Major Depressive Disorder,

Suicide, and Mortality

Bradley N. Gaynes, MD, MPH
Professor of Psychiatry and Associate Chair of Research and Education
University of North Carolina School of Medicine
American Society of Clinical Psychopharmacology
Phoenix, Arizona
May 29, 2019
Disclosures
• Advisory Board / Consultation
• LivaNova Cyberonics
• Medscape
• Janssen Pharmaceuticals

• Research Support (Federal and Non-Profit)

• Agency for Healthcare Research and Quality (AHRQ)
• National Institutes of Health (NIH)
• National Institute of Mental Health (NIMH)
• Patient Centered Outcomes Research Institute (PCORI)
• United States Agency for International Development (USAID)
Objectives
• Understand the risk of suicide attempts, completed suicide, morbidity,
and early mortality in patients with Major Depressive Disorder (MDD)

• Understand the current effectiveness of strategies to identify and

treat these life-threatening complications

• Appreciate key unmet needs for addressing these complications

Somatic Consequences of MDD

Otte et al. 2016

• Meta-analysis of 293 studies, depression was associated with a 50%
increased risk of mortality
• No strong indications that excess mortality associated with depression
is significantly higher in particular patient groups or in community-
based samples (except for a significantly higher risk in studies of COPD
patients)
• Authors concluded that “the association between depression and
mortality may be explained better by generic mechanisms, such as
biological dysregulations and lifestyle factors that have a general
impact on health, than by disorder-specific mechanisms.”

Cuijpers P, Vogelzangs N, Twisk J, Kleiboer A, Li J, Penninx BW

Am J Psychiatry. 2014 Apr; 171(4):453-62.
 Average remaining years of life expectancy at age 25 by sex and
depression status for the 1952, 1970 and 1992 Stirling County Study
samples.

Stephen E. Gilman et al. CMAJ 2017;189:E1304-E1310

©2017 by Canadian Medical Association

Suicidality, suicide attempts, and suicide
completions are a key part of this mortality risk
• In the general population, studies consistently lifetime serious
suicidal ideation prevalence rates of up to 16.5%.
• In primary care settings, 40% of depressed patients express suicidal
thoughts
• While suicidality is common, attempts and completions, respectively,
are much less common.
• Approximately 15% of those with suicidal ideation attempt suicide at some
point in their lives, while 3% of those who attempt will ultimately complete
suicide.

Brown et al, J Cons Clin Psych, 2000

Gaynes et al, Psych Serv, 2009
Gilman et al, 2017 CMAJ
Risk of suicide completion varies by clinical
factors
• Among those ever treated for depression
• In an outpatient setting: 2% will complete suicide
• In an inpatient hospital setting: 4 percent will complete suicide
• Those treated for depression as inpatients following suicidal ideation
or suicide attempts are three times as likely to die by suicide (6%) as
those who were only treated as outpatients.
• There are also dramatic gender differences in lifetime risk of suicide in
depression.
• While 7 percent of men with a lifetime history of depression will die by
suicide, only 1 percent of women with a lifetime history of depression will die
by suicide.
Health and Human Services data, accessed May 7, 2019
Suicidality, suicide attempts, and suicide
completions
• While suicidality is common, with 40% of depressed patients
expressing suicidal thoughts, attempts and completions, respectively,
are much less common.
• Approximately 15% of those with suicidal ideation attempt suicide at
some point in their lives, while 3% of those who attempt will
ultimately complete suicide.

https://www.nimh.nih.gov/health/statistics/suicide.shtml
Increased mortality risk in MDD due in large part
to suicide—more likely over the short term
• This loss is due, in part, to the increased risk of suicide in this
population. In one analysis, the risk of suicide in MDD was almost
20‑fold higher than in the general population.

• Mortality risk over relatively short periods of time could be attributed

to unnatural causes of death, including suicide and unintentional
injuries.

Otte et al. 2016

But it’s more than suicide—the association between
depression and mortality persists over long periods
• MDD is a strong risk factor for developing metabolic and
cardiovascular diseases, and for a worse course and outcome in these
chronic diseases
• It is key to learn more about the mechanisms of association between
MDD and other medical diseases, such as diabetes mellitus or
coronary heart disease.
• Future research should also examine whether treatment of comorbid
MDD reduces morbidity and mortality in medical patients.

