Hero

Videos

Slideshows

Articles

Podcasts

Poll

Suicide and cancer are among the top 10 causes of death in the adult population of the United States. Although the overall prevalence of mortality due to cancer has been decreasing, it is still the second leading cause of US deaths, 

 In comparison, suicide ranks 10th in this list, with 1.7% of total deaths.

Cancer and suicide have both plagued humanity since the beginning of recorded history. The first recorded mention of cancer appears in the Edwin Smith papyrus, dating from about 3000 BCE. Surviving documents from ancient Greek and Roman physicians detail attempts at diagnosing and curing the disease and give us the language we use today (oncology, from the Greek oncos, and cancer, from the Latin cancer, respectively). Suicide, too, has been a factor in death for millennia. The desire to control, to some extent, the timing and manner of one’s death has always been a human temptation, and this draw increases when physical or emotional distress are present.

Although estimates vary, patients with cancer (PWC) are at least twice as likely to die by suicide than people who do not have cancer. Moreover, having had psychiatric care prior to one’s diagnosis of cancer may not mitigate this increased risk.

The most common cancers worldwide are lung, breast, colorectal, prostate, skin, and stomach; lung, colorectal, stomach, liver, and breast cancers account for 

 Suicide risk is not the same for all types of cancer, nor is it consistent over the disease course (

 Several studies have found that suicide risk is highest immediately after diagnosis.11 Prostate cancer has a higher suicide rate in the first year after diagnosis, but it is associated with a lower overall rate unless metastatic disease is found, with additional increased risk when treatment is defined but not received. Unique to cancer is that the 

persists more than 15 years past diagnosis.

In addition to increased suicide risk, patients with head and neck cancers have higher depression scores than the general population, even before a cancer diagnosis. Therefore, the question arises of whether this subset of patients struggles with a biological cause in addition to diagnosis-related symptoms.10 Complicating these cases is the well-known association of many head and neck cancers with the use of tobacco, alcohol, and other substances, leading to the question of whether the preexisting mood disorders lead to substance use that increases the risk of cancer. However, the relative increase in number of cases of head and neck cancers linked to human papillomavirus instead of substance use may alter this picture.

, the risk of suicide has been decreasing, but Rahouma and colleagues

 found that these patients are at a higher risk than those with breast, prostate, or colorectal cancer. Furthermore, a 

of suicides may occur in patients with possibly nonfatal disease.

The suicide risk in patients with breast cancer has been relatively stable over the last 4 decades and may be linked to whether the patient has undergone surgery. Findings from Simpson and colleagues

have one of the lowest suicide rates and, in their study, all patients who died by suicide had undergone surgical intervention. The link between surgical intervention and suicide risk may be linked to cosmetic effects, particularly when they affect sexual organs and can potentially alter patients’ view of their desirability and sexual roles.

In colorectal cancer, risk differs depending on the site of the lesion. Distally located disease is linked to a higher rate of suicide. This effect may be due to the more severe effects of distal disease on quality of life. Suicide risk in 

was independently correlated with diarrhea, which can have a significant impact on lifestyle.

 It is not surprising that patients with terminal cancers report significantly more suicidal ideation.

Very little information has been collected regarding 

 found that health care providers did not feel adequately prepared 

or to provide support and resources to patients. 

The Columbia Suicide Severity Rating Scale is widely used for assessing suicidal intent, acts of furtherance, and suicide attempts. It is available at no cost and is designed to be used by anyone, including individuals without prior mental health care experience; there are versions specifically for individuals with cognitive impairments and for children. However, it does not provide guidance regarding full assessments or further steps if a screening is positive.

The Beck Hopelessness Scale asks true/false questions about future orientation, motivation, and expectations in order to assess negative feelings about the future. It can be used as an indirect evaluation of suicidal thoughts, but it does not address suicidal ideation directly. The detailed interpretation report can be very useful in assessing changes over time. Again, although the questions can be asked by anyone, the interpretation requires a trained professional.

The Hamilton Depression Scale (HAM-D) is a relatively brief questionnaire that asks about a variety of symptoms of depression. Suicide is mentioned in 1 of the 17 questions, which are on a graded scale. It does not ask about atypical symptoms and, while it has relatively high sensitivity, specificity is low.

