Integrative Medicine for Suicide Prevention:

Effective Models to Prevent a Global Public Health Epidemic

Part 1

by James M. Greenblatt, MD, and Virginia Ross Taylor, PhD

Suicide rates have climbed to their highest level in three decades, according to a recent call to alarm by the Centers for Disease Control and Prevention (CDC). After a period of nearly consistent decline between 1986 and 1999, rates have risen steadily since 2000. In 2014, 42,773 Americans died by suicide, making suicide the 10th leading cause of death in the US. More than twice as many Americans died by suicide than by homicide or of Parkinson’s disease. And among middle-aged men and young girls, the news is even more dire. In girls ages 10 to 14, the suicide rate has skyrocketed a staggering 200%. Although this report documents changes in suicide rates since 2000, the greatest annual increases in all age groups occurred after 2006 (CDC, National Center for Health Statistics).

Suicide is a devastating public health problem not only in the U.S. but around the world. It causes immeasurable loss not only to the individuals whose lives are abruptly cut short but also to their families and communities. The World Health Organization (WHO) estimates that each year more than 800,000 people die from suicide. Someone in the world commits suicide every 40 seconds. By 2020, the rate of suicide is predicted to increase to one death every 20 seconds (WHO).

Neglected Area of Research

Despite its enormous impact on society, suicide remains something of a mystery not only to victims’ families but also to health professionals. Although psychiatry devotes considerable resources to investigating the mood disorders that are risk factors for suicide, the field has focused little attention on suicide itself. Suicide or attempted suicide is the most common emergency in psychiatry, yet the DSM-V does not code suicidal behavior. For every study on suicide-related behavior published in the American Journal of Psychiatry and JAMA Psychiatry in the past 5 years, there were six papers on schizophrenia, which is only one-quarter as common as suicidal behavior. And in contrast to studies on schizophrenia, those on suicidal behavior focus mostly on epidemiology and do not investigate mechanisms that underlie the behavior (Aleman & Denys).

When a person attempts or commits suicide, professionals tend to attribute the behavior to a traumatic life event in combination with a psychiatric diagnosis, most commonly depression. But not all depressed people who undergo life crises attempt suicide, and all too often, someone without a psychiatric diagnosis kills him- or herself.

No single method has been demonstrated to be the best way to prevent suicide, according to results of a 10-year systematic review published in the Lancet Psychiatry in June 2016. While psychiatry has yet to identify a single best strategy to address the nation’s steadily rising suicide rates, researchers agree that understanding the factors that increase the likelihood of suicide should be the foundation of prevention efforts.

I believe that it is now critical to apply a biological framework to the understanding of suicide and to draw on strategies to address these biological factors. This article, the first in a two-part series, concentrates on several factors that can increase the risk of suicide: genetics, the use of antidepressant medications, and inflammation. The second article addresses nutritional deficiencies – low cholesterol, omega-3 fatty acids, vitamin D, and lithium – and uses of social media that increase suicide risk.

Genetics

An estimated 90% of people who commit suicide in the US are struggling with a mood disorder or a substance abuse disorder in combination with a mood disorder (Rihmer). The regulation of the neurotransmitters norepinephrine and serotonin, which control mood, is influenced by genetics.

That genetics underlies a predisposition for suicide is confirmed by studies of monozygotic twins. A monozygotic twin of a person who attempted suicide has a 17-fold greater risk than a dizygotic twin of also making a suicide attempt. Some investigators estimate the heritability of suicide risk is as high as 55% (Akbarian & Halene).

In their attempts to isolate genes that mark risk of suicide, researchers recently profiled genes of the major excitatory neurotransmitters GABA and glutamate. They discovered one genotype, a protein coding transcript of GABA receptor, with consistently lower expression in the postmortem brains of patients who died by suicide than in those who died of natural causes. They speculate that this genotype is linked to suicide risk (Yin, Pantazatos, Galfalvy, et al).

Suicide risk can also increase because of epigenetic changes. New studies suggest that gene SKA2, which regulates the brain’s response to stress, may undergo an epigenetic change in people likely to commit suicide. This epigenetic modification adds a methyl group to the gene, leaving the underlying DNA unchanged. As a result of this change, called methylation, the prefrontal cortex, which is involved in inhibiting negative thoughts and controlling impulsive behaviors, cannot suppress the release of cortisol. This change increases the patient’s vulnerability to suicide (Guintivano, Brown, Newcomer, et al).