Whooley and Wong, 2013

Otte et al. 2016
How well do we address mortality?
Do antidepressants affect suicidality? Evidence
from meta-analyses of randomized trials
• For suicide deaths
• Meta-analyses indicate no evidence for higher or lower risk of suicide death during acute-
phase treatment with antidepressants compared with risk during treatment with a placebo.
• For new onset of suicidal behavior
• Five re-analyses of data from randomized trials suggested that treatment with
antidepressants was associated with an increased risk of nonfatal self-harm (attempt) or
preparatory acts, compared with placebo
• The increased risk appeared to reside primarily in patients under the age of 25 years.
• For new onset of suicidal ideation
• Antidepressants do not increase the incidence of suicidal ideation
• For reduction of existing suicidal ideation
• Among patients with suicidal ideation at the start of treatment, antidepressants reduce
suicidal thoughts and behavior

Simon, UpToDate 2019

• The effectiveness of behavioral and psychosocial interventions to
prevent suicide and suicide attempts has been supported by a recent
meta-analysis, particularly for interventions that directly address
suicidal thoughts.
• Psychosocial and behavioral interventions that directly address
suicidal thoughts and behavior are effective immediately post-
treatment and long term (~ 13 months).

Meerwijk et al., 2016

Effectiveness of depression treatment to
increase lifespan
• No direct evidence
• Improving depression treatment in patients with comorbid
cardiovascular disease improved control of medical disease and
depression at 12 months, although concrete indicators of medical
disease did not improve
• Many mechanisms
• Unhealthy lifestyle
• Poorer self care/adherence
• Shared pathophysiology (e.g., upregulation of immune-endocrine stress
systems that are present in MDD and obesity)
Katon et al. NEJM, 2010
Otte et al, 2016
Therapeutic implications for biological
dysregulation in depression
• Targeting inflammatory and metabolic dysregulations

• Behavioral interventions (e.g., exercise)

• Integrating psychopharmacology with focused psychotherapies

• Understanding the role of neuromodulation (e.g, TMS)

Conclusions
• The mortality associated with depression, both acute and chronic,
remains an unaddressed need
• Acute treatments are needed to address short term mortality, and
likely require new mechanisms and treatment models—immediate
action
• Management approaches that can address the long term mortality
risk are also needed
• The remaining question: can recovery from depression reverse the
elevated mortality risk associated with depression?
 Case-Based Question
• Ms. C is a 28-year-old woman who presents with a first episode of major depressive disorder (MDD). She
is getting married soon and is thinking about starting a family. She meets with you to discuss treatment
options. She has a strong family history of depression, and no one in her family has ever received
depression treatment. Her family medical history is notable for cardiovascular disease and some deaths
for family members in their 60’s. She has a few general questions about how her depression might affect
her in the future. She knows that effective treatment exists, but she is wondering how important it is to
receive treatment. Which of the following statements is least accurate?
a) Those with MDD have a 50% greater risk of mortality than those without MDD.
b) Depression is associated with a shorter lifespan on the order of years, and is a risk factor for
metabolic and cardiovascular diseases.
c) Increased mortality risk in MDD is due in part to suicide, most likely over the long term.
d) Mechanisms that contribute to somatic consequences of MDD include unhealthy lifestyle, poor
self-care and adherence to treatments, adverse effects of medications and shared pathophysiology
of MDD, and physiologic stress systems.
References
• Brown, G. K., Beck, A. T., Steer, R. A., & Grisham, J. R. (2000). Risk factors for suicide in psychiatric outpatients: A
20-year prospective study. Journal of Consulting and Clinical Psychology, 68(3), 371-377.
• Cuijpers P, Vogelzangs N, Twisk J, Kleiboer A, Li J, Penninx BW Am J Psychiatry. 2014 Apr; 171(4):453-62.
• Gaynes BN, Warden D, Trivedi MH, Wisniewski SR, Fava M, Rush AJ. What did STAR*D teach us? Results from a
large-scale, practical, clinical trial for patients with depression. Psychiatr Serv. Nov 2009;60(11):1439-1445.
• Gilman SE, Sucha E, Kingsbury M, Horton NJ, Murphy JM, Colman I. Depression and mortality in a longitudinal
study: 1952–2011. Canadian Medical Association Journal. 2017;189(42):E1304-E1310.
• Health and Human Services data, https://
www.hhs.gov/answers/mental-health-and-substance-abuse/does-depression-increase-risk-of-suicide/index.ht
ml
(accessed May 7, 2019)
• Katon WJ, Lin EH, Von Korff M, et al. Collaborative care for patients with depression and chronic illnesses. N
Engl J Med. Dec 30 2010;363(27):2611-2620.
• Meerwijk EL, Parekh A, Oquendo MA, Allen IE, Franck LS, Lee KA. Direct versus indirect psychosocial and
behavioural interventions to prevent suicide and suicide attempts: a systematic review and meta-analysis. The
lancet. Psychiatry. Jun 2016;3(6):544-554.
• Otte C, Gold SM, Penninx BW, et al. Major depressive disorder. Nature Reviews Disease Primers. 09/15/online
2016;2:16065.
• Simon, G. Effect of antidepressants on suicide risk in adults. UpToDate, https://
www.uptodate.com/contents/effect-of-antidepressants-on-suicide-risk-in-adults, accessed May 7, 2019