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From the Townsend Letter
November 2016

Integrative Medicine for Suicide Prevention:
Effective Models to Prevent a Global Public Health Epidemic
Part 2
by James M. Greenblatt, MD, and Virginia Ross Taylor, PhD
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The rate of suicides in the US has increased steadily during the past three decades, as reported by the Centers for Disease Control and Prevention (CDC). To address this disturbing increase, health-care professionals and families need to better understand factors that increase suicide risk. Part 1 in this series addressed several of these factors: genetics, use of antidepressants, and inflammation. Part 2 focuses on nutritional deficiencies – including low levels of cholesterol, omega-3 fatty acids, vitamin D, and lithium – and uses of social media that can contribute to the risk of suicide. Finally, this article suggests interventions from the field of integrative medicine that we can mobilize to reverse the trend of suicide increases in our nation.
Nutritional Deficiencies
Cholesterol. An increasing number of studies reveal a high correlation between nutritional deficiencies and increases in depression, anxiety, and suicidal thoughts. Because of its association with neuron signaling, cholesterol has long been recognized as a possible influence on mood disorders. Low cholesterol reduces the ability of serotonin to bind to the serotonin receptors, thereby impairing their function. Serotonin receptors play a major role in the brain and other organs, regulating aggression, anxiety, and impulsiveness (Engleberg).
Several studies have shown that low cholesterol may also contribute to dramatic increases in suicide risk. An early alert that low cholesterol might heighten suicide risk came from a study investigating deaths not related to illness in patients taking statin drugs. Scientists speculated that the statin drugs interfered with the body's mechanism for stabilizing serotonin and oxytocin receptors (Muldoon, Manuck, Mendelsohn, et al.). Based on this and other evidence of the unintended cognitive effects of these drugs, the FDA issued a warning to consumers and health professionals, urging them to routinely monitor possible psychiatric effects of cholesterol-lowering medications (http://www.fda/gov/ForConsumerUpdates/ucom23330.htm).
More than 20 years ago, researchers uncovered a link between low cholesterol and elevated risk of suicide in patients with mood disorders. In 1995, scientists reported that among psychiatric patients, those whose cholesterol levels were less than or equal to the 25th percentile were twice as likely as others to have made a medically serious suicide attempt (Engleberg; Golier, Marzuk, Leon, et al.).
Although the study received little follow-up at the time, low cholesterol has recently been identified as a risk factor for suicide in several other trials. A trial involving 584 medical records of both suicide attempters and non-suicide attempters evaluated serum cholesterol 24 to 48 hours after patients were admitted to the hospital. The study found that the inpatients who had attempted suicide had significantly lower serum cholesterol than nonsuicidal inpatients (DeBerardis, Marini, Piersanti).
A connection between suicide and low cholesterol has also been studied in young people. In research based on a national survey, investigators examined the relationship between suicide and serum cholesterol in a population of 3237 healthy young adults. A significant asso-cia-tion between low HDL chol-ester-ol and the prevalence of lifetime suicide attempts was observed in young men. No association, however, was observed between serum cholesterol and suicidal behavior in young women. The investigators suggested that serum cholesterol was associated with suicidal impulsivity, defined as the rapidity and probability of acting on powerful feelings (Zhang & McKeown).
Other research has also identified a link between cholesterol status and suicide in women. One study analyzed cholesterol levels of 155 female psychiatric inpatients and controls. Levels of cholesterol found in women who had attempted suicide before they were hospitalized were significantly lower than in controls. A further study showed that female patients who had attempted suicide and whose HDL levels remained low were at significantly greater risk of reattempting suicide the following year than female patients who had attempted suicide but whose HDL had been restored to normal levels (Ernet, Yucel, Ozcan, et al.).
Researchers in other countries have also connected low cholesterol levels and suicide risk. A Japanese study found that suicide attempters had significantly lower cholesterol than both patients with other psychiatric problems and normal controls (Kunugi, Takei, Aoki, et al.). A study in Greece measured total cholesterol levels in patients after a suicide attempt and found levels lower than controls not only immediately after the attempt but also later, when the patients had resumed their normal activities (Papadopoulou, Markianos, Christodoulou, et al.). In a Finnish study, 30,000 men were followed for 5 to 8 years. The study investigators found lower serum cholesterol associated with both major depression and death from suicide (Partonen, Haukka, Virtamo, et al.).
Low cholesterol levels appear especially prevalent in those who die by violent suicide. In one study, those who committed suicide by violent means had lower gray-matter cholesterol content compared with the gray-matter content of nonviolent suicides and controls (Lalovic, Levy , Luheshi, et al.).