The Patient Health Questionnaire-9 is a brief set of questions designed to be asked and reviewed by any health care professional, with recommendations of when to advise further assessment by a mental health professional. It has been shown to be reliable and valid in multiple studies. Like the HAM-D, it has relatively high sensitivity and low specificity.

Multiple studies have shown cancer as an independent risk factor for completed and attempted suicide. Spoletini and colleagues

 contrasted suicide in the general population, which they attributed to “genetic and psychological vulnerability to stress,” to suicide in PWC, which involved the “

intrinsic bio-psychological vulnerability to distres

s” linked to changes in the immune system associated with cancer. Thus far, research has not identified consistent risk factors that make the vault from suicidal ideation to suicide attempt more likely. Underlying factors such as mood disorders may increase risk but require “additional precipitating events or conditions.”

Depression is a major risk factor, as it is in the general population, but the population with cancer is at 

, which has been linked to immunological changes.

has been shown to decrease morbidity and mortality.

 of those who historically have higher rates of suicide (

 Physical illnesses in general, particularly those associated with physical pain with consequent lifestyle limitations, are consistent 

that play a role in at least 25% of suicides, and the correlation increases with age.

 Patients with significant uncontrolled pain are at higher risk—thus a key component of cancer treatment must be adequate pain control. Minimal information has been collected on how substance use as reaction to a cancer diagnosis contributes to the risk of suicide. 

Although few thorough examinations of the methods typically used for suicide have been conducted, the 

reports that overdose with painkillers and sedatives is the most common method of suicide used by PWC, and most of these occur at home.

 Despite this, screening for other methods of suicide (particularly firearms) should not be neglected.

A general understanding of suicidal ideation and behaviors involves alterations in the serotonin and hypothalamic-pituitary-adrenal axis (HPA) systems. Diseases like cancer that alter immune system function can also alter these axes, which may result in increased risk of suicide. Independently of co-occurring cancer, the immune system is altered in depression (eg, changes in cytokine and cell-mediated immunity; changes in HPA axis) and may contribute to the development of depression in a reciprocal manner.

Depression secondary to medical causes should be ruled out in PWC. This typically includes an evaluation of B12 and folate levels and checking for the presence of anemia, thyroid hormone imbalance, or adrenal hormone imbalance. The utility of assessing abnormalities in levels of electrolytes, including sodium, potassium, and magnesium, remains unclear, although there is considerable interest in the effect of imbalances on mental health.

To further complicate this picture, several medications used to treat cancer have been linked to depression, such as 

 Careful review of medication regimens and treatment alternatives may offer options for minimizing the effect of cancer therapy on mental health.

The escape model of suicidal drive may play a role, particularly in patients with a terminal diagnosis. This model postulates that the 

from intolerable distress, combined with increased awareness of the factors contributing to that distress, leads to suicide.

 Accordingly, cancers associated with rates of survival of less than 5 years have correlated with higher suicide risk, leading some to wonder whether the type of cancer is more important than the cancer diagnosis.

There are confusing data regarding the complicated mix of desire to speed up death, depression, hopelessness, and suicide risk. It appears that patients with baseline depression are more likely to want hastened death, expressing this desire up to 4 times as often, but Porta-Sales and colleagues

for more rapid death did not cause distress, and that nearly 80% of patients felt it was an important topic for the care team to discuss.

Studies of suicidal ideation and completed suicide in adult PWC and survivors make up the bulk of the research in this area. As treatments and survival rates for childhood cancers improve, long-term studies of this population must include this information to more fully understand the lifelong effects of cancer treatment in children and adolescents, particularly since suicide is the top cause of death in the young adult populations of many developed countries. Gunnes and colleagues

 showed an increased risk of suicide in Norwegian patients aged 23 to 48 years who had a 

. At exceptional risk were survivors of brain and testicular tumors, as well as of leukemia. An American study did not replicate this finding but reported an 

of suicidal ideation compared with sibling controls.

 The average age of those who reported a first incident of suicidal ideation was 34 years, and they were, on average, 26 years past diagnosis. This is a serious example of how the sequelae of childhood cancer treatment can persist far into adulthood.