Effects of DNA methylation have been consistently identified in the brains of people who committed suicide. DNA methylation can be triggered by stressful or traumatic life experiences. It is therefore a molecular link between the genome and the strain and challenges of life. The discovery of this link reveals that suicidal behavior results from an interplay between genetics and the environment. Understanding the effects of methylation changes in genes may be key to identifying a heightened risk for suicide (LaBonte, Suderman, Maussion, et al).

Both suicide and depression are associated with extensive changes in the molecular structure of nerve cells, yet the hippocampal tissue of suicidal patients is distinct from that of those who are vulnerable to depression but not suicidal (Yen, Shea, Sanislow, et al). The brains of those who committed suicide show more extensive methylation. This distinction sheds light on particular neurobiological mechanisms that may predispose a person to suicide.

Researchers speculate that a blood test to reveal epigenetic changes like methylation could help identify people at risk and develop measures to help keep them safe, such as reducing their access to firearms. The pinpointing of epigenetic changes underscores the biological basis of suicidal behavior and confirms the link between mind and body that is the foundation of integrative medicine.

Antidepressant Medications

For patients who contemplate or attempt suicide, physicians frequently prescribe antidepressants, most commonly one of the selective serotonin reuptake inhibitors (SSRIs). The SSRIs were heralded as wonder drugs when they were first approved for treating depression because they seemed to cause fewer side effects and present a lower risk of overdose than earlier antidepressant medications.

The reputation of SSRIs has shifted several times since this hopeful welcome. Soon after they were approved by the Food and Drug Administration (FDA) for treating depression, a number of young patients taking SSRIs attempted or committed suicide. An influential randomized controlled study sponsored by SmithKline Beecham challenged the developing view that SSRIs were dangerous for young people. Writing in the Journal of the American Academy of Child and Adolescent Psychiatry, the authors of what became identified as Study 329 concluded that SSRIs, particularly paroxetine, were generally well tolerated and effective for major depression in adolescents. They concluded that the benefits of antidepressants clearly outweigh the risks of untreated depression in patients, including younger ones.

Exploring a possible link between these drugs and suicidal thinking, however, other researchers found that younger patients on SSRIs were twice as likely to harm themselves as those taking placebo. Then, in 2004, the FDA mandated that every bottle of SSRIs sold be accompanied with a black box warning, a written advisory cautioning health-care professionals and patients that this medication may cause serious side effects.

A reanalysis of the results of early influential studies endorsing the benefits of SSRIs led to a dramatic reinterpretation of the outcomes of Study 329. Joanna LeNoury and colleagues, who examined the same data from the randomized control trial of 2001, found evidence of bias and underreporting of side effects. They concluded that the original study investigators had reversed their earlier stance about a possible connection between suicidal ideation and Paxil use. Indeed, the original investigators had coded information in a way that minimized patients’ thoughts and behavior related to self-harm and suicide. The new conclusion based on the reanalysis found clinically significant increases in suicide-related adverse events, and asserted that antidepressants were not more effective than placebo. Meanwhile, doctors in the US wrote 2 million SSRI prescriptions for children and adolescents the same year that the study was published.

It remains unclear how SSRIs increase suicide risk. Yet the risks of SSRIs must also be weighed against the risks of untreated depression in adolescents. Current guidelines for prescribing antidepressants are based in part on a recent study reported in the Journal of the American Medical Association that followed 162,000 patients ages 10 to 64 who were taking Celexa, Zoloft, or Prozac. The study found that patients under age 24 who began the medication on higher doses had twice the risk of suicidal behavior. There was no increase in suicidal thinking or behavior among those young people treated with recommended dosages of the drug. Another large study concluded that the risk of suicidal behavior was 4 times higher during the 10 days after SSRI treatment began and 3 times more likely in the first month than at any time afterward.

As the SSRIs appear to induce obsessive suicidal thoughts and trigger agitation and a greater tendency to act impulsively, monitoring is especially important during the critical early period when a patient begins to take the drug. Recently, a genetic variant that interferes with the liver’s ability to metabolize SSRIs has been identified in many patients who respond to these drugs with agitation (Teicher, Glod, & Cole).

Given the recent increases in suicide among young people and concerns that SSRIs intensify susceptibility to suicide, it is important to rely on additional strategies besides antidepressant medications for treating depressed adolescents.

Inflammation

Another factor important to explore is the link between inflammation and suicidal thinking and behavior.

Only in the past two decades have scientists begun to understand the molecular mechanism between the immune system and brain. The discovery in 2007 of a type of brain inflammation, anti-NMDA receptor encephalitis, provided direct evidence of an association between the immune system and psychiatric symptoms. This discovery opened a new line of investigation into whether the same kind of mechanism could explain other psychiatric illnesses (Benros, Waltoft, Nordentoft, et al).

The hypothesis that the immune system is implicated in psychiatric problems represents a paradigm shift that not only points to a biological basis for many formerly inexplicable conditions; it also invites the possibility of diagnosing, treating, and preventing them by focusing on the immune system and managing inflammation. Some individuals are more prone to neurological and psychiatric symptoms from inflammation because of their own genetic susceptibility. The longer the immune system has gone haywire, the more psychiatric symptoms can spiral out of control.

Key to the relationship between inflammation and psychiatric disorders are the cytokines, proteins manufactured by immune cells that govern responses to foreign antigens and germs and are the principal chemical mediators of the inflammatory response. Pro-inflammatory cytokines, which include the interleukins, trigger inflammation; while anti-inflammatory cytokines limit the inflammation. These cytokines with their contradictory effects are critical to promote the body’s healing response at the same time they stay within bounds to reduce the risk of chronic disease and protect against depression (Kin, Lee, Shim, et al).

Aberrant cytokines have been associated with both psychiatric disorders in general and specifically with suicidal behavior. Researchers performed a meta-analysis of cytokine levels in patients who had exhibited suicidal behaviors and those who had not. They found evidence of cytokine levels out of balance in blood, cerebrospinal fluid, and postmortem brain samples only in the patients who had attempted or committed suicide. Of all the pro-inflammatory cytokines, the interleukin levels were most significantly associated with suicide-related behaviors. (Rudolff, Greggerson, Kahl, et al). The researchers concluded that high levels of cytokines help distinguish between suicidal and nonsuicidal patients and may thereby offer a key to suicide prevention (Black & Miller; Pandey).

One study investigated differences in inflammatory markers between patients with major depressive disorder and high versus lower levels of suicidal ideation and then compared inflammation in these two groups with that in nondepressed healthy controls. The patients with strong inflammatory markers had considered suicide and had thought more often about suicide than patients in the other two groups (Brundon, Erhardt, Bryleva, et al.).

While accumulating evidence suggests that levels of inflammation may be particularly high in suicidal depressed patients, the connection could occur in several possible ways. First, inflammation may promote suicidal thinking. Conversely, suicidal thinking may promote inflammation. Moreover, the impulse that leads individuals to contemplate suicide may activate a biological stress response, which includes an inflammatory reaction. These links could explain why patients with suicidal depression may have higher levels of inflammation than depressed patients who are not suicidal. The exact biological mechanisms linking inflammation with suicidal thinking are not yet clear, but the connection between them is strong and warrants further research.

One study has identified a particular biological factor underlying the connection. Researchers examined the cerebrospinal fluid postmortem of suicide victims and measured the immunoreactive corticotropin-releasing factor. They found higher CRF levels in the cerebrospinal fluid of suicide victims than in those who died from other causes. The study investigators posit that excessive stress leads to an increase in CRF and possibly a breakdown in psychological defense mechanisms and on to suicide (Pandey GN).

In addition to prompting further research, the connection between inflammatory markers and suicide-related behaviors makes a strong case for testing cytokine levels in patients with psychiatric problems, especially depression. Aberrant cytokine levels are biomarkers that signal suicide risk. Targeting the immune system in patients who have psychiatric problems through treatment with antibiotics or intravenous immunoglobulin shows promise as one strategy to help prevent suicide (Brundon, Erhardt, Bryleva, et al.).

Eating Disorders

The preceding parts of this article have concentrated on biological factors that can heighten suicide risk instead of on particular diagnoses. But because of the striking overlap between patients in the age of greatest increased risk of suicide and patients with eating disorders, I believe that this group warrants special attention. Eating disorders have the highest death rate of any psychiatric disorder. They remain prevalent across the US despite increasing awareness and subsequent innovations in treatment. Hospitalization rates for patients with eating disorders increased 18% between 1999 and 2006 (Zhao & Encinosa). The incidence of anorexia in young women aged 15 to 19 has risen each decade since 1930 (Hoek & van Hoeken, 2003).

While eating disorders are often overlooked as risks for suicide, several studies highlight a strong association. A meta-analysis estimates that rates of suicide attempts among people with eating disorders range from 13% to 31% (Acta Psychiatrica Scandinavica 1999). Furthermore, researchers have found that eating disorders are associated with an almost 5-fold risk of suicide attempts requiring hospital treatment (Suokas 2014).

The same study showed that almost 3% of patients with eating disorders had attempted suicide before seeking treatment, and a history of previous suicide attempts increased the risk of future attempts 11-fold during the follow-up period (Suokas 2014). Taken together, these studies demonstrate that individuals suffering from eating disorders are 4 to 5 times more likely to die as a result of suicide than as a result of the eating disorder itself or complications arising from it.

A framework called the interpersonal theory of suicide (IPTS) highlights characteristics of eating disorders that place these patients at increased risk. The theory asserts that people commit suicide when three causes are present together: a sense of belonging, the feeling of being a burden, and an acquired capability for suicide, which develops through a process of repeated exposure to painful and provocative events. Repeated exposure ultimately decreases the fear of pain and death through habituation. Repetitive, painful, and provocative behaviors, including self-induced vomiting, laxative use and self-injury, may lead to suicidal behavior among people with the binge-purge subtype of anorexia nervosa. The painful experience of continuous dietary restriction is linked to with suicidal behavior among patients with the restricting subtype of anorexia (Selby).

Similarly, in a study of patients with bulimia nervosa, researchers found overexercise the only disordered eating variable related to suicidal behavior, which they explain as leading patients to lose sensitivity to pain and acquire the capability for suicide. The researchers also examined the relationship between disordered eating, the sense of being a burden, and the absence of belonging or affiliation. They suggest that dietary restraint leads to negative life events, which in turn diminishes a sense of belonging and increases the sense of being a burden. The coexistence of these interpersonal factors associated with suicide in light of the CDC’s report on the 200% increase in suicide among young girls raises special alarm about eating disorders as a risk factor.

All of these issues – eating disorders, genetic susceptibility, antidepressant use, inflammation – are critical to consider in our efforts to turn around the rising trend of suicide and suicidal behavior among the American population. Suicide is a tragic outcome that results from a constellation of factors. The factors discussed here are themselves interwoven. Genetics can both increase risk of inflammation and interfere with metabolism of antidepressant medication. We must address all these factors and the nutritional deficiencies, including cholesterol, Vitamin D, Omega-3 fatty acids, and lithium, which are discussed in the next article, in order to prevent suicides in the future. We owe this to our patients and to all of those whose lives they touch.

References

Akbarian S, Halene T. The neuroepigenetics of suicide. Am J Psychiatry. 2013;170:462–465.

Aleman A, Denys D. Mental health: A road map for suicide research and prevention. Nature. 2014;509:421–423.

Arcelus J, Mitchell A, Wales J, et al. Mortality rates in patients with anorexia nervosa and other eating disorders. Arch Gen Psychiatry. 2011;68:724–731.

Benros ME, Waltoft BL, Nordentoft M, et al. Autoimmune diseases and severe infections as risk factors for mood disorders: A nationwide study. 2013. JAMA Psychiatry. 70, 812–820.

Black D, Miller BJ. Meta-analysis of cytokines and chemokines in suicidality: distinguishing suicidal versus nonsuicidal patients. 2015. Biological Psychiatry, 78, 28–37.

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 297, 1683–1696.

Brundon L, Erhardt S, Bryleva EY, et al. The role of inflammation in suicidal behavior. 2015. Acta Psychiatrica Scandinavica 132, 193–203.

Chesney E, Goodwin GM, Fazel S. Risks of all-cause and suicide mortality in mental disorders: a meta-review. 2014. World Psychiatry 13, 153–160.

Curtin S, Reidenberg D, Stone D, et al. U.S. Centers for Disease Control and Prevention. 5/22/16. NCIS Data Brief, Increase in Suicide in the U.S., 1999–2014.

Dodd, D., Smith, A., Bodell, L. 2014. Restraint feeds stress: the relationship between eating disorder symptoms, stress generation, and the interpersonal theory of suicide .Eating Behaviors 15, 567–573.

Gabbay V, Klein RG, Guttman LE, et al. A preliminary study of cytokines in suicidal and nonsuicidal adolescents with major depression. 2009. Journal of Child and Adolescent Psychopharmacology 19, 43–430.

Gananca L, Oquendio MA, Tyrka AR, et al. The role of cytokines in the pathophysiology of suicidal behavior. Psychoneuroloendocrinology. @www.elsevier.com/locate/psyneur.

Guintivano J, Brown T, Newcomer, A, et al. Identification and replication of a combined epigenetic and genetic biomarker predicting suicide and suicidal behaviors. 2014. American Journal of Psychiatry. doi: 10.1176/appi.a-jp.2014.14010008.

Kin YK, Lee SW, Shim SH, et al. Differences in cytokines between non-suicidal patients and suicidal patients in major depression. 2008. Progress in Neuropsychopharmacological Biological Psychiatry 32, 356–361.

LaBonte B, Suderman M, Maussion G, et al. Genome-side methylation changes in the brains of suicide completers. 2013. American Journal of Psychiatry 170, 511–520.

Nischal A, Tripalti A., et al. Suicide and antidepressants: what current evidence indicates. 2012. Mens Sana Mongraph 10, 22–44.

Noury JL, Nardo JM, Healy D, et al. 2015. Restoring study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence. British Medical Journal 351, 1–16.

Pandey GN. Cytokines as suicide risk biomarkers. 2015. Biological Psychiatry 78, 15–16.

Perlis RH, Huang J, Purcell S, et al. Genome-wide association study of suicide attempts in mood disorder patients. 2010. American Journal of Psychiatry 167, 1499–1507.

Preti A, Rocchi M, Sisti D, et al. A comprehensive meta-analysis of the risk of suicide in eating disorders. 2011. Acta Psychiatrica Scandinavica 124: 6–17.

Rihmer Z. Suicide risk in mood disorders. 2007. Current Opinions in Psychiatry 20, 17–22.

Rudolf S, Greggersen W, Kahl KG, et al. Elevated IL-6 levels in patients with atypical depression but not in patients with typical depression.2014. Psychiatry Research 217, 34–38.

Selby, E., Smith, A., Bulik C, et al. Habitual starvation and provocative behaviors: two potential routes to extreme suicidal behavior in anorexia nervosa. 2010. Behavior Research and Therapy 48, 634–645.

Smith, A., Fink, E., Anestis, M., et al. Exercise caution: over-exercise is associated with suicidality among individuals with disordered eating. 2013. Psychiatry Research 206, 246-255.

Suokas, J., Suvisaari, J., Grainger, M., et al. Suicide attempts and mortality in eating disorders: a follow-up study of eating disorder patients. 2014. General Hospital Psychiatry, http://dx.doi.org/10.1016/j.genhosppsych.2014.01.002.

Teicher MH, Glod C, Cole JO. Emergence of intense suicidal preoccupation during fluoxetine treatment. 1990. American Journal of Psychiatry 147, 207-210.

World Health Organization. Preventing Suicide, A Global Imperative. 2014. Geneva: WHO.

Wu S, Ding Y, Wu F, et al. Serum lipid levels and suicidality: a meta-analysis of 65 epidemiological studies. 2016. Journal of Psychiatry and Neuroscience 41, 56-68.

Yen S, Shea MT, Sanislaw CA, et al. Personality traits as prospective predictors of suicide attempts. 2009. Acta Psychiatrica Scandinavica 9, 120-122.

Yin H, Pantazatos SP, Galfalvy H, et al. A pilot integrative genomics study of GABA and glutamate neurotransmitter systems in suicide, suicidal behavior, and major depressive disorder. 2016. American Journal of Medical Genetics 171B, 414-426.

Zalsman G Hawton K, Wasserman D, et al. 2016. Suicide prevention strategies revisited: ten-year systematic review. The Lancet Psychiatry.[Epub ahead of print, 6/8/16.0].