicidal Behavior (MDD-SB) Compared With MDD-Non-SB, Sensitivity Analysis

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 Year 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

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Lundberg J , Cars T , Lampa E, et al. Determinants and Outcomes of Suicidal Behavior Among Patients With Major Depressive Disorder. JAMA Psychiatry. 2023;80(12):1218–1225. doi:10.1001/jamapsychiatry.2023.2833

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

• 1 Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, and Stockholm Health Care Services, Stockholm, Sweden
• 2 Sence Research AB, Uppsala, Sweden
• 3 Department of Medical Sciences, Uppsala University, Uppsala, Sweden
• 4 Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden
• 5 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
• 6 Janssen-Cilag AB, Solna, Sweden

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.

Importance   Major depressive disorder (MDD) is an important risk factor of suicidal behavior, but the added burden of suicidal behavior and MDD on the patient and societal level, including all-cause mortality, is not well studied. Also, the contribution of various prognostic factors for suicidal behavior has not been quantified in larger samples.

Objective   To describe the clinical and societal outcomes, including all-cause mortality, of suicidal behavior in patients with MDD and to explore associated risk factors and clinical management to inform future research and guidelines.

Design, Setting, and Participants   This population-based cohort study used health care data from the Stockholm MDD Cohort. Patients aged 18 years or older with episodes of MDD diagnosed between January 1, 2012, and December 31, 2017, in any health care setting were included. The dates of the data analysis were February 1 to November 1, 2022.

Exposures   Patients with MDD with and without records of suicidal behavior.

Main Outcomes and Measures   The main outcome was all-cause mortality. Secondary outcomes were comorbid conditions, medications, health care resource utilization (HCRU), and work loss. Using Region Stockholm registry variables, a risk score for factors associated with suicidal behavior within 1 year after the start of an MDD episode was calculated.

Results   A total of 158 169 unipolar MDD episodes were identified in 145 577 patients; 2240 (1.4%) of these episodes, in 2219 patients, included records of suicidal behavior (mean [SD] patient age, 40.9 [18.6] years; 1415 episodes [63.2%] in women and 825 [36.8%] in men). A total of 11 109 MDD episodes in 9574 matched patients with MDD without records of suicidal behavior were included as controls (mean [SD] patient age, 40.8 [18.5] years; 7046 episodes [63.4%] in women and 4063 [36.6%] in men). The all-cause mortality rate was 2.5 per 100 person-years at risk for the MDD-SB group and 1.0 per 100 person-years at risk for the MDD-non-SB group, based on 466 deaths. Suicidal behavior was associated with higher all-cause mortality (hazard ratio, 2.62 [95% CI, 2.15-3.20]), as well as with HCRU and work loss, compared with the matched controls. Patients with MDD and suicidal behavior were younger and more prone to have psychiatric comorbid conditions, such as personality disorders, substance use, and anxiety, at the start of their episode. The most important factors associated with suicidal behavior within 1 year after the start of an MDD episode were history of suicidal behavior and age, history of substance use and sleep disorders, and care setting in which MDD was diagnosed.

Conclusions and Relevance   This cohort study’s findings suggest that high mortality, morbidity, HCRU, and work loss associated with MDD may be substantially accentuated in patients with MDD and suicidal behavior. Use of medication aimed at decreasing the risk of all-cause mortality during MDD episodes should be systematically evaluated to improve long-term outcomes.

According to the World Health Organization, approximately 5% of the adult population worldwide experienced depression in 2021. 1 Depression is associated with increased all-cause mortality. 2 A recent populationwide study showed that all-cause mortality was more than doubled in patients with major depressive disorder (MDD) compared with population controls and that mortality is further increased in patients with treatment-resistant MDD. 3 , 4 Suicidal thoughts or behaviors are recognized as diagnostic criteria for MDD in the DSM-5 , and suicidal behavior, defined as self-inflicted harm with or without concurrent suicidal ideation, has been reported in up to 50% of patients with MDD; the longer the episodes, the higher the occurrence. 5 , 6 Furthermore, suicidal behavior and previous suicide attempts have been shown to increase the risk of death from suicide. Approximately 7% to 13% of patients with nonfatal suicide attempts have been reported to die from suicide at a later time, 7 , 8 and up to 7% of patients with MDD who are in contact with specialized psychiatric care have been reported to die from suicide. 6

However, most patients with MDD are not treated in specialized care, 9 , 10 and studies to date have been limited by nonrandom sampling due to nonuniversal access to health care and/or exclusion of primary care data. Thus, it is not established to what extent the aforementioned estimates are representative of patients with MDD as a whole or to what extent suicidal behavior is a risk factor for all-cause mortality. The focus on a specific cause of death (ie, suicide) may underestimate the overall risk of death in the population of patients with MDD and suicidal behavior. Thus, focusing on suicidal behavior and all-cause mortality in a population-wide observational study may result in more clinically relevant and replicable data. In Sweden, all residents have universal access to health care, 11 with a nominal copayment for health care visits, hospitalizations, and drugs. The opportunities for individual record linkage, together with near-complete information on population health care coverage, including mortality, help to overcome some of the limitations in data that may exist in other countries and from clinical cohorts.

In this study, we investigated the all-cause mortality associated with MDD episodes with suicidal behavior (MDD-SB) compared with MDD episodes without records of suicidal behavior (MDD-non-SB). We also aimed to describe patient clinical characteristics, such as comorbid conditions, treatment patterns, health care resource utilization (HCRU), and work loss. Furthermore, in a separate analysis, we identified risk factors of suicidal behavior in patients with MDD based on information available at the start of an MDD episode.

In this population-based cohort study, we used data from the Stockholm MDD Cohort (SMC), 3 , 4 which comprises all patients diagnosed with MDD according to International Classification of Diseases, Tenth Revision ( ICD-10 ) codes F32 to F33 in any health care setting in the region of Stockholm (approximate population, 2.4 million) between 2010 and 2018. 12 The data in SMC are based on the Regional Healthcare Data Warehouse of Region Stockholm, including information on all individual contacts with health care in Region Stockholm. The information in the data warehouse includes date of death but not cause of death. This project is a part of a framework to facilitate research collaboration between research-based companies and Region Stockholm and registered at the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (European Union Electronic Register of Post-Authorisation Studies No. 256646). The study was approved by the regional ethics committee, Stockholm, Sweden (No. 2018/546-31), with a waiver for informed consent because all analyses were performed using pseudonymized data. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology ( STROBE ) reporting guideline.

We identified all recorded MDD episodes between January 1, 2012, and December 31, 2017, when patients were aged 18 years or older at the start of the episode (MDD baseline) (eAppendix in Supplement 1 ). Each patient could contribute more than 1 episode. To allow for analyses of MDD baseline conditions, patients residing in Stockholm for 12 months or less before the start of the MDD episode were excluded. We also excluded patients with a history of psychosis, bipolar disorder, manic episode, or dementia. Diagnostic criteria for MDD include suicidal thoughts or attempts (suicidal behavior); therefore, suicidal behavior was defined as ICD-10 codes for intentional self-harm (X60-X84). Diagnoses of harm of undetermined intent ( ICD-10 codes Y10-Y34) were not included in this study. Records in outpatient or inpatient health care settings were collected, and the date of the first recorded diagnosis of suicidal behavior within an MDD episode was set as the index. At the start of an MDD episode (MDD baseline), patients with MDD and suicidal behavior (MDD-SB group) were compared with all patients with MDD. At index, patients in the MDD-SB group were compared with patient with MDD but without records of suicidal behavior (MDD-non-SB group) by matching each patient in the MDD-SB group (ie, cases) on age (within 2 years), sex, year of MDD diagnosis, and sociodemographic status with up to 5 patients in the MDD-non-SB group (ie, controls). To be eligible for matching, controls were required to have an MDD episode duration at least as long as their matched case’s time from the start of MDD until record of first suicidal behavior. Controls were given the same index date as their matched case (eFigure 1 in Supplement 1 ). Definitions of inclusion and exclusion criteria are presented in eTable 1 in Supplement 1 .

The data analysis for this study was performed between February 1 and November 1, 2022. All data management and analyses were performed using R, version 3.6.0 software (R Foundation for Statistical Computing). Patient characteristics were described at MDD baseline and index (date of suicidal behavior). In the time-to-event analyses, patients were censored at first instance of emigration from Stockholm, death, a record of an exclusion criterion, or end of follow-up, whichever came first. The time to first suicidal behavior was calculated as the time from MDD baseline until index, and in this analysis, end dates of MDD episodes also qualified as censoring events. To evaluate the association of suicidal behavior with all-cause mortality, we used the Kaplan-Meier method and Cox proportional hazards regression models. Robust SEs were used to account for nonindependence (ie, that 1 patient could have had >1 case of suicidal behavior per MDD episode). Episodes of MDD-SB and MDD-non-SB were followed up from index until the outcome. In a sensitivity analysis, end dates of MDD episodes were also included as censoring events. Departures from the proportional hazards assumption were evaluated using Schoenfeld residuals.

We analyzed psychiatric comorbid conditions, ongoing antidepressant therapy, HCRU, and work loss from 12 months before to 12 months after the index date. Psychiatric comorbid conditions were expressed as cumulative proportions per month; ie, patients were included the first month they were diagnosed with a psychiatric comorbid condition, and this information was carried forward to all later time points. Ongoing treatment with antidepressant therapy (antidepressants, add-on medication, electroconvulsive therapy [ECT], repetitive transcranial magnetic stimulation, and psychotherapy) (eTable 1 in Supplement 1 ) was calculated as the proportion of patients treated per month. To be defined as receiving ongoing treatment with antidepressant and add-on medication, each patient had to have at least 1 pharmacy dispensation of medication that month or be covered with a medical supply from a previous dispensation. For electroconvulsive therapy, repetitive transcranial magnetic stimulation, or psychotherapy, patients were required to have at least 1 record of a clinical procedure code for that procedure that month. Health care resource utilization was defined as the mean number of outpatient physician visits and inpatient bed days per month, and work loss was defined as the mean number of days not worked per month. Analyses of work loss were performed for patients aged between 20 years and 64 years. Sick leave episodes lasting 14 days or less were not included, as they are not recorded in patient records.

Risk factors for suicidal behavior among patients with MDD were assessed using a study sample restricted to MDD episodes between 2015 and 2017. Only patients residing in Stockholm for 3 years or more prior to the start of the MDD episode were included to ensure a sufficient period of baseline data. Episodes where the start date of the MDD and date of suicidal behavior coincided were excluded. In the model, the outcome of interest was a record of suicidal behavior within 1 year after the start of an MDD episode. Potential risk factors (eTable 2 in Supplement 1 ) were selected based on previous reports and data availability, 13 - 16 and a Cox proportional hazards regression model was fitted following the steps by Harrell 17 (details provided in eFigure 6 in Supplement 1 ). The final prediction model was presented as a nomogram. The importance of each risk factor was measured by partial Wald χ 2 minus the predictor df . We adhered to the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis ( TRIPOD ) statement 18 in reporting of the results of the prediction model.

A total of 158 169 unipolar MDD episodes were identified between January 1, 2012, and December 31, 2017 ( Figure 1 ). Among these episodes, 2240 (1.4%) in 2219 patients had at least 1 record of suicidal behavior (MDD-SB group; mean [SD] patient age, 40.9 [18.6] years; 1415 episodes [63.2%] in women and 825 [36.8%] in men), and 552 (24.6%) of these contained 2 or more records of suicidal behavior. In MDD episodes lasting 5 years or more, 430 of 14 170 (3.0%) had at least 1 suicidal behavior (eFigure 2 in Supplement 1 ). The most common form of suicidal behavior was intentional self-poisoning (eTable 3 in Supplement 1 ). The median time from MDD baseline (ie, from start of episode until first suicidal behavior) was 165 days (IQR, 12-510 days). The matched MDD-non-SB control group included 11 109 MDD episodes in 9574 patients (mean [SD] patient age, 40.8 [18.5] years; 7046 episodes [63.4%] in women and 4063 [36.6%] in men) ( Figure 1 ). Patient characteristics at the time of the first suicidal behavior within an MDD episode (index) for the matched study sample are presented in the Table .

The all-cause mortality rate was 2.5 per 100 person-years at risk for the MDD-SB group and 1.0 per 100 person-years at risk for the MDD-non-SB group, based on 466 deaths. This rate corresponds to a hazard ratio of 2.62 (95% CI, 2.15-3.20) ( Figure 2 ). In a sensitivity analysis, MDD episodes were censored at the end of the MDD episode (eFigure 3 in Supplement 1 ).

Already at the start of the MDD episode, patients in the MDD-SB group appeared different compared with all patients with MDD. For example, they were younger, more often diagnosed while in specialized care, and had higher work loss (eTable 4 in Supplement 1 ). Patients in the MDD-SB group also had a gradual increase in the prevalence of comorbid conditions from approximately 12 months before index (eFigure 4 in Supplement 1 ). This increase was most pronounced for anxiety, stress, substance use, and personality disorders. These differences persisted at index between the MDD-SB and MDD-non-SB groups ( Table ). eFigure 5 in Supplement 1 displays the temporal distribution of monthly HCRU and work loss, with a clear peak at index for the MDD-SB group.

Up until index, 1880 patients (83.9%) in the MDD-SB group and 9012 patients (81.1%) in the MDD-non-SB group were treated with antidepressants ( Table ). The proportion of patients treated with add-on medication (including lithium in 21 patients [0.9%] and 25 patients [0.2%] in the MDD-SB and MDD-non-SB groups, respectively) and ECT was higher among those in the MDD-SB group both at index and 12 months after compared with the MDD-non-SB group. A total of 82 patients (3.8%) in the MDD-SB group received ECT during the index month, and the provision of psychotherapy ranged between 248 (11.5%) and 275 (14.2%) patients starting at the index month and through the 12 months after the index month ( Figure 3 ).

A risk score for factors associated with suicidal behavior within 1 year after the start of an MDD episode (outcome) was calculated using available variables. The 2 most important risk factors for suicidal behavior were a history of suicidal behavior together with age, which had a U-shaped association with the outcome, with individuals younger than 20 years or 70 years or older having the highest risks. The final risk score also included the following factors (in descending order), the presence of which increased the risk for the outcome: history of substance use, history of sleep disorders, health care level in which MDD was diagnosed, history of antidepressant use, and history of anxiety disorders. eFigure 6 in Supplement 1 displays the final prediction model, presented as a nomogram; all variables evaluated for entry are defined in eTable 2 in Supplement 1 . The risk score yielded a C index of 0.78, and the internal bootstrap validation indicated only minimal overfitting. The risk score was well calibrated (eFigure 7 in Supplement 1 ).

In this cohort study, we analyzed more than 158 000 MDD episodes during 6 years, of which 2240 (1.4%) also included suicidal behavior, with an average time from MDD diagnosis to first record of suicidal behavior of less than 6 months. We found that all-cause mortality was more than doubled in adults with MDD who had a diagnosis of suicidal behavior compared with those with MDD without suicidal behavior, which in and of itself is associated with a doubled risk compared with control patients without MDD. 2 , 3 We found an immediate increase in mortality after the first suicidal behavior event, which appeared to be elevated throughout the whole observation period. This suggests that suicidal behavior may be a marker for MDD episodes with an increased risk of mortality; although the SMC data were not linked to information regarding cause of death, and any inference regarding causality remains speculative. However, the incidence of somatic disorders was not increased in the MDD-SB group, indicating that unnatural causes, such as accidents and suicides, may have been the main contributors to the increased mortality.

The proportion of patients with suicidal behavior in our study appears to be lower than in other registry-based studies of patients with MDD 19 and compared with self-reports from a general population. 5 A possible explanation could be the virtually full coverage of the patient population with MDD with data from all health care settings in our study, thus not limiting the sample to populations that could be considered to have a higher risk of suicidal behavior, such as patients treated in hospitals or other specialized settings. To reduce the risk of misclassifications, we also chose a stricter definition of suicidal behavior by only including self-harm with intent diagnosed during an ongoing MDD episode. Although previous studies have shown that suicidal behavior is underdiagnosed, 5 our findings suggest that suicidal behavior in all patients with MDD may not be as common as previously described, although any estimate of suicidal behavior and/or suicide attempt could be subject to uncertainty and methodological considerations. However, in our data, suicidal behavior might be seen as a marker for a subgroup of MDD episodes with more psychiatric comorbidity, higher work loss, and substantially higher all-cause mortality. Thus, developing an evidence-based clinical guideline for both acute and long-term interventions for patients with MDD and suicidal behavior may be warranted.

In our study, the majority of patients were treated with antidepressants at the time of their suicidal behavior, indicating that the treatment may not have been sufficiently effective in ameliorating depressive symptoms and associated suicidal behavior. Although the proportion of patients in the MDD-SB group treated with add-on medications, ECT, and/or psychotherapy increased after the first record of suicidal behavior, the proportions were still low. This finding suggests that treatments for a majority of patients with MDD and suicidal behavior could be improved both before and especially after an suicidal behavior event. Specifically, long-term lithium treatment could be indicated given its suggested association with decreased all-cause mortality in affective disorders. 20 Still, our findings showed that less than 1% of patients with MDD and suicidal behavior had initiated treatment with lithium at the time of their first recorded suicidal behavior.

The baseline prevalence of nonpsychiatric comorbid conditions was lower in patients with MDD and suicidal behavior compared with all patients with MDD. This finding could be explained by the lower age at baseline, as the differences disappeared after matching. At baseline, patients in the MDD-SB group also had greater proportions of anxiety disorders and substance use than the MDD-non-SB group, which have previously been shown to be factors linked to suicide, suicide attempts, and deliberate self-harm. 13 , 15 , 21 - 25 Sleep disorders and substance use disorders have previously been reported to be associated with increased all-cause mortality, 26 , 27 whereas anxiety has not. 28 These specific comorbidities were all found to be associated with suicidal behavior in our data. Personality disorders have been linked to suicidal behavior, 13 and they constituted the highest relative difference in proportions between the MDD-SB group and MDD-non-SB group in our study. In addition, the number of patients with personality disorders almost doubled during the follow-up period, suggesting that they were previously underdiagnosed. In absolute numbers, however, the majority of suicidal behavior events were not linked to personality disorders.

The frequency of health care contacts and high rates of psychiatric comorbidity among patients with MDD who later develop suicidal behavior presents important opportunities for health care to identify and treat these patients at an early stage. A comprehensive approach that also includes diagnosing and addressing these comorbidities, in addition to treating depressive symptoms, would be beneficial. Should evidence-based guidelines be developed on how to best optimize treatments to avoid suicidal behavior, they should include early detection of potential patients with MDD and suicidal behavior. With future evidence-based guidelines in mind, we calculated a risk score based on variables present in our data. The risk score could be explored as a tool to help identify the risk of suicidal behavior among patients with MDD in clinical practice. In the risk score, the most important factors associated with suicidal behavior within 1 year after the start of an MDD episode were history of suicidal behavior and age, followed by history of substance use and sleep disorders. However, it is important to emphasize that the predictive ability of this tool needs to be evaluated in other patient populations and to acknowledge that some important variables, such as family history of psychiatric conditions, were not included. 23 Thus, this tool should be used as a complement and should not supersede a thorough clinical evaluation. It is important to acknowledge that not all patients with suicidal behavior present for treatment, 29 even in a universal health care system, which limits the assessment of risk factors and possibilities for prevention.

This study had several limitations. We defined suicidal behavior as any diagnosis of intentional self-harm ( ICD-10 codes X60-X84) and did not include diagnoses of harm of undetermined intent ( ICD-10 codes Y10-Y34). Even so, this broad definition probably gives a comprehensive picture of suicidal behavior among patients with MDD. An suicidal behavior episode was defined by records of consecutive events, and any additional records of suicidal behavior at later time points were attributed to a new episode. This strict definition might have slightly overestimated the number of suicidal behavior episodes, which should be contrasted to previous reports that suicidal behavior is underdiagnosed. 5 The study population consisted of unipolar MDD episodes and excluded patients with records of bipolar disorder, dementia, or psychosis before or at baseline, and patients who developed any of these conditions later were censored in time-to-event analyses, limiting our ability to draw conclusions on MDD-SB in these patient groups. However, suicidal behavior may also be associated with an increased risk of mortality in other psychiatric disorders. Other comorbid conditions, such as anxiety, substance use, and personality disorders, were included, which is important since they are common among patients with MDD in general, as well as among patients with MDD and suicidal behavior in particular.

In this cohort study, we found that 1.4% of MDD episodes in Stockholm, Sweden, involved records of suicidal behavior, which is lower than previously reported. 6 - 8 Among these patients, the all-cause mortality was more than doubled compared with MDD episodes without records of suicidal behavior. Our results also indicate that patients at risk for suicidal behavior can be identified at an early stage to allow for enhanced monitoring and optimized treatment with the goal of preventing suicidal behavior and reducing mortality.

Accepted for Publication: June 9, 2023.

Published Online: August 16, 2023. doi:10.1001/jamapsychiatry.2023.2833

Open Access: This is an open access article distributed under the terms of the CC-BY License . © 2023 Lundberg J et al. JAMA Psychiatry .

Corresponding Author: Johan Lundberg, MD, PhD, Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, and Stockholm Health Care Services, Region Stockholm, Norra Stockholms Psykiatri, Vårdvägen 3, SE-112 81 Stockholm, Sweden ( [email protected] ).

Author Contributions: Drs Lundberg and Cars had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Lundberg, Cars, Leval, Gannedahl, Själin, Björkholm, Hellner.

Acquisition, analysis, or interpretation of data: Lundberg, Cars, Lampa, Ekholm Selling, Leval, Själin, Björkholm, Hellner.

Drafting of the manuscript: Lundberg, Cars, Lampa, Ekholm Selling, Gannedahl, Björkholm, Hellner.

Critical review of the manuscript for important intellectual content: Lundberg, Cars, Lampa, Ekholm Selling, Leval, Själin, Björkholm, Hellner.

Statistical analysis: Lundberg, Cars, Lampa, Ekholm Selling.

Obtained funding: Leval.

Administrative, technical, or material support: Lundberg, Ekholm Selling, Leval, Björkholm, Hellner.

Supervision: Själin, Hellner.

Conflict of Interest Disclosures: Dr Car reported being a co-owner of Sence Research, which is an independent company in epidemiology and biostatistics; Janssen-Cilag AB has funded Sence Research for statistical analyses within this research project. Dr Lampa reported receiving consulting fees from Biogen outside of the submitted work. Dr Leval reported holding shares from Johnson and Johnson outside the submitted work. No other disclosures were reported.

Funding/Support: This study was funded by Region Stockholm and Janssen-Cilag AB. This research project is part of a framework aimed to facilitate research collaborations between the public health care authorities in Stockholm County, Sweden, and research-based companies. All pharmaceutical companies in Sweden were invited to participate in this depression research program via the pharmaceutical industry trade association. Region Stockholm was the initiator of this research project and governed all research data. Region Stockholm further supported this project with scientific and clinical expertise.

Role of the Funder/Sponsor: The sponsor (research authority) Region Stockholm was responsible for the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Janssen-Cilag participated, provided scientific expertise, and supported the analytic work for this project via an external company in biostatistics (Sence Research). No financial transfers were made between Janssen-Cilag AB and Region Stockholm.

Data Sharing Statement: See Supplement 2 .

Additional Contributions: The authors thank Karolinska University Hospital, Danderyds sjukhus AB, Södersjukhudet AB, TioHundra AB, Södertälje sjukhus, Stockholms läns sjukvårdsområde, and the public Health Care Services Administration for providing data for this study.

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• > Volume 19 Issue 4
• > To be or not to be: legal and ethical considerations...

Article contents

To be or not to be: legal and ethical considerations in suicide prevention.

Published online by Cambridge University Press:  02 January 2018

Making potentially critical clinical decisions in complex cases with the real risk of death by suicide is a most challenging job in psychiatry. Sadly, risk assessment and management of harm to self is a largely ignored area compared with risk of harm to others. The legal and ethical challenges are more nuanced, and contemporary training schemes and textbooks on psychiatry have not always done justice to this area, where front-line clinicians require probably most assistance. This article is an attempt to integrate the seemingly disparate threads from legal, ethical and clinical realms to assist decision-making, and it introduces a set of principles for managing these in clinical practice. It refers in particular to legislation in England and Wales, but the clinical and ethical issues discussed are universal.

‘There is but one truly philosophical problem and that is suicide. Judging whether life is or is not worth living amounts to answering the fundamental question of philosophy.’

Albert Camus ( The Myth of Sisyphus , 1942)

Psychiatrists in England have found themselves at the centre of government strategy following its proposed reduction of the suicide rate by one fifth by 2010 ( Department of Health 1999 ). However, Camus' words reflect the enormity of the challenge faced by doctors and nurses asked to assess a person who is thought to be suicidal. The act of suicide is no longer illegal in the UK (in light of the Suicide Act 1961), but aiding and abetting a suicide remains so. Although mental health legislation does not mandate clinicians to prevent a person putting themselves at risk, failure to prevent suicide in an identifiable victim may put hospital trusts and clinicians at risk of civil suits for negligence. Recent case law has found trusts liable for failure to prevent the suicide of patients known to pose a ‘real and immediate’ risk of taking their own lives ( Savage v South Essex Partnership NHS Foundation Trust 2008 ) and has considered the deaths of both formal and informal patients to be the result of negligence ( Rabone v Pennine Care NHS Foundation Trust 2012 ), ordering trusts to pay pecuniary damages to next of kin ( Reynolds v United Kingdom 2012 ). Heading a five-member judicial bench, Lord Walker in the Rabone case stated: ‘if there was a real and immediate risk of suicide at [the material] time of which the trust was aware or ought to have been aware, then in my view the trust was under a duty to take reasonable steps to protect [the patient] from it’. He defined real risk as ‘a substantial or significant risk and not a remote or fanciful one’ and immediate risk as ‘present and continuing’ ( Rabone v Pennine Care NHS Foundation Trust 2012 ).

Notably, there is major criticism of the way that risk was quantitatively calculated by the psychiatric experts in the Rabone case. The defence expert cited a risk ‘of the order of 70%’, whereas the trust expert accepted a ‘50% risk’ ( Rabone v Pennine Care Trust 2009 ). No rationale was provided as to how these risk probabilities were calculated, and Reference Large, Ryan and Callaghan Large et al (2012) suggest that they might be affected by hindsight bias.

It is notoriously difficult to gauge the risk of suicide in self-harming individuals or to decide what treatment should be provided, who should provide it and where. One of the best validated instruments, Beck's Suicide Intent Scale, has a positive predictive value (PPV) of only 4%, i.e. it successfully predicts only 4 out of 100 self-harming patients who will later die by suicide ( Reference Harriss and Hawton Harris 2005 ). Nevertheless, individual professionals are likely to be seen as negligent if a patient at high risk of suicide dies in their care. Perhaps a doctor does not detain the patient ‘at the right time’ or a nurse meant to be observing the patient leaves their post for a few minutes. They are now more than ever likely to be exposed to legal action in the wake of these case judgments. At the very least, they will face disciplinary and professional hearings by their respective regulatory bodies.

In this article, I discuss three aspects of clinical decision-making with regard to suicidal or self-harming patients. First, I set out the empirical challenges encountered by clinicians in assessing risk. Second, I explore the ethical questions that arise from cases involving suicide and self-harm: especially the balance between respect for patient autonomy and the exercise of healthy paternalism in a climate of risk-averse health policy. Finally, I offer a set of principles that busy clinicians can use to deal with common clinical, legal and ethical problems in practice. I do not claim that these are definitive or exhaustive: only that they are based on practical experience of managing cases of high-risk, repetitive self-harm by patients with extremely complex needs.

Clinical conundrums

Clinical conundrums come in the form of problems such as how to differentiate a patient who is suicidal from one who is self-harming but has no wish to die. As it is notoriously difficult to treat a behaviour, for that is what suicidal acts are, should one focus on clinical syndromes? But patients with clinical syndromes such as personality disorders are very difficult to manage as they alienate carers, and those with substance use disorders cannot be treated involuntarily under English mental health law. Should one instead focus on high-risk periods or methods of self-harm?

Whom to treat?

Although the risk factors for suicide are well established, predicting who will actually take their own life is not so easy. For example, patients with a history of self-harm are more than four times as likely to die by suicide than those without such a history. However, people who self-harm outnumber those who take their own life, i.e. although most people who die by suicide have self-harmed, only a subgroup of those who self-harm go on to kill themselves ( Reference Appleby, Shaw and Kapur Appleby 2006 ). As noted earlier, the use of psychometric risk measures adds little in these cases.

There is also a complication and expense in enforcing mental health legislation. Many who repeatedly self-harm are not seeking help or care; indeed, some actively refuse it or assault those who are trying to prevent them from self-harming ( Reference Sarkar Sarkar 2011a ). Reducing their risk of dying by suicide often requires detention under the Mental Health Act 1983, at a time when there are fewer beds for this purpose. Detention may also imply support under Section 117 of the Act, which includes assertive attempts at engaging patients (e.g. telephone calls, home visits or contact with the patient's family) ( National Confidential Inquiry into Suicide and Homicide by People with Mental Illness 2009 ). Following the Wooltorton case ( Box 1 ), capacitous patients may refuse medical treatment after self-poisoning and may also refuse to engage with psychological therapies recommended by clinicians. It seems clinically futile to detain someone under the Mental Health Act to prevent them from harming themselves if they are simultaneously refusing to be helped. However, the legal position is that if there is ‘real and immediate risk to life’ about which the authorities know or ought to know, they have a duty to do ‘all that reasonably could [be] expected’; failing to do so will lead to (legal) consequences that can be devastating, not just for the patient but also for the staff and the service ( Savage v South Essex Partnership NHS Foundation Trust 2008 ).

BOX 1 Capacitous refusal of life-saving treatment for self-harm

In 2007, Ms Kerrie Wooltorton was not prevented from dying by suicide by her local hospital. She was a 26-year-old woman with a history of depression and some evidence of disordered personality traits. In the previous 12 months, she had been admitted to mental health units on several occasions; and there were nine separate incidents where she had drunk industrial antifreeze. In September 2007, in accordance with the Mental Capacity Act 2005, Ms Wooltorton made an advance refusal of life-saving medical treatment in the event of her poisoning herself. She indicated that she was fully aware of the consequences of refusing such treatment. Three days after drafting the advance refusal, she made her final suicide act of drinking antifreeze. She called an ambulance, not from a desire to have life-saving treatment, but because she did not want to die in her flat alone.

At the subsequent Coroner's hearing, there was considerable controversy. On the one hand, a young woman was deemed to have capacity to make a decision that her life was no longer worth living, despite having recognised mental disorders and having had previous psychiatric treatment. Her history of mental disorder and treatment were not considered adequate reasons preventing her from making a capacitous decision to end her life. On the other hand, it was possible to see the mental health services as having abandoned their duty of care to a young person in a highly distressed and disordered state of mind. Note that her history and presentation contained several high-risk factors associated with completed suicide, which often lead to detention for treatment:

• she had a known, treatable mental disorder

• in the previous 12 months she had made several attempts to take her life

• she had received previous psychiatric treatment

• she gave advance notice of her intention to die through a potentially fatal method of self-harm.

Ms Wooltorton's parents threatened to sue for medical negligence, and the government of the day stated that ‘it was not the intention of the [mental capacity] law to give legal force to such suicidal advance decisions’ ( Reference Bingham Bingham 2009a ). Contrary to the case of Savage ( Savage v South Essex Partnership NHS Foundation Trust 2008 ) the Coroner's Court did not criticise the clinicians, but acknowledged that doctors who were aware of her history had judged Ms Wooltorton to be capacitous at the time of drafting the advance refusal. The coroner concluded that it would have been ‘unlawful’ for doctors to intervene in the wishes of a person with ‘full knowledge’ of what she was doing at the time she drafted her advance directive ( Reference Bingham Bingham 2009b ).

There is an interesting overlap here in terms of the ethical duties of doctors. Treating every individual who self-harms as though they are at potential risk of suicide will entail a significant increase in clinical resources. It may also result in so many false positives that true positives may be missed. In terms of best use of resources, it might be better to focus on high-risk individuals, and not only on anyone who cuts themselves ( Reference Runeson, Tidemalm and Dahlin Runeson 2010 ). However, such an approach means that some individuals will die by suicide because no algorithm is 100% accurate, and cases deemed to be low-risk will turn out to be occult ‘high-risk’.

What to treat?

Might it make more sense clinically to focus on high-risk factors such as diagnosis, not behaviours? This is true to an extent. The two most common single diagnoses among those who die by suicide are affective disorders (46%) and schizophrenia (19%); next, a large proportion (29%) have diagnoses of personality disorder, drug and alcohol misuse, anxiety or adjustment disorders ( Reference Appleby, Shaw and Kapur Appleby 2006 ). So even if clinicians targeted the two categories of serious mental illnesses that can be easily treated with pharmacotherapy, there would still be a sizeable group who would need more complex care packages; and (as already mentioned) might refuse to engage. Similarly, the sheer numbers would be a challenge for current resources. For example, if every person with a drug or alcohol problem is assessed for suicide risk, and offered treatment, this would mean offering therapy to thousands more people.

When to treat?

Does knowledge of high-risk periods help the clinician? A study by Reference Gunnell, Hawton and Ho Gunnell et al (2008) found that the risk of suicide in the month after psychiatric in-patient care was around 100 times greater than that for general population. More than 6.5% of all patients discharged from psychiatric in-patient care were readmitted for an episode of self-harm within 12 months, with a third of these episodes occurring in the 4 weeks after discharge, thereby sharing many of the features of suicide after discharge. The risk of self-harm in this period was higher in females, younger people, those with diagnoses of depression, personality disorder and substance misuse, and those with shorter lengths of stay. However, these data do not help clinicians to easily determine who should be allowed to go home with advice, who should be persuaded to stay voluntarily in hospital and who should be detained against their will. They also do not often tell the clinician who should receive the full force of psychiatric input in terms of monitoring and support.

In summary, assessing and acting on the risk of suicide presents many of the same clinical challenges as managing the risk of violence ( Reference Sarkar, Agrawal, Bolton and Gaind Sarkar 2011b ). There are a number of well-established actuarial risk factors (age, gender, diagnosis and past behaviour), but no accurate algorithm for establishing which of the people with these risk factors are actually at high risk of completing a suicidal act. Further, it is in the nature of suicide (as it is in fatal violence to others) that some deaths occur impulsively, in the absence of any known risk factors, or unintentionally. Hindsight bias may make such cases appear ‘obvious’ later, but this is a cognitive illusion ( Reference Kahneman Kahneman 2011 ).

Ethical considerations

Philosopher and ethicist Tom Beauchamp has argued that, in Western society, people are allowed to take risks with their lives if their decisions are made capacitously, which requires that they have ‘the ability to grasp, appreciate the significance of, form relevant intentions and not be controlled by either internal or external forces that [they] cannot resist’ ( Reference Beauchamp, Regan, Beauchamp and Callicott Beauchamp 1993 ). This capacitous autonomy over one's life is protected if a decision emerges out of rational logic, even though it results in one's death – the so-called ‘rational suicide’ ( Reference Brandt, Battin and Mayo Brandt 1980 ). Most modern societies consider this to be morally permissible as long as the decision is understandable or the individual's actions bring benefit to society (e.g. soldiers going to war, fire-fighters risking their lives or astronauts going into outer space). However, when a risky course of action by an individual is driven solely by personal wishes and desires that appear to lack logic or reason, or have little or no benefit to society, most modern societies do not unconditionally support the individual's personal autonomy and self-determination. For example, people who engage in extreme sports may not be able to take out life insurance: even though it is not their intention to kill themselves, society speaks through tacit discouragement of such behaviours.

But what of individuals who are under the legal age of consent, or who have intellectual disabilities or mental disorder? Are they permitted a ‘rational suicide’? No. Our society considers that the decision by such a person to take their own life is ‘irrational’ (as judged by clinicians and approved by law) and therefore morally impermissible ( Reference Brandt, Battin and Mayo Brandt 1980 ), for their lives are considered to be ‘worth living’ ( Reference Glover Glover 1990 ).

The notion of sanctity of life is championed by theologians of all hues, and most religions assert that life is a gift from the creator and taking it shows disrespect towards God ( Reference Baelz, Battin and Mayo Baelz 1980 ). It is likely that someone who is depressed forgets all that they usually get out of life. This is probably true regardless of the cause of the depression: long-term severe depressive disorder, a transient episode associated with a personality disorder, or a challenging life event such as bereavement, injury or unemployment. On the other hand, someone who fears death, possibly because of the belief that they would go to hell, may wish they had never been born, but still not want to die.

Who decides?

Clinicians are sometimes required to make judgements on life and death issues on behalf of their patients. The risks of allowing someone other than the person whose life it is to determine which lives are ‘worth living’ and ‘worth saving’ is a highly controversial matter ( Reference Glover Glover 1990 ). It may be difficult to separate one's own views from those of society about what constitutes a life worth living or a life worth saving. This moral decision is what often determines to which individuals a society will ‘cause death to save other lives’ ( Reference Glover Glover 1990 ), which individuals are ‘allowed’ to take their own lives, which ones are forced to endure lives of tremendous hardship and pain, and which individuals are taken care of by society irrespective of how intensely they wish to die. The eugenics programmes of several nations in the early 20th century and the excesses of Nazi Germany are not too distant reminders of the risks implicit in such a process.

Mental health law is a social response to the profound ethical dilemmas posed by adults who are a risk to themselves or others as a result of mental disorder or distress. The ethical tension is between respect for autonomy and liberty to be left alone and the public duty of society to protect those who are vulnerable. All mental health legislation is a trade-off between the principles of respect for autonomy and liberty on one side and the principle of respect for welfare on the other ( Reference Adshead and Sarkar Adshead 2005 ), and on occasion it leads to medical paternalism.

Medical paternalism

For a clinician to decide whether it is ‘appropriate’ to prevent someone from taking their own life is an example of medical paternalism. The Mental Health Act 1983, which governs England and Wales, allows for individuals with a recognised (in international classificatory systems) mental disorder to be detained for appropriate treatment if their illness is of a sufficient nature or degree to require hospital treatment. This ultimately boils down to an assessment as to whether the person, as a result of the mental disorder, poses a significant danger to themselves, their own health or to others. Amendments to the Act in 2007 require a demonstration by the detaining authority that ‘appropriate medical treatment’ exists to treat the condition that the potentially detained patient has. In terms of a suicidal patient, this requires the clinician to consider whether it is appropriate to detain the person simply to prevent suicide or whether appropriate treatment can ameliorate the condition to the extent that the person no longer remains at risk of suicide at the end of treatment. This determination allows that clinician to override the person's wishes, even if they retain mental capacity to make a reasoned decision.

There has been particular concern about the mental legislation of England and Wales because it is strongly paternalistic in that it allows for the detention and involuntary treatment of capacitous, and therefore autonomous, individuals because clinicians consider it is ‘appropriate’ to do so. The consequence of this is a coercive anomaly in that, if one has full mental capacity, one can refuse any medical treatment; but it is not possible to refuse admission to a psychiatric hospital or even physical/pharmacological treatment. An attempt to introduce a capacity-based mental health act (whereby one would have to show that a person lacked capacity before involuntary detention and/or treatment) ( Reference Richardson Richardson 1999 ) failed under the Labour government of 1999 and the current coalition government has done nothing to change the status quo . This suggests a political will to ensure that those considered to be mentally disordered are treated differently from the rest of the society when it comes to autonomy; a sad commentary on Liberal Democrat principles.

Autonomy and best interests

In psychiatry, respect for autonomy may mean that a clinician will allow a patient to make decisions free of coercion, even if this may appear to go against the patient's best interests – the basis of assessing capacity in statute law. Ethical principles for assessing capacity are now enshrined in law, in the Mental Capacity Act 2005 for England and Wales. They are as follows:

• people are assumed to have capacity to make their own decisions unless otherwise proven

• everything should be done to help a person arrive at a decision before declaring them incapable of making it

• whatever is done for a person lacking capacity should be done in their best interests

• the decision maker should choose the least restrictive intervention.

For instance, where someone is found in a state of semi-consciousness following a large overdose and their life is at stake, the Mental Capacity Act would require that immediate action be taken in the person's best interests to save life. It would not be practical or reasonable to go on an exhaustive fact-finding mission before initiating treatment. However, beyond the emergency phase, while a person still lacks capacity, the Act requires a much more concerted assessment of the person's capacity, the views of their carers or appointed attorneys, formal assessment of their best interests and consideration of any advance decisions. Within this Act, an advance decision is specifically a decision to refuse treatment made in advance and in writing. If it was prepared at a time when the patient had capacity, an advance decision is legally binding unless there are legitimate questions as to its validity or applicability (see the Wooltorton case outlined in Box 1 ). Further guidance is contained in the Code of Practice accompanying the Mental Capacity Act ( Department for Constitutional Affairs 2007 ).