Complicating the discussion of suicide in PWC is the subject of refusal of treatment—should this be considered suicide? Frenkel

conventional treatment are at times self-directed, confident, and active, and have thought deeply about the meaning of life and cancer and about their cancer treatment options.” What does it mean to have the ability to choose, to some extent, when we will die? This controversy has been taken all the way to the Supreme Court, with Justice Louis Brandeis writing in 

 that “the right to be left alone . . .is the most comprehensive of rights and the right most valued by civilized men,” and Justice Burger clarifying that “nothing in this utterance suggests that Justice Brandeis thought an individual possessed their rights only as to sensible beliefs, valid thoughts, reasonable emotions.”

 Physicians are trained that the ultimate goal is to save or at least prolong life, but often neglected is the consideration of quality of life and patients’ desire to live, and die, in a manner they can, to some extent, control. Isenberg-Grzeda and colleagues

 reported on 3 patients who attempted suicide after being deemed 

ineligible for medical assistance in dying

, further exemplifying the desire to have some say over the end of their lives.

Treatment for depression in PWC can be quite similar to the treatment of depression in the general population, with psychotherapy and pharmacotherapy (ie, selective serotonin reuptake inhibitors, selective serotonin-norepinephrine reuptake inhibitors, mirtazapine, trazodone) at its core. The most recent review of antidepressant therapy for depression in PWC did not show a significant improvement from placebo, but Ostuzzi and colleagues

from which to draw this information and that much more research is needed.

Psychotherapy, no matter how brief, can help patients adjust to their new health circumstances and to reassess their view of their life up until their diagnosis and their goals going forward. In addition, special considerations, such as the influence of altered immune activity and the effects of chemotherapy, must also weigh into treatment decisions. Moreover, prescribers must be judicious in choosing medications that can be expected to show some positive effect within the patient’s expected lifetime, which may be significantly shortened. Stimulants may be useful in treating the fatigue and inattention that are common during cancer treatment. Close collaboration with the oncologic team can help to optimize mental health during cancer treatment.

Patients with cancer are at increased risk for both suicidal ideation and completed suicide. Factors contributing to this increase are biological and psychological, and both components must be addressed in a timely fashion to increase quality of life. A refusal of treatment must not automatically be considered an instrument of suicide, but should be viewed as a complex decision, factoring in goals of care, particularly quality of life.

is a faculty member of the Department of Psychiatry, Albert Einstein Medical Center, Philadelphia, PA. The authors have nothing to disclose regarding this article.

. CDC. Accessed July 14, 2020. https://www.cdc.gov/healthreport/publications/compendium.pdf

. World Health Organization. Updated March 3, 2021. Accessed July 14, 2020. https://www.who.int/news-room/fact-sheets/detail/cancer

3. Zaorsky NG, Zhang Y, Tuanquin L, et al.

5. Al-Ghazal SK, Fallowfield L, Blamey RW. 

Comparison of psychological aspects and patient satisfaction following breast conserving surgery, simple mastectomy and breast reconstruction

6. Pham TT, Talukder AM, Walsh NJ, et al. 

Clinical and epidemiological factors associated with suicide in colorectal cancer

Suicide and accidental deaths among patients with non-metastatic prostate cancer

8. Klaassen Z, Arora K, Wilson SN, et al. 

Decreasing suicide risk among patients with prostate cancer: implications for depression, erectile dysfunction, and suicidal ideation screening

Suicide ideation in stomach cancer survivors and possible risk factors

Depression and anxiety in patients undergoing diagnostic investigations for head and neck cancers

11. Kumar V, Chaudhary N, Soni P, Jha P. 

Suicide rates in cancer patients in the current era in United States

12. Rahouma M, Kamel M, Abouarab A, et al. 

Lung cancer patients have the highest malignancy-associated suicide rate in USA: a population-based analysis

13. Simpson WG, Klaassen Z, Jen RP, et al. 

Analysis of suicide risk in patients with penile cancer and review of the literature

How can a suicide screening and prevention procedure be implemented in a cancer center?

15. Anguiano L, Mayer DK, Piven ML, Rosenstein D. 

A literature review of suicide in cancer patients

16. Granek L, Nakash O, Ben-David M, et al.

 Oncologists’, nurses’, and social workers’ strategies and barriers to identifying suicide risk in cancer patients.

17. Spoletini I, Gianni W, Caltagirone C, et al. 

Suicide and cancer: where do we go from here?

Mental health services utilization and expenditures associated with cancer survivorship in the United States.

19. Sherrill C, Smith M, Mascoe C, et al. 

Effect of treating depressive disorders on mortality of cancer patients

20. McFarland DC, Walsh L, Napolitano S, et al. 

Suicide in patients with cancer: identifying the risk factors

21. Abourmrad M, Shiner B, Riblet N, et al. 

Factors contributing to cancer-related suicide: a study of root-cause analysis

National Cancer Institute. Depression (PDQ®) – patient version

. Updated July 19, 2019. Accessed July 14, 2020. https://www.cancer.gov/about-cancer/coping/feelings/depression-pdq

23. Kenna HA, Poon AW, de los Angeles CP, Koran LM. 

Psychiatric complications of treatment with corticosteroids: review with case report

24. Celano CM, Freudenreich O, Fernandez-Robles C, et al. 

Depressogenic effects of medications: a review

Interferon-related depression: a primer on mechanisms, treatment, and prevention of a common clinical problem

Delirium and depression associated with amphotericin B

28. Porta-Sales J, Crespo I, Monforte-Royo C, et al. 

The clinical evaluation of the wish to hasten death is not upsetting for advanced cancer patients: a cross-sectional study

29. Gunnes MW, Lie RT, Bjørge T, et al. 

Suicide and violent deaths in survivors of cancer in childhood, adolescence, and young adulthood: a national cohort study

30. Brinkman TM, Zhang N, Recklitis CJ, et al. 

Suicide ideation and associated mortality in adult survivors of childhood cancer

33. Isenberg-Grzeda E, Bean S, Cohen C, Selby D. 

Suicide attempt after determination of ineligibility for assisted death: a case series

34. Ostuzzi G, Matcham F, Daughy S, et al. 

Antidepressants for the treatment of depression in people with cancer

Although estimates vary, patients with cancer are at least twice as likely to die by suicide than people who do not have cancer. By identifying those at greatest risk, these treatment modalities can help support patients.     

New Approaches and Considerations to Cancer and Suicide

, a research team at Icahn School of Medicine at Mount Sinai Health System in New York City made a fascinating discovery: Early life stress in mice resulted in an epigenetic modification of methyl groups on histone-3 in neurons in the nucleus accumbens, which in turn led to a lifelong increase in the mice’s vulnerability to stress. The team then demonstrated that treating the mice during exposure to early life stress with pinometostat, a drug currently in clinical trials to treat acute myeloid leukemia in humans, inhibited the enzyme responsible for this epigenetic methylation modification and decreased the effect of early-life stress exposure on 

This study is but one of a growing number of publications demonstrating the essential role of epigenetics in animal development, health, and disease. Without much fanfare, our understanding of epigenetics has been a significant paradigm shifter. Before we explore epigenetics, we need to review the foundational field of genetics.

The 3 billion base pairs that constitute the human genome is the sequence of covalently bonded nucleic acids—adenine (A), thymine (T), cytosine (C), and guanine (G)—that form the double helix of DNA. This sequence forms the basis of the field of genetics and is created when the sperm joins the egg to form a zygote, which will contain this unique DNA sequence that remains constant throughout our life. In the case of identical twins, 100% of this DNA sequence is exactly the same, as both twins derive from the same zygote. With fraternal twins, 2 different sperm fertilize 2 different eggs to create 2 unique zygotes that have DNA sequences as different as 2 siblings with the same parents.

Let’s look at the genetic risk of schizophrenia, for example. In the general population, the risk of developing schizophrenia is about 1%, but if your identical twin develops schizophrenia, your risk increases to 50% due to the identical shared genome. In fraternal twins, the risk drops to roughly 16%, and in siblings it further drops to 9%. This demonstrates the role genetics plays on increasing or decreasing a person’s risk for various medical conditions. Significantly, the identical twin also has a 50% likelihood of not developing schizophrenia, which is attributed to numerous nongenetic factors. One of these factors is the individual’s epigenome, which can be different than 

In 2001, the Human Genome Project (an international consortium of research labs spearheaded by the US National Institutes of Health) and Celera Genomics (a private research company) announced they had independently completed a first draft of the sequencing of the human genome’s 3 billion base pairs. By 2003, the final draft was complete. Speculation by scientists, world leaders, and the media projected that, over the next decade, science and medicine would discover the genetic basis to many human diseases and disorders, with associated novel treatments. The complete sequencing of the human genome was an incredible achievement that continues to advance our understanding of the role of genes on health and disease. However, 20 years later it is disappointing to see how few actionable treatments have been developed. So, what’s next?

The foundation of the epigenome involves covalent changes on certain areas of our chromosomes that will either increase or decrease the amount of activity at genes, hence impacting which gene products will be made in each particular cell. Think of the epigenetic processes like the software that determines which programs on a computer’s hard drive (the DNA genome) will be opened in RAM (in our analogy the genes that are ultimately expressed, creating our phenotype). The zygote has access to 100% of the genome. As embryological development occurs, cells begin to specialize and only require a small subset of the 20,000 or so protein coding genes that are available. One line of cells will begin to only produce proteins necessary for skin, while another set of cells will produce proteins for muscle, and yet another for neurons. This is an energy efficient process.

 that the chromosomal DNA/histone complex can be covalently modified to decrease or increase gene expression: methylation of the gene, or adding chemical tags to histones (the proteins around which the DNA is wrapped).

 In humans, the part of the gene that is methylated is the “promoter sequence,” a specific sequence of nucleotides, including a large density of CpG sites, which serve as a beacon and landing pad for the proteins that will then transcribe the messenger RNA (mRNA). mRNA will ultimately code for the gene’s protein. The more methyl groups attached to the promoter sequence, the less gene product will be synthesized. In specialized cells, the unneeded genes are heavily methylated and buried deep in the histones, likely never to be transcribed again.

The 3-dimensional shape of a histone can vary depending on chemical groups that can be covalently added depending on the degree of access needed to the gene associated with a particular histone. There are many chemical tags for histones, but the 2 best understood are methyl groups, which generally help the histone fold to hide the gene; and acetyl groups, which generally help the histone open up and make the gene more accessible.

There are enzymes that exist with job descriptions to either add or remove these methyl groups or acetyl groups to gene promoter sequences or histones, which in turn will be induced or repressed depending on the organism’s environment. At any given moment in time, an individual’s epigenome is unique and reflects the infinite number of events that determine what genes are turned on, or off, or somewhere in the middle.

Remember those identical twins that share 100% of the same DNA sequence? Epigenetic processes are already at work creating different expressions of this identical genome as soon as the shared zygote splits in 2 to create the twins.

, baby rats respond to stress differently (throughout their lives) depending on how much grooming and licking they receive from their mother in the first week of their life.

 Some mother rats provide abundant grooming and licking to their babies, while other mother rats are less interactive with their babies, paying less attention with significantly less grooming and licking. Research found that the baby rats that received plenty of grooming and licking during that first week of life remained notably calm when exposed to stressful situations as adults. Meanwhile, the baby rats deprived of their mother’s attention during the first week of life responded with distress when exposed to the same stressful situations as adults.

The researchers then swapped the baby rats at birth: Babies of low grooming/licking mothers were switched to mothers that were high groomers/lickers, and vice versa. Remarkably, the first week of life for the baby rats was the determining factor for stress response as adults, rather than any inheritance from their biological mother. In addition, the stress-tolerant adult rats had lower levels of cortisol, adrenocorticotrophic hormone, and corticotrophin-releasing hormone than the adult rats that were neglected during that first week of life. Further research demonstrated that the stress-tolerant adult rats had decreased methylation of their cortisol receptor gene, in contrast to the neglected rats. Hence, that initial increased grooming created an epigenetic change that resulted in a lifelong increased expression of the cortisol receptor, creating greater resilience to stress.

Can epigenetic modifications that occur during a person’s life be passed on to their offspring and future generations? From November 1944 through the spring of 1945 of World War II, the Germans, who controlled the Western Netherlands, set up a blockade that created a scarcity of food and severe starvation. From the detailed historical health care records, we have been able to study the long-term effects of the famine. Babies born to women who experienced starvation for the first 3 months of pregnancy and then resumed a normal diet when the blockade ended and food was available were likely to have a normal body weight at birth. However, babies born to women who were 6 months pregnant when the famine began were more likely to be underweight at birth.

These babies were followed by the health care system for decades. Remarkably, researchers discovered that the low-birth-weight babies continued to have body weights below average throughout their lives, including decreased rates of obesity as compared to the general population. The babies whose mothers experienced starvation during the first trimester of their pregnancy and had normal body weights at birth, had higher rates of obesity as compared to the general population decades later. Moreover, the grandchildren of the women who were starved during their first trimester also demonstrated some similar effects, suggesting a transgenerational inheritance.

One current hypothesis is that epigenetic changes to genes associated with nutrition and metabolism in the fetus would occur during a state of starvation to maximize the utilization of each calorie available. Significant epigenetic processes are in play during the first 3 months of fetal development, and these epigenetic modifications can then persist throughout life. Subsequent studies have shown that DNA methylation patterns in survivors of the Dutch Hunger Winter have demonstrated epigenetic modifications at genes involved in metabolism. The tragic circumstances of the Dutch Hunger Winter have provided a rare opportunity to study the potential effects of epigenetic changes early in life being passed on to future offspring. This is just one study; there is a growing literature in support of transgenerational epigenetic inheritance.

 for epigenetics in the National Library of Medicine generated 107,287 results, and 105,343 of these were published since the year 2000, demonstrating the explosion in this field over the past 2 decades.

Epigenetic modifications sculpt an individual’s phenotype 

 Epigenetic processes are most active, ubiquitous, and consequential throughout fetal development, as well as during the first 2 decades of life.

Returning to our identical twins, epigenetic differences are evident at birth, and these differences increasingly diverge throughout the twins’ lives. Research abounds comparing epigenetic profiles of individuals with and without a specific disease state to better understand the role of epigenetics in contributing to disease processes.

One significant consequence of the epigenetic contribution to phenotype is our growing understanding that genes that code for cytochrome P450 (CYP450) metabolic enzymes can be silenced or amplified, rendering the genotype of an individual’s CYP450 pharmacogenomic profile incomplete and unreliable. A recent study of CYP450 2E1 has demonstrated this 

 This growing understanding of the epigenetic effects on CYP450 gene expression calls into question the reliability of pharmacogenomic testing that reports a genotype, but does not factor in the epigenetic phenotype that ultimately will determine CYP450 metabolic enzyme activity.

Epigenetics has provided fertile ground to understand how early life experience can directly increase or decrease the risk and severity of psychiatric disorders such as schizophrenia, bipolar disorder, and 

The epigenetic paradigm shift has received relatively little attention compared to the human genome sequencing, despite the broad and significant impact it has had on our understanding of how environmental factors during a single lifetime can covalently regulate which genes are expressed, and to what degree, from the fixed human genotype. In fact, it is the epigenome that ultimately determines the individual’s phenotype for increasing or decreasing the risk of various diseases and the functioning of 

In the field of oncology, drugs that treat some cancers by epigenetic mechanisms are already FDA approved and in clinical use. Azacitidine and decitabine are both inhibitors of DNA Methyltransferase-1 and are approved for myelodysplastic syndrome—a disease of the bone marrow. Vorinostat and romidepsin both inhibit a histone deacetylase and are approved for the treatment of refractory cutaneous T-cell lymphoma. Time will tell if epigenetic modifying drugs will become part of our treatment arsenal in psychiatry.

In this issue we are delighted to present 2 important articles by Bursztajn et al expanding on the field of epigenetics. Their first article, “Harnessing Epigenetic Knowledge to Promote Resilience while Avoiding the Historical Pitfalls of Genetic and Social Reductionism,” provides a historical overview of the field of epigenetics, as well as offering some philosophical reflections. Their second article, “Transgenerational Transmission of Resilience After Catastrophic Trauma,” our featured CME article, explores the rapidly evolving understanding of the potential epigenetic role on resilience after severe trauma, and how this resilience may be passed along to the traumatized individual’s offspring.

is Medical Director, Brain Health, Exeter, NH; Editor in Chief, 

Staff Psychiatrist, Seacoast Mental Health Center, Exeter, NH; Consulting Psychiatrist, Exeter Hospital, Exeter, NH; Consulting Psychiatrist, Insight Meditation Society, Barre, MA.

1. Kronman H, Torres-Berrio A, Sidoli S, et al. Long-term behavioral and cell-type-specific molecular effects of early life stress are mediated by H3K79me2 dynamics in medium spiny neurons. 

2. Dempster EL, Pidsley R, Schalkwyk LC, et al. Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder. 

3. Kular L, Kular S. Epigenetics applied to psychiatry: Clinical opportunities and future challenges. 

6. Kanherkar RR, Bhatia-Dey N, Csoka AB. Epigenetics across the human lifespan. 

7. Kronfol MM, Jahr FM, Dozmorov MG, et al. DNA methylation and histone acetylation changes to cytochrome P450 2E1 regulation in normal aging and impact on rates of drug metabolism in the liver. 

8. Blacker CJ, Frye MA, Morava E, et al. A review of epigenetics of PTSD in comorbid psychiatric conditions. 

9. Mazzone R, Zwergel C, Artico M, et al. The emerging role of epigenetics in human autoimmune disorders. 

10. Ling C, Ronn T. Epigenetics in human obesity and type 2 diabetes. 

Early-life stress can modify an individual's genetic code, leading to mental health problems later in life. But by understanding the science of epigenetics, psychiatrists can treat these conditions, and prevent intergenerational trauma. 

Exploring the Epigenetic Paradigm Shift

To minimize renal side effects, lithium is best administered 

 at night, and one should routinely use the regular-release (24-hour half-life) preparation.

 It comes in tablets or capsules. Capsules are sometimes better tolerated because they do not have the salty taste that can contribute to nausea. They also are available in 150-mg doses, which is a convenient size for some patients on doses like 450 or 750 mg daily. Plasma levels during acute treatment should not be allowed to go higher than 1.0 mEq/L for a lower risk of 

The regular-release formulation is preferred over the sustained release version (

; now available as a generic) because it provides superior pharmacokinetics for sparing the kidney of potential harm. Studies have shown that once-a-day lithium at night, compared with multiple daily doses, 

 and other symptoms of the lithium-induced diabetes insipidus-like syndrome.

 After the patient reaches the 12-hour postdose level following their evening dose (eg, 0.7 mEq/L), the patient’s level continues to drop during the day, reaching a low point just before the next once-daily dose. This low level is thought to give the kidneys an opportunity to have relatively little lithium coursing through them, which aids recovery from dysfunction, such as increased urine volume. When using a longer-acting preparation, further lowering the level during the second half of the day is minimal and, hence, the protective effect should be lower.

Trials examining renal biopsy results also found that multiple daily doses were associated with more pathological changes to the kidneys.

 Why doesn’t the higher peak lithium level associated with a large once-daily dose harm the kidneys? We can only say, based on the studies, that this effect must be less harmful than the absence of the daily low trough level. 

 in effectiveness has been noted in any of the trials of once-daily lithium.

Another possible advantage of giving the whole dose at night is that the 

 filter lithium more slowly at night. The net effect is that you only need 80% of the daily divided doses when changing patients to a once-nightly regimen. For instance, if someone was on 1500 mg daily in divided doses, they would usually need 1200 mg at night to get the same 12-hour postdose level. The once-daily dose at night reduces the total exposure and need to excrete lithium as compared with the divided doses. It is also possible that tremors will be less bothersome with the once-daily dose: the worst of the tremors will occur in the middle of the night when the patient is (hopefully) sleeping, and the lowest level of severity will be in late afternoon and evening.

The optimal level for maintenance treatment with lithium is 0.6 mEq/L to 0.8 mEq/L, according to a recent 

 Higher maintenance levels are associated with a 

 of long-term kidney harm and (surprisingly) more frequent depressive episodes.

 If patients are having breakthrough manias or hypomanias despite optimal maintenance levels of lithium and are also prone to serious depressions, it is better to add another antimanic agent instead of increasing lithium. Most patients with bipolar disorder experience more time in depressive states than manic states, so this will be a very common situation. If there are breakthrough depressions, 

 adding lamotrigine, lurasidone, quetiapine, or cariprazine.

is associate professor of psychiatry at Harvard Medical School and colead psychiatrist at the US Department of Veterans Affairs, National Telemental Health Center, Bipolar Disorders Telehealth Program, Brockton, Massachusetts. The author reports no conflicts of interest concerning the subject matter of this article.

An updated review of the optimal lithium dosage regimen for renal protection.

2. Kirkham E, Skinner J, Anderson T, et al. 

One lithium level >1.0 mmol/L causes an acute decline in eGFR: findings from a retrospective analysis of a monitoring database

Less frequent lithium administration and lower urine volume

What is the optimal serum level for lithium in the maintenance treatment of bipolar disorder? A systematic review and recommendations from the ISBD/IGSLI Task Force on treatment with lithium

5. Severus WE, Kleindienst N, Seemüller F, et al. 

What is the optimal serum level in the long-term treatment of bipolar disorder? A review

The Psychopharmacology Algorithm Project at the Harvard South Shore Program: An update on bipolar depression

Higher lithium levels are associated with a greater risk of long-term kidney harm and more frequent depressive episodes. This bipolar update reviews ways to minimize renal side effects.

Tips for Lithium Dosing for Optimal Renal Safety 

The history of psychiatry does not lack for great names. One of the greatest must be Helen Flanders Dunbar, MD, PhD. Widely recognized as the prime mover behind the psychosomatic medicine movement, she was a clinician, writer, the inaugural editor of 

 In addition, Dunbar’s work was essential to the development of consultation-liaison psychiatry. She also dedicated her professional life to promoting the role of clergy in medicine and exploring accident proneness. She lived a full, brilliant, and ultimately tragic life.

 Her father was a mathematician, engineer, and patent attorney; her mother a genealogist; and her brother, Francis, earned a master’s degree in botany at Stanford University. She, too, received a remarkable education. At Bryn Mawr College and Columbia Universityshe majored in mathematics and psychology. She then went on to earn 4 advanced degrees in 7 years. Dunbar attended 

 for medicine and obstetrics. She wrote a doctoral thesis on Dante at Columbia, while graduating magna cum laude from nearby Union Theological Seminary.

Her Episcopalian faith was a guiding light in her life, and she believed it should inform her medical practice. Dunbar worked closely with Anton Boisen, a clergyman inpatient at Westboro Mental Hospital who was convinced that religion and psychiatry needed to be connected on a professional level. Together they trained ministers to work in medical settings.

In 1929, Dunbar broadened her medical and spiritual horizons by traveling to Europe. She met the day’s leading figures in psychiatry and visited Lourdes, the world’s most famous healing shrine in France. This visit had a profound spiritual effect.

She legally changed her name to Flanders Dunbar in 1938. It is disappointing that such an accomplished woman had to change her name to overcome the prevailing misogyny.

From 1930 to 1942, Dunbar was the medical director of the Council for Clinical Training of Theological Students and director of the Joint Committee on Religion and Medicine. During this time, she earned the sobriquet of “mother of holistic medicine” with her 1935 publication of 

Emotions and Bodily Changes: A Survey of Literature on Psychosomatic Interrelationships: 1910-1933.

 In 1939, she became the first editor of the journal Psychosomatic Medicine.

American psychosomatic medicine was born in the 1930s. According to this school of thought, illnesses arose from the physiological effects of emotional stimuli. It was thought that certain psychodynamic patterns created typical illnesses, known as organ specificity. Repressed (and forgotten) emotions emerged from the unconscious to target certain organs, producing psychosomatic disorders. Somatic dysfunctions thus arose from patients’ emotional problems, which led practitioners of psychosomatic medicine to search for psychological profiles characteristic of specific syndromes. This expanded further to the belief that many diseases were psychogenic in origin and stressors, albeit undefined. Dunbar believed that having accidents was similar to the process by which other patients transformed psychological conflicts into somatic symptoms. Their personality styles and neuroses translated into accident proneness.

After 1939, Dunbar gave up academic commitments, drank heavily, alienated followers, and left the American Psychosomatic Society. On August 22, 1959, the publication day of her landmark book Psychiatry in the Medical Specialties,

Widely recognized as the prime mover behind the psychosomatic medicine movement, Helen Flanders Dunbar, MD, PhD. was a clinician, writer, and founder of the American Psychosomatic Society.

Psychosomatics

New Approaches and Considerations to Cancer and Suicide

Exploring the Epigenetic Paradigm Shift

Tips for Lithium Dosing for Optimal Renal Safety

A Pioneer of Psychