Each year 800,000 people worldwide die from completed suicide (herein, also referred to as suicide). For every person who suicides, many more have attempted to end their lives (Suicide Fact Sheet, 2016). Globally, suicide is the second leading cause of death among 15 to 29 year-olds, striking individuals during the formative years of their lives. The ingestion of pesticide, hanging, and firearms are the most commonly employed methods (Suicide Fact Sheet, 2016). Statistics Canada summarized important information related to suicide (Navaneelan, 2012). I included some of the statistical findings from the report below:

  • In 2009, suicide was the ninth leading cause of death in Canada;
  • Hanging (44%), poisoning (25%), and firearm use (16%) were the most used methods of suicide;
  • Mental illness is the foremost risk factor for suicide since more than 90% of people that commit suicide have an addictive or mental disorder, and 60% of the suicides attributed to mental illness involve depression;
  • For every suicide, there have been as many as 20 attempts;
  • 3,890 suicides happened in 2009, with a suicide rate of 11.5 per 100,000 people;
  • The suicide rate is three times higher in men compared to women;
  • Males are more likely to die from suicide, but females are three to four times more likely to attempt it;
  • Females are hospitalized 1.5 times more frequently than males for attempted suicide; and
  • Even though suicide happens across all ages, in Canada the age group with the highest rates are between 40 and 59 years old.

The impact of suicide is not only devastating for patients and their families, friends, and acquaintances of the individual that died by suicide, but it remains one of the most shocking events that can happen to clinicians who work with mentally distressed and vulnerable patients. A patient’s suicide results in a tremendous amount of clinician overwhelm, often resulting in questions about what could have been done, whether there were blind spots that could have been addressed clinically, whether some responsibility for the suicide could be attributed to the medical care provided, and concerns about possible litigation (Plakun & Tillman, 2005).

Efforts to understand suicide have focused on psychosocial factors that prompt individuals to end their lives. Many such factors have been identified as contributing to suicide – i.e., personality and individual differences, cognitive factors, social factors, and negative life events (O’Connor & Nock, 2014). The treatment of suicide has evolved to suicide-specific therapy (e.g., Collaborative Assessment and Management of Suicide or CAMS; Jobes, 2009), which attempts to prevent suicide by engaging with the patient actively, addressing underlying health issues and collaborating on specific treatment plans aimed at restoring mental health and reducing the risk of suicide.

To complement suicide-specific therapy or any psychological approach aimed at lessening the risk of suicide, certain novel sources of published information suggest that a rational and essentially risk-free orthomolecular strategy involving specific orthomolecules might help to mitigate suicide risk if used on a timely basis by clinicians instead of watching vulnerable patients suffer and deteriorate while waiting for higher levels of evidence. Orthomolecules refer to substances found naturally or normally in the human body, such as amino acids, essential fatty acids, hormones, minerals, and vitamins. In this paper, I will review various sources of published information to build a case for specific orthomolecular interventions that could be offered to all patients that have attempted suicide and/or to patients vulnerable to suicide. While this will not be an exhaustive review of all available evidence, I will review publications related to suicide that implicate cholesterol, omega-3 essential fatty acids, kynurenine pathway modulators, 25-hydroxyvitamin D (25OHD) levels, and lithium levels in drinking water. Then, I will comment on the evidence and advance a clinical strategy aimed at reducing the risk of suicide among vulnerable patients.


Cholesterol and Suicide

In their 2010 article, Fiedorowicz and Haynes reviewed evidence linking low serum (total) cholesterol, (herein referred to as cholesterol), to mood, suicide risk, and suicide. They mentioned evidence from the 1990s that showed a relationship between low cholesterol (<160 mg/dL; approx: <4.1 mmol/L) to “unnatural deaths, including suicide” (p. 17). The first section of their paper discussed the neurobiology of cholesterol. They noted a relationship between low cholesterol and serotonergic hypofunction, and considered whether this mediates “impulsive, aggressive, and violent behaviors that may predispose individuals to suicide” (p. 18). They further highlighted that the central nervous system (CNS) is comprised of “one-fourth of the body’s free cholesterol” synthesized primarily in situ, and explained some of cholesterol’s important functions, such as improving membrane stabilization and permeability, synaptic formation, and myelin production (p. 18). They cited studies that linked low cholesterol to depressive symptoms, and suggested that the low serum cholesterol association with mood disorders might be a state-dependent effect. They also noted that (1) epidemiological studies have shown an association between low cholesterol and increased risk of suicide, (2) individuals having attempted suicide by violent means had lower cholesterol when compared to individuals having attempted suicide by less violent means, and (3) comparison studies found cholesterol levels to be lower among individuals following violent suicide attempts than those of individuals following non-violent suicide attempts. Furthermore, they linked adverse psychiatric symptoms – such as agitation, anxiety, depression, emotional lability, euphoria, panic, and suicidality – to lipid-lowering medication, but noted that the evidence did not support an association between lipid-lowering medication and suicide. Lastly, they discussed the “chicken or the egg” question and deliberated about whether low cholesterol is a state-dependent marker, or perhaps a trait-dependent marker of depression (Table 1). They concluded that the evidence points to both being implicated in the relationship between low cholesterol, depression, and possibly suicide.

The relationship between low cholesterol and suicide was not supported by a retrospective study completed by Park, Yi, Na, Lim, & Hong (2013). This study used electronic medical records to identify adult patients that were admitted to a psychiatric ward at a university hospital in Seoul, Korea. Primary psychiatric diagnoses were identified, and lipid metabolites upon admission (or as of the most recent admission) were used in the analysis. Overall, the data did not find an association between cholesterol and deaths by suicide among patients with primary psychiatric diagnoses of schizophrenia (SCZ), bipolar disorder (BPD), or major depressive disorder (MDD). The authors pointed out several limitations in their study, such as the following: (1) low cholesterol might be a risk factor for suicidal behavior, but might not be different among patients that completed suicide; (2) the findings might not be generalizable to patients outside of the university hospital; and (3) there were no standardized procedures to arrive at the psychiatric diagnoses. While their data did not show statistically significant differences, I found it interesting that the cholesterol levels of the SCZ patients that died by suicide were closer to 160 mg/dL (approx. 4.1 mmol/L) than patients in the control group. The average cholesterol level among patients with SCZ that died by suicide was 162.9 ±36.1 mg/dL (approx. 4.2±0.9 mmol/L) compared to the control group of SCZ patients with an average value of 172.3 ±41.1 mg/dL (approx. 4.5±1.1 mmol/L). The patients with BPD and MDD that died by suicide, on the other hand, had an average cholesterol level almost identical to their respective control groups.



In a publication by Ainiyet and Rybakowski (2014a), lipid levels and other data were analyzed from 148 adult patients with SCZ admitted to an inpatient facility in Poland. Patients were admitted due to an acute exacerbation of their illness. The results demonstrated striking statistically significant differences in mean lipid levels between SCZ patients symptomatic for suicidal thoughts, suicidal tendencies, and suicide attempts in the recent 3 months compared to SCZ patients not symptomatic for suicidal thoughts, tendencies, and attempts in the recent 3 months (Table 2).



Ainiyet and Rybakowski (2014a) concluded that lipid abnormalities can serve as state-dependent markers of suicidal behavior in recently admitted Polish SCZ patients. They also highlighted other research that showed similar findings, i.e., an association between lower levels of cholesterol and LDL-C and suicidal behavior, among patients with acute depressive episodes (Rabe-Jablonska & Poprawska, 2000).

Other research by Ainiyet and Rybakowski (2014b) pertaining to male and female adult patients (n=223) with unipolar and bipolar depression (i.e., having been recently admitted due to an acute depressive episode) showed lower mean levels of cholesterol, LDL-C, and total lipids to be associated with suicidal thoughts, tendencies, and attempts compared to similarly matched patients not symptomatic for suicidal behaviors in the recent 3 months (Table 3).



When explaining how these lipid abnormalities might result in suicidal behavior, Ainiyet and Rybakowski (2014a) noted the link between low cholesterol and serotonergic hypofunction, and referred to this relationship as the cholesterol-serotonin-impulsivity model. Other research was described that demonstrated a link between: (1) low cholesterol and low levels of 5-hydroxyindoleacetic acid (5-HIAA; the main serotonin metabolite) in the serum and cerebrospinal fluid (CSF); and (2) low levels of 5-HIAA in the CSF and low cholesterol among individuals that attempted suicide (Ainiyet & Rybakowski, 2014b).

They also discussed other research looking into oxysterol levels (i.e., oxidation products of cholesterol) in the prefrontal cortex of suicide victims, and pointed out that increased cholesterol turnover within the brain likely corresponds to reduced levels of cholesterol both centrally and peripherally (Ainiyet & Rybakowski, 2014a; Ainiyet & Rybakowski, 2014b). They noted that the prevalence of metabolic syndrome (and the corresponding elevated lipid levels) was lower among SCZ patients that attempted suicide compared to SCZ patients that did not attempt suicide. In other words, SCZ patients that attempted suicide were less likely to have metabolic syndrome and more likely to have lower lipid values (Ainiyet & Rybakowski, 2014a).

A study by Cantarelli et al (2015) showed results that contrast with the findings noted above. This study evaluated lipid levels and other parameters among 50 patients with mood disorders (i.e., BPD and MDD) that attempted suicide in the recent past (i.e., during the past 15 days), and among 36 similarly-matched patients with mood disorders without any lifetime history of suicide attempts. The results demonstrated a statistically significant difference (p=0.001; p. 404) in the mean level of triglycerides among the patients that attempted suicide (103.45±31.72 mg/dL or approx. 1.2±0.4 mmol/L) compared to those without any history of suicide attempts (144.15±74.48 mg/dL or approx. 1.6±0.8 mmol/L). No statistically significant differences were found among the other lipid levels and parameters assessed in the study.

It should be noted that the use of selective serotonin reuptake inhibitors (SSRIs) and anticonvulsants were lower among the patients that attempted suicide, which means that these psychiatric medications likely moderated suicide risk because of their effects, and/or because of the impact of anticonvulsants upon triglycerides (Cantarelli et al, 2015). The authors were unable to determine the cause of the lower levels of triglycerides among the patients that attempted suicide. Either the decreased levels of triglycerides “caused a mood episode with suicidal ideation that led to a suicide attempt,” or “the presence of a mood episode originated a loss of appetite and consequent loss of weight, therefore decreasing triglyceride levels” (p. 408). Less metabolic stress was identified among the patients that attempted suicide because, in addition to their lower mean level of triglycerides, they also had reduced adiposity, body mass indexes, and waist circumferences. One of the main conclusions from this paper was that the differences in adiposity among the patients that attempted suicide suggest some alteration in “adipose tissue-brain communication” (p. 408).

In the largest analysis of this topic to date, Wu et al (2016) assessed serum lipid levels and suicidality in a meta-analysis of 65 epidemiological studies. The results demonstrated “an inverse association between serum lipids levels and suicidality” (p. 56). Table 4 shows the results, expressed as the weighted mean difference (WMD) in lipid levels, between suicidal patients and non-suicidal patients and between suicidal patients and healthy controls.



The most striking data from the meta-analysis showed that when compared to the highest cholesterol level, a lower cholesterol was associated with 112% increased risk of suicidality, a 123% increased risk of suicide attempt, and an 85% increased risk of suicide completion (Wu et al, 2016). One of the main conclusions from this meta-analysis was that low serum lipid levels were not only predictive of completed suicide, but were also predictive of suicidal behavior, which encompasses suicidal ideation, tendencies, and attempts. The authors also highlighted some of the detrimental psychiatric effects attributed to lipid-lowering statin medication, such as adverse cognitive, mood, and behavioral effects, and violence, depression, and suicide. Like prior reports discussed above, they linked low peripheral cholesterol to that of a hypofunctioning serotonergic system, giving rise to impulsivity and violent behavior. They also reported on the previously mentioned relationship between depression and loss of appetite, followed by weight loss, and low lipid levels. Lastly, they mentioned fatty acids and docosahexaenoic acid (DHA), but did not elaborate on how low lipid levels could influence the levels of this particular omega-3 essential fatty acid, and how this could result in suicide or suicidal behaviors.

Given the serious adverse effects linked to low serum cholesterol, LDL-C, and triglycerides, it would seem prudent to encourage patients to eat regularly and not skip any meals. The challenge is that severely depressed patients often do not feel like eating and can lose their appetites and taste for food. Even so, the risks to vulnerable patients that miss meals, refrain from eating, and lose weight are too great, so there should be discussions about food and the importance of eating at each clinical encounter. Eating something is better than nothing so discussions should encourage regular eating.

On the other hand, if a patient is willing and showing motivation to follow specific dietary advice, a modified Mediterranean diet (ModMedDiet) ought to be advocated since a randomized controlled trial showed the diet to significantly lower symptoms of depression among patients that had moderate to severe depression (p<0.001), with clinical remission happening among 32% of the intervention group (Jacka et al, 2017). Patients should be encouraged to eat liberally and as often as they like from the following 12 food groups: whole grains (5-8 servings/day); vegetables (6/day); fruit (3/day); legumes (3-4/week); low-fat and unsweetened dairy foods (2-3/day); raw and unsalted nuts (1/day); fish (2/week); lean red meats (3-4/week); chicken (2-3/week); eggs (up to 6/week); and olive oil (3 tablespoons/day). There should also be a reduction in the intake of extra foods, such as sweets, refined cereals, fast-food, fried food, processed meats, and sugary drinks (3 or less/week). Lastly, the diet also affords red or white wine consumption (i.e., limited to 2 drinks/day) and should preferably be consumed with meals. This latter recommendation is contraindicated for patients with a history of an alcohol-use disorder, and/or for patients in whom a prior suicide attempt included alcohol.

In this clinical context, depressed and vulnerable patients willing to follow specific dietary advice should be encouraged to adopt a ModMedDiet. This recommendation could be challenged since the ModMedDiet has been shown to very modestly lower cholesterol, but this would only happen among patients in whom high cholesterol is a clinical issue (Rosenthal, 2000). In the context described here, however, the ModMedDiet is advocated to depressed patients that are skipping meals and not eating regularly or sufficiently, and thus this approach is likely to lessen depressive symptoms and raise cholesterol, and not lower it. Thus, the ModMedDiet is advocated because it is satiating, palatable, easy to follow, possesses antidepressant effects, and should likewise raise the dietary quality and lipid levels among patients that had been missing meals, not eating regularly, and/or losing weight.


Omega-3 Essential Fatty Acids and Suicide

An article by Sublette, Hibbeln, Galfalvy, Oquendo, & Mann (2006) documented the impact of DHA upon suicide risk. All the subjects (n=33; mean age=40.4 years, standard deviation [SD]=11.9 years) had depression and met the clinical criteria for a major depressive episode. They were provided naturalistic psychopharmacological inpatient treatment for 8 weeks, or outpatient treatment from the research team for 6 months; all subjects were then managed by community-based treatment. Evaluations were performed at 3, 12, and 24 months. All subjects had their baseline fasting plasma polyunsaturated fatty acid (PUFA) composition analyzed. Three of the subjects were lost to follow-up. Among the remaining subjects, 23 did not attempt suicide, and 7 made suicide attempts with 2 being fatal. Fifty-three percent of the subjects had previously attempted suicide. The results demonstrated that low DHA percentages of total phospholipid fatty acids (p=0.002, hazard ratio=0.29), and an elevated omega-6/omega-3 ratio (p=0.008, hazard ratio=1.36) “predicted subsequent suicide attempts” (p. 1101). When adjusting for the use of medications during the follow-up period, they had no impact on “DHA percentages of total phospholipid fatty acids or omega-6/omega-3 ratio regarding time to suicide attempt” (p. 1101).

These results, according to Sublette et al (2006), suggested that low DHA percentages of total phospholipid fatty acids, and an elevated omega-6/omega-3 ratio might predict suicidal behavior among a population of depressed subjects. They noted the relationship between suicide and low levels of 5-HIAA in the CSF (Mann et al, 1996), and that levels of 5-HIAA in the CSF correlate with long-chain PUFA levels (Hibbeln, Umhau, George, & Salem, 1997); this latter finding was identified in normal subjects only. Sublette et al (2006) also noted a link between increased suicide risk and increased CSF corticotropin releasing factor (CRF) levels (Arató, Bánki, Bissette, & Nemeroff, 1989), the latter being associated with low plasma DHA status (Hibbeln, Bissette, Umhau, & George, 2004). Thus, they proposed that increased suicidal vulnerability could be related to DHA status, and serotonergic and corticotropin function. While they commented that these results might not be generalizable to a broader community, they did recommend that supplemental omega-3 essential fatty acids should be studied further as a possible treatment for reducing suicide risk.

In a larger, somewhat similar study, fasting PUFA levels were evaluated among United States military active duty personnel (2002-2008) that died due to suicide (n=800) and controls (n=800) matched for age, date of collection, sex, rank, and year of incident (Lewis et al, 2011). The age range at death was between 17 and 59 years (mean age: 27.3 years, SD=7.3 years). The results showed that there was a 14% increased risk of suicide (OR=1.14, 95% CI: 1.02-1.27; p<0.03) with each SD decrement in DHA status. When analyzing subjects by octiles, the DHA ranges were broader among subjects in the top octile (n=200; 1.67-4.50%) compared to those in the bottom octile (n=200; 0.29-0.72%). The subjects with the highest DHA levels were more protected against suicide compared to subjects with lowest DHA levels. The risk of suicide death was 62% greater among men having the lowest DHA levels (adjusted OR=1.62, 95% CI: 1.12-2.34; p<0.01, comparing DHA below 1.75% [n=1,389] to above [n=141]). Lower levels of two other fatty acids – i.e., stearic acid and dihomo-gamma-linolenic acid – were also associated with an increased risk of suicide but the impact of these PUFAs were not as strong compared to DHA. Even though Lewis et al proposed that the low DHA status might have been the result of an altered dietary intake, they were not confident in this possibility because their work did not find differences in fatty acid status between “personnel with and without mental health and substance abuse diagnoses” (p. 1589).

With respect to the mechanisms implicated in suicide deaths, Lewis et al (2011) reviewed evidence pertaining to prefrontal cortex activity. They cited research (Mann, 2003) linking reduced prefrontal cortical activity on positron emission tomography (PET) and suicidal and aggressive behaviors, and impulsivity. Other evidence demonstrated that DHA supplementation amplifies prefrontal cortical activity during sustained attention as per functional magnetic resonance (MRI) imaging (McNamara et al, 2010). Additionally, Lewis et al (2011) cited observational studies linking lower plasma DHA levels to that of lower levels of 5-HIAA (Hibbeln et al, 1998) and CRF in the CSF (Hibbeln et al, 2004). These latter relationships are important since serotonergic deficits and an abnormal stress response have been implicated in the neurobiology of suicidal behavior. Deficits of other neurotransmitters – i.e., dopamine and norepinephrine – are also implicated in the neurobiology of suicidal behavior. Deficient levels of dopamine and serotonin in the frontal cortex were shown in an animal study to be associated with dietary deficiencies of DHA and arachidonic acid (de la Presa Owens & Innis, 1999). Likewise, deficiencies of serotonin and norepinephrine in the frontal cortex in chronically stressed mice were shown to be reversed by eicosapentaenoic acid (EPA) and DHA supplementation (Vancassel et al, 2008). Thus, it is conceivable that low DHA status increases suicide by reducing or impairing prefrontal cortical activity as a consequence of impaired neurotransmitter function, and impacting some aspect of the hypothalamic-pituitary-adrenal (HPA) stress response.

Another study relied on validated food-frequency questionnaires to assess the relationship between omega-3 PUFAs and completed suicide, and did not find a lowered risk of completed suicide with dietary intakes of omega-3 PUFAs (Tsai et al, 2014). While this study relied on a large number of people (i.e., data derived from 205, 357 U.S. men and women followed for a duration of 14-22 years), the intakes were not correlated to fasting plasma PUFA composition. The results from this study, therefore, are difficult to interpret since it would have been much more rigorous if completed suicides were also correlated to measurable PUFAs, such as DHA, EPA, and other fatty acids.

Precisely how DHA works to lessen the risk of suicide and completed suicide remains uncertain, although several hypothetical mechanisms were described above. DHA and the ratio of omega-6/omega-3 likely play an important role in moderating vulnerability toward suicidal behavior. For instance, Vas, Kac, Nardi, and Hibbeln (2014) determined that a higher serum status of two omega-6 fatty acids – i.e, arachidonic acid and adrenic acid – among pregnant Brazilian women increased the risk of suicide and experiencing a major depressive episode. Another study showed that supplementing with omega-3 fatty acids daily (i.e., 1,220 mg EPA and 908 mg DHA) among patients with recurrent self-harm for 12 weeks resulted in marked reductions in surrogate markers of suicidal behavior – i.e., depression, perceived stress, and daily hassles (Hallahan, Hibbeln, Davis, & Garland, 2007). There is even evidence that the daily use of omega-3 fatty acids (i.e., 700 mg of EPA and 480 mg of DHA for 12 weeks) can prevent transition to psychosis among vulnerable patients over a 12 month duration (Amminger et al, 2010), and with beneficial effects that protected against the development of psychosis among the majority of the original cohort that persisted 7 years later (Amminger, Schäfer, Schlögelhofer, Klier, & Mcgorry, 2015). It seems conceivable then that omega-3 essential fatty acids would also provide some protection against the development of suicidal ideation and even suicide by being able to abrogate the development of psychosis.

The data presented in this section revealed a correlation between completed suicide and suicidal behavior and (1) low serum DHA status, (2) an elevated ratio of omega-6/omega-3 fatty acids, and (3) elevated levels of specific omega-6 fatty acids. Some data was also presented demonstrating that treatment with EPA and DHA can moderate potential surrogate markers of suicidal behavior. It is difficult to know the precise doses of EPA and DHA that are needed to moderate suicide risk, but the data (as presented in this paper) suggests that improving DHA status would be most important even though improving EPA status would also provide benefit. An approximate EPA range of 700-1,300 mg and DHA range of 500-1,000 mg should increase their concentrations in the serum and reduce the ratio of omega-6/omega-3 fatty acids, which should provide some protection against suicide over time. While all of this data is preliminary, a robust intervention study named the “Better Resiliency Among Veterans and non-Veterans with Omega-3’s” (i.e., BRAVO) should more firmly establish the efficacy of omega-3 fatty acids against completed suicide (Marriott et al, 2016).


The Kynurenine Pathway and Suicide

Sublette et al (2011) were the first team of investigators to document a relationship between plasma kynurenine (KYN) levels and suicide attempters with MDD. The KYN pathway plays a major role in tryptophan (TRY) degradation and accounts for some 90% of its degradation in the periphery (Leklem, 1971). The basis for this relationship stems from the known association between neuroimmune factors and the role they play in the pathogenesis of major depression (Dantzer et al, 2011; Maes et al, 2009). Depressive behaviors have been connected to the inflammatory activation of the enzyme indoleamine-2,3-dioxygenase (IDO), which increases the production of KYN from tryptophan (TRP), thus depleting both TRP and its metabolite, i.e., serotonin (Sublette et al, 2011). This is clinically important since both major depression and suicidal behavior are associated with decreased serotonin function (Mann, 2003), and depression itself is associated with cytokine-stimulated KYN production even when the levels of TRP are not depleted within the CSF (Raison et al, 2010). It should be emphasized that “there is no clear evidence demonstrating that inflammation causes a decrease in brain serotonin levels through the induction of the kynurenine pathway in depressed and suicidal patients” (Bryleva & Brudine, 2017, p. 325). However, there is much speculation that with an increased production of KYN there would be a corresponding decrease in serotonin within the CNS, and/or other adverse consequences would ensue, all of which could increase suicide vulnerability.

In the study by Sublette et al (2011), the mean plasma KYN level among suicide attempters (n=14) with MDD (1.64 ± 0.33 umol/L) was higher compared to patients (n=16) with MDD that had no history of attempting suicide (1.37 ± 0.30 umol/L), and these results were statistically significant (p=0.04). In a further analysis, plasma KYN levels, but not plasma levels of TRP, were associated with suicide attempt status (p=0.032). Also, among suicide attempters with MDD, the cytokine activation marker known as neopterin was positively correlated with the ratio of KYN/TRP (i.e., provides an estimate of TRP metabolism and is a marker of IDO activity), and these results reached statistical significance (p=0.043). All of these findings suggest that the production of KYN is mediated by inflammatory processes among suicide attempters with MDD. These effects were not influenced by the severity of depression, or the presence or absence of psychiatric medication. A possible confounding variable that was mentioned in the study concerned vitamin B6 deficiency, which was not evaluated for, and is known to inhibit the breakdown of KYN.

With respect to the mechanisms involved that could increase the vulnerability to suicide attempt, Sublette et al (2011) proposed several logical biochemical pathways that might become triggered among patients with MDD having attempted suicide. While it is possible that an increased production of KYN could result in TRP depletion, followed by the depletion of 5-hydroxytryptophan, and serotonin (as mentioned previously), they posited that that more likely pathway involves proinflammatory cytokines that activate the IDO enzyme, which results in increased levels of KYN within the brain. Once in the brain, the increased levels of KYN can lead to the production of either quinolinic acid (QA) or kynurenic acid (KA), with the former functioning as an agonist to the N-methyl-D-aspartate receptor (NMDA-R), and the latter functioning as an antagonist to the NMDA-R. It is presumed that patients with MDD that attempted suicide would have produced more QA from KYN, resulting in a net excitation of NMDA-R activity (Figure 1).



A similar study (Bradley et al, 2015) investigated the role of the KYN pathway among suicidal adolescents with MDD (n=20), non-suicidal adolescents with MDD (n=30), and healthy controls (n=22). The results from this study showed that “Suicidal adolescents with MDD had significantly lower TRP than both healthy controls (p=0.006) and non-suicidal adolescents with MDD (p=0.013)” (p. 209). Specifically, the mean plasma concentration of TRP among suicidal adolescents with MDD was lower (609.07 ± 343.00 ng/ml) compared to higher mean values among non-suicidal adolescents with MDD (1092.13 ± 782.39 ng/ml) and healthy controls (982.97 ± 406.31 ng/ml). The mean KYN/TRP ratio levels were also significantly elevated among suicidal adolescents with MDD (0.69 ± 0.38 ng/ml) compared to both healthy controls (0.49 ± 0.27 ng/ml; p=0.043), and non-suicidal adolescents with MDD (0.50 ± 0.29 ng/ml; p=0.019).

When additional analyses were performed, except that medicated adolescents with MDD were excluded, the results showed similar levels of statistical significance. Unmedicated suicidal adolescents with MDD had significantly lower mean levels of TRP than both healthy controls (p=0.005) and non-suicidal adolescents with MDD (p=0.008). The mean KYN/TRP ratio levels were more significantly elevated among unmedicated suicidal adolescents with MDD compared to both healthy controls (p=0.018), and non-suicidal adolescents with MDD (p=0.011).

These results, according to Bradley et al (2015), implicate KYN in suicidality among adolescents with MDD, especially those considered to be at high risk for suicide. Suicidal adolescents with MDD (whether medicated or not) had decreased levels of TRP and increased KYN/TRP ratios when compared to healthy controls and non-suicidal adolescents with MDD. The authors also reported that their findings suggest that the KYN pathway and neurotoxicity, and not serotonin deficiency is more prominent among suicidal adolescents with MDD. They pointed to an increased production of KYN, with increased amounts of KA and QA in the brain, with the former metabolite representing a neurotrophic pathway via astrocytes, and the latter metabolite being produced in greater quantities, and representing a neurotoxic pathway via microglia. Since the latter pathway would be more activated in situations where the risk of suicidality is greater, the neurotoxic pathway via QA could also be considered suicidogenic. Figure 2 below shows additional demarcations of the KYN pathway described earlier. Similar to the previous study (Sublette et al, 2011), vitamin B6 deficiency was not evaluated for, and could have confounded the results (Bradley et al, 2015).



In a related study, Brundin et al (2016) evaluated the CSF, plasma, and genome to further understand specific KYN pathway metabolites and their relationship to suicide risk. The CSF cohort involved patients (n=64) with various mental disorders who were hospitalized after having attempted suicide (i.e., between 1988 and 2001). The CSF patient group was compared to controls (n=36) who were free of medication, were healthy, and had no prior or current mental disorder or substance abuse problem. The CSF patient group went through a washout period (14.6 ± 9 days) before having lumbar punctures and psychiatric evaluations. The results demonstrated that the levels of picolinic acid (PIC) were markedly decreased in the CSF of the patient group compared to the healthy controls (p<0.001). The PIC/QA ratio was also reduced in the CSF patient group compared to the healthy controls (p<0.001). Similarly, the CSF KYN/TRP ratio was increased in the CSF patient group compared to healthy controls (p<0.01), suggesting increased activation of the KYN pathway. Some patients (n=29) were followed-up at different random intervals over a 2-year duration (i.e., at 6, 12, 18, and 24 months), and their CSF PIC levels remained markedly lower than values obtained from healthy controls (i.e., for all four time periods; p<0.01).

In the plasma cohort from Brundin et al (2016), the PIC level was decreased among patients that attempted suicide (n=73) compared to healthy controls (n=35; p=0.001). Similar to the CSF cohort, the PIC/QA ratio was reduced in the patient group compared to the healthy controls (p<0.05). Unlike the CSF cohort, however, there was no difference in the KYN/TRP ratio between the patients that attempted suicide and healthy controls. There was a positive association between neopterin levels and both the KYN/TRP ratio (p<0.0005) and QA level (p<0.01) among patients that attempted suicide (n=54), but not among the healthy controls (n=29). Medications from different classes were analyzed and none, except for propiomazine, had any influence upon the PIC levels of patients that attempted suicide (see page 6 from Brundin et al for the classes of medication that were assessed). Also, the levels of PIC or QA did not differ between untreated patients that attempted suicide (i.e., not having received any medication), and patients that attempted suicide who were treated with psychiatric medication.

In the genotyping cohort from Brundin et al (2016), the sample involved 34 subjects (10 healthy controls and 24 patients that attempted suicide). The aim here was to evaluate the effect of amino-β-carboxymuconate-semialdehyde-decarboxylase (ACMSD) “variants on CSF QA levels in all genotyped patients and controls with available CSF data” (p. 6). It should be noted that ACMSD is the rate limiting enzyme in the production of PIC. One of the hypotheses put forth was that decreased activity of this enzyme would be associated with increased QA levels in the plasma and CSF of suicide attempters, decreased PIC levels in the plasma and CSF of suicide attempters, and a reduced ratio of PIC/QA. The genotyping results demonstrated that the identified single nucleotide polymorphism (SNP) – shown to be the minor C allele of rs2121337 – was associated with an increased QA/PIC ratio in the CSF (p=0.02). The C allele was found more often among patients that attempted suicide (n=72) compared to healthy control (n=135; p=0.03).

The aforementioned findings provide additional clarity regarding the relationship between KYN metabolites and suicide. From Brundin et al (2016), the results showed that PIC levels, and the PIC/QA ratio were reduced in both the plasma and CSF among patients that attempted suicide, and these findings were not present among healthy controls. The CSF PIC levels also remained low among patients that attempted suicide when followed-up for a 2-year duration. Another notable finding among patients that attempted suicide was that medications (except for propiomazine) did not influence plasma PIC levels, and psychiatric medication did not alter the plasma levels of PIC or QA. Lastly, a SNP of the ACMSD enzyme was linked to increased QA levels in the CSF, and this was more commonly found among patients that attempted suicide. Based on these additional findings, it is possible that the production of QA and PIC modulate suicide risk, with an increased production of QA increasing suicide risk, and an increased production of PIC via ACMSD lowering suicide risk. Figure 3 below shows how these additional KYN pathway metabolites might moderate suicide risk.



Given the potential deleterious effects of QA, it appears to possess neurotoxic effects that are associated with an increased suicide risk. KA, on the other hand, appears to be a neurotrophic agent that lessens or moderates suicide risk. Given how these KYN pathway metabolites function to either promote or lessen suicide risk, it would be in the best interest of vulnerable patients to consider treatments that could lessen suicide risk by lessening the production of implicated KYN metabolites. Likewise, raising the levels of PIC within the CSF and plasma would also represent a viable treatment strategy aimed at lowering suicide risk because it antagonizes QA neurotoxicity (Bryleva & Brundin, 2017).

One possible treatment is the amide of vitamin B3 (i.e., niacinamide or nicotinamide) that functions as an inhibitor of the liver enzyme, tryptophan pyrrolase (i.e., an older name for IDO), which inhibits the metabolism of tryptophan by the KYN pathway (Cho-Chung & Pitot, 1968). There have been several published reports documenting antidepressant benefits when niacinamide (i.e., 500 mg/day initially and then increasing to 1,500 mg/day) was given in combination with L-tryptophan to theoretically push the pathway toward serotonin synthesis (MacSweeney, 1975; Chouinard, Young, Annable, & Sourkes, 1977; Chouinard, Young, Annable, Sourkes, & Kiriakos, 1978). One of the clinical reports also postulated that niacinamide might possess antidepressant effects on its own (MacSweeney, 1975). I have also summarized these reports in a more current publication that includes clinical commentary (Prousky, 2010). It appears that niacinamide can alter tryptophan metabolism by globally limiting the formation of KYN metabolites, which might also moderate depressive symptoms by increasing the production of serotonin.

Hoffer (1962) compared a group of schizophrenic patients (n=73) given niacinamide or niacin in addition to standard treatment that sometimes included electroconvulsive therapy, to a group of schizophrenic patients (n=98) given standard treatment only. This study began in 1951 and the results were reported up until 1955. There were no suicides among the patients given vitamin B3, but four suicides among the group given standard treatment only. Hoffer (2004) also described an extension of the aforementioned study that continued to follow patients from 1955 to 1962. Seventy-six patients were given niacin or niacinamide during the seven-year period, and none died by suicide. Among 226 patients that did not take either form of the vitamin during this period, 4 of them died by suicide. Hoffer and Osmond (1978) later reported that niacin or niacinamide – when given in large doses in conjunction with other treatments, such as antipsychotic medications and electroconvulsive treatment – reduced suicides to zero among a cohort of 242 patients with schizophrenia that were followed for 10 years. They believed this to be striking given the number of suicides (i.e., 9) among a larger cohort of patients (n=450) with schizophrenia that were treated with standard treatment only, and observed for 7 years on average.

Even though this data is preliminary and has never been formally tested in a randomized controlled trial or rigorous prospective naturalistic study, it is possible that niacinamide (or niacin) possesses some anti-suicide effects when optimal doses are taken because of its antidepressant and biochemical effects that result in IDO enzyme inhibition. Hoffer and Osmond (1978) unfortunately did not provide specific details on the average daily dose of niacinamide that was taken among the more recent cohort of patients (n=242) given standard treatment plus large daily doses of the vitamin. When reviewing Hoffer’s work, it is apparent that the likely daily dose of niacinamide given to each patient ranged from 3,000-4,000 mg (Hoffer, 1972). As for adverse effects, patients can experience nausea and rarely vomiting from niacinamide, especially if it is taken away from food. Clinically significant increases in transaminase levels and liver toxicity are unlikely to happen unless the daily dose of niacinamide is well above 4,000 mg (Winter, & Boyer, 1973). Since 1,500 mg/day of niacinamide was the dose cited previously that lessens depressive symptoms, this could be an effective dose to provide patients at risk for suicide. Then, based on their clinical responses to the vitamin (and other treatments) over some circumscribed period of time, clinicians might consider increasing to maximum dose of 3,000-4,000 mg/day.

It might also be possible to mitigate suicide by increasing the levels of PIC within the plasma, but it remains unknown if PIC crosses the blood-brain-barrier from the periphery to raise CSF levels (Bryleva & Brundin, 2017). Brundin et al (2016) cited evidence that PIC possesses growth-factor-like properties, can trigger the differentiation of stem cells, and may thwart depressive and anxiety-like behaviors. Since PIC is not available on its own for oral consumption, it would seem biologically plausible to raise PIC levels by taking supplemental chromium picolinate and/or zinc picolinate. Randomized clinical trials have shown that both of these trace minerals can markedly reduce symptoms of depression. Chromium picolinate (i.e, 600 mcg/day) was shown to reduce symptoms of depression among patients with atypical depression (Davidson, Abraham, Connor, & McLeod, 2003), and among obese individuals with atypical depression and severe carbohydrate craving (Docherty, Sack, Roffman, Finch, & Komorowski, 2005). Chromium was well tolerated in both trials, and no worrisome or clinically significant adverse effects were reported among the patients randomized to the trace mineral. With respect to its purported mechanism of action, chromium affects insulin and serotonin functioning, and possesses the ability to likewise influence dopamine functioning (Davis & Vincent, 1997; McCarty, 1994). Thus, it makes sense to provide any patient expressing suicidal behavior with 600 mcg/day of chromium picolinate since it might lessen both depressive symptoms and vulnerability to suicide.

Randomized controlled trials have also shown that supplemental zinc can reduce symptoms of depression when administered adjunctively with antidepressant medication (Nowak, Siwek, Dudek, Zieba, & Pilc, 2003; Siwek et al, 2009). The beneficial properties of supplemental zinc are linked to data suggesting that lower peripheral zinc concentrations (i.e., as measured in the plasma or serum) are a sensitive state marker for depression among patients that are treatment-resistant to antidepressant medication (Siwek et al, 2010), and among depressed subjects in general (i.e., as per the results of a meta-analysis that evaluated peripheral zinc concentrations from 17 studies that encompassed 1,643 depressed subjects and 804 control subjects; Swardfager et al, 2013a). With respect to zinc’s mechanism of action, the trace mineral is an allosteric modulator of NMDA, gamma-aminobutyric acid, metabotropic glutamate, serotonin receptors and other ion channels, and helps to prevent long-term depression (Swardfager et al, 2013b).

The cited randomized controlled trials used 25 mg of elemental zinc (as hydroaspartate), but this form of elemental zinc would not impact PIC levels directly. As an alternative, I recommend 25 mg of elemental zinc (as picolinate) since raising peripheral zinc concentrations would assist in lowering depressive symptoms while also mitigating suicide risk by similarly raising the levels of PIC presumably in the plasma and hopefully in the CSF. Apparently, zinc picolinate is a superior form of zinc with respect to its intestinal absorption (Birdsall, 1996). Supplemental zinc should not result in any adverse effects since the randomized controlled trials demonstrated the trace mineral to be well tolerated when used adjunctively with antidepressant medication (Nowak, Siwek, Dudek, Zieba, & Pilc, 2003; Siwek et al, 2009).

Table 5 below lists specific orthomolecules and their corresponding mechanisms of action that might lessen the risk of suicide by manipulating KYN metabolites.



Vitamin D and Suicide

A study by Umhau et al (2013) assessed if low vitamin D status was “a predisposing factor for suicide” (p. 1). The study compared mean serum levels of 25OHD among active duty service members of the United States military deployed between 2002 and 2008 who died by suicide (n=495) to a control sample of active duty service members deployed during the same time period that did not die by suicide (n=495). While the results did not show any difference between the mean serum levels of 25OHD (whether adjusted or unadjusted) between the suicide cases and controls, higher concentrations of 25OHD were associated with a decreased suicide risk compared to subjects with the lowest concentrations of 25OHD. There was a decreased risk of suicide among subjects with 25OHD levels in the second to eighth octiles (i.e, mean levels ≥15.6 ng/mL; ≥38.9 nmol/L) compared to subjects in the lowest octile (i.e., mean levels <15.5 ng/mL; <38.7 nmol/L). Similarly, there was an increased risk of suicide among subjects in the lowest octile (i.e., mean levels <15.5 ng/mL; <38.7 nmol/L) compared to subjects in the subsequent higher octiles. When analyzed further, this data shows an excess of about 25 suicide deaths linked to levels of 25OHD <15.5 ng/mL (<38.7 nmol/L) in octile 1 that included 84 subjects in total that died by suicide. This translates to some 30% of subjects from octile 1, and 5% of subjects when considered amongst all octiles.

In another study, Grudet, Malm, Westrin, and Brudin (2014) assessed mean levels of 25OHD among adult patients having various psychiatric diagnoses that attempted suicide (n=59), to that of adult patients with MDD who did not attempt suicide (n=17), and healthy controls (n=14). The suicide attempters had lower mean serum levels of 25OHD compared to the non-suicidal depressed patients and healthy controls, and the results reached statistical significance (p<0.05). The mean level of 25OHD among the suicide attempters was lower (19±8 ng/mL; 47±20 nmol/L) compared to the level among non-suicidal depressed patients (25±11 ng/mL; 62±27 nmol/L) and healthy controls (26±10 ng/mL; 65±26 nmol/L). Psychiatric medications and anti-seizure medications did not have any impact on the levels of 25OHD. The results also showed that lower levels of 25OHD were associated with higher levels of the pro-inflammatory cytokine (i.e., IL-1β) in the blood of suicide attempters, and this result also reached statistical significance (p<0.05).

The first study cited in this section (Umhau et al, 2013) showed that the lowest mean levels of 25OHD were associated with an increased risk of suicide, suggesting that increasing the levels of 25OHD through vitamin D3 supplementation might mitigate suicide risk. The second study (Grudet et al, 2014) demonstrated that low levels of 25OHD and inflammation might contribute to neural mechanisms involved in suicidal behavior, which also points to the possibility that raising the levels of 25OHD through adequate vitamin D3 supplementation might lessen suicidal behavior. In the “Discussion” sections of both cited papers (Umhau et al, 2013 and Grudet at al, 2014), two interconnected mechanisms were put forth to link deficiency of vitamin D to suicide risk. The first mechanism associates deficiency of the vitamin to that of elevated brain inflammatory (or pro-inflammatory) cytokines, and the second mechanism associates the inflammatory state within the brain to reduced serotonergic activity (Dantzer et al, 2011), and impulsive suicide (Mann, 2003).

The question to answer, or at least to attempt to answer, is what daily dose of vitamin D3 is needed to optimize the levels of 25OHD? In a study that assessed vitamin D3 doses among adults, by evaluating subjective well-being, mean levels of 25OHD, parathyroid hormone (PTH), and plasma calcium, an intake of 4,000 IU/day for 6 months was associated with the most antidepressant, well-being effects (Vieth, Kimball, Hu, & Walfish, 2004). The authors of this study concluded that the 4,000 IU/day dose produced the greatest dose response, with the levels of 25OHD averaging 45±16 ng/mL (112± 41 nmol/L), and lowering PTH without having any effect upon plasma calcium. In a randomized controlled trial that assessed adult patients with MDD, a weekly dose (once/week) of 50,000 IU of vitamin D3 for 8 weeks was associated with an increase in the mean levels of 25OHD (34±9.1 ng/mL; 85±22.7 nmol/L), and lower depressive symptoms as measured by the Beck Depression Inventory (Sepehrmanesh et al, 2016). Thus, it would seem that a daily dose of 4,000 IU or a weekly dose of 50,000 IU of vitamin D3 would be a safe and reasonable strategy when pushing the levels of 25OHD levels well above those associated with suicide and suicide attempters.


Lithium and Suicide

While much has been written about the pharmacological application of lithium and its effects against suicide, its clinical use has been primarily advocated for the treatment of mood disorders (Grof & Müller-Oerlinghausen, 2009). What seems missing from this important discussion is the potential impact that low daily doses of lithium might have upon suicide. Published data since 1990 has consistently demonstrated that lithium levels in drinking water possesses effects that moderate suicide, whereby higher lithium levels in drinking water are associated with reduced risk of suicide in the general population (Terao, Goto, Inagaki, & Okamoto, 2009).

In a study by Schrauzer and Shrestha (1990), the drinking water of 27 Texas counties was analyzed for its lithium content. The counties with the highest lithium levels had the lowest rates of suicide and crime. The lithium content in the counties deemed to have the highest levels (mean lithium content: 123±25 ug/L; range: 70-160 ug/L) were compared to those with medium, and the lowest levels (mean lithium content: 5±4 ug/L; range: 0-12 ug/L). The suicide rates (i.e., per 100,000 population) were reported, and the counties with the highest lithium levels had rates of 8.7 compared to 14.2 in counties with the lowest lithium levels.

In a similar study (Ohgami, Terao, Shiotsuki, Ishii, & Iwata, 2009), lithium levels in the drinking (tap) water of 18 municipalities of the Oita prefecture of Japan was analyzed to determine if there was an association with suicide rates (study population=1,206,164; years assessed 2002-2006). The lithium levels ranged from 0.7-59 ug/L. The results demonstrated an inverse correlation between lithium levels in the drinking water and mortality rates for suicide for this particular region in Japan (β=-0.65;p<0.004). These results remained significant, however, only for male individuals (β=-0.61;p<0.008), and only reached marginal significance among female individuals (β=-0.46;p<0.06).

In yet another study examining the relationship between lithium in drinking water and suicide, Kapusta et al (2011) conducted 6,460 lithium measurements and assessed suicide rates per 100,000 of the population across 99 Austrian districts. The mean level of lithium in the Austrian drinking water was 0.0113 mg/L (SD=0.027; i.e., 11.3±27 ug/L). The overall suicide rate (p=0.000073) and standardized mortality ratio (SMR; p=0.000030) for suicide were inversely associated with lithium levels in the drinking water. Once again, a higher lithium level in the drinking water was associated with lower suicide rates. The authors estimated that increasing the lithium content of drinking water by 0.01 mg/L (10 ug/L) would result in a decreased suicide rate of 1.4 per 100,000, which equates to a 7.2% reduction in the SMR for suicide, and remarkably this could be accomplished by adding one 75 mg dose of a conventional lithium pill to 7,400 L (i.e., 1,995 gallons) of drinking water. In a related study, Helbich, Leitner, and Kapusta (2012) used a more refined statistical model on the data from Kapusta et al (2011), and confirmed an inverse association between mortality rates for suicide and lithium concentrations in drinking water (via a geographical weighted regression analysis; p<0.005).

There are other published studies that have found lower suicide rates to be associated with higher lithium levels in the drinking water (Giotakos, Nisianakis, Tsouvelas, & Giakalou, 2013; Blüml et al, 2013). Not all studies, however, have shown clear associations since Sugawara, Yasui-Furukori, Ishii, Iwata, and Terao (2013) only found a statistical trend toward significance between lithium levels and the average suicide SMR among females. Kabacs, Memon, Obinwa, Stochl, and Perez (2011) assessed the drinking water in 47 subdivisions of the East of England and did not find any associations between lithium levels in the drinking water and suicide SMRs. However, this study has been criticized because of methodological weaknesses noted with the sample numbers and narrow range of lithium concentrations obtained from the surveyed regions (Vita, De Peri, & Sacchetti, 2015). Another study (Helbich, Leitner, & Kapusta, 2015) assessed the impact of lithium prescriptions and lithium in the drinking water, and did not find any protective effects against suicide or any relevant interactions with drinking water. Lastly, a review of the aforementioned evidence has been conducted by Vita, De Peri, and Sacchetti (2015), and they noted the consistency of most studies “in demonstrating a highly significant inverse correlation between lithium levels in drinking water and suicide rates” (p. 4).

With respect to the lithium’s possible mechanism of action, Kapusta et al (2011) cited research linking the mineral’s antidepressant and anti-suicidal effects to interactions with the serotonergic system, and having “stimulating effects upon neurogenesis” (p. 350). Terao et al (2009) posited that lithium in pharmacological amounts exerts both a “bottom-up drive” to moderate the amygdala and related limbic areas implicated in aggressivity, and “top-down brakes” via the orbital prefrontal cortex and anterior cingulate gyrus to suppress amygdala activity (p. 812). These effects might not happen when consuming the very low levels of lithium found in drinking water.

The fact remains, however, that lithium, even in small amounts, does have effects that moderate suicide and mood. Most of the studies cited did show moderating effects upon suicide when consuming drinking water containing higher lithium levels. Also, a placebo-controlled trial that used only 400 mcg/day of lithium from lithium-rich brewer’s yeast resulted in mood enhancing and mood stabilizing effects after 4 weeks of use among adult subjects that were former drug-users (Schrauzer & Vroey, 1994). Given this data, it seems clinically plausible that very low daily amounts of lithium possess effects that would protect against suicide directly or indirectly by moderating moods that could be suicidogenic.

With respect to providing an adequate daily dose of lithium that exerts anti-suicide effects, at this point no such dose has been established. One paper determined that the mean daily intake was 730 micrograms/day based upon the average hair lithium concentrations among 2,648 predominantly American adults (Schrauzer, Shrestha, Flores-Arce, 1992). Data cited by Kapusta et al (2011) showed that some geographic regions may possess concentrations of lithium up to 5.2 mg/L (i.e., 5,200 ug/L), which equates to an intake of 10 mg/day. It seems reasonable, then, that an effective daily dose of lithium to prevent suicide could lie somewhere between 730 mcg and 10 mg.

While concerns have been raised about the neurodevelopmental and endocrinological impacts to populations exposed to artificially-raised levels of lithium in the drinking water (Kapusta et al, 2011; Vita, De Peri, & Sacchetti, 2015), lithium in such low daily doses is unlikely to be toxic and to produce levels that would be measureable in the serum. A study by Sartori (1986) documented the positive therapeutic effects when 150 mg of lithium orotate was given daily to adult patients in an alcoholic rehabilitation program for 6 months. Following their stay at the rehabilitation facility, some patients stopped the supplement at the 6-month mark, whereas some other patients took it for up to 10 years. The author determined that it was not necessary to follow or guide lithium orotate treatment with serum levels since it had an inconsequential impact upon normal serum levels of the mineral. Its use was not associated with any concerning adverse effects and, to the contrary, it appeared to help prevent alcoholic relapses, to improve liver and cardiovascular functions, and to reduce (or in some cases abolish) migraine headaches, stop attacks from Meniere’s syndrome, allow several patients to discontinue medications for hyperthyroidism, and moderate mood among several patients with manic depressive psychosis. Lastly, a review article by Marshall (2015) discusses the vast differences between pharmacological doses of lithium and nutritional doses. He cogently summarizes the evidence to date on lithium’s safety as a nutrient, and compares it to that of other “biologically compatible (nontoxic)” nutrients like zinc, and noted that daily doses in the range of 1-20 mg have been safely recommended by practitioners of functional medicine for years with a very low incidence of adverse effects (p. 107).



When assessing a patient with a major depressive disorder or another serious mental health condition, it is prudent to discuss whether a seriously ill patient may be ruminating about ending his/her own life. If so, a clinician may wish to consider whether a range of underlying medical and/or metabolic conditions may be causing or contributing to the patient’s distress, thereby straining the patient’s resilience to the breaking point. Basic medical testing of thyroid hormones, blood sugar levels, sex steroid hormones, cortisol, homocysteine, vitamin B12 or even food allergies and sensitivities may yield clues to treatable medical or metabolic conditions.

When integrating the information in this paper into clinical practice, clinicians might consider running specific laboratory tests on vulnerable patients to arrive at specific orthomolecular and/or dietary interventions that have potential anti-suicide effects. Clinicians could run fasting lipids (e.g., to assess cholesterol, LDL-C, and triglycerides), red blood cell membrane fatty acids (e.g., to assess the levels of EPA and DHA), serum levels of KYN metabolites (e.g., to assess the levels of QA, KA, PIC, and the PIC/QA ratio), and 25OHD. Patients could have these tests done at baseline, and then following some negotiated treatment period, the tests could be done again to assess for positive changes. Positive changes from treatment would hopefully mitigate suicide and correlate with some combination of the following: a rise in cholesterol, LDL-C, and triglycerides; an increase in EPA and DHA as per red blood cell membrane fatty acid analysis; an alteration of KYN metabolites with increases in KA, PIC, and the PIC/QA ratio, and a decrease in QA; and an increase in 25OHD.

A more pragmatic and less expensive approach that does not require regular monitoring with specific laboratory tests involves the recommendation that patients take a combination of the orthomolecules discussed as a multi-nutrient, anti-suicide strategy. For patients who are losing weight and skipping meals, they might also be advised to follow the ModMedDiet. Table 6 below lists all the orthomolecules and dose ranges that should be provided to vulnerable patients at the outset of any treatment plan, and could easily be integrated with virtually all psychiatric medications without interference or increased adverse effects. Nutritional doses of lithium would not be needed among patients already taking pharmacological doses of the mineral. All of the selected orthomolecules may possess antidepressant effects, which could further improve clinical outcomes.





Life is both precious and fleeting. Every vulnerable patient should be given expeditious care to reduce the risk of suicide. Quality medical care should include a review of medical test results, differentiation of diagnoses that may not have been previously identified or treated, and when appropriate, considering combinations of the aforementioned orthomolecules since they all possess some modicum of biological and clinical plausibility as a treatment strategy aimed at preventing suicide. While this paper and the proposed treatment strategy could be criticised as experimental and lacking robust clinical validation, I assert that with patients’ lives at stake, the risks of adopting this clinical approach would be minimal and the potential benefits could be significant particularly if a number of patients and their families are spared the ravages of suicide.



I thank Mr. Bob Sealey for his helpful editing suggestions and input on the contents of this paper.


Competing Interests

The author declares that he has no competing interests.



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