Challenges in judging capacity

Doctors, by virtue of their professional training, have access to people at their most vulnerable; and duties that entail physical contact that may even cause harm or damage. For this reason, the law on consent is a dominant component of medical jurisprudence. No medical intervention can be imposed on an individual without consent; and to do so would amount to an assault. The legislation on consent reflects the respect of the law for individual autonomy and choice, as indicated in Collins v Wilcox [1984] : ‘The integrity of every person's body, save by consent, is established in law’.

This principle was made explicit in the case of Re T (Adult: Refusal of Treatment) [1992] , where it was specifically emphasised that, ‘ prima facie , every adult has the right and capacity to decide whether or not he will accept medical treatment, even if a refusal may risk permanent injury to his health or even premature death’.

It is now established that competent adults can refuse life-saving treatment. This is consistent with the repeal of the Suicide Act 1961, and in light of other legal decisions about the capacity to make unwise decisions. Debate still continues with regard to situations in which competent adults want to end their lives, but need assistance to do so. This debate is typically couched in terms of voluntary euthanasia or the ‘right to die’. In some jurisdictions, such as Oregon, USA, and The Netherlands, it is legally possible for competent adults to be assisted to die by licensed physicians.

Such debates are problematic for psychiatric services, where the wish to die is usually taken to be prima facie evidence of a disordered mind. Indeed, in both the USA and The Netherlands those who wish to end their lives are required to undergo a psychiatric assessment that excludes the possibility of the decision being a ‘symptom’ of any of the diagnoses known to be associated with a risk of suicide. As described earlier, a person who attempts suicide can be detained under the Mental Health Act if they have a mental disorder and if it is appropriate to detain them. The purpose of the detention is to prevent them from killing themselves, even if they possess the capacity to make the decision to do so.

The law currently implies that it is clinically straightforward to distinguish between a wish to die that is the result of a competently made decision that must be respected in law, and a wish to die that is a symptom of a treatable mental illness. In reality, it is not as simple.

Fluctuating capacity and the tripartite model

What is a clinician to do when a patient's capacity changes from day to day and week to week? Severe disturbances of affect and arousal regulation cause rapid oscillations in a person's perceptions about themselves, their world and their anticipated future ( Reference Sarkar and Adshead Sarkar 2006 ); and equally oscillating decisions about accepting or refusing life-saving care and treatment ( Reference Sarkar Sarkar 2008 ). These are states of mind in which there is fluctuating capacity, a phenomenon that has been largely ignored in capacity judgments to date ( Reference Sarkar and Beeley Sarkar 2011c ). Despite a slew of legislation that can bewilder clinicians, fluctuating capacity raises the problem that theoretical principles do not necessarily address real, complex clinical issues ( Reference Mogg and Bartlett Mogg 2005 ). The bar in assessing capacity must be set high when clinicians make best interests decisions when someone's life is at stake, as in the case of suicidal patients. This approach was recognised by the Court of Appeal in Re MB (An Adult: Medical Treatment) [1997] when it was stated that ‘the graver the consequences of the decision, the commensurately greater the level of competence required to make that decision’.

Case law on capacity suggests that temporary factors such as confusion, shock, fatigue, pain, drugs or panic can completely erode capacity ( Royal College of Psychiatrists 2004 ). Clinicians will add to this list other factors, such as dissociation and problems of self-identity, rapidly fluctuating mood and behaviours, and concomitant risk of harm to others ( Reference Gallagher and Sheldon Gallagher 2010 ; Reference Sarkar Sarkar 2011a ). This highlights the real clinical challenge of working out a person's real intent and choices and decisions when they are in great distress. I argue that it is imperative to consider a third element in capacity decisions ( Reference Sarkar Sarkar 2008 ). This is the determination of how ‘stable’ or ‘settled’ a decision judged to be capacitous actually is. If it is affected by or a product of underlying mental disorder, it may change with the illness over time. Therefore, a written decision cannot simply be accepted as the final and enduring decision of the individual. English capacity legislation requires that the person's past and present wishes and feelings – expressed verbally, in writing or through behaviour or habits – beliefs and values (e.g. religious, cultural, moral or political) that would be likely to influence the decision in question are taken into consideration when best interests judgements are made by others.

It is critical that clinicians take a longitudinal view of the capacity of all patients. In other words, just because a person appears to be capacitous at the time of assessment (a cross-sectional view) does not mean that they will be capacitous the next week, the next day or even the next hour. A useful strategy is to go beyond the current approach to capacity assessment based on the Mental Capacity Act, which is often limited to two specific elements: that the decision be informed and that it be clearly communicated to others.

Reference Eastman and Hope Eastman & Hope (1988) state that capacity decisions are not binary (present or absent) but graded, i.e. there are degrees of capacity. Different decisions about treatment that a patient is required to make would demand different levels of capacity. They suggest combining the complexity of the decision and the significance of outcome (based on the decision made) in what they call ‘the balance model’. However, this approach has been criticised as being potentially too paternalistic because it can have a tendency to focus too much on the desirability of outcome ( Reference Mogg and Bartlett Mogg 2005 ).

I propose an ‘enhanced’ approach to the balance model of capacity judgements if there are relatively rapid changes in the person's mental state, leading to rapid changes in capacity and risks. The ‘enhanced’ tripartite model requires three elements to be assessed: the rationale or logic behind the decision made; the conviction with which the decision is held and is aligned with the patient's life narrative, beliefs and values; and the clarity with which this decision is communicated to others ( Table 1 ). It is suggested that these three elements, when assessed together, are likely to address the confounding effect that fluctuating capacity has on issues of consent ( Reference Mogg and Bartlett Mogg 2005 ), which can often lead to reluctance of clinicians to treat in difficult cases ( Reference McCall Smith McCall Smith 2001 ). By trying to ensure that the decision is stable, enduring and consistent with the patient's frameworks of value and meaning, this approach provides the clinician with a strategy to limit paternalism as much as possible. The clinician's tasks therefore include:

• judging whether the decision (e.g. to self-harm, discharge from voluntary admission, go on leave from hospital) is informed and balanced

TABLE 1 A tripartite model of capacity judgement in relation to a wish to die

• judging whether it is communicated clearly and unambiguously

• judging the conviction with which it has been made by assessing its stability and endurance over time: the more important the decision and the more final its consequences, the longer the time frame should be over which its stability is assessed.

Conclusions

Managing self-harm and risk of suicide are complex tasks. Although recent case law directs the clinician's mind to assessing risk of suicide and acting according to it in a longitudinal way, current clinical practice often lags behind on account of categorisation of such risk. Risk of self-harm and suicide and, by extension, a patient's capacity to make rational choices are most often categorised as ‘present’ or ‘absent’. Clinical decisions that flow from such cross-sectional categorical determinations of risk are likely to be truncated judgements on a matter that needs to be judged in a more dynamic and longitudinal manner. The proposed tripartite model can be used to eliminate difficulties associated with fluctuating capacity in patients with complex needs and risks. In practice, it has been found to add a certain degree of rigour to clinical decision-making. Time will tell whether such an approach is widely adopted by clinicians.

Select the single best option for each question stem

1 The balance model of Eastman & Hope states that capacity:

a is a binary concept

b decisions are easy to make

c is either present or absent

d is graded into degrees

e need not be always assessed.

2 Fluctuating capacity refers to:

a capacity that is either present or absent

b decisions that are rapidly changing

c decisions made in an intoxicated state

d the approach recommended in the Mental Capacity Act 2005

e an issue routinely addressed by clinicians.

3 In the Rabone suicide case, the Court made a landmark judgment in terms of:

a making hospitals not liable for irresponsible acts of their patients

b making hospital authorities remove all ligature points in psychiatric wards

c making consultants legally responsible for deaths of their patients

d holding the carers of patients legally responsible for their deaths

e making hospitals legally responsible for preventing suicide where a ‘real and immediate’ risk has been identified.

4 Under the mental health legislation of England and Wales, people with terminal physical illness but no mental illness:

a are permitted to take their own life regardless of their mental capacity

b can get help from their carers to assist them in taking their own life

c can appeal to the European Court of Human Rights if they are prevented from taking their own life

d cannot be prevented from taking their own life if they are demonstrably capacitous in the opinion of consultant psychiatrists

e are not required to demonstrate capacity.

5 Suicidal individuals with mental illness who possess capacity:

a pose significant challenges in terms of society's duty to save their lives

b can be prevented under the Mental Capacity Act from taking their own life

c are always allowed to take their own lives, under mental health legislation of England and Wales

d should not be detained under the Mental Health Act

e are not encountered in practice.

MCQ answers

This is the last of four articles in this issue of Advances discussing suicide. See also pp. 276–283, 284–291, 292–294.

Declaration of Interest

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• Volume 19, Issue 4
• Jaydip Sarkar
• DOI: https://doi.org/10.1192/apt.bp.112.010595

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Case Examples

Examples of recommended interventions in the treatment of depression across the lifespan.

Children/Adolescents

A 15-year-old Puerto Rican female

The adolescent was previously diagnosed with major depressive disorder and treated intermittently with supportive psychotherapy and antidepressants. Her more recent episodes related to her parents’ marital problems and her academic/social difficulties at school. She was treated using cognitive-behavioral therapy (CBT).

Chafey, M.I.J., Bernal, G., & Rossello, J. (2009). Clinical Case Study: CBT for Depression in A Puerto Rican Adolescent. Challenges and Variability in Treatment Response. Depression and Anxiety , 26, 98-103.  https://doi.org/10.1002/da.20457

Sam, a 15-year-old adolescent

Sam was team captain of his soccer team, but an unexpected fight with another teammate prompted his parents to meet with a clinical psychologist. Sam was diagnosed with major depressive disorder after showing an increase in symptoms over the previous three months. Several recent challenges in his family and romantic life led the therapist to recommend interpersonal psychotherapy for adolescents (IPT-A).

Hall, E.B., & Mufson, L. (2009). Interpersonal Psychotherapy for Depressed Adolescents (IPT-A): A Case Illustration. Journal of Clinical Child & Adolescent Psychology, 38 (4), 582-593. https://doi.org/10.1080/15374410902976338

© Society of Clinical Child and Adolescent Psychology (Div. 53) APA, https://sccap53.org/, reprinted by permission of Taylor & Francis Ltd, http://www.tandfonline.com on behalf of the Society of Clinical Child and Adolescent Psychology (Div. 53) APA.

General Adults

Mark, a 43-year-old male

Mark had a history of depression and sought treatment after his second marriage ended. His depression was characterized as being “controlled by a pattern of interpersonal avoidance.” The behavior/activation therapist asked Mark to complete an activity record to help steer the treatment sessions.

Dimidjian, S., Martell, C.R., Addis, M.E., & Herman-Dunn, R. (2008). Chapter 8: Behavioral activation for depression. In D.H. Barlow (Ed.) Clinical handbook of psychological disorders: A step-by-step treatment manual (4th ed., pp. 343-362). New York: Guilford Press.

Reprinted with permission from Guilford Press.

Denise, a 59-year-old widow

Denise is described as having “nonchronic depression” which appeared most recently at the onset of her husband’s diagnosis with brain cancer. Her symptoms were loneliness, difficulty coping with daily life, and sadness. Treatment included filling out a weekly activity log and identifying/reconstructing automatic thoughts.

Young, J.E., Rygh, J.L., Weinberger, A.D., & Beck, A.T. (2008). Chapter 6: Cognitive therapy for depression. In D.H. Barlow (Ed.) Clinical handbook of psychological disorders: A step-by-step treatment manual (4th ed., pp. 278-287). New York, NY: Guilford Press.

Nancy, a 25-year-old single, white female

Nancy described herself as being “trapped by her relationships.” Her intake interview confirmed symptoms of major depressive disorder and the clinician recommended cognitive-behavioral therapy. 

Persons, J.B., Davidson, J. & Tompkins, M.A. (2001). A Case Example: Nancy. In Essential Components of Cognitive-Behavior Therapy For Depression (pp. 205-242). Washington, D.C.: American Psychological Association. http://dx.doi.org/10.1037/10389-007

While APA owns the rights to this text, some exhibits are property of the San Francisco Bay Area Center for Cognitive Therapy, which has granted the APA permission for use.

Luke, a 34-year-old male graduate student

Luke is described as having treatment-resistant depression and while not suicidal, hoped that a fatal illness would take his life or that he would just disappear. His treatment involved mindfulness-based cognitive therapy, which helps participants become aware of and recharacterize their overwhelming negative thoughts. It involves regular practice of mindfulness techniques and exercises as one component of therapy.

Sipe, W.E.B., & Eisendrath, S.J. (2014). Chapter 3 — Mindfulness-Based Cognitive Therapy For Treatment-Resistant Depression. In R.A. Baer (Ed.), Mindfulness-Based Treatment Approaches (2nd ed., pp. 66-70). San Diego: Academic Press.

Reprinted with permission from Elsevier.

Sara, a 35-year-old married female

Sara was referred to treatment after having a stillbirth. Sara showed symptoms of grief, or complicated bereavement, and was diagnosed with major depression, recurrent. The clinician recommended interpersonal psychotherapy (IPT) for a duration of 12 weeks.

Bleiberg, K.L., & Markowitz, J.C. (2008). Chapter 7: Interpersonal psychotherapy for depression. In D.H. Barlow (Ed.) Clinical handbook of psychological disorders: a treatment manual (4th ed., pp. 315-323). New York, NY: Guilford Press.

Peggy, a 52-year-old white, Italian-American widow

Peggy had a history of chronic depression, which flared during her husband’s illness and ultimate death. Guilt was a driving factor of her depressive symptoms, which lasted six months after his death. The clinician treated Peggy with psychodynamic therapy over a period of two years.

Bishop, J., & Lane , R.C. (2003). Psychodynamic Treatment of a Case of Grief Superimposed On Melancholia. Clinical Case Studies , 2(1), 3-19. https://doi.org/10.1177/1534650102239085

Several case examples of supportive therapy

Winston, A., Rosenthal, R.N., & Pinsker, H. (2004). Introduction to Supportive Psychotherapy . Arlington, VA : American Psychiatric Publishing.

Older Adults

Several case examples of interpersonal psychotherapy & pharmacotherapy

Miller, M. D., Wolfson, L., Frank, E., Cornes, C., Silberman, R., Ehrenpreis, L.…Reynolds, C. F., III. (1998). Using Interpersonal Psychotherapy (IPT) in a Combined Psychotherapy/Medication Research Protocol with Depressed Elders: A Descriptive Report With Case Vignettes. Journal of Psychotherapy Practice and Research , 7(1), 47-55.

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• Antidepressant use and...

Antidepressant use and risk of suicide and attempted suicide or self harm in people aged 20 to 64: cohort study using a primary care database

• Related content
• Peer review
• Carol Coupland , associate professor and reader in medical statistics 1 ,
• Trevor Hill , research statistician 1 ,
• Richard Morriss , professor of psychiatry and community mental health 2 ,
• Antony Arthur , professor of nursing science 3 ,
• Michael Moore , professor of primary care research 4 ,
• Julia Hippisley-Cox , professor of clinical epidemiology and general practice 1
• 1 Division of Primary Care, School of Medicine, University of Nottingham, University Park, Nottingham NG7 2RD, UK
• 2 Institute of Mental Health, Jubilee Campus, Nottingham, UK
• 3 School of Health Sciences, Faculty of Medicine and Health Sciences, University of East Anglia, Norwich, UK
• 4 University of Southampton Medical School, Primary Care and Population Sciences, Aldermoor Health Centre, Southampton, UK
• Correspondence to: C Coupland carol.coupland{at}nottingham.ac.uk
• Accepted 30 December 2014

Objective To assess the associations between different antidepressant treatments and the rates of suicide and attempted suicide or self harm in people with depression.

Design Cohort study.

Setting Patients registered with UK general practices contributing data to the QResearch database.

Participants 238 963 patients aged 20 to 64 years with a first diagnosis of depression between 1 January 2000 and 31 July 2011, followed up until 1 August 2012.

Exposures Antidepressant class (tricyclic and related antidepressants, selective serotonin reuptake inhibitors, other antidepressants), dose, and duration of use, and commonly prescribed individual antidepressant drugs. Cox proportional hazards models were used to calculate hazard ratios adjusting for potential confounding variables.

Main outcome measures Suicide and attempted suicide or self harm during follow-up.

Results During follow-up, 87.7% (n=209 476) of the cohort received one or more prescriptions for antidepressants. The median duration of treatment was 221 days (interquartile range 79-590 days). During the first five years of follow-up 198 cases of suicide and 5243 cases of attempted suicide or self harm occurred. The difference in suicide rates during periods of treatment with tricyclic and related antidepressants compared with selective serotonin reuptake inhibitors was not significant (adjusted hazard ratio 0.84, 95% confidence interval 0.47 to 1.50), but the suicide rate was significantly increased during periods of treatment with other antidepressants (2.64, 1.74 to 3.99). The hazard ratio for suicide was significantly increased for mirtazapine compared with citalopram (3.70, 2.00 to 6.84). Absolute risks of suicide over one year ranged from 0.02% for amitriptyline to 0.19% for mirtazapine. There was no significant difference in the rate of attempted suicide or self harm with tricyclic antidepressants (0.96, 0.87 to 1.08) compared with selective serotonin reuptake inhibitors, but the rate of attempted suicide or self harm was significantly higher for other antidepressants (1.80, 1.61 to 2.00). The adjusted hazard ratios for attempted suicide or self harm were significantly increased for three of the most commonly prescribed drugs compared with citalopram: venlafaxine (1.85, 1.61 to 2.13), trazodone (1.73, 1.26 to 2.37), and mirtazapine (1.70, 1.44 to 2.02), and significantly reduced for amitriptyline (0.71, 0.59 to 0.85). The absolute risks of attempted suicide or self harm over one year ranged from 1.02% for amitriptyline to 2.96% for venlafaxine. Rates were highest in the first 28 days after starting treatment and remained increased in the first 28 days after stopping treatment.

Conclusion Rates of suicide and attempted suicide or self harm were similar during periods of treatment with selective serotonin reuptake inhibitors and tricyclic and related antidepressants. Mirtazapine, venlafaxine, and trazodone were associated with the highest rates of suicide and attempted suicide or self harm, but the number of suicide events was small leading to imprecise estimates. As this is an observational study the findings may reflect indication biases and residual confounding from severity of depression and differing characteristics of patients prescribed these drugs. The increased rates in the first 28 days of starting and stopping antidepressants emphasise the need for careful monitoring of patients during these periods.

Introduction

Rates of suicide and self harm are greatly increased in people with depression 1 2 and reduction of these risks is a major consideration when treating such patients. Paradoxically, although antidepressants have been shown to be effective in reducing the symptoms of depression 3 4 there is concern that rates of suicide and self harm may actually be increased by treatment, particularly in younger people. 5 6 A meta-analysis of 372 randomised placebo controlled trials of antidepressants found that among adults aged less than 25 the risk of suicidal behaviour was increased during treatment with antidepressants, whereas no association was found in adults aged 25 to 64, and in those aged 65 or more the risk was reduced. 7 These findings were supported by a meta-analysis of eight observational studies involving more than 200 000 patients, 8 which found an increased risk of suicide among adolescents treated with selective serotonin reuptake inhibitors compared with no antidepressant treatment, but a reduced risk among adults.

The meta-analysis by Stone 7 indicated possible differences in risk of suicidal behaviour between different antidepressants, but these findings were based on a small number of events. In a cohort study, venlafaxine was associated with an increased risk of suicide and attempted suicide compared with three other antidepressants, 9 although the authors concluded that this may have been due to residual confounding. In another cohort study the reported rates of suicide and attempted suicide were similar for different antidepressants, except for a higher rate of suicidal acts in users of venlafaxine compared with selective serotonin reuptake inhibitors, but this association was reduced in secondary analyses. 10 In a cohort study of adults aged 65 or more with depression the highest rates of attempted suicide or self harm were in those treated with venlafaxine, mirtazapine, or trazodone. 11

Uncertainty remains about the risks of suicide and self harm for different antidepressants and whether these risks vary by dose and duration of use. This is particularly important to determine, now that suicide rates in the United Kingdom and many other countries have started to increase after a period when they were decreasing. 12 13 14 We carried out a cohort study in people aged 20 to 64 to investigate the associations between different antidepressants and the risk of suicide and attempted suicide or self harm.

This cohort study was designed to assess the associations of antidepressant treatment and several different adverse outcomes, including suicide and attempted suicide or self harm. Full details of the study design and methods are in the study protocol. 15

Study cohort

The study cohort was selected from a large primary care database (QResearch, version 34). QResearch is derived from the anonymised health records of over 12 million patients from more than 600 general practices across the United Kingdom. The practices record data using the Egton Medical Information Systems medical records system. Recorded information includes data on patients’ diagnoses, symptoms, consultations, referrals, test results, and prescriptions. The database is linked at patient level to Office for National Statistics mortality data.

The study sample comprised an open cohort of patients with a first recorded diagnosis of depression between 1 January 2000 and 31 July 2011, at age 20 to 64. We used diagnostic Read codes to identify patients with a diagnosis of depression, using case definitions that have been used in previous studies. 11 16 17 Patients were eligible for inclusion only if their diagnosis occurred at least 12 months after registration with a study practice and the date of the installation of the practice computer system. Patients were eligible for inclusion regardless of whether they received prescriptions for antidepressants. To reduce the risk of indication bias, we considered patients who received prescriptions for antidepressants but did not have a recorded diagnosis of depression to be ineligible, as the prescriptions may have been for conditions other than depression.

We excluded patients from the cohort if they had a previous recorded diagnosis of depression; were temporary residents; had a diagnosis of schizophrenia, bipolar disorder, or other type of psychosis; or had been prescribed lithium or antimanic drugs at the study entry date. Patients were also excluded if they had received prescriptions for an antidepressant either before the study start date (1 January 2000), before their date of registration with the practice (if later), before the age of 20, or more than 36 months before their first recorded diagnosis of depression.

We defined the date of entry into the study (index date) as the date of the first recorded diagnosis of depression, or the date of the first prescription for an antidepressant if earlier. Participants were followed up until the earliest of date of death, date of leaving the practice, or the end of follow-up (1 August 2012). Most analyses were restricted to the first five years of follow-up.

We identified suicides during follow-up as patients with either a code for suicide or an open verdict on their linked death certificate (using international classification of diseases codes, ninth and 10th revisions) or patients with a Read code in their medical record for attempted suicide or self harm who died within 30 days. We identified cases of attempted suicide or self harm from the patients’ medical records, based on Read codes used in other studies. 9 16 18 We only considered the first attempted suicide or self harm event in the analysis of this outcome, and excluded patients with a previous attempted suicide or self harm event recorded at baseline.

Exposure data

We extracted details of all individual prescriptions for antidepressants during follow-up, including the issue date, the type and dose of antidepressant, dosage instructions, and quantity of tablets prescribed. To determine the duration of each prescription in days we divided the number of tablets prescribed by the dosing instructions (for example, number of tablets to be taken each day). Where the number of tablets prescribed was recorded but dosing instructions were missing or not sufficiently detailed (<5% of prescriptions) we used an assumed duration, taking account of the number of tablets prescribed as in our previous study. 19 We calculated the daily dose of each prescription by multiplying the specified dose of each tablet by the number of tablets to be taken each day. Prescriptions for the same drug issued on the same day were counted as a single prescription and the doses combined.

For the main analyses we grouped antidepressants according to the major classes as given in the British National Formulary —namely, tricyclic and related antidepressants (section 4.3.1), selective serotonin reuptake inhibitors (section 4.3.3), monoamine oxidase inhibitors (section 4.3.2), and other antidepressants (section 4.3.4). Where patients received prescriptions for different drugs within a class or for drugs from different classes on the same date we classified these as combined prescriptions.

To enable a comparison of dose between the antidepressant classes, for each prescription we converted the prescribed daily dose to a number of defined daily doses, using the values assigned by the World Health Organization’s Collaborating Centre for Drug Statistics Methodology ( www.whocc.no/atc_ddd_index ). WHO’s definition of a defined daily dose is the assumed average maintenance dose each day for a drug used for its main indication in adults (for example, the defined daily dose for citalopram is 20 mg, for fluoxetine is 20 mg, and for amitriptyline is 75 mg), although this may not necessarily reflect the recommended dose, and individual patients may be prescribed higher or lower doses.

Where numbers were sufficient, we also assessed individual antidepressants. As in our previous study, we examined the 11 most commonly prescribed individual antidepressants separately. 11

Confounding variables

We considered as confounding variables those likely to be associated with the risk of suicide or attempted suicide or self harm, or with the likelihood of receiving treatment for different antidepressants, based on variables included in our previous study of antidepressants in people aged 65 or more. 11

Confounders were age at study entry date, sex, year of diagnosis of depression, severity of index diagnosis of depression (categorised as mild, moderate, or severe based on the Read code for the index diagnosis, using codes published by Martinez and colleagues 16 and some additional classification by a member of the study team), deprivation (Townsend deprivation score corresponding to the patient’s postcode, in fifths), smoking status (non-smoker, former smoker, light smoker (1-9 cigarettes/day), moderate smoker (10-19 cigarettes/day), heavy smoker (≥20 cigarettes/day), not recorded), alcohol intake (none, trivial (<1 UK unit/day), light (1-2 units/day), medium (3-6 units/day,) heavy (7-9 units/day,) very heavy (>9 units/day), not recorded), ethnic group (categorised as white/not recorded or non-white (Indian, Pakistani, Bangladeshi, other Asian, black African, black Caribbean, Chinese, other including mixed)), comorbidities at baseline (coronary heart disease, diabetes, hypertension, cancer, epilepsy or seizures, hypothyroidism, osteoarthritis, asthma or chronic obstructive airways disease), and use of other drugs at baseline (statins, non-steroidal anti-inflammatory drugs, aspirin, antihypertensive drugs, anticonvulsants, hypnotics or anxiolytics, oral contraceptives, hormone replacement therapy). In addition, the analysis of suicide as an outcome included attempted suicide or self harm at baseline as a confounding variable. In the analysis of attempted suicide or self harm we also adjusted for stroke or transient ischaemic attack, rheumatoid arthritis, osteoporosis, liver disease, renal disease, obsessive-compulsive disorder, antipsychotics, bisphosphonates, and anticoagulants. These were not included in the analysis of suicide because of the smaller number of events, and the prevalence of these confounders was less than 1% in the study cohort.

Statistical analysis

We used Cox’s proportional hazards models to assess the associations between exposure to antidepressant drugs and the two outcomes (suicide and attempted suicide or self harm). To account for patients starting and stopping treatment during follow-up and also changing between treatments, we treated antidepressant exposure as a time varying exposure. We considered patients to have been exposed to a drug if there were no gaps of more than 90 days between the end of one prescription and the start of the next. In the analysis of attempted suicide or self harm we excluded patients who already had the outcome recorded at baseline. The main analyses were based on the first five years of follow-up after the study entry date, by censoring any follow-up after this date. We used robust standard errors to account for clustering of patients within practices. 20

In the analysis we calculated unadjusted and adjusted analysis hazard ratios for antidepressant class, by comparing current treatment using tricyclic and related antidepressants, other antidepressants, and combined antidepressants with treatment using selective serotonin reuptake inhibitors. We included a category of “no current treatment” for periods of time where patients were not treated with antidepressants, which also included follow-up time for patients who were not prescribed any antidepressants during follow-up. The number of patients prescribed monoamine oxidase inhibitors was too small for this group to be analysed, so we excluded from the analyses those patients prescribed monoamine oxidase inhibitors at any time.

Analyses were also carried out for dose categories within each antidepressant class (≤0.5, >0.5 and ≤1.0, and >1.0 defined daily doses) using the middle dose category for selective serotonin reuptake inhibitors as the reference group, and we carried out tests for trend using the doses within each class as continuous variables. We analysed duration of antidepressant use and time since stopping within each antidepressant class as a time varying exposure (categorised as no use (reference group), 1-28 days, 29-84 days, and ≥85 days after starting treatment, and 1-28 days, 29-84 days, and 85-182 days after stopping treatment). We only allocated follow-up time to the time since stopping treatment categories if patients did not switch directly to another antidepressant, otherwise we allocated their follow-up time to time since starting categories for the new drug. Analyses were carried out for the 11 most commonly prescribed antidepressants, with the most commonly prescribed antidepressant (citalopram) as the reference category.

To determine whether significant differences existed between the antidepressant classes and between the individual drugs, we carried out Wald’s tests. We tested for interactions between drug class and age (continuous) and carried out subgroup analyses split by age band (20-29, 30-39, 40-49, and 50-64 years). We assessed the proportional hazards assumption using log minus log plots.

As a sensitivity analysis we repeated the analyses restricted to patients who received at least one prescription for an antidepressant during follow-up, excluding untreated patients. We carried out this analysis because patients who were untreated during follow-up might differ from treated patients in ways that would be difficult to account for in the analysis (such as having a dislike of tablets, a preference for non-drug treatments, or less severe depression), so we carried out this sensitivity analysis to test whether our results were robust to exclusion of these patients. We also carried out an analysis restricted to the first year of follow-up and a further analysis including all outcome events that occurred within the entire follow-up period. These analyses were done to assess whether any associations between antidepressant drugs and the risks of suicide and attempted suicide or self harm for five years’ follow-up were also present in analyses over one year and over the entire follow-up period. In particular the baseline characteristics are less likely to change during one year, and fewer switches occur between different antidepressant drugs, so the results from the one year analysis are less likely to be influenced by residual confounding. We performed analyses for the entire follow-up since these have increased power and include long durations of use. In an additional analysis we used a minimum gap of 30 days between the end of one prescription and the start of the next rather than 90 days to classify periods of non-use. We carried out a further analysis of the suicide outcome restricted to deaths specifically coded as suicide on the linked death certificate and not including open verdicts or suicides only identified from the medical records.

We calculated absolute risks of both outcomes over one year, accounting for the confounding variables using adjusted hazard ratios from the analysis for one year of follow-up based on the method described by Altman et al. 21

To maximise power we included all eligible patients from the database in the analyses. We used a P value of less than 0.01 (two tailed) to determine statistical significance. Analyses were carried out using Stata (v12.1).

From 1 January 2000 to 31 July 2011, 327 235 patients had a first diagnosis of depression between the ages of 20 and 64. A total of 88 272 (27.0%) patients were excluded from the study cohort because they had schizophrenia, bipolar disorder, or other psychoses or had been prescribed lithium or antimanic drugs (7152 patients, 2.2%) and/or had been prescribed an antidepressant before the study entry date aged less than 20, or more than 36 months before the recorded date of depression (83 824 patients, 25.6%); 2704 patients met both exclusion criteria. This left 238 963 patients from 687 practices in the study cohort (fig 1 ⇓ ).

Fig 1 Flow chart showing selection of patients included in study cohort. 2704 patients met both exclusion criteria

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Table 1 ⇓ shows the baseline characteristics of the study cohort. The mean age was 39.5 (SD 11.1) years, and there were 92 935 men (38.9%) and 146 028 (61.1%) women. The total number of person years of follow-up was 1 307 326, with a median of 5.2 (interquartile range 2.5-8.2) years.

Characteristics of study cohort at baseline. Values are numbers (percentages) unless stated otherwise

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Antidepressant treatment during follow-up

During follow-up, 87.7% of patients (n=209 476) received one or more prescriptions for an antidepressant, with 3 337 336 prescriptions for antidepressants received in total; 29 708 patients (14.2%) only received a single prescription during follow-up. The median duration of treatment with antidepressants during follow-up was 221 (interquartile range 79-590) days, with 36.6% of treated patients having one or more years of treatment and 5.5% having five or more years.

Selective serotonin reuptake inhibitors were the most commonly prescribed drug class, comprising 71.3% (2 379 668) of prescriptions for antidepressants; there were 533 798 prescriptions (16.0%) for tricyclic and related antidepressants and 422 079 (12.7%) for the group of other antidepressants. Monoamine oxidase inhibitors were the least commonly prescribed class, comprising only 1791 prescriptions (0.05%) in 156 patients. There were 83 784 combined prescriptions where two or more different antidepressant drugs were prescribed on the same day.

Figure 2 ⇓ shows the number of prescriptions during follow-up for the 11 most commonly prescribed antidepressants, which comprised 97.7% of all prescriptions for antidepressants. Citalopram was the most commonly prescribed antidepressant (1 023 255 prescriptions, 31.5% of total). Citalopram and fluoxetine accounted for 77.6% of prescriptions for selective serotonin reuptake inhibitors, amitriptyline and dosulepin for 77.3% of prescriptions for tricyclic and related antidepressants, and venlafaxine and mirtazapine for 90.7% of prescriptions for other antidepressants. Supplementary tables 1s to 3s show the distributions of baseline characteristics according to the first antidepressant prescribed for these 11 drugs.

Fig 2 Total number of prescriptions issued during follow-up for most commonly prescribed antidepressants

Associations with suicide

After omitting the patients with prescriptions for monoamine oxidase inhibitors, there were 238 807 patients in the study cohort. During the first five years of follow-up 198 cases of suicide occurred in this study cohort, giving an incidence rate of 22 per 100 000 person years (43 per 100 000 in men and 9 per 100 000 in women). Of these suicide cases, 156 were only identified from the linked death records, 18 only from primary care records, and 24 from both sources. Among the 180 cases identified from linked death records, 48 were coded as open verdicts.

Suicide rates did not differ significantly when comparing periods of tricyclic antidepressant treatment with selective serotonin reuptake inhibitor treatment (adjusted hazard ratio 0.84, 95% confidence interval 0.47 to 1.50), but rates increased significantly during periods of treatment with the other antidepressants compared with selective serotonin reuptake inhibitors (2.64, 1.74 to 3.99, table 2 ⇓ ). Adjusted hazard ratios tended to increase with dose for selective serotonin reuptake inhibitors (P=0.02), but not for tricyclic antidepressants (P=0.6) or other antidepressants (P=0.9) (table 2).

Unadjusted and adjusted hazard ratios for suicide by antidepressant class, dose, and individual drug, over a five year follow-up period

In the analysis of the 11 most commonly prescribed drugs, the adjusted hazard ratio was significantly increased (at P<0.01) for mirtazapine compared with citalopram (3.70, 2.00 to 6.84). There was also some indication of an increased risk for venlafaxine compared with citalopram (2.23, 1.14 to 4.39, P=0.02).

Hazard ratios were highest in the first 28 days after starting treatment for tricyclic antidepressants, selective serotonin reuptake inhibitors, and, particularly, for other antidepressants, and also in the first 28 days after stopping treatment (fig 3 ⇓ ).

Fig 3 Adjusted hazards and 95% confidence intervals for suicide according to time since starting and stopping different classes of antidepressant compared with untreated periods. Numbers of events are included

Hazard ratios changed little when patients who had not received any antidepressant prescriptions during follow-up were removed from the analysis. Hazard ratios were also generally similar when either just the first year of follow-up (see supplementary table 4s) or the entire follow-up period was used in the analysis, or when a 30 day gap was used to define unexposed periods (see supplementary table 6s). Hazard ratios tended to be higher, although confidence intervals were wider, when the analysis was restricted to the 132 cases with specific codes for suicide on the linked death certificate (see supplementary table 7s).

Associations with attempted suicide or self harm

At baseline 10 174 patients (4.3%) had a record of attempted suicide or self harm. We omitted these patients from the analyses of attempted suicide or self harm, and also those with prescriptions for monoamine oxidase inhibitors, leaving 228 643 in the study cohort. During the first five years of follow-up there were 5243 cases of attempted suicide or self harm, giving an incidence rate of 613 per 100 000 person years (737 per 100 000 in men and 517 per 100 000 in women).

The rates of attempted suicide or self harm did not differ significantly for tricyclic antidepressants compared with selective serotonin reuptake inhibitors (0.96, 0.87 to 1.08) but hazard ratios were significantly increased during periods of treatment with other antidepressants (1.80, 1.61 to 2.00) or with combined prescriptions (2.00, 1.54 to 2.59, table 3 ⇓ ). In analyses of dose, adjusted hazard ratios increased significantly with dose for selective serotonin reuptake inhibitors and other antidepressants (both P<0.001) and also tended to increase with dose for tricyclic antidepressants (P=0.013) (table 3).

Unadjusted and adjusted hazard ratios for attempted suicide or self harm by antidepressant class, dose, and individual drug over five year follow-up period

Hazard ratios were significantly increased for three of the most commonly prescribed drugs compared with citalopram (table 3); venlafaxine (adjusted hazard ratio 1.85, 95% confidence interval 1.61 to 2.13), trazodone (1.73, 1.26 to 2.37), and mirtazapine (1.70, 1.44 to 2.02). The hazard ratio for amitriptyline compared with citalopram was significantly reduced (0.71, 0.59 to 0.85).

Rates of attempted suicide or self harm were highest in the first 28 days after starting treatment, particularly for other antidepressants (fig 4 ⇓ ).

Fig 4 Adjusted hazards and 95% confidence intervals for attempted suicide or self harm according to time since starting and stopping different classes of antidepressant compared with untreated periods. Numbers of events are included

Hazard ratios were slightly reduced when patients who had not received any prescriptions for antidepressants during follow-up were removed from the analysis. Results were generally similar when either just the first year of follow-up (see supplementary table 5s) or the entire follow-up period was used in the analysis, and also were similar when a 30 day gap was used to define unexposed periods (see supplementary table 7s).

Interactions with age

Overall there was no significant interaction between drug class and age at baseline for suicide (P=0.09), although numbers were small. In a subgroup analysis split by age band the rates of suicide were lower for tricyclic antidepressants and other antidepressants compared with selective serotonin reuptake inhibitors in patients aged 20 to 29 (table 4 ⇓ ), but these were not statistically significant. In patients aged 40 to 49 and 50 to 64, the adjusted hazard ratios were significantly increased for other antidepressants compared with selective serotonin reuptake inhibitors.

Adjusted hazard ratios for suicide and attempted suicide or self harm by antidepressant class: subgroup analyses by age group at baseline for five year follow-up period

There was some indication of an interaction between drug class and age for attempted suicide or self harm (P=0.02). Adjusted hazard ratios were similar for tricyclic antidepressants compared with selective serotonin reuptake inhibitors in all age bands, but increased slightly with age for other antidepressants compared with selective serotonin reuptake inhibitors, from 1.62 (1.33 to 1.97) in patients aged 20-29 to 2.29 (1.75 to 3.00) in patients aged 50-64.

Absolute risks of suicide and attempted suicide or self harm

Table 5 ⇓ shows the absolute risks of suicide and attempted suicide or self harm over one year. For suicide the absolute risks over one year ranged from 0.02% for amitriptyline to 0.19% for mirtazapine. For attempted suicide or self harm the absolute risks ranged from 1.02% for amitriptyline to 2.96% for venlafaxine.

Absolute risks of attempted suicide or self harm and suicide over one year by antidepressant class and antidepressant drugs

In this large cohort study of patients aged 20 to 64 with a diagnosis of depression, we found significant associations between different classes and types of antidepressants and rates of suicide and attempted suicide or self harm. The group of antidepressants classified as “other antidepressants” (mainly comprising venlafaxine and mirtazapine) was associated with the highest rates of both of these outcomes, whereas among individual drugs mirtazapine, venlafaxine, and trazodone were associated with increased risks of attempted suicide or self harm compared with the most commonly prescribed antidepressant, citalopram.

Rates of suicide and attempted suicide or self harm were lowest during periods when patients were not taking antidepressants, but this is likely to reflect the absence of current depression or less severe depression during those periods rather than an indication that antidepressant treatment in itself increases the risks of suicide and attempted suicide or self harm.

The higher hazard ratios for death from suicide in association with venlafaxine and mirtazapine compared with those for attempted suicide or self harm could be due to the higher lethality of these drugs in overdose than selective serotonin reuptake inhibitor antidepressants, 22 but this would not explain their higher hazard ratios compared with tricyclic antidepressants, which have much higher toxicity. Also numbers of suicide events were small, so these results should be interpreted with caution.

Strengths and limitations of this study

This study was large and population based with broad inclusion criteria. We included all eligible patients in the study, so the findings are generalisable to people aged 20 to 64 years with a diagnosis of depression in primary care. Recall bias is not an issue as we used data on prescriptions for antidepressants and potential confounding variables, which were prospectively recorded before the occurrence of the outcomes. We had detailed information on prescriptions for antidepressants issued in primary care throughout the follow-up period, so we were able to investigate associations with individual drugs, dose, and duration of treatment.

Although all the participants had a diagnosis of depression, no specific studies have been carried out into the validity and reliability of diagnosis data for depression recorded by doctors in primary care contributing to the QResearch database. However, there is evidence from the United Kingdom and the Netherlands that the diagnosis of depression by general practitioners is valid and reliable. 23 24

Drug safety can be assessed through meta-analyses of trials reporting adverse outcomes, 7 but in the case of antidepressants and suicide or attempted suicide these trials tend to be short term and generally exclude patients with any major suicide risk or with physical or psychiatric comorbidity. Indication bias is the main concern with observational studies assessing drug safety, which occurs when patients are prescribed drugs for a condition that is itself associated with the risk of the adverse outcome. To reduce this bias we only included patients with a recorded diagnosis of depression, so that patients had the same indication for treatment. This is important, as depression is associated with a substantially increased risk of suicide and self harm. 1 2

Direct comparisons between groups receiving different treatments for the same condition are still subject to channelling bias, where the selection of a particular antidepressant depends on the characteristics of the patient. This could have occurred in this study if drugs such as mirtazapine, venflaxine, and trazodone were more likely to be prescribed to patients at increased risk of suicide or attempted suicide. This may apply to venlafaxine, particularly since guidelines from the National Institute for Health and Care Excellence suggest switching people with depression that does not respond well to initial treatment firstly to a different selective serotonin reuptake inhibitor or a better tolerated newer generation antidepressant and subsequently to an antidepressant of a different drug class—for example, venlafaxine, a tricyclic antidepressant, or a monoamine oxidase inhibitor. 25 To reduce the effect of channelling bias we adjusted for a range of potential confounding factors that could influence the choice of antidepressant; for example, in the analysis of suicide we adjusted for attempted suicide at baseline as well as for many other confounders, including severity of depression. However, we could only use a basic measure of the severity of the initial diagnosis of depression based on Read codes, as depression severity scores are not routinely recorded in general practice. The Read codes used to record depression were generally not specific in terms of severity. Also we were not able to account for changes in severity of depression during follow-up since the severity is not recorded consistently over time, so we could only include it in the analysis as a single baseline variable rather than a time varying variable; this means that the severity of depression is likely to still have a confounding influence on our results. In addition there may be other potential confounding variables, such as drug misuse or family history of psychiatric disorder, 26 which were either not recorded on the database or not recorded in sufficient detail for their confounding effect to be completely removed by analysis. Differences in characteristics between patients prescribed different antidepressants could therefore account for some of the associations we found between the drugs and suicide and self harm, and we cannot therefore exclude the possibility of residual confounding.

Misclassification of drug use may have occurred, as patients might not have taken their prescribed antidepressant. This may particularly be the case for the 14% of patients who only received a single prescription. We cannot be certain of the exact dates when patients started and stopped taking their prescribed drug. Since we did not have a precise stopping date we assumed patients to be exposed to an antidepressant where there were no gaps of more than 90 days between the end of one prescription and the start of the next, to allow for any antidepressant use if patients had accumulated extra tablets over time and also so that outcomes occurring during withdrawal periods would be attributed to the antidepressant. This misclassification could underestimate associations with drug use if non-differential but could exaggerate the associations, since patients missing antidepressants for only a few days or weeks may have substantial changes in mood and suicidal ideation. When we changed the gap to 30 days, however, the results were similar. The increased rates we found during periods shortly after antidepressants were started might be a consequence of patients switching between treatments, making these associations difficult to disentangle.

Some outcomes may also have been misclassified, especially where episodes of attempted suicide or self harm are not reported. This could lead to underestimation of absolute risks but is unlikely to vary according to the antidepressant prescribed so this would not explain the associations we have found. We included information from linked death certificates to identify additional cases of suicide, including those recorded as open verdicts, which will have reduced misclassification for this outcome; however, we might still have underestimated suicide rates since some suicides may have been recorded as unintentional incidents. 27

The numbers of events in the suicide analyses were small, particularly when split into different antidepressant exposure categories. So while there was sufficient power to detect large differences, such as between other antidepressants and selective serotonin reuptake inhibitors (adjusted hazard ratio 2.6, 95% confidence interval 1.7 to 4.0), the power would have been low for smaller differences. Therefore we cannot rule out relatively small differences between, for example, selective serotonin reuptake inhibitors and tricyclic antidepressants. Furthermore the small number of suicide events means that the multivariable models may be overfitted, so for individual drugs in particular the adjusted hazard ratios and absolute event rates derived from them should be interpreted with extreme caution.

A further limitation is that the underlying biology of suicide and attempted suicide is poorly understood so there is no established pharmacological rationale for the relations we have identified; rather, these are statistical associations worthy of further investigation to understand any underlying biological mechanisms.

Comparison with other studies

The suicide rates in our study cohort (43 per 100 000 in men and 9 per 100 000 in women) are higher than those in the general population in England 28 (three year average rates of 12.4 per 100 000 in men and 3.7 per 100 000 in women for 2010-12). Larger differences than this might be expected since our rates are in patients with a diagnosis of depression rather than in the general population. Studies showing greater differences, however, have tended to be in secondary care settings, where patients have more severe depression.

These results are consistent with those of our previous cohort study in older people with depression, 19 which found that trazodone, mirtazapine, and venlafaxine were associated with the highest rates of attempted suicide or self harm in people aged 65 or more. The number of recorded suicides in that study was too small (43 cases) to carry out an analysis by individual drug, but the analysis by drug class found that the suicide rate was highest for the group of other antidepressants.

Some other observational studies of antidepressants and risk of suicide or attempted suicide have also found increased risks among patients prescribed venlafaxine, although fewer studies have reported increased risks for mirtazapine or trazodone. A cohort study 9 in patients aged 18 to 89 using the general practice research database found that venlafaxine use was associated with a higher risk of suicide and attempted suicide than was citalopram, fluoxetine, and dothiepin. The authors concluded that this could reflect residual confounding since they found that venlafaxine users had a higher burden of risk factors for suicide, as was also the case in a previous study using the general practice research database. 29 A study of US veterans 30 with diagnosed depression comparing seven antidepressant medications found that crude suicide rates were highest among those prescribed mirtazapine, and venlafaxine had the second highest crude rate. In adjusted analyses, however, the suicide rates were not significantly higher for these drugs than for citalopram. A cohort study comprising all patients in Finland admitted to hospital because of a suicide attempt between 1997 and 2003, excluding patients with a diagnosis of psychosis, found that venlafaxine was associated with a significantly increased risk of suicide during follow-up and fluoxetine with a significantly reduced risk when compared with no antidepressant treatment, even after adjusting for confounders. 31 Mirtazapine was associated with an increased risk of suicide in the crude analysis, but not after adjustment. In the adjusted analysis all individual antidepressant drugs were associated with an increased risk of further suicide attempts compared with no antidepressant use, and although the adjusted relative risk was highest for venlafaxine it was only slightly larger than the relative risks for the other antidepressants studied. A cohort study 10 based on incident users of antidepressants also found a significantly increased risk of suicide acts (suicide attempts and completed suicides) for venlafaxine users compared with selective serotonin reuptake inhibitor users, although the association was attenuated in a secondary analysis restricted to treatment naïve patients.

Although randomised controlled trials of antidepressants are not influenced by residual confounding, they tend to be small, of short duration, and often exclude people who are actively suicidal or have comorbidities. 32 Several meta-analyses of randomised controlled trials have been conducted, 7 33 34 35 36 although few have looked at individual antidepressant drugs. The meta-analysis of 372 randomised controlled trials conducted by Stone et al 7 included an analysis of suicidality risk (suicide, attempted suicide, preparatory acts, or ideation) for 18 individual drugs compared with placebo. This meta-analysis included a total of 530 outcome events, of which only eight were completed suicides and 134 were attempted suicides. The numbers of events for individual drugs were small and statistical tests found no significant differences among drugs and drug classes, with the exception of some indication of differences among selective serotonin reuptake inhibitors, where odds ratios for suicidality ranged from 0.51 (95% confidence interval 0.29 to 0.91) for sertraline to 2.44 (0.90 to 6.63) for escitalopram compared with placebo.

Clinical implications and future research

The results of this study and others on self harm, suicide, and all cause mortality increasingly suggest that adults prescribed drugs such as mirtazapine and venlafaxine and possibly trazodone seem to be at higher risk of self harm and suicide. These associations might be due to these patients having different characteristics or more severe depression than patients prescribed other antidepressants rather than a direct causal effect of the drugs, but irrespective of the reason for the increased risks these patients need particularly close monitoring during treatment and shortly after stopping. The benefits and risks of different antidepressant treatments will vary between patients, 37 and these should be considered carefully when antidepressants are prescribed.

At present NICE guidelines for depression 25 recommend the use of a selective serotonin reuptake inhibitor first but if there is a lack of response to use another selective serotonin reuptake inhibitor or a better tolerated newer generation antidepressant, and subsequently an antidepressant from a different drug class, such as venlafaxine or a tricyclic antidepressant. The British Association of Psychopharmacology guidelines 38 recommend the use of venlafaxine, escitalopram, or older tricyclic antidepressants at a higher dose in patients with severe depression. If our findings are confirmed this advice may require further consideration. Our results, showing an association of an increased risk of attempted suicide or self harm with combinations of antidepressants compared with selective serotonin reuptake inhibitors is, in addition to adverse physical outcomes, another reason for careful monitoring of patients taking combinations of antidepressants by specialists in the management of depression. 25 The results also confirm that the risk of self harm and suicide is increased in the first 28 days of stopping antidepressants, so guidelines might place greater emphasis on the need for monitoring anyone after a planned withdrawal of antidepressants or an indication of any unplanned or sudden withdrawal. Further research might examine if such risk is universal or only applies to patients with symptoms of depression and other risk factors for suicide and self harm.

Conclusions

This study has found that rates of suicide and self harm were similar during periods of treatment with selective serotonin reuptake inhibitors and tricyclic antidepressants, but were higher for the group of other antidepressant drugs, with mirtazapine, venlafaxine, and trazodone being associated with the highest risks. The number of suicide events was small so the results for suicide should be interpreted with caution. Rates tended to be highest in the first 28 days after starting treatment and remained increased in the first 28 days after stopping treatment. These findings are of associations rather than causal effects and are particularly susceptible to confounding by indication, channelling bias, and residual confounding; further research is needed to confirm them. The results of this study indicate that patients taking antidepressant drugs should be carefully monitored, especially during early treatment with antidepressants and when stopping treatment.

What is already known on this topic

Depression is a common condition, and antidepressants are used extensively in its treatment

Rates of suicide and attempted suicide are higher in people with depression

It is unclear to what extent suicide and attempted suicide rates vary when people with depression are treated with different antidepressants

What this study adds

Rates of suicide and attempted suicide or self harm were similar during periods of treatment with selective serotonin reuptake inhibitors and tricyclic and related antidepressants overall, but were higher during periods of treatment with other antidepressants, although this may reflect indication biases and residual confounding

Suicide and self harm rates tend to be higher when antidepressants are started or stopped so the same care over risk assessment should be carried out when treatment is stopped as when it is started

Cite this as: BMJ 2015;350:h517

We thank those practices who use EMIS (Egton Medical Information Systems) and contribute to QResearch, and we thank EMIS and the University of Nottingham for expertise in establishing, developing, and supporting the database.

Contributors: CC, JH-C, RM, AA, and MM contributed to the overall conception and design of the study. CC wrote the first draft of this manuscript. JH-C undertook the data extraction. TH and CC carried out the statistical analyses of the study. All authors contributed to the interpretation of results and drafting of this manuscript. All authors read and approved the final manuscript. The views expressed are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health. CC is the guarantor.

Funding: This project was funded by the National Institute for Health Research (NIHR) School for Primary Care Research (project No 81). RM’s contribution to the study has been funded through the NIHR Collaboration for Leadership in Applied Health Research and Care East Midlands (CLAHRC EM).The funding body did not play a role in the study design, writing of the manuscript, or the decision to submit the manuscript for publication.

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: financial support from NIHR for the submitted work; JH-C is director of QResearch, which is a not for profit venture between the University of Nottingham and Egton Medical Information Systems (commercial supplier of general practice clinical systems); no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

Ethical approval: The project has been independently peer reviewed and accepted by the QResearch Scientific board and has been approved in accordance with the agreed procedure with the Trent Research Ethics Committee (reference No MREC/03/4/021).

Data sharing: The patient level data from the QResearch are specifically licensed according to its governance framework. See www.qresearch.org for further details.

Transparency: The lead author (CC) affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ .

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• Case report
• Open access
• Published: 31 May 2019

Critical appraisal of major depression with suicidal ideation

• Maurizio Pompili   ORCID: orcid.org/0000-0003-1886-4977 1  

Annals of General Psychiatry volume  18 , Article number:  7 ( 2019 ) Cite this article

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Regardless of its nature, suicidal ideation, in the absence of another diagnosis, is quintessentially associated with major clinical depression. Although for the characteristics of being depressed it is reasonable to have some wish to die, there is no real attempt to understanding the suicidal mind. Clinicians are therefore often inclined to consider suicidal ideation a symptom of major depression. Yet, most depressed patients do not die by suicide, and many of them never experience suicidal ideation even in the most severe depressing scenario. At a closer look, when one works with suicidal individual, suicide appears complex and not line with the obsolete medical model. There are often warning signs for suicide, and suicidal individuals experience mental pain as a common denominator of many adverse events.

Case presentation

A case report of an entrepreneur with no previous psychiatric history describes the process of meditating suicide as a dimension overlapping the depressive disorder. Details of how this 63-year-old male developed high suicide risk are reported, and clinicians are guided into the understanding of suicide risk.

Conclusions

Nowadays, clinicians are requested to provide an in-depth investigation into the suicidal mind, an assessment adjunctive to the psychiatric evaluation. A phenomenological approach may be the key to unlock the suicidal mind. Clinicians may use such tool in light of the need for the empathic understanding of human suffering as well as a paradigm shift in the care of suicidal individuals.

Notwithstanding the strong association between suicidal ideation and depression, it is time to re-consider both major depression and suicide risk. For both scholars and laypeople, depression does result in the wish to die, and clinicians are often inclined to include suicidal ideation as well as a suicidal crisis into the clinical manifestations of major depression. This assumption is reasonable for any patient. An individual who is depressed, with insomnia, anhedonia, and facing dysphoria and overall hopelessness about the future could easily conclude that life is not worth living, especially if a rapid reduction of such misery is not readily available or not possible. Moreover, lack of joy and pleasure, impaired ability to concentrate and unpleasant future expectations, as well as feeling of worthlessness and guilt, are all symptoms that can result in the wish to die. As Esquirol [ 1 ] noted, “Suicide presents all the characteristics of insanity of which it is but a symptom.”

Only a minority of depressed patients die by suicide, and a large percentage of severely depressed patients never think about suicide [ 2 ]. Although some researchers count the lives of those who die by suicide as part of the burden of depression, recent statistics challenge this view, indicating that more than the half of suicides do not merit a psychiatric diagnosis [ 3 ]. Furthermore, The US Centers for Disease Control and Prevention has launched an information campaign to shed light on suicide pointing to contributing factors other than mental illness [ 4 ].

Contrary to the obsolete medical model of suicide, pharmacological treatment results in the reduction of suicide risk, and this implies that these agents target the components of the suicidal scenario rather than the psychopathological symptoms of major depression. The evidence supporting this hypothesis suggests that there are two separate dimensions, one involving features of a psychiatric disorder and the other one presenting the characteristics of a suicidal crisis, often overlapping but still distinct. Such a conclusion emerges from various studies, among which, those involving lithium [ 5 ], ketamine [ 6 , 7 , 8 ] and clozapine [ 9 , 10 , 11 , 12 ]. Furthermore, some evidence supports the notion that being suicidal may limit response to antidepressant treatment in depressed major affective disorder patients, independent of overall symptomatic severity [ 13 , 14 ]. Such evidence seems to suggest that depressed, suicidal individual represent a peculiar subgroup of patients that request in-depth clinical observation.

Modern psychiatry now needs a new medical model with clinicians being able to appraise depressed individuals with suicidal ideation critically. Depression per se is not a useful tool for a proper understanding of the complexity of suicide, and suicidal ideation is not a proxy for the diagnosis of major depression. The uniqueness of each patient determines the variability of the threshold for sustaining mental pain, a condition dependent on personal experiences starting from childhood. This mental suffering, which has been shown to share the same neuroanatomical circuits of somatic pain [ 15 ], is referred to the hurt, anguish, or psychache that takes hold in the mind. Such negative emotions are tied to thoughts that erode the perspective of future expectations, making the future seem ominous. Efforts to manage psychological pain can last weeks, months and sometimes years and, at times, the suffering overcomes the threshold very rapidly, and suicide occurs.

It is possible that human sadness (such as in response to loss, grief, etc.) shares feature with major depression even in the absence of a validated psychiatric diagnosis. Clinical judgment is required to distinguish between the two entities [ 16 , 17 ].

In line with this, the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) states, “Diagnosis of a mental disorder should have clinical utility” but “the diagnosis of a mental disorder is not equivalent to a need for treatment. Need for treatment is a complex clinical decision that takes into consideration symptom severity, symptom salience (e.g., the presence of suicidal ideation), the patient’s distress (mental pain)” and “Clinicians may thus encounter individuals whose symptoms do not meet full criteria for a mental disorder but who demonstrate a clear need for treatment or care. The fact that some individuals do not show all symptoms indicative of a diagnosis should not be used to justify limiting their access to appropriate care” ([ 18 ], p. 20).

Mr. SL is a 63-year-old entrepreneur who has been running his own business for about 30 years, achieving success and admiration from his peers. However, due to the economic crisis, he started facing financial difficulties and had problems in carrying out his business, paying salaries to his long-lasting employees, and supporting his family. After trying many options to get support from banks, he realized that his company was in danger. Because of this situation, he started experiencing sadness, insomnia, loss of appetite, hopelessness, and irritability. He described how he saw no way out, and he described himself as in a tunnel with no real solution to his economic problems. Things got worse as the crisis eroded the money he had saved for emergencies.

He also experienced unimaginable physical suffering with unpleasant sensations at the hypochondrium (the upper part of the abdomen) related to anxiety, and he sometimes had dyspnea. Despite these symptoms, he tried his very best to continue and attend to his work activities. After almost 3 months of feeling depressed, he started thinking about suicide. He reported that suicidal ideation gradually became the companion that could provide help and relief from the pain he was experiencing. Having realized that he could rely on suicide as a way out from his problems, he experienced both the pressure of the precarious economic state and a state of relief when lousy news regarding his debts continued to arrive. He thought that he would not be alive anymore in a week or two. A peculiar aspect of his psychopathological state was an “ossimoric” feature, that is, while he was experiencing the sadness and despair for what has happened to his life, he was still able to enjoy some activities such as maintaining his status and playing at his tennis club, as well as going out for dinner and other leisure activities.

After experiencing depression with suicidal ideation for a while, he then concluded that suicide was the only option left. Although he had spent a pleasant bank holiday, early in the morning on returning to work, he thought that he had to put an end to his life. He went to his office, got his gun and started driving at random for hours. He had left two letters for his children explaining what was behind his choice. He had switched off his cellular phone, and his family lost his track oh him for hours. Just before the moment when he decided to use the gun for killing himself, he thought he wanted to speak to a friend to ask him to support his family. This friend proved to be skilled in maintaining a conversation and supporting the patients’ wish to live. The conversation on the cellular phone helped police to trace the patient. Police officers stopped him and brought to a psychiatrist who diagnosed major depression and the need for psychiatric hospitalization.

However, after a few days, he was able to decide whether to remain or discharge himself. After returning home, his children noticed the poor mental state of their father and sought a consultation with the author. The patient underwent a full psychiatric evaluation, as well as an in-depth assessment of suicide risk, with an analysis of his reasons for living versus his reasons for dying. Although the patient was depressed, an intervention for the treatment of depression would not have provided relief for this man. Lithium was prescribed, in association with small doses of an atypical antipsychotic at night, and regular sessions of psychiatric evaluation combined with sessions of psychotherapy were scheduled. This treatment proved to be of great relief for the patient, and he reported a feeling of being understood by my collaborators and by me. He improved dramatically over 2 months and, despite having the same economic problems that had led him to contemplate suicide; he never reported suicidal ideation again.

Discussion and conclusions

Suicidal individuals have many unmet needs, and they may not fit into diagnostic categories and may lack a full clinical picture. They should not be left alone with no treatment as if therapeutic options would prove to be of no use.

Psychological pain, as a main ingredient of suicide, is the pain of excessively felt shame, guilt, fear, anxiety, loneliness, and angst. This very human condition points to the fact that the nature of suicide is first mental, meaning that each suicidal drama occurs in the mind of a unique individual [ 19 ]. Depressed individuals are suicidal only when negative emotions are so painful that suicide is the only option left and when the suicidal mind is hosted in an individual’s depressed brain. Such individuals conclude that life cannot be accepted with unbearable suffering. Suicide is not, therefore, a specific and narrow symptom of depression. Instead, it is a behavior “combining features of a declaration of war with a petition for bankruptcy” [ 20 ].

What emerged from the case reported above is the fact this man was experiencing a narcissistic failure from having his business closed down, and his employees fired. He was between life and death, hoping somebody would rescue him and reduce his suffering. From the clinical picture, there also emerged a feature always traceable in suicidal individuals, that is, ambivalence. He was contemplating suicide, but he also was attached to life’s activities, such as his duties and his family, and he ultimately phoned a friend. This feature can be a crucial element in suicide prevention, providing a period available for rescuing the individual in crisis. During this phase, suicidal individuals often communicate, either covertly or explicitly, their intention to die [ 21 ]. The suicidal crisis is also often anticipated or accompanied by three symptoms: anxiety (inner turmoil), agitation and irritability [ 22 ], key features also found patients with depressive symptoms during mania [ 23 ]. Sleep symptoms are often reported occurring well before the emergence of the suicidal ideation. People contemplating suicide, but experiencing ambivalence, often consider what has been crucial in their lives. They may give away books, jewelers, and symbolic objects to someone who will take care of such things after their death.

From the case report above, we learn that two other essential items were at work in the suicidal mind: hopelessness (such as not having positive future expectations) and dramatic mood changes. Hopelessness has been reported as more indicative than depression in the prediction of suicide [ 24 , 25 ]. The patient, although continuing to work, saw no future in his activity, dismissing claims for payment as something, which he would not deal with anymore. He also alternated pessimistic thoughts with some recreational activities. Of note is that, before the final decision to die and collecting the gun, he had experienced a good mood and a state of enjoyment (playing golf with friends). Suicidal individuals often switch from sadness to positive and enthusiastic thinking, a feature that has been interpreted with having decided to die by suicide and eliminating the ambivalence. What causes suffering is the ruminations and thoughts that reiterate the failures, the shame, the loss and the rejections (to name just a few) so that imagining the abolition of the flow of thoughts in the conscious mind is seen as the ultimate relief. Clinicians must explore death fantasies in suicidal individuals. When suicide risk is deemed to be high, I always ask if the patients have ever thought about his or her afterlife, that is, the funeral, who will attend, or the reaction of the people who will discover the body. In highly suicidal individuals, such fantasies are reported, whereas they often (although not always) evoke horror if the risk of suicide is low.

Clinicians who consider suicidal ideation to be merely a symptom of depression may miss the rare opportunity to get to know a very private aspect of patients and reduce their suffering. They may even uncover the fact that what they are treating is not necessarily major depression with suicidal ideation but rather severe human sadness emerging with suicidal wishes. This critical distinction may dramatically change the outcome for patients. Treatments and therapeutic options depend on the clinical manifestations. Clinicians may use available treatments for targeting symptoms such as insomnia, agitation, and dysphoria. At the same time, major depression with suicidal ideation may benefit from both pharmacological and non-pharmacological interventions, while not ignoring the motives for wishing to be dead which should be at the center of the psychiatric intervention.

Modern psychiatry needs a better interpretation of suicide risk as compared with old models and reductionist explanations of a complex phenomenon. Rather than confining suicidal ideation to the realm of a symptom, clinicians should relocate such event in the complexity of each human being. Defining it as a symptom inevitably suggests that it is a manifestation of a given disease. We are however dealing with disorders rather than diseases, and suicidal ideation may emerge from the unfortunate combinations of various factors that threaten the stability of an individual. The result of such a state may belong to a different domain than the criteria of major depression. Despite the centrality of perspectives derived from genetics and epigenetics, neurobiology, psychobiology, far from being a manifestation of “normality,” suicide risk is ultimately a manifestation of overwhelming mental pain for which clinicians should be able to provide relief. Such clinical task reveals that suicidal impulses (thoughts and actions) are better understood as a pervasive condition whose roots originate from the internalization of pain-producing inner patterns derived from unsolved past experiences. Such vicissitudes influence proximal risk factors for suicide and exacerbate reactions to present adverse events.

Notions presented in this paper are in line with significant campaigns for preventing suicide, which point to the fact that any single factor rarely causes suicide. Factors can include relationship problems, substance misuse, a recent crisis as well as job, financial or legal stress [ 4 ]. Furthermore, recent results highlight the role of childhood traumatic experiences in determining vulnerability to both depression [ 26 ] and suicide [ 27 ]. Recent findings demonstrated that childhood traumatic experiences negatively influence the outcome of major depression in adulthood [ 28 ]. Besides, depressed patients who experienced trauma in childhood may be less likely to respond to treatment and achieve remission [ 29 ]. Such evidence goes to show that the focus is the person rather than the disorder and that a comprehensive analysis of both clinical assessments of major depression according to psychiatric criteria as well as an empathic understanding of what energizes mental pain is the key role of anyone who is professionally involved in helping such suicidal individuals.

Clinicians should put themselves into the shoes of the individual with whom they are dealing with. They should discern whether it is major depression or sadness and misery derived from accumulating adverse events. A more phenomenological approach would be of help in assessing the suicidal risk formulation in patients with major depression.

Availability of data and materials

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Pompili, M. Critical appraisal of major depression with suicidal ideation. Ann Gen Psychiatry 18 , 7 (2019). https://doi.org/10.1186/s12991-019-0232-8

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Suicide Risk: Case Studies and Vignettes

Identifying warning signs case study.

Taken from Patterson, C. W. (1981). Suicide. In Basic Psychopathology: A Programmed Text.

Instructions: Underline all words and phrases in the following case history that are related to INCREASED suicidal risk. Then answer the questions at the end of the exercise.

History of Present Illness

The client is a 65-year-old white male, divorced, living alone, admitted to the hospital in a near comatose condition yesterday because of an overdose of approximately thirty tablets of Valium, 5 mgm, combined with alcoholic intoxication. The client was given supportive care and is alert at the present time.

A heavy drinker, he has been unemployed from his janitorial job for the past three months because of his drinking. He acknowledges feeling increasingly depressed since being fired, and for the past two weeks has had insomnia, anorexia, and a ten pound weight loss. He indicates he wanted to die, had been thinking of suicide for the past week, planned the overdose, but had to “get drunk” because “I didn’t have the guts” [to kill myself]. He is unhappy that the attempt failed, states that, “nobody can help me” and he sees no way to help himself. He denies having any close relationships or caring how others would feel if he committed suicide (“who is there who cares?”). He views death as a “relief.” His use of alcohol has increased considerably in the past month. He denies having any hobbies or activities, “just drinking.”

Past Psychiatric History

Hospitalized in 1985 at Pleasantview Psychiatric Hospital for three months following a suicide attempt after his fourth wife left him. Treated with ECT, he did “pretty good, but only for about two years” thereafter.

Social History

An only child, his parents are deceased (father died by suicide when client was eight years old; mother died of “old age” two years ago). Raised in Boston, he moved to Los Angeles at twenty-one and has lived here since. Completed eighth grade (without any repeat) but quit to go to work (family needed money). Has never held a job longer than two years, usually quitting or being fired because of “my temper.” Usually worked as a laborer. Denies any physical problems other than feeling “tired all the time.” Currently living on Social Security income, he has no other financial resources. He received a bad conduct discharge from the army after three months for “disobeying an order and punching the officer.” He has had no legal problems other than several arrests in the past two years for public intoxication. Married and divorced four times, he has no children or close friends.

Mental Status Examination

65 y.o. W/M, short, thin, grey-haired, unkempt, with 2-3 day-old beard, lying passively in bed and avoiding eye contact. His speech was slow and he did not spontaneously offer information. Passively cooperative. Little movement of his extremities. His facial expression was sad and immobile.

Thought processes were logical and coherent, and no delusions or hallucinations were noted. Theme of talk centered around how hopeless the future was and his wishes to be dead. There were no thoughts about wishing to harm others.

Mood was one of depression. He was oriented to person, place, and time, and recent and remote memory was intact. He could perform simple calculations and his general fund of knowledge was fair. His intelligence was judged average.

Diagnostic Impression

• drug overdose (Valium and alcohol)
• Dysthymic Disorder (depression)
• Substance Use Disorder (alcohol)

Questions for Exercise

You have interviewed the client, obtained the above history, and now have to make some decisions about the client. He wants to leave the hospital.

• Is he a significant risk for suicide?
• discharging him as he wishes and with your concurrence?
• discharging him against medical advice (A.M.A.)?
• discharging him if he promises to see a therapist at a nearby mental health center within the next few days?
• holding him for purposes of getting his psychiatric in-client care even though he objects?
• Discuss briefly why you would not have chosen the other alternatives in question #2.

Identifying Warning Signs Case Study: Feedback/Answers

The client is a  65-year-old   white male ,  divorced ,  living alone , admitted to the hospital in a near comatose condition yesterday because of an overdose of approximately thirty tablets of Valium, 5 mgm, combined with alcoholic intoxication. The client was given supportive care and is alert at the present time. A  heavy drinker , he has been  unemployed  from his janitorial job for the past three months because of his drinking. He acknowledges feeling increasingly depressed since being fired, and for the past two weeks has had  insomnia  and a  ten pound weight loss . He indicates he wanted to die, had been thinking of suicide for the past week, planned the overdose, but had to “get drunk” because “I didn’t have the guts” [to kill myself]. He is  unhappy that the attempt failed , states that, “ nobody can help me ” and he sees no way to help himself. He  denies having any close relationships  or caring how others would feel if he committed suicide (“who is there who cares?”). He  views death as a “relief.”  His  use of alcohol has increased  considerably in the past month.  He denies having any hobbies or activities , “just drinking.”

Hospitalized in 1985 at Pleasantview Psychiatric Hospital for three months following a suicide attempt  after his  fourth wife left him . Treated with ECT, he did “pretty good, but only for about two years” thereafter.

An only child, his  parents are deceased  ( father died by suicide  when client was eight years old; mother died of “old age” two years ago). Raised in Boston, he moved to Los Angeles at twenty-one and has lived here since. Completed eighth grade (without any repeat) but quit to go to work (family needed money).  Has never held a job longer than two years , usually quitting or being fired because of “ my temper .” Usually worked as a laborer. Denies any physical problems other than feeling “tired all the time.” Currently living on Social Security income, he has  no other financial resources . He received a  bad conduct discharge from the army  after three months for “disobeying an order and punching the officer.” He has had no legal problems other than several arrests in the past two years for public intoxication.  Married and divorced four times , he  has no children or close friends .

65 y.o. W/M, short, thin, grey-haired, unkempt, with 2-3 day-old beard, lying passively in bed and avoiding eye contact.  His speech was slow and he did not spontaneously offer information . Passively cooperative. Little movement of his extremities. His facial expression was sad and immobile. Thought processes were logical and coherent, and no delusions or hallucinations were noted. Theme of talk centered around how  hopeless the future was and his wishes to be dead . There were no thoughts about wishing to harm others. Mood was one of depression . He was oriented to person, place, and time, and recent and remote memory was intact. He could perform simple calculations and his general fund of knowledge was fair. His intelligence was judged average.

• Is he a significant risk for suicide?  Yes. The client presents a considerable suicidal risk, with respect to demographic characteristics, psychiatric diagnosis and mental status findings.
• Discuss briefly why you would not have chosen the other alternatives in question #2.  The client appears to be actively suicidal at the present time,and may act upon his feelings. Nothing about his life has changed because of his attempt. He still is lonely, with limited social resources. He feels no remorse for his suicidal behavior and his future remains unaltered. He must be hospitalized until some therapeutic progress can be made.

Short-Term Suicide Risk Vignettes

*Case study vignettes taken from Maris, R. W., Berman, A. L., Maltsberger, J. T., & Yufit, R. I. (Eds), (1992). Assessment and prediction of suicide. New York: Guilford. And originally cited in Stelmachers, Z. T., & Sherman, R. E. (1990). Use of case vignettes in suicide  risk assessment. Suicide and Life-Threatening Behavior, 20, 65-84.

The assessment of suicide risk is a complicated process. The following vignettes are provided to promote discussion of suicide risk factors, assessment procedures, and intervention strategies. The “answers” are not provided, rather students are encouraged to discuss cases with each other and faculty. Two examples of how discussions may be facilitated are provided.

37-year-old white female, self-referred. Stated plan is to drive her car off a bridge. Precipitant seems to be verbal abuse by her boss; after talking to her nightly for hours, he suddenly refused to talk to her. As a result, patient feels angry and hurt, threatened to kill herself. She is also angry at her mother, who will not let patient smoke or bring men to their home. Current alcohol level is .15; patient is confused, repetitive, and ataxic. History reveals a previous suicide attempt (overdose) 7 years ago, which resulted in hospitalization. After spending the night at CIC and sobering, patient denies further suicidal intent.

16-year-old Native American female, self-referred following an overdose of 12 aspirins. Precipitant: could not tolerate rumors at school that she and another girl are sharing the same boyfriend. Denies being suicidal at this time (“I won’t do it again; I learned my lesson”). Reports that she has always had difficulty expressing her feelings. In the interview, is quiet, guarded, and initially quite reluctant to talk. Diagnostic impression: adjustment disorder.

49-year-old white female brought by police on a transportation hold following threats to overdose on aspirin (initially telephoned CIC and was willing to give her address). Patient feels trapped and abused, can’t cope at home with her schizophrenic sister. Wants to be in the hospital and continues to feel like killing herself. Husband indicates that the patient has been threatening to shoot him and her daughter but probably has no gun. Recent arrest for disorderly conduct (threatened police with a butcher knife). History of aspirin overdose 3 years ago. In the interview, patient is cooperative; appears depressed, anxious, helpless, and hopeless. Appetite and sleep are down, and so is her self-esteem. Is described as “anhedonic.” Alcohol level: .12.

23-year-od white male, self-referred. Patient bought a gun 2 months ago to kill himself and claims to have the gun and four shells in his car (police found the gun but no shells). Patient reports having planned time and place for suicide several times in the past. States that he cannot live any more with his “emotional pain” since his wife left him3 years ago. This pain has increased during the last week, but the patient cannot pinpoint any precipitant. Patient has a history of chemical dependency, but has been sober for 20 months and currently goes to AA.

22-year-old black male referred to CIC from the Emergency Room on a transportation hold. He referred himself to the Emergency Room after making fairly deep cuts on his wrists requiring nine stitches. Current stress is recent breakup with his girlfriend and loss of job. Has developed depressive symptoms for the last 2 months, including social withdrawal, insomnia, anhedonia, and decreased appetite. Blames his sister for the breakup with girlfriend. Makes threats to sister (“I will slice up that bitch, she is dead when I get out”). Patient is an alcoholic who just completed court-ordered chemical dependency treatment lasting 3 weeks. He is also on parole for attempted rape. There is a history of previous suicide attempts and assaultive behavior, which led to the patient being jailed. In the interview, patient is vague regarding recent events and history. He denies intent to kill himself but admits to still being quite ambivalent about it. Diagnostic impression: antisocial personality.

19-year-old white male found by roommate in a “sluggish” state following the ingestion of 10 sleeping pills (Sominex) and one bottle of whiskey. Recently has been giving away his possessions and has written a suicide note. After being brought to the Emergency Room, declares that he will do it again. Blood alcohol level: .23. For the last 3 or 4 weeks there has been sleep and appetite disturbance, with a 15-pound weight loss and subjective feelings of depression. Diagnostic impression: adjustment disorder with depressed mood versus major depressive episode. Patient refused hospitalization.

30-year-old white male brought from his place of employment by a personnel representative. Patient has been thinking of suicide “all the time” because he “can’t cope.” Has a knot in his stomach; sleep and appetite are down (sleeps only 3 hours per night); and plans either to shoot himself, jump off a bridge, or drive recklessly. Precipitant: constant fighting with his wife leading to a recent breakup (there is a long history of mutual verbal/physical abuse). There is a history of a serious suicide attempt: patient jumped off a ledge and fractured both legs; the precipitant for that attempt was a previous divorce. There is a history of chemical dependency with two courses of treatment. There is no current problem with alcohol or drugs. Patient is tearful, shaking, frightened, feeling hopeless, and at high risk for impulsive acting out. He states that life isn’t worthwhile.

Vignette Discussion Examples

Vignette example 1.

Twenty-six year old white female phoned her counselor, stated that she might take pills, and then hung up and kept the phone off the hook. The counselor called the police and the patient was brought to the crisis intervention center on a transportation hold. Patient was angry, denied suicidal attempt, and refused evaluation; described as selectively mute, which means she wouldn’t answer any of the questions she didn’t like.

Facilitator: How high a risk is this person for committing suicide? Low, moderate or high? Student Answer 1: Maybe moderate because the person is warning somebody, basically a plea for help. Facilitator: Okay, so we have suicidal talk. That’s one of our red flags. What else? She said she might take pills, so we didn’t know if she does have the pills. So she has a plan. The plan would be to take pills, but we don’t know if we have means. Student Answer 2: High. She’s also angry. I don’t know if she’s angry often. Facilitator: A person in this situation who is really thinking about killing themselves tends not to deny it. They tend not to deny it. There are exceptions to everything, but most of the time, for some reason, this is one of the things where people tend to mostly tell you the truth. If you ask people, they tend to tell you the truth. It’s a very funny thing about suicide that way. That’s certainly not true about most things. If you ask people how much they drink…But, “Are you thinking about killing yourself?” “Well, yes.” If you ask a question, you tend to get a more or less accurate, straight answer. Student question: Is that because it doesn’t matter anymore? If they’re going to die anyway, who’s going to care about what anybody thinks or what happens? Facilitator: My hypothesis would be, when someone is at that point, they’re talking about real, true things. They’re not into play. This is where they are. If they’re really looking at it, then they’re just at that place. What’s to hide at that point? You don’t have anything to lose. It’s a state of mind. And then if you’re not in that place—it’s like, how close are you to the edge of that cliff? “I’m not there. I know where that is, and I’m not there.” “If you get there, will you tell me?” “Yeah, I’m not there.” So, people have a sense—if they’ve gotten that close, they know where that line is, and they know about where they stand in regard to it, because it’s a very hard-edged, true thing.

Twenty-three year old white male, self-referred. Patient bought a gun two months ago to kill himself and claims to have the gun and four shells in his car. Police found the gun but no shells. Patient reports having planned time and place for suicide several times in the past. States that he cannot live anymore with his emotional pain since his wife left him three years ago. This pain has increased during the last week, but the patient cannot pinpoint any precipitant. Patient has a history of chemical dependency but has been sober for 20 months and currently goes to AA.

Facilitator: How high a risk is this person for committing suicide? Low, moderate or high? On a scale from 0 to 7 (7 being very high). Student Answer 1: High. On a scale of 0 to 7? Student Answer: Six. Student Answer 2: I would say three. I think it would be lower because if he’s already bought the gun two months ago and he’s self-referring himself to get help, he wants to live. He has not made peace with whatever, and he’s more likely not give away his things, and he’s going to AA meetings. I think it’s lower than really an extreme…I would say a three or four. Student Answer 3: I would say a four or five, moderate. Student Answer 4: About a five..several times and hasn’t followed through, tells me he doesn’t really want to follow through with it. Facilitator: And there are no shells, right? So we can see some of the red flags are there, but some of them aren’t. He’s still sober… Student: He has a support group. Student: He’s not using, though he bought a gun—so that’s a concern. There is a lot there. Student: He may not have the shells so he doesn’t have the opportunity to. So does that make him more…? Student 2: Think I’ll change mine to a five. Facilitator: So the mean was 4.68, so 5 was the mode. If we’re saying this is a moderate risk, what things would we look for that would make this a high risk? Student: Take away AA. Student: If he falls off the wagon, he goes right to the top. Student: And if he finds the shells. Facilitator: Because it probably is not that hard to find shells. All these stores around here, you can get shells quicker than you can get a gun, so he’s only a five-minute purchase away from having lethal—in contrast to not having the gun. Student: Could there be a difference in the time? Let’s say his wife left him just four to six months ago rather than three years. Would that be something that would be more serious? Facilitator: Yes, or if his wife just left him. So, say his wife left him a month ago that would bump it up. So that’s unresolved. That’s taking a person that was worried and that’s pushing him higher. Student: It also raises the homicide rate. Facilitator: Yes, because these tend to be murder-suicides. How often have we seen that? Murder-suicide is a big deal. If she won’t be with me, she won’t be with anybody.

The Relationship Between Antidepressant Initiation and Suicide Risk

Ten years ago, the FDA placed a black box warning on all antidepressants because of concerns that the medications increase risk of suicidal thoughts and behavior in youths. It's time for the FDA reevaluate that decision.

Figure 1. Suicide rate multipliers for SSRIs, SNRIs, and TCAs relative to antidepressants

Figure 2. Suicide rate vs SSRI dose in Japan stratified by age

Figure 3. Nonproportional hazards model for suicide attempts over time

Figure 4. Probabilities of suicide risk in adult and geriatric fluoxetine and venlafaxine studies

There has been much debate about whether certain classes of medications (eg, antidepressants) increase the risk of suicidal behavior and whether that risk is greater in children, adolescents, and young adults. In 2004, the FDA placed a black box warning on all antidepressants because of concerns that the medications increase risk of suicidal thoughts and behavior in youths; in 2006, the warning was extended to include young adults (up to age 26). The FDA based its black box warning on results of its meta-analyses of randomized controlled trials (RCTs) conducted in pediatric and adult psychiatric and nonpsychiatric populations.

Questions regarding a possible relationship between antidepressants and suicide were first raised in 1990 with the publication of a series of case reports in which the then newly introduced SSRIs were associated with the apparent emergence of suicidal thoughts and behavior. 1 This led to FDA hearings in 1991, but no evidence of an increased risk of suicidal acts associated with antidepressants was found. In October 2004, concerns raised over paroxetine use in children and adolescents eventually led the FDA to issue a black box warning regarding antidepressants and suicide for children younger than 18 years.

The evidence supporting the first black box warning came from a meta-analysis that combined spontaneous reports of suicidal thoughts and behaviors from pediatric RCTs of newer antidepressants, mostly SSRIs. 2 The risk of suicidal ideation and behavior, or suicidality, was found to be higher for children treated with antidepressants than for those given placebo (odds ratio [OR] = 1.78; 95% confidence interval [CI], 1.14, 2.77). The FDA also presented results of an analysis of prospective data (suicidal ideation or behavior rating-scale item) that showed no effect for emergence (OR: 0.93; 95% CI: 0.75, 1.15) or emergence and/or worsening of suicidal thoughts and behavior in the active-drug group compared with the placebo group (OR = 0.92; 95% CI, 0.76, 1.11).

The inconsistency between the prospective clinician ratings and spontaneous patient reports has not been adequately explained. It may be due to bias because patients randomized to active drug treatment have a greater likelihood of adverse effects in general, leading to more contact or conversation with study staff and increased chance of having any suicidal thoughts observed. Similarly, overdose on study medication is more likely to be reported if it results in the need for medical attention, as would be true for patients who receive active treatment rather than placebo.

Systematic questioning in a setting such as the emergency department or inpatient service generally gives a more accurate rate of suicidal ideation and behavior than do spontaneous reports. The FDA based its decision on the “signal” of risk from spontaneous adverse-event reports and not on the absence of a signal of risk from systematic clinician evaluations.

In January 2006, the FDA conducted a second meta-analysis of 372 RCTs of newer antidepressants in an adult population of approximately 100,000 patients. 3 This analysis was based on spontaneous adverse-event reports from the RCTs and did not provide data from prospective clinician ratings. Overall, the analysis revealed no evidence of more suicide-related adverse reports in the antidepressant group than in the placebo group. Stratification by age showed that for the primary endpoint of suicidal ideation or behavior, for 18- to 24-year-olds, the risk was increased with medication compared with placebo, and the risk approached significance (OR = 1.62; 95% CI, 0.97, 2.71); for adults aged 25 to 64 years, the risk was significantly decreased (OR = 0.79; 95% CI, 0.64, 0.98); and for geriatric patients, the risk was markedly decreased (OR = 0.37; 95% CI, 0.18, 0.76) with antidepressants relative to placebo. On the basis of these results, the FDA extended the black box warning to cover 18- to 24-year-olds.

More recent data

Since the FDA warnings, studies have been conducted to explore the relationship between initiation of antidepressant treatment and suicidal events. We review several lines of evidence that range from the weakest data based on spontaneous reports to the most rigorous data based on RCTs.

Spontaneous reports. Spontaneous reports to the FDA can be made by anyone; most are from patients, physicians, pharmaceutical companies, and plaintiff attorneys. They report both an adverse event and a listing of one or more medications that a patient is taking at the time of the event. Use of the spontaneous reporting systems for drug safety determination is highly problematic. Some limitations regarding these data are:

• Confounding by indication (ie, patients taking a particular drug may have a disease that is itself associated with a higher incidence of the adverse event)

• Systematic underreporting

• Effects of publicity in the media on numbers of reports

• Duplication of reports

• Attribution of the event to a single drug when patients may be taking multiple drugs

• Missing data

These limitations degrade the capacity for optimal data mining and analysis, and any conclusions must be tentative and require validation by another data source. 4

Data from the FDA Adverse Event Reporting System (MedWatch) from 1998 to 2004 for all antidepressants and completed suicide were analyzed by our group. 5 The dataset comprised a total of 28,317,382 records, including all reported adverse events and drug combinations. A national prescription rate for each antidepressant by year is the denominator in the analysis. Figure 1 presents a plot of the estimated rate multipliers and confidence limits for each drug. As a class, both SSRIs and SNRIs have rate multipliers that are significantly less than 1.0 (ie, lower than the national average suicide adverse-event report rate for antidepressants as a class). By contrast, TCAs have rate multipliers that are significantly above the national average suicide rate for antidepressants. TCAs have a significantly higher risk of suicide adverse-event reports than do SSRIs and SNRIs.

This is striking because one might anticipate an increase in reports related to SSRIs given the highly publicized concern over a possible link between suicide and the use of SSRIs. However, TCAs are much more toxic than SSRIs on overdose and are much more likely to produce a medically serious outcome. Therefore, it may be important to separate reports of medically serious overdoses using TCAs or SSRIs. Comparing the incidence of other types of suicide-related reports for these classes of medication may clarify the situation.

Ecological studies . For very rare events, such as those that occur at rates of 1 in 10,000 or less (eg, death by suicide), there are few options for routine drug surveillance because very large populations of patients are needed to detect enough events to be informative. One approach is to use ecological data that relate changes in drug prescription rates to suicide rates in large populations.

Decreases in suicide rate over time have been shown to correlate with increased antidepressant use in many studies around the world, including those in Europe, Scandinavia, the US, and Australia. In Sweden, the doubling of prescriptions for SSRIs correlated with a 25% decrease in the suicide incidence. 6 In an analysis of 27 countries, Ludwig and Marcotte 7 showed that an increase of 1 pill per capita (a 13% increase over 1999 levels) was associated with a 2.5% reduction in suicide rates, a relationship that was more pronounced in adults than in children.

Japan is a curious anomaly. Researchers there found a positive association between suicide rates and antidepressant prescriptions. 8 Figure 2 clearly shows an overall positive association between SSRI prescriptions and suicide rates; however, stratification by age reveals that within each age stratum, an inverse association is observed. This is a classic illustration of Simpson’s paradox. What it indicates is that in Japan, both suicide rates and use of antidepressants increase with age; however, for a given age-group, suicide rates have decreased with increasing SSRI prescriptions over time.

Another anomaly is Iceland, where antidepressant prescription rates seemed unrelated to lower suicide rates. Part of the reason for this are the traditionally extremely low suicide rates in Iceland. This is a floor effect; there is so little room for a further decline in suicide rates that the relationship to prescription rates is extremely hard to detect. Italy has had a decline in suicide rates linked to prescriptions for women but not for men. Most antidepressants in Italy are prescribed for women, and so the ability to detect such a relationship is greater in women.

Ecological modeling from large numbers of small areas can also provide a stronger basis for understanding the association between antidepressant medication use and suicide completion. US county-level data on suicide rates and antidepressant prescription rates were analyzed for 1996 to 1998. 9 After adjusting for sex, race, age, income, and unobservable county-level effects, the analyses revealed that increases in SSRI and SNRI prescriptions were associated with decreases in suicide rates both between and within counties over time. Conversely, counties with higher rates of TCA prescriptions were associated with higher suicide rates; this may be because of the greater toxicity of this class of agents and/or their more frequent use in areas with poorer access to quality mental health services. This finding has been replicated in children and young adolescents (aged 5 to 14 years) and indicates that the relationship is robust and manifest across the life cycle, from childhood to adulthood. 10

Large-scale observational studies . Valuck and colleagues 11 examined the effects of antidepressants on 24,119 adolescents with a first diagnosis of major depression. At least 6 months of follow-up data were available, which showed that treatment with SSRIs, other antidepressants, or combinations of antidepressants did not increase the risk of suicide attempts. Similar results were seen by Simon and colleagues. 12,13

In contrast, Olfson and associates 14 conducted a case-control study in depressed children and found a significant association for both suicide attempts (n = 263) and suicide completion (n = 8) in children treated with antidepressants. Tiihonen and colleagues 15 found that current antidepressant use was associated with increased risk of suicide attempts but lower risk of suicide completion in youths who had been treated with an antidepressant.

A cohort study of 226,866 veterans with newly diagnosed depression indicated that the attempted suicide rate was lower in those treated with only an SSRI (monotherapy) than in those who did not receive an antidepressant (123/100,000 vs 335/100,000, respectively; OR = 0.37; 95% CI, 0.29, 0.47). 16 In SSRI-treated patients, the rate of suicide attempts was lower after treatment (123/100,000) than before treatment (221/100,000; relative risk = 0.56; 95% CI, 0.44, 0.71). Analyses stratified by age showed that the benefit for 18- to 24-year-olds was comparable to that for the older age-groups: this contrasts with the FDA findings of greater risk in young adults that prompted the extension of the black box warning to include this age-group.

These data have been reanalyzed using discrete-time survival analysis and showed a robust decrease in suicide attempt rate with SSRI monotherapy (hazard ratio = 0.17; 95% CI, 0.10, 0.28). 17 As shown in Figure 3 , the incidence of attempted suicide decreased concurrently with time from the index episode, and the hazard rate was much lower for treated patients during the first few months following treatment initiation; however, the difference becomes indistinguishable by 9 months following the index episode. The lack of detectable benefit 9 months later may reflect a combination of spontaneous remission of major depression in the placebo group and declining compliance over time with treatment in the medicated group.

Randomized controlled trials . Bridge and colleagues 18 analyzed an expanded set (27 studies) of pediatric RCTs of antidepressant treatment and suicidality and found less correlation between the two than the FDA’s original findings. Their report used a larger data set than the FDA’s and found a more favorable risk to benefit ratio.

In our research synthesis of longitudinal data, fluoxetine in youths, adults, and the elderly and venlafaxine in adults were shown to be efficacious in all age-groups. Children experienced the maximum benefit and the elderly only marginal benefit following 6 weeks of treatment. 19,20 Adults and the elderly had significant benefit from antidepressant treatment in terms of reduction of suicidal thoughts and behavior; however, this improvement was mediated by a decrease in depressive severity. Figure 4 reveals that over time in both treated and control patients, there was a decrease in the frequency of suicidal thoughts and behavior; however, the decrease was significantly more pronounced in patients randomized to antidepressant treatment.

The magnitude of the difference between active treatment and control in terms of suicidal thoughts and behavior increases over time in adults and the elderly; however, there was no effect of treatment on suicidal thoughts and behavior in children, despite statistically and clinically significant benefits in terms of depression observed with active treatment. These findings suggest that suicidal thoughts and behavior in adults are largely driven by depression severity; however, this does not appear to be the case for children.

Clinicians who treat adults need to focus on maximizing the degree of improvement in depression to maximize the decrease in suicidal ideation and thereby acute suicide risk. These findings are consistent with a recent report in which most suicidal adolescents (more than 80%) received some form of mental health treatment, but such treatment failed to prevent suicidal behavior from occurring. 21

What happened following the black box warning?

Ecological studies revealed that there may have been unintended consequences of the black box warning. Evidence now shows that antidepressant prescription rates dropped precipitously beginning with the public health advisory in March 2004, which preceded the black box warning in October 2004. Since the initial public health advisory, antidepressant prescriptions for children and adolescents decreased, with a consequent increase (14%) in incidence of suicide in these populations. 22,23 No increase in suicide was found in the elderly, for whom antidepressant prescription rates continued to increase.

Libby and colleagues 24,25 found significant decreases in the number of new cases of child and young adult depression that were diagnosed by general practitioners following the black box warning (44% reduction in pediatric patients and 37% in young adults). Isacsson and Ahlner26 looked at 845 suicides in the 10- to 19-year-old group in Sweden from 1992 through 2010. After the 2004 warning, the suicide rate increased for 5 consecutive years (60.5%), largely in those who were not treated with antidepressants.

Busch and colleagues 27 studied academic and behavioral outcomes in more than 100,000 adolescents aged 12 to 17 using a difference-in-difference design. They found that grade point averages (GPAs) for depressed children decreased 0.20 points following the black box warning in the US; however, there was no change in GPAs in non-depressed children. They also found increases in delinquency and use of tobacco and illicit drugs among depressed adolescents.

The FDA implementation of a black box warning had the purpose of reducing suicide rates in children, adolescents, and young adults. The picture following the FDA warning and implementation of the black box warning is not that of a lower suicide rate as intended or hoped for by the FDA. Instead, we see fewer antidepressant prescriptions, an increase in youth suicides, and negative effects on human capital. That outcome is difficult to reconcile with a model of an increase in youth suicide risk when antidepressants are prescribed. The findings fit better with a model of a net reduction in suicide risk when antidepressants are prescribed.

The data show that in adults, antidepressants appear to protect against suicidal events. SSRIs are associated with lower overall suicide rates compared with other classes of antidepressants (eg, TCAs). Antidepressants are effective in reducing symptoms, which, in turn, mediates suicidal events in adults and the elderly. This does not appear to be the case for youths, for whom antidepressant medications can reduce the severity of depression but appear to have no effect one way or the other on suicidal thoughts and behavior. Conversely to what is seen in adults, it may be that aggressive-impulsive traits play a more important role in youth suicide than does depressed mood. The impact of antidepressants on these traits remains unclear. Youth suicide may also be potentially related to illicit drug use and social factors, such as bullying, that are not directly affected by antidepressants.

The black box warning and the earlier public health advisory have shown that discouraging the medication treatment of depression in children is not an effective solution in preventing suicidal behavior. Careful monitoring and treatment of depression and monitoring suicide risk in children is clearly essential. Overall, the clinical evidence is that the majority of patients, young and old, benefit from antidepressants, without increased risk of suicide.

Ten years after the introduction of the black box warning, it is time that the FDA reevaluates this decision and that the results be made public. Moreover, the labeling language should be rewritten to clearly delineate the risks of treatment compared with the risks of no treatment.

Disclosures:

Dr Gibbons is Professor of Biostatistics in the departments of medicine, public health sciences, and psychiatry, and Director of the Center for Health Statistics at the University of Chicago. Dr Mann is the Paul Janssen Professor of Translational Neuroscience in the department of psychiatry at Columbia University, and Director, Molecular Imaging and Neuropathology Division, the New York State Psychiatric Institute, New York. The authors report no conflicts of interest concerning the subject matter of this article.

References:

1. Teicher MH, Glod C, Cole JO. Emergence of intense suicidal preoccupation during fluoxetine treatment. Am J Psychiatry . 1990;147:207-210.

2. Hammad TA, Laughren T, Racoosin J. Suicidality in pediatric patients treated with antidepressant drugs. Arch Gen Psychiatry . 2006;63:332-339.

3. Food and Drug Administration. Clinical review: relationship between antidepressant drugs and suicidality in adults. http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf. Accessed November 5, 2014.

4. Hauben M, Riech L, DeMicco J, Kim K. ‘Extreme duplication’ in the US FDA adverse events reporting system database. Drug Saf . 2007;30:551-554.

5. Gibbons RD, Segawa E, Karabatsos G, et al. Mixed-effects Poisson regression analysis of adverse event reports: the relationship between antidepressants and suicide. Stat Med . 2008;27:1814-1833.

6. Isacsson G. Suicide prevention-a medical breakthrough? Acta Psychiatr Scand . 2000;102:113-117.

7. Ludwig J, Marcotte DE. Anti-depressants, suicide, and drug regulation. J Policy Anal Manage . 2005;24:249-272.

8. Nakagawa A, Grunebaum MF, Ellis SP, et al. Association of suicide and antidepressant prescription rates in Japan, 1999-2003. J Clin Psychiatry . 2007;68:908-916.

9. Gibbons RD, Hur K, Bhaumik DK, Mann JJ. The relationship between antidepressant medication use and rate of suicide. Arch Gen Psychiatry . 2005;62:165-172.

10. Gibbons RD, Hur K, Bhaumik DK, Mann JJ. The relationship between antidepressant prescription rates and rate of early adolescent suicide. Am J Psychiatry . 2006;163:1898-1904.

11. Valuck RJ, Libby AM, Sills MR, et al. Antidepressant treatment and risk of suicide attempt by adolescents with major depressive disorder: a propensity-adjusted retrospective cohort study. CNS Drugs . 2004;18:1119-1132.

12. Simon GE, Savarino J, Operskalski B, Wang PS. Suicide risk during antidepressant treatment. Am J Psychiatry . 2006;163:41-47.

13. Simon GE, Savarino J. Suicide attempts among patients starting depression treatment with medications or psychotherapy. Am J Psychiatry . 2007;164:1029-1034.

14. Olfson M, Marcus SC, Shaffer D. Antidepressant drug therapy and suicide in severely depressed children and adults: a case-control study. Arch Gen Psychiatry . 2006;63:865-872.

15. Tiihonen J, Lönnqvist J, Wahlbeck K, et al. Antidepressants and the risk of suicide, attempted suicide, and overall mortality in a nationwide cohort. Arch Gen Psychiatry . 2006;63:1358-1367.

16. Gibbons RD, Brown CH, Hur K, et al. Relationship between antidepressants and suicide attempts: an analysis of the Veterans Health Administration data sets. Am J Psychiatry . 2007;164:1044-1049.

17. Gibbons RD, Amatya AK, Brown CH, et al. Post-approval drug safety surveillance. Annu Rev Public Health . 2010;31:419-437.

18. Bridge JA, Iyengar S, Salary CB, et al. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials. JAMA . 2007;297:1683-1696.

19. Gibbons RD, Hur K, Brown CH, et al. Benefits from antidepressants: synthesis of 6-week patient-level outcomes from double-blind placebo-controlled randomized trials of fluoxetine and venlafaxine. Arch Gen Psychiatry . 2012;69:572-579.

20. Gibbons RD, Brown CH, Hur K, et al. Suicidal thoughts and behavior with antidepressant treatment: reanalysis of the randomized placebo-controlled studies of fluoxetine and venlafaxine [published correction appears in Arch Gen Psychiatry. 2013;70:881]. Arch Gen Psychiatry . 2012;69:580-587.

21. Nock MK, Green JG, Hwang I, et al. Prevalence, correlates, and treatment of lifetime suicidal behavior among adolescents: results from the National Comorbidity Survey Replication Adolescent Supplement. JAMA Psychiatry . 2013;70:300-310.

22. Gibbons RD, Brown CH, Hur K, et al. Early evidence on the effects of regulators’ suicidality warnings on SSRI prescriptions and suicide in children and adolescents. Am J Psychiatry . 2007;164:1356-1363.

23. Centers for Disease Control and Prevention. Suicide trends among youths and young adults aged 10-24 years-United States, 1990-2004. MMWR Morb Mortal Wkly Rep . 2007;56:905-908.

24. Libby AM‚ Brent DA‚ Morrato EH‚ et al. Decline in treatment of pediatric depression after FDA advisory on risk of suicidality with SSRIs. Am J Psychiatry . 2007;164:884-891.

25. Libby AM, Orton HD, Valuck RJ. Persisting decline in depression treatment after FDA warnings. Arch Gen Psychiatry . 2009;66:633-639.

26. Isacsson G, Ahlner J. Antidepressants and the risk of suicide in young persons-prescription trends and toxicological analyses. Acta Psychiatr Scand . 2014;129:296-302.

27. Busch SH, Golberstein E, Meara E. The FDA and ABCs: unintended consequences of antidepressant warnings of adolescent human capital. J Hum Resour . 2014;49:540-571.

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• v.10(1); Jan-Dec 2012

Suicide and Antidepressants: What Current Evidence Indicates

Anil nischal.

Department of Psychiatry, C.S.M. Medical University, Lucknow, U.P. – 226 003, India

Adarsh Tripathi

Anuradha nischal, j. k. trivedi.

The documented efficacy and long-term benefit of antidepressants in patients with recurrent forms of severe anxiety or depressive disorders support their use in those individuals with these disorders, who experience suicidal thoughts or behavior. In general, it is assumed that antidepressants are beneficial for all symptoms of depression, including suicidality. However, some evidence suggests that Selective Serotonin Reuptake Inhibitors [SSRIs] may cause worsening of suicidal ideas in vulnerable patients. Systematic reviews and pooled analysis of experimental, observational, and epidemiological studies have investigated the use of SSRIs and their association with suicidality. Taking account of the methodological limitations of these studies, the current evidence fails to provide a clear relationship between their use and risk of suicidality in adults. However, in children and adolescents, there appears to be a bit of increased risk of suicidal ideations and attempts, but not of completed suicides. This risk can be anticipated and managed clinically. Clinicians are, therefore, advised to maintain a close follow-up during the initial treatment periods and remain vigilant of this risk. This advisory, however, should not deter clinicians from the use of effective dosages of antidepressants for a sufficient period of time, in every age group of patients, when clinically needed, and if found suitable otherwise.

Introduction

Debate persists on whether some antidepressant drugs (ADs), in particular the Selective Serotonin Reuptake Inhibitors (SSRIs), cause the emergence or worsening of suicidal ideas in vulnerable patients. Across the globe, ADs, especially SSRIs, are among the most commonly prescribed medications (Stafford, 2001[ 26 ]). Large amounts of prescriptions are written because of the perception and knowledge that they are largely safe and effective across a wide variety of common disorders, namely depression and anxiety disorders. Concerns related to safety were initially raised in the early 1990s, with reports that described a possible association with suicidality (Teicher et al ., 1990[ 28 ]), and from time to time later (Healy, 2004[ 11 ]). However, inferences regarding the plausibility and strength of the association between suicidality and the use of SSRIs have been conflicting and inconclusive (Khan et al ., 2000[ 15 ], 2003[ 16 ]; Simon et al ., 2006[ 24 ]).

In recent times, in order to get more information on the issue, many different study designs, including randomized clinical trials, observational studies, and ecological time trend analyses have been performed. Each of these research designs, with their unique strengths and limitations, have contributed by generating information that may be used to guide clinical practice patterns.

We summarize the current evidence, to generate evidence-based suggestions, for day-to-day clinical work. We have adopted a descriptive view of data presentation in this article to elucidate the relevant findings and produce useful clinical insights into this highly conflicting issue.

Ecological Studies

Ecological analyses have investigated whether the increasing use of SSRIs is associated with benefits in terms of decreasing rates of suicide. Evidence that antidepressants and other interventions offered by mental health professionals yield the expected reductions in risk of suicides or attempts is mixed (Singh, 2004[ 25 ]). Correlative pharmacoepidemiological studies have compared suicide rates by regions or years with the concurrent rates of prescriptions for antidepressants (Baldessarini and Tonda, 2007[ 3 ]). Several studies in US and Nordic countries (Scandinavian countries of northern Europe) have shown that emergence of modern, less toxic antidepressants, over the past decade, which dominate the current clinical practice, was associated with a generally moderate decrease in the overall suicide rates, varying in sex and age groups. Isacsson, 2000,[ 12 ], analyzed national statistics on suicide, alcohol consumption, unemployment, and the use of Ads, for the period 1978 – 1996, in Sweden, Denmark, Norway, and Finland. The study reported a reduction in suicide rates by 19%, in parallel with the increased use of ADs in these countries. However, in women under the age of 30 and over 75 years, the suicide rates remained unchanged, despite an increased consumption of ADs. Overall, Isacsson[ 12 ] concluded that the increased use of ADs appeared to be one of the contributing factors to the decrease in suicide rate.

However, evidence also suggests that similar trends of reduction in suicide rates were observed at least a decade ago, before the introduction of the first SSRI, Fluoxetine, in the US market and in some Nordic nations (Reseland et al ., 2006[ 21 ]). This suggests that many other factors were also operational in the reduction of suicide rates in these nations. Baldessarini and Tonda, 2007,[ 3 ], reported that only nine of the 29 ecological studies found significant inverse correlations of the increased use of modern antidepressants with diminishing national, regional or temporal trends in suicide rates; another 14 studies found correlations in some sex or age subgroups, who were inconsistent across the studies; and six found no significant relationships. Same analysis of the data from 78 reporting countries indicated that about half (54%) experienced a decrease in annual suicide rates between the 1950s (when antidepressants were not available) and early 2000s (a decade after the introduction of modern antidepressants); and a similar proportion (46%) reported an increase. Moreover, both types of changes have been reported from similar world regions, including a decrease and increase in Western and Eastern Europe, Latin America, and Asia. These outcomes suggest random or at least highly complex phenomena, likely to reflect the impact of many contributing factors.

Studies looking for suicide rates in a specific age group have shown different results. Pharmacoepidemiological data from the US suggest that paralleling the widespread use of SSRIs, the suicide rates among those aged 15 – 19 years fell from 11 / 100,000 in 1990 to 7.3 / 100,000 in 2003; and synchronous with the US FDA black box warning on antidepressants and the likely reduction in antidepressant usage in 2004, the suicide rates climbed to 18 for those younger than 20 years — from 1,737 to 1,985 deaths (Hamilton et al .,2005[ 9 ]).

Results of such ecological studies are influenced by a variety of factors, like improvement in public health, changes in legal, cultural or social prohibitions against suicide, improvement in identifying and reporting suicides, and increased access of more people to modern antidepressants (Barbui et al .,2007[ 4 ]). Tonda et al .,2006[ 30 ], found a strong correlation between state suicide rates and economic and demographic measures, likely to be associated with access to clinical care in general, including population density, clinician / 100,000 population, per capita income, access to medical insurance, and public support of mental health services. Although such studies may suggest hypothesis to be tested by more sophisticated measures, they cannot prove a direct, casual relationship between antidepressant treatment and reduced risk of suicide at the level of individuals.

Barring a few studies, the ecological studies in general, suggest the possible benefits of ADs exposure in the needy population. It is also important to emphasize that all ecological studies suffer from a fundamental inability to relate antidepressant exposure to suicidal behavior, at the level of the individual.

Case Control and Cohort Studies / Observational Studies

Observational evidence is present from large cohorts of depressed patients from general practice or the health maintenance organizations’ data source and from the relatively large case control comparisons of subgroups, varying in exposure to antidepressants. Olfson et al ., 2006,[ 19 ] in a matched case-control study, estimated the relative risk of suicide attempts and suicidal deaths in severely depressed children and adults treated with ADs versus those not treated with AD drugs. In these high-risk patients, AD drug treatment did not seem to be related to suicide attempts and deaths in adults, but it might be related in children and adolescents. Juurlink et al ., 2006,[ 14 ] studied population-based coroner's records and found that during the first month of therapy, SSRI use was associated with a nearly five-fold higher risk of completed suicide than other ADs. However, the absolute risk was low in comparison to untreated patients. This suggests that an idiosyncratic response to SSRIs may provoke suicide in a vulnerable subgroup of patients.

Simon et al ., 2006,[ 24 ] assessed the suicide risk during antidepressant treatment by computerized health plan records and identified around 65,000 individuals with 82,000 episodes of AD treatment. The study did not suggest significant increased risk of suicide or serious suicide attempts after starting treatment with newer AD drugs.

Martinez et al ., 2005,[ 18 ] conducted a nested case-control study based on information extracted from the General Practice Research Database, and analyzed the risk of non-fatal self-harm and suicide in patients with a new diagnosis of depression, who were prescribed SSRIs or tricyclics. The cohort included 146,095 patients. Patients taking SSRIs were not at an increased risk of suicide or non-fatal self-harm. However, in patients aged 18 years or less, weak evidence indicated a higher risk of non-fatal self-harm.

Isacsson et al ., 2005,[ 13 ] adopting a different approach, analyzed detection of different ADs in the forensic toxicological screening of 14,857 suicides compared to 26,422 cases of death by natural or accidental causes in Sweden from 1992 to 2000. This analysis did not support the increased risk of suicidality following AD treatment in Sweden over a period of nine years.

Interpretation of finding from these studies is significantly compromised by the risk of ‘confounding by morbidity or by indication.’ That is, medical treatment in general is more likely to be sought and given to more severely ill patients at a higher risk of suicide, and lesser toxic drugs are likely to be selected for patients at an increased risk for suicide. The non-randomized, clinically selected treatment in such studies can severely distort the observed associations between a greater suicide risk and use of particular treatments. Although many studies statistically adjusted for this possible confounder, the possibility that other known and unknown variables might have acted in unpredictable ways, cannot be ruled out. However, these studies do not provide information about any risk of suicidality with ADs in adults with depression. The need for more supervision in children and adolescents regarding suicidality subsequent to exposure of ADs is advised.

Randomized Controlled Trials

Randomized Controlled Trials (RCTs) should be the best source of data on the effects of antidepressant treatment on suicidal risks, and hundreds of RCTs support the licensing and clinical utility of ADs in a variety of psychiatric disorders. Several systemic reviews and pooled analysis of RCTs have evaluated this issue.

Fergusson et al ., 2005,[ 7 ] reviewed all published 702 RCTs, which included 87,650 patients, comparing SSRIs with placebo or other antidepressants. Almost a two-fold increase in the odds of suicidal attempts, but not in completed suicides, in SSRI users, was found compared to placebo or other therapeutic interventions. However, no difference was observed when a comparison between SSRIs and TCAs was made. Some serious limitations to this review were present, most important being lack of any information on adverse events for 58% of the patients eligible for analysis. Many other meta-analyses had also found an overall greater risk with antidepressants (Tollefson et al ., 1994[ 29 ], Khan et al ., 2000[ 16 ], 2003[ 15 ]; Storosum et al ., 2001[ 27 ]).

In contrast, Gunnell et al ., 2005[ 8 ], reviewed both published and unpublished randomized trials submitted by pharmaceutical companies to the safety review of the Medicine and Healthcare products Regulatory Agency (MHRA), pn depression and other clinical conditions. The outcome measures were completed suicide, non-fatal self-harm, and suicidal thoughts. This study reported no evidence of an increased risk of completed suicide, weak evidence of increased risk of self-harm, and inconclusive evidence of an increased risk of suicidal thoughts, with estimates compatible with modest protective or adverse effects.

The largest of these analyses was recently organized by the US Food and Drug Administration (FDA) to review all available data from 386 controlled trials of modern antidepressants involving 112,875 patient-subjects with major depressive or other disorders (Laughren, 2006[ 17 ]). This found no overall difference in the risk of ‘Suicidality’ (mainly suicidal ideation). However, on performing a secondary analysis by age-stratified measures, they suggested a differential risk of antidepressant-induced suicidality across the age spectrum, with a greater risk at the younger end of the spectrum, and a declining risk with aging, and perhaps even a protective effect in the elderly.

Concerns over safety of the use of SSRIs in children and adolescents have become paramount following the extensive review by British and American regulatory agencies. Hammad et al ., 2006[ 10 ], in a review of both published and unpublished clinical trials using SSRIs in children and adolescents with depression and other indications (N > 4,400 subjects, across 26 controlled trials, 16 of them for depression), revealed an increased risk of new onset suicidal ideation between SSRI- and placebo-treated individuals (occurring at the respective rates of 4 and 2%, for a risk ratio of 1.95). However, all reported events refer to suicidal ideation rather than suicidal acts or completed suicide.

Trials of ADs in adults have found a substantially larger reduction in the average rating of suicidal ideations with AD than placebo (Pedersen, 2005[ 20 ]; Acharya et al .,2006[ 1 ]). However, these findings were based on post hoc analysis of individual items on standard depression symptom rating scales (HAM-D, MADRS), which could shift coincidently with overall clinical improvement. Studies with ADs that explicitly considered suicidal ideation and behavior as outcome measures remain to be carried out.

Randomized Controlled Trials have limitations that can lead to uncertainties and artefacts. These include potentially unreliable, incidental, passive reporting of suicidal thoughts or behaviors in most RCTs, based on conditions not designated explicitly to detect suicidal events. The short-term bases of most clinical trials for acute depression also do not provide an adequate basis of evaluating the effect of ADs on rare suicidal behavior. Much of the reported events involve suicidal ideation of highly uncertain clinical significance and quantitatively very limited relationship to actual life-threatening behavior. In the placebo arm, the dropout rates are significantly higher owing to perceived lack of treatment efficacy, which can limit observable suicidal risk in the placebo arm, leading to an interpretation that active treatment is ‘riskier’ than placebo. Although procedure of pooling data from a large number of trials increases the overall sample, the absolute number of patients attempting or committing suicide remained low. This leaves a possibility that even reporting or not reporting a few cases could have completely changed the overall outcome (Cipriani et al .,2005[ 5 ]). Reduction in risk might not be observed as readily over short time periods, or in studies in which suicidality was used as an exclusion criterion.

The preceding findings have been widely debated and have created a huge attention of the lay media and public to this issue. Responding to this, the US FDA recommended revision of drug manufacturers’ information bulletins to include a highlighted ‘Black Box’ warning of the risk for possible emergence of suicidality.

Therefore, data pooled from relatively brief, randomized controlled trials in acute major depression in the young and elderly adults fail to suggest the risk of suicidality. In children and adolescents, few vulnerable cases may experience increase in suicidal ideations at the start of treatment. Hence, a clinician should routinely assess the risk and benefit ratio of an individual case, before prescribing ADs for them.

Possible reasons why ADs might increase the risk of suicide are discussed herewith.

Antidepressant therapy typically involves a substantial delay before clinically obvious improvements occur. During initial, partial recovery, it is possible that suicidal impulses as well as the energy to act on them may increase. Patients should be forewarned of this likely delay in treatment effects, should be given encouragement and monitored especially closely in the initial days and weeks of treatment. If full response to treatment is not observed, adjustments in medication dosage, or a change to a different antidepressant, may be necessary.

Heterogeneity in the psychopharmacological effects of SSRIs suggests that some patients might experience a worsening of mood with SSRI treatment. Undiagnosed bipolar disorder, especially Type II, may be present in patients presenting with depression. Recent studies suggest that antidepressants might worsen the mood in patients with undiagnosed bipolar disorder (Baldessarini et al ., 2006[ 2 ]) and may cause agitation and impulsivity, and exacerbate psychosis, resulting in an increased risk of suicide. If such symptoms emerge during the course of treatment of depression, the ADs should be stopped and appropriate treatment for Bipolar Disorder started.

Pharmacotherapy of mild depression is under greater scrutiny and should be decided on a case-to-case basis. Higher risk in children and adolescents should encourage clinicians to be more cautious in their management: they should resort to pharmacotherapy only after considering the risk / benefit ratio in each patient. Guidelines from the US FDA and American Academy of Child and Adolescent Psychiatry (AACAP) call for intensive monitoring during the early phase of treatment: as often as weekly for the first four weeks, fortnightly for the next month, and monthly thereafter (FDA, 2007[ 6 ]; Rey and Martin, 2006[ 22 ]). However, concerns have been raised that such guidelines may deter some clinicians from using ADs if they are unable to provide such monitoring, especially in underserved areas, and thus deserving patients may be denied the right treatment (Scahill et al ., 2007[ 23 ]).

Conclusions [See also Figure 1 : Flowchart of Paper]

Flowchart of the paper

Understanding the effects of SSRI antidepressants on suicide is important for government regulators as well as for doctors, patients, and the family and friends of those suffering from illnesses requiring AD treatment. Taking into account available evidence, and limitations of the evidence available, following insights for clinical practice can be highlighted:

• Available evidence is in favor of effectiveness of these agents in many clinical conditions; so clinicians should prescribe effective dosage of medications to those in need.
• The current evidence fails to conclusively establish a relationship between increased suicidal ideation and behavior after use of AD medications. At best it suggests some increased risk for children and adolescents.
• Clinicians should be aware of the fact that both TCAs and SSRIs may induce or cause worsening of suicidal ideations; hence, there is a need for early follow-up and encouraging support and supervision of patients, especially in the early phase of treatment.
• However, this adverse effect can usually be anticipated and identified clinically, and treatment can be appropriately modified in time, such as, offering greater psychological support, removing ADs, adding anxiolytics, antipsychotics or mood-stabilizing agents, as may be deemed necessary.

Take home message

• Caution is advisable during prescription of antidepressants to patients, especially in children and adolescents, as it may precipitate suicidal ideation in some vulnerable patients.
• However, this can be readily identified and managed clinically, and it should not deter clinicians from providing effective pharmacological treatment to those in need.

Questions that this Paper Raises

• What are the reasons for the age-wise distribution of change in suicidality subsequent to exposure to antidepressants, in patients with depression?
• Is there a deferential risk of antidepressants for increased suicidality in children and adolescents? What is their relative risk?
• What are the determinants of increased suicidal risk in these patients?
• Do ADs reduce suicidal ideation, attempts, or completed suicides in patients?

About the Author

Dr. Anil Nischal currently holds the position of Associate Professor of Psychiatry at the CSM Medical University (Erstwhile King George's Medical College), Lucknow, UP, India. He completed his MD in psychiatry in 2000, from KGMC and has worked at various institutions, including Institute of Human Behavioral and Allied Sciences, New Delhi; Lady Harding Medical College, New Delhi; Dr. RML Hospital, New Delhi, and the Himalayan Institute of Medical Sciences, Dehradun. He has also worked with the Royal College of Psychiatry, UK, and has been involved with the preparation of the Hindi adaptation for various patient information leaflets of that College. He has about 15 national and international publications and two book chapters to his credit. His main areas of interest are Anxiety Disorder, Stress Management, and burden of care of Psychiatric Disorders .

Dr Adarsh Tripathi is MD in Psychiatry and currently working as an Assistant Professor in Psychiatry at the C.S.M. Medical University, Lucknow, India. He has more than 25 national and international publications and four book chapters to his credit and has worked in six international and national researches of repute. His areas of interest include Addictions, Bipolar Disorder, Cognition, Adult ADHD, and Psychopharmacology. .

Dr Anuradha Nischal is currently working as an Associate Professor in Pharmacology, Chhatrapati Shahuji Maharaj Medical University, Lucknow, Uttar Pradesh, India. She has been associated with institutions like the Lady Harding Medical College, New Delhi; Institute of Human Behavior and Allied Sciences, New Delhi; Himalayan Institute of Medical Sciences, Dehradun, Uttarakhand, India. With the learning and experiences at these places, she has written a book Viva questions in pharmacology for the benefit of students (published 2011). She has eight national and international publications to her credit. She has supervised and co-supervised various MD and PhD theses. Her chief area of interest is Neuro-Psychopharmacology .

Dr. Jitendra Kumar Trivedi is a Professor in the Department of Psychiatry, Chhatrapati Shahuji Maharaj Medical University, U.P., (formerly King George Medical University, Lucknow) India. He has been a member of The Royal College of Psychiatrists, U.K. since 2005. He has been the Fellow member of the American Psychiatric Association since 2007, and nominated Honorary Member of the World Psychiatric Association in 2008, and Fellow of the National Academy of Medical Sciences. He has been a principal investigator for more than 25 multinational clinical trials as well as ICMR and WHO sponsored projects. He has around 240 publications in national and international Journals as well as chapters in books. He has been an Editor, in the Indian Journal of Psychiatry, President of the Indian Psychiatric Society, and a Zonal Representative for Southern Asia – Zone-XVI of the World Psychiatric Association. He is Vice President, Indian Association for Social Psychiatry; Chairperson, Ethics Committee, IPS, and has been a member of the International Advisory Committee for the 2011 ISSPD Congress. He has also been Advisor, SAARC Psychiatric Federation, and Editor, Journal of SAARC Psychiatric Federation (2007 – 2008).

Conflict of interest: None declared

Declaration

This is our original unpublished work, not under consideration for publication elsewhere.

CITATION: Nischal A, Tripathi A, Nischal A, Trivedi JK. Suicide and Antidepressants: What Current Evidence Indicates. Mens Sana Monogr 2012; 10: 33-44.

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Suicide in depressive disorders: a retrospective case-control study of 127 suicides

Affiliation.

• 1 Centre for Suicide Research, UK. [email protected]
• PMID: 15913784
• DOI: 10.1016/j.jad.2005.03.001

Background: Depressive disorders are associated with a significant risk of suicide. Inpatient status and recent discharge from hospital have been identified as times of high risk of suicide within the course of illness.

Method: A matched retrospective case control study of 127 patients with depression requiring inpatient care who died by suicide as inpatients or in the 12 months following discharge from hospital. Single and multivariable conditional logistic regression identified independent risk and protective factors for suicide.

Results: A history of deliberate self harm is a significant risk factor for suicide in patients with depression (OR 6.96; 95% CI 3.41-14.19), as is living alone (OR 2.11; 95% CI 1.15-3.87) and paid employment (OR 2.80; 95% CI 1.48-5.32). Admission to hospital during social crisis is associated with a reduction in suicide risk (OR 0.43; 95% CI 0.24-0.75).

Limitations: This is a retrospective case-control study, using clinical data not originally collected for research purposes.

Conclusions: General population risk factors for suicide are less predictive of suicide in patients with depression requiring inpatient treatment. Clinicians need to be aware of factors which increase or reduce the risk of suicide in this group.

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