Suicide in Parkinson’s disease.

Abstract

Persons with Parkinson’s disease (PwP) have many known risk factors for suicide and suicidal ideation. Despite this, there is limited understanding of suicidality in this population. We conducted a systematic review to synthesize the available literature on suicidality in PwP and highlight areas for potential intervention and further research. We identified 106 articles discussing suicidal ideation, suicidal behaviors, suicide attempts and/or fatal suicide in PwP. These articles describe prevalence, suicide methods, anatomy and biomarkers of suicide, risk factors for suicide and suicidal ideation, risk compared to the general population and other diseases, and treatment of suicidality. We summarize the current literature in each of these categories and provide suggestions for how clinicians may use this information to identify and treat PwP who are at risk for suicide, for example, through aggressive treatment of depression and improved screening for access to lethal means.

Introduction

Parkinson’s disease (PD) is a neurodegenerative disorder first described as the “Shaking Palsy” in 1817 by James Parkinson.¹ PD is estimated to occur in 1,903 per 100,000 individuals over age 80 worldwide, and rates will likely continue to increase as the population ages.² PD is primarily diagnosed by the presence of motor symptoms including bradykinesia, resting tremor, and muscle rigidity.³ However, non-motor symptoms of PD are being increasingly recognized as a cause of decreased quality of life,⁴ nursing home placement,⁵ and as predictors of overall mortality⁶ in PD. Depression in particular is common in PD, with one meta-analysis suggesting that 17% of persons with PD (PwP) suffer from major depressive disorder and 35% suffer from clinically significant symptoms of depression.⁷ Insomnia⁸ and anxiety⁹ are also common in PwP.

Suicide is the most feared outcome in psychiatry. Suicide is consistently listed among the top ten causes of death in the US, with rates steadily climbing throughout the 21^st century and reaching an annual rate of 13.4 deaths per 100,000 in 2016.^10,11 It is a dominant cause of mortality amongst the elderly^12,13 and persons with neurological diseases including stroke,¹⁴ Huntington’s disease,¹⁵ and epilepsy.¹⁶ Suicide is a behavioral outcome with a complex etiology. In the general population and among elderly individuals, depression is a major risk factor for suicide.^17,18 However, suicide cannot be understood merely as the most extreme manifestation on the spectrum of depressive disorders. Other identified risk factors for suicide in the general population include substance dependence, access to firearms, anxiety, insomnia, and physical disability.^12,19–27 Researchers have used this knowledge to develop ways to treat those at risk for suicide.^28–30

PwP have many risk factors for suicide. Surprisingly, despite these risk factors, there is little consensus on the association between suicide and PD. Scoping reviews are designed to provide an overview of the current state of the literature, contextualize what is known about a subject thus far, and identify areas for future research.³¹ To our knowledge, there have been no such reviews of suicidality in PD. In this review, we attempted to meet these goals with the aim of better understanding risk factors, mechanisms, and prevention of suicide in PwP.

Methods

A search of the literature was conducted using Medline (PubMed), Embase, The Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Methodology Register), PsycINFO (Ebsco), and Web of Science (Science and Social Science Citation Index). No restrictions were placed on the publication dates or language. For the search strategies designed for Medline (PubMed), the Cochrane Library, Embase, and PsycINFO, controlled vocabulary terms for each concept were identified and combined with keyword synonyms. Web of Science was searched using keyword terms only. Additional methods for finding articles included searching key journals, the references of the identified articles, and the grey literature (Appendix A).

Two reviewers (MS, KP) independently excluded articles based on title and abstract screening. Conflicts were resolved through discussion or a third reviewer’s (MB) evaluation. The remaining articles underwent independent full text evaluation, again by two authors (MS, KP). Inclusion criteria for title and abstract screening as well as full text review were: includes patients with idiopathic Parkinson’s disease; discusses suicidal ideation (SI), suicidal behaviors including suicide attempts (SAs), and/or fatal suicide; English language version available; includes original research. Meta-analyses and review articles were excluded. Conflicts were again resolved by discussion or adjudication by a third reviewer (MB). See Figure 1 for flow diagram.

Figure 1.

Flow Diagram of Review Process

Existing literature on PD and suicidality fell into the following categories: prevalence studies, comparison of risk to the general population and other diseases, suicide methods, anatomy and biomarkers, risk factors for suicide, and treatments for suicidality. Studies falling into more than one category were included in each.

Results

Prevalence and Risk of Attempted and Fatal Suicide

The first paper to report on suicide in PD was the 1967 article by Hoehn and Yahr, which described causes of mortality in parkinsonism. Among 340 parkinsonian patients who died during the study period, three died by suicide.³²

While subsequent reports of suicide prevalence exhibit marked variability, most articles suggest elevated suicide risk in PD.^33–37 These results vary by population; for example, a group in South Korea found a standardized mortality ratio for suicide in PwP to be 1.99 (95% CI= 1.33–2.85).³⁵ In the Netherlands, the OR for having a diagnosis of PD was 2.9 (95% CI=1.8–4.6) in those who attempted suicide via poisoning. ³⁷ Studies of Serbian and British populations have demonstrated a suicide risk greater than five times that of the general population matched for age and sex.^36,38 In British Columbia, suicide was the second most common cause of injury-related mortality in PwP.³⁹

Researchers in other populations have found no increased risk of suicide in PwP. In Denmark, Finland, the United States and Canada, suicide rates among PwP are comparable to the general population when adjusting for confounding factors.^40–42

Only one study suggested a decreased suicide rate in PwP. Using United States National Center for Health Statistics data (n=12,430,473), Myslobodsky et al⁴³ identified a cumulative incidence of suicide ten-times lower in PwP compared to the general population (0.08%, n=122 v. 0.8%). Cause of death was determined from a computerized death registry, and unknown causes of death were not classified as suicide. One French study found that suicide occurred in 1% of PwP, however it is unclear how this relates to suicide rate in a matched group of the general population.⁴⁴

Unlike deaths, SAs are difficult to accurately measure in large retrospective studies. Several researchers have noted no SAs in their study population.^45,46 Others have found that PwP have a lifetime rate of SAs similar to the general population (around 5%).^47–50

Prevalence and Risk of Suicidal Ideation (SI)

Most studies have found rates of SI among PwP around 30% with outlying estimates as low as 4%.^{38,46,48,49,51,52} Three studies have noted rates of SI lower than 15%, with only two others suggesting PwP are at decreased risk of SI compared to the general population. ^{42,45,47,52,53}

Suicide Methods

Two studies have directly compared suicide methods in PwP to those of the general population. Mainio and colleagues⁴¹ compared characteristics of nine suicide victims with PD to 546 suicide victims over age 50 without PD and found that PwP were more likely to use violent means (such as hanging or firearms). Similarly, a Canadian study noted that suicide victims with PD (n=25) were more likely to die by suffocation, excluding hanging, as compared to suicide victims in the general population (n=1304).⁵⁴ Suicide by defenestration and poisoning (including drug overdose) have also been reported in PwP.^37,55–58

Anatomy, Physiology and Biomarkers

In the general population, several biological correlates of suicide have been identified including abnormalities in serotonergic neurotransmission, epigenetic changes⁵⁹, and alterations in hypothalamic-pituitary-adrenal axis function.^60–62 Only two studies have investigated these phenomena in PD. Neither investigated suicide as a primary outcome and the implications of their findings are unclear.^63,64

Risk Factors for Suicide in PD

Demographics

Suicide victims with PD are on average 12.6 years older than suicide victims in the general population (72.2 years versus 59.6 years).⁴³ PwP who die by suicide are younger than those who die of other causes, with fewer medical comorbidities.^43,65 PwP who die by suicide are more likely to be of male gender, Caucasian ancestry and from a rural area than PwP who die of other causes, mirroring the risk factors in the general population.^35,41,43 There is no clear impact of marital status or education level on suicide in PD. ^43,65 However, suicide victims with PD are more likely to be married than suicide victims in the general population.⁴³

Demographic risk factors for SI in PwP follow similar trends. SI has been more commonly associated with younger age, although one study showed an association between SI and older age.^38,45,52,66 SI has not been associated with marital status in PD.^38,52 The role of education level is unclear: some studies have shown no association with SI, while others have associated SI with lower education level.^38,45,52 In contrast to the literature on suicide, SI may be more frequent in PwP who have more comorbidities, and rates of SI do not appear to differ by gender.^52,66 Unemployment has not been studied as a risk factor in PwP.

Neuropsychiatric Symptoms

Two large studies in Northern Finland and South Korea have found a significant association between suicide in PwP and history of any mental illness.^35,41 Depression is nearly invariably associated with SI and SAs in relevant publications,^{35,38,45,46,48,49,51,52,66,67} with only one study failing to find an association.⁶⁵ SI has been found to be a valid marker of PD depression.^68,69

To a lesser extent, psychosis is also associated with suicidality in PwP.^38,48,49 Delusions in particular were associated with the risk of suicide in one large study. ³⁵ Anxiety disorders^46,52 and impulse control disorders^45,48,51 have been correlated with SI in PwP. Only one study has looked at the role of substance abuse, finding that alcohol use contributed to suicide in PwP at rates similar to the general population.⁴¹ Importantly, PwP who die by suicide are much more likely to have a past SA compared to suicide victims in the general population (44% versus 9.9%).⁴¹ Increasing scores on the Beck Hopelessness Scale, Hamilton Depression Rating Scale, and Beck Depression Inventory have been associated with SI in PwP.^38,52

Cognition

Most of the literature reviewed excluded patients with dementia or MMSE (Mini-Mental State Examination) < 24. Of those that did investigate cognition, the findings are varied. One abstract detailing a cross-sectional study of 1783 PwP found that those with SI were significantly more cognitively impaired.⁶⁶ In contrast, two much smaller studies found an association between suicide or SI and higher MMSE score.^38,65 Others have found no association.⁵²

Motor Symptoms and Other PD-Related Variables

Findings have varied in studies looking at motor symptoms and suicide. Lee et al³⁵ showed that motor impairment severity, Hoehn and Yahr (H&Y) stage and illness duration were not associated with suicide risk, but that suicide was more common in PwP who had generalized or upper extremity onset of motor symptoms.³⁵ Several smaller studies have found no association between SI and disease severity, stage, or duration.^38,48,52

In contrast, some have reported a correlation between increased motor severity^45,46,66 or longer disease duration^42,45 and SI. PwP who die by suicide have also been found to have lower H&Y stage and UPDRS scores compared to those who die from other causes.⁶⁵ Suicidality has also been correlated with bradykinesia, rigidity, axial impairment, posture and gait disturbance items on the UPDRS.^70,71 There is limited and conflicting evidence on the impact of earlier disease onset.^72,73

The presence of dyskinesias or off periods has not been associated with SI in two studies.^38,48 There is some evidence that motor fluctuations, especially those perceived as untreated, are associated with suicidality.^65,74 Tremor and akathisia have been studied and have not been associated with SI.^70,71,75

Suicide Risk Compared with Other Populations

Two studies have compared the risk of suicide in depressed individuals with and without PD. Merschdorf et al⁷⁶ looked at depressive symptoms among German inpatients admitted to psychiatric or neurological hospitals. They compared symptoms in 49 depressed PwP with 38 patients with major depression alone. Fewer depressed PwP reported SAs (4% v. 42%), despite no difference in the frequency of SI (reported in 76% of both groups).⁷⁶ Similarly, Zhou et al⁷⁷ found no significant differences in the frequency of SI in depressed individuals with or without PD.

There has been limited research comparing suicide risk in PD to other movement disorders. One study found higher rates of suicidality in PwP and multiple system atrophy when compared to those individuals with progressive supranuclear palsy, despite similar rates of depression in all three groups.⁷⁸ There appears to be no difference in rates of SI between patients with idiopathic PD, monogenic PD, and spinocerebellar degeneration.^71,72

In the only study comparing suicidality among PwP to other chronically disabled individuals, PwP had significantly higher rates of depression and suicidality despite less severe disability.⁷⁹

Effects of PD Treatments

Dopamine and Dopamine Agonists

While clearly invaluable for management of PD overall, the role of dopamine replacement therapy (DRT) in suicide risk is unclear. In the first study to comment on the effect of DRT, Cherington⁸⁰ reported on three PwP who developed suicidality after several months of treatment with L-dopa. This led the authors to caution that L-dopa may be limited by the development of severe depressive symptoms including suicidality.⁸⁰ Soon after, two other groups reported cases of suicide in PwP after starting L-dopa.^81,82

Subsequent studies have been less consistent, possibly due to more sophisticated DRT regimens. Many case reports have described suicidality after withdrawal of levodopa or dopamine receptor agonists which resolves when the medications are resumed.^83–85 One group found an association between suicide and higher L-dopa dosage which persisted after adjusting for age, sex and other clinical variables.³⁵ Other reports have found weak or non-statistically significant associations between higher L-dopa dose or dopamine agonist use and suicidality.^42,52,65 Mania in the setting of misuse of levodopa/carbidopa has also led to suicide.⁸⁶

Other medications

There have been several case reports and one open-label study describing suicide in PwP after starting Duodopa/Levodopa-Carbidopa Intestinal Gel (LCIG). These suicides occurred between three months and five years after starting LCIG.^57,87–91

Recently, safety and tolerability studies have included the Columbia-Suicide Severity Rating Scale (C-SSRS) in their standard assessment battery. Pardoprunox (a relatively novel dopamine agonist), tozadenant (a selective adenosine A_2A antagonist effective for motor symptoms in animal models) and the catechol-O-methyl transferase (COMT) inhibitors opicapone and entacapone have been studied in this manner and have shown no increase in suicide risk.^92–96 Two randomized controlled trials (RCTs) and one open-label study have shown no association of transdermal rotigotine with suicidality.^97–99 Li and colleagues⁶⁵ found no association between PD suicide and entacapone, trihexyphenidyl and selegiline.

Deep Brain Stimulation (DBS) and Other Procedural Interventions

Overall, DBS may be perceived as a risk factor for suicide, and most DBS centers exclude patients with active SI.^100–102 Despite this, there is little agreement among published reports on whether DBS impacts suicidality.

Voon and colleagues¹⁰³ conducted a multicenter retrospective study investigating suicide after subthalamic nucleus (STN) targeted DBS. Out of 5311 patients, 24 died by suicide (0.45%) and 48 attempted suicide (0.9%). Compared to the general population, suicide rates were elevated for the first year post-operatively and remained elevated for four years after surgery. Notably, 75% of attempted and fatal suicides occurred within 17 months postoperatively. A follow-up nested case-control study found that only post-operative depression was significantly associated with suicide or attempted suicide after correction for multiple comparisons. In fact, over 40% of patients had a diagnosis of depression or apathy at the time of SA. Approximately half of those who attempted or died by suicide had expressed SI and a similar number had seen a healthcare provider within a month prior to death.¹⁰³

In another landmark study, Weintraub et al¹⁰⁴ sought to determine the impact of DBS on SI and suicidal behaviors using retrospectively analyzed data from an RCT for efficacy and safety of DBS versus best medical therapy. In the first phase of the trial, they compared rates of SI and suicidal behaviors in 255 PwP undergoing DBS versus best medical therapy and found no suicidal behaviors in either group. SI was rare, and rates were not significantly different between groups. Several “proxy symptoms” for SI including anergia, anxiety, depressed mood, and hopelessness showed a trend for decreased frequency in the DBS group. In phase two of the trial, the authors randomized 299 patients to receive DBS in the STN or internal globus pallidus (GPi). Rates of SI were similar between these two groups, but several proxy symptoms were worse in the STN group. Specifically, patients who underwent STN-DBS reported decreased happiness, increased anger/bitterness and increased fatigue.¹⁰⁴ Importantly, this is the only RCT looking at the effect of DBS on suicidality.

Smaller and less rigorous studies have added to these findings. Several cases have described new onset SI after STN-DBS.^83,105,106 One retrospective analysis of 113 patients found that most new instances of SI developed within six months post-operatively.¹⁰⁷ Others have found that DBS does not increase suicidality.^{42,48,108–111}

Prevalence of suicide in the reviewed literature ranged from 0.5–2% up to five years after STN-DBS.^{55,56,112–116} Only one study (n=17) fell outside this range, reporting a 5% suicide rate.¹¹⁷ In contrast, the reported prevalence of SAs varies widely. An earlier study by Voon and colleagues¹¹³ found that 1.7% of 406 PwP undergoing STN-DBS attempted suicide. Two other studies have reported SA rates around or below 1%.^118,119 However, several small studies have reported SAs in 3–6% of patients after DBS.^{114,118,120,121} These attempts have occurred anywhere from one month to four years after STN-DBS, with an average of one year.^{58,113–115,122–125} Others have found no SAs or suicides over up to ten years of follow-up.^{126–128,129}

Several authors have investigated predictors of suicidality post-DBS. There is some evidence that early-onset PD may be a risk factor, but this is contested.^{58,125,130–132} Surprisingly, one retrospective review found no predictors of suicide based on pre-operative psychological evaluation.¹³³ In contrast, another study found that most patients who develop depression after STN-DBS have a history of depression.⁵⁵ The role that active depressive symptoms play in the development of suicidality after DBS is also unclear. There have been case reports of suicide after DBS in individuals with and without evidence of an active depressive syndrome.^56,83 Interestingly, one study of 22 PwP undergoing STN-DBS found a significant increase in the prevalence of SI post-operatively despite no change in depressive symptoms.¹²² Similarly, Funkiewiez et al¹²³ noted a mild increase in apathy symptoms but mild improvement in depressive symptoms after STN-DBS. Despite this, of 77 individuals followed for three years there was one suicide and four SAs.¹²³ One group created a screening tool to encourage patients to disclose psychiatric symptoms prior to DBS however it is unclear whether such an intervention would impact suicide rate post-DBS.¹³⁴

Changes in DBS settings have been implicated in suicidality post-DBS. Some case reports have described SAs after changes in DBS stimulation intensity.^83,130 Suicidality has resolved in some cases after DBS was turned off or reverted to its original settings, but this has not been consistent.^84,135 Case reports have implicated changes in both the left and right STN electrodes.^83,136 Several studies with varying evidence levels have noted that motor outcome after DBS does not appear to effect suicide risk, and in fact, many of the patients who attempt suicide report improvement in motor symptoms after STN-DBS.^{58,83,103,118,124,137} In some cases, the depressive symptoms and suicidality that develops after STN-DBS is described as having an acute onset.^56,83,136

Most literature on suicide after DBS is focused on STN-DBS. Few groups have looked at outcomes after GPi-DBS or compared suicidality in patients receiving different types of DBS. One group found no difference in rates of SI in patients undergoing STN versus GPi-DBS.^138,139 As noted above, Weintraub and colleagues¹⁰⁴ also found no statistically significant difference between patients undergoing STN versus GPi-DBS, but did note a worsening of “proxy” symptoms for suicide in the STN group. There is one case report of a patient developing SI after GPi-DBS; this resolved after discontinuation of stimulation.¹⁴⁰

Several authors have suggested that post-DBS suicide risk may be related to post-operative changes in DRT.^83,84,137 In support of this point, the study by Voon and colleagues¹⁰³ above showed increased suicidality postoperatively in the setting of a 50–60% DRT dose reduction, while the study by Weintraub et al¹⁰⁴ did not show an increase in suicidality in the setting of only a 25% DRT dose reduction after surgery.^103,104,121 This would also explain the finding by Weintraub and colleagues¹⁰⁴ that proxy symptoms for suicide were worse in patients undergoing STN-DBS as compared to those undergoing GPi-DBS, as STN-DBS typically results in a more significant reduction in DRT dose.¹⁰⁴ Even so, the role of DRT itself remains unclear^35,83–85 and one prospective study reported that reductions in anti-parkinsonian medications were similar between PwP who developed SI after DBS and those who did not.¹⁰⁵

There is little information on the impact of other procedural treatments. Isolated suicides have been reported after STN gamma knife radiosurgery and pallidotomy.^141–143

Treatment of Suicidality in PD

No RCTs have investigated treatment of suicidality in PD. As described above, multiple case reports have noted resolution of suicidality with adjustment of DBS settings, although the directionality of this change does not show a consistent pattern and other case reports have conflicted.^83,84,135 Resolution of suicidal depression has been associated with resumption of DRT or increases in dosage as noted above.^83–85 Selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors including fluoxetine, sertraline, escitalopram, mirtazapine and venlafaxine have been successfully used to treat suicidal depression with and without simultaneous changes to DRT.^{83–85,125,144} Quetiapine and clonazepam have also been used in this population.⁸⁵ Case reports have suggested that electroconvulsive therapy (ECT) may relieve suicidality as well as other depressive symptoms in PwP, even those with a DBS in place.^{85,135,145–147}

A recent abstract found that group psychoeducation improved SI immediately after the intervention. However, this effect did not persist at follow-up six months later.¹⁴⁸ Therapy has not otherwise been studied in suicidal PwP.

Discussion

In this scoping review aimed to better understand the current literature on suicide in PwP, we identified 106 relevant papers including information on the prevalence of suicide in PD, demographic profiles of victims, risk factors for suicide, the effect of PD treatments including DBS, and the treatment of suicidality in PwP. We identified a relative dearth of good quality studies, with the literature primarily limited to case reports, abstracts, or small studies in which suicidality was a secondary outcome or incidental finding. There were few large, longitudinal studies and even fewer RCTs.

The current literature is sparse and often conflicting. While this is certainly attributable at least in part to the complex nature of both PD and suicidality, the lack of validated scales for suicidality in PwP likely contributes as well. SI or SAs are far more common than suicide and thus easier to study, though we should not assume that the epidemiology of SI/SA in PD can be generalized to understand fatal suicidal acts.The lack of consistent operationalization of these terms is also a limitation.

We found that PwP are much more likely to suffer from SI than the general population.¹⁴⁹ What remains less clear is whether PwP are more likely to attempt or die by suicide. Prevalence studies vary widely depending on the population. PwP have decreased or unchanged suicide risk in the United States, Denmark, Finland and Canada, while those in South Korea, England, Netherlands and Sweden are at increased risk. Perhaps this is related to general cultural differences or differences in the standard management of PD and PD depression. Psychiatric illness (especially depressive disorders and hopelessness) clearly increases the risk of SI and death by suicide in PwP. PwP share many risk factors for suicide with the general population; however, prior SA may be a more significant risk factor for PwP. There have been many studies investigating treatment of SI in the general population and similar studies are greatly needed in the PD population.^29,30 At this time, the literature suggests that aggressive management of depression may be the best approach.

We were struck by the limited research on access to lethal means and suicide risk in PwP. There has been extensive research on this issue in the general population.^26,27,157 Elderly men have the highest rate of suicide by firearm,¹⁵⁸ and the Alzheimer’s Association, Veterans Health Association and others have recommended screening persons with dementia for firearm access.¹⁵⁹ While the effectiveness of restricting access to lethal means in PwP has not been studied, given their risk factors it may be prudent to screen PwP similarly and discuss firearm safety early in the disease course.

The impact of DRT on suicidality is unclear: some studies suggest a dopamine withdrawal syndrome as a precipitant of suicidality while others seem to imply an increased risk of suicidality with higher doses of DRT. The rate of change of DRT has not been studied and could potentially account for some of these discrepancies. Similarly, the role of DBS is poorly understood. The only RCT to date found no suicidal behaviors and no difference in SI between patients assigned to DBS versus best medical therapy. However, multiple non-RCTs and case reports continue to suggest an association. Perhaps some of this variability provides evidence for depressive subtypes in PD or a more subtle but significant role for impulsivity, apathy, delirium or other neuropsychological changes. In the general population, much is known about the specific neuropsychological profile seen in suicidal individuals, such as attentional biases and executive dysfunction.^150,151 This remains an area in need of study in PwP. Finally, alterations in immune function and serotonin neurotransmission have been implicated in suicide in the general population.^60,152 PD is known to cause aberrations in these systems, however the impact of such changes on suicidality has not yet been investigated.^153,154

Moving forward, it may be important to consider the stress-diathesis model used to explain suicide in the general population. The stress-diathesis model proposes that the development of suicidality requires an interaction between stressors and an individual’s traits which modulate their reaction to those stressors.¹⁵⁵ While there are several studies on the role of stressors in PD suicide, the diathesis component of this model has been largely neglected. This is important, as there is some evidence that the individual’s subjective perception of a stressor may matter more than the stressor itself.¹⁵⁶

Given the variety of studies included, we were unable to perform standardized quality appraisals or conduct meta-analyses of the data. However, we felt that a broad review of the literature was crucial to identify these gaps in our understanding and suggest directions for future research.

Table 1.

Summary of Risk Factors for Suicide in the General Population and their Association with Suicide in Persons with Parkinson’s Disease. ^12,19,20

Risk Factors for Suicide in the General Population	Evidence in Parkinson’s Disease
Male Gender	Increased risk
European American Ethnicity	Increased risk
Education Level	No effect
Unemployment	Not studied
Single/Divorced/Bereaved	Decreased risk
Comorbid Medical Illness	Decreased risk
Depressive Disorder	Increased risk
Bipolar Disorder	Not studied
Alcohol/Substance Use Disorder	Increased risk
Psychosis	Increased risk
Personality Disorder	Not studied
Anxiety Disorder	Increased risk
Multiple Psychiatric Disorders	Not studied
Hopelessness	Increased risk
Impulsivity	Increased risk
History of Self-Harm or Past Suicide Attempt	Increased risk
Access to Lethal Means	Not studied
Stressful Life Events	Not studied
Childhood Maltreatment/Abuse	Not studied
Alterations in serotonergic function	Not studied
Hypothalamic-pituitary-axis abnormalities	Not studied
Epigenetic changes	Not studied