Research in the military has also highlighted a link between low serum cholesterol and suicide. In a study of 4462 male US veterans, investigators found that veterans with low serum cholesterol and depression were seven times more likely than veterans with normal cholesterol to die prematurely from suicide and accidents (Boscarino, Erlich, & Hoffman).
A meta-analysis of studies enrolling a total of more than 500,000 patients clearly confirmed a link between low cholesterol and suicidal behavior. Suicide was associated with lower total cholesterol, lower HDL, and lower LDL cholesterol. Compared with patients with the highest level of total cholesterol, the patients with the lowest total cholesterol had a 112% greater risk of suicide and suicidal behaviors (Wu, Ding, Wu, et al.).
The exact mechanism that explains the connection between low cholesterol and suicide is not yet clear. Low cholesterol could lead to alterations in synaptic plasticity in brain regions important in impulse inhibition. Another hypothesis is that lower cholesterol disrupts serotonergic neurotransmission, possibly intensifying depression and suicidal thinking. A possible mediator between both suicidal behavior and low cholesterol is impulsivity. Thus, cholesterol may influence suicide risk through a direct effect on serotonergic activity and traits related to aggression and impulsivity (Favaro, Caregaro, DiPascoli, et al.).
Discovery of a link between cholesterol and suicidal behavior is promising. Low cholesterol levels may be a biological marker that could improve assessment of suicide risk. Detecting this marker might get clinicians closer to identifying potentially suicidal patients before they act. 
Vitamin D. A deficiency in Vitamin D also appears to heighten suicide risk. The influence of vitamin D on brain serotonin levels may explain its role in mood regulation. Vitamin D deficiency may also increase the production of inflammatory cytokines, discussed in Part 1 of this series as a risk factor for suicide.
Given that suicide rates in many countries are highest in the spring, when vitamin D status is lowest, and that low vitamin D status can affect brain function, researchers evaluated whether a low level of 25-hydroxyvitamin D could be a predisposing factor for suicide. After conducting a prospective case-control study among men and women in the military, the investigators concluded that those servicemen and -women with the lowest octile of vitamin D levels had the greatest the risk of suicide. Those in the highest octile of vitamin D levels had the lowest suicide rates. The researchers speculate that additional sunlight exposure and vitamin D supplementation may decrease the risk of suicide among men and women in military service (Umhau, George, Heaney, et al.).
Other research has yielded similar results. One study compared the vitamin D levels of 59 suicide attempters, 17 nonsuicidal depressed patients, and 14 healthy controls, and found that suicide attempters had significantly lower vitamin D levels than either the nonsuicidal depressed patients or the healthy controls (Grudet et al.). A study of young adults suggested that vitamin D predicts depression symptomatology and possibly suicidal thinking (Polak et al.).
Adolescents now tend to spend less time in the sun and consume fewer milk products than the young people of earlier generations, which places them at an increased risk for vitamin D deficiency. They often subsist on diets of fast food, which have been shown to increase depression risk by 36% (Sanchez-Villegasa et al.). Moreover, diets high in omega-6s, which are found in the oils of french fries, chips, and other processed food, crowd out omega-3s in the red blood cells, which can skew the ratio of omega-3s to omega-6s. All of these factors heighten suicide risk for preteens and teenagers.  
Omega-3 Essential Fatty Acids. The essential fatty acids (EFAs) include omega-3s and omega-6s. Both groups are needed by the body, but an imbalance in the two – a higher ratio of omega-6s to omega-3s – may contribute to depression. Omega-3 acids are concentrated in neural tissues and are required for optimal neural functioning. In fact, numerous studies report an association between depressive disorders and low levels of omega-3 fatty acids.
Because of the neurobiological abnormalities they cause, deficiencies in omega-3 fatty acids have been hypothesized to increase suicide risk. Researchers have found that a higher omega-6 to omega-3 ratio predicted suicide attempts among depressed patients (Sublette, Hibbeln, Galfalvy, et al.).
Both cross-national and cross-sectional epidemiological surveys suggest that lower dietary omega-3 fatty acid intake is associated with higher prevalence of suicide-related behaviors. A study in China found that the percentage of omega-3s was significantly lower among suicide attempters than among those who did not attempt suicide (Huan, Hamazaki, Sun, et al.).
A connection between omega-3s and suicide has also been studied in the military. One investigation compared the military records of 800 US servicemen and -women who committed suicide between 2002 and 2008 with the records of 800 who had no history of suicide attempts. The servicemen and -women with low blood omega-3 levels were 62% more likely to have committed suicide than those with high levels. Low levels of the omega-3 fatty acid DHA strongly predicted suicide (Lewis, Hibbeln, et al.).
Data from epidemiological studies have also indicated that low consump-tion of fish, which is rich in omega-3s, may be a risk factor for suicide. In a study of 256,118 Japanese participants that continued for 17 years, those who ate fish every day had a significantly lower risk of death from suicide than those who ate fish less often. Another large epidemiologic study, this time in Northern Finland, examined data from 1767 participants and found that frequent fish consumption – twice or more each week – significantly reduced depressive symptoms and suicidal thinking (Timonem et al.).
Longitudinal studies have found that increasing omega-3 fatty acid intake is associated with both reduced risk of depressive symptoms and suicidal ideation. In a randomized controlled intervention trial, the treatment group who received omega-3 supplementation experienced a 45% reduction in suicidal thinking (Hallahan, Hibbeln, et al.). Similarly, research in the military also suggests that raising the blood levels of omega-3s and lowering levels of omega-6s decreases the risk of suicidal behavior (Hibbeln & Gow).
Adolescents with eating disorders are even more vulnerable to low levels of omega-3 fatty acids. With periods of prolonged starvation or cycles of binging and purging, they can deprive their bodies of essential vitamins and nutrients and hinder their bodies' ability to absorb them.
Lithium. A deficiency in lithium also increases suicide risk. In fact, no overview of risk and protective factors for suicide would be complete without a discussion of lithium, which has consistently been shown to be effective in suicide prevention. While the SSRIs may exacerbate symptoms of agitation, restlessness, irritability, or anger that can lead to impulsivity and aggression, lithium may have specific effects against suicide that are independent of mood stabilization. It appears to decrease impulsivity and hostile or aggressive behavior. An association has been demonstrated between reduced suicide risk and long-term lithium treatment in patients with borderline personality disorder (Tondo et al.).
A randomized controlled study of patients with mood disorders and a recent suicide attempt sought to test the role of lithium as a suicide preventative. Contrary to prediction, the survival analysis showed no significant difference in suicidal behaviors between the patients treated with lithium and those treated with placebo. However, later analysis indicated three completed suicides in the placebo group, significantly affecting incidence rates. The researchers concluded that lithium may be effective in lowering the risk of completed suicides in individuals with mood disorders (Lauterbach et al.).
One study examined life-threatening or fatal suicidal acts in more than 300 bipolar patients before, during, and after long-term lithium treatment. The patients had been ill for more than 8 years. When the patients were taking lithium, the rate of suicides and suicide attempts decreased nearly 7-fold. When lithium was discontinued, suicidal acts increased 14-fold over the rates found during treatment. The first year that the patients were off lithium, the suicide rate rose 20-fold (Tondo et al.) Epidemiological research reflects these findings, showing a connection between regions with higher lithium prescription rates and reduced suicide risk.
In a recent large systematic review, scientists sought to discover the specific effects of lithium on reducing risks of suicide in patients with unipolar and bipolar mood disorders. They found lithium 60% more effective than placebo in lowering the number of suicides and deaths from any cause in all patients with mood disorders; the benefits were most significant in those with unipolar depression. They speculate that the lithium works not only to prevent relapse of the mood disorder but perhaps also to decrease aggression and impulsivity that often lead to suicide. A better understanding of the mechanism by which lithium reduces suicide risk will lead to a clearer picture of the neurobiology of suicide (Cipriani & Hawton).
Study of the connection between lithium levels in tap water and the rate of suicide has yielded dramatic results in at least four countries on three continents. Lithium levels in tap water were examined in 27 counties in Texas from 1978 to 1987. They were also studied in 18 municipalities in Japan, and in Austria in a nationwide sample of 6460 households. All of these studies yielded striking results: the overall suicide rate and the suicide mortality ratio were inversely associated with lithium levels (Schrauzer & Shrestha; Ohgami; Napusta et al.).
More precise understanding of how lithium acts on neurotransmission and cell signaling pathways will lead to better suicide prevention and treatment strategies. While scientists proceed with this research, practitioners should act on the unequivocal knowledge already available by prescribing maintenance lithium for patients with mood disorders who may be at risk of suicide. Lithium is the only drug that has demonstrated such clear benefits. With safe and inexpensive lithium maintenance treatment, the suicide risk for patients with mood disorders – generally estimated at 15% higher than the rate in the general population – is reduced to the suicide rate in the general population.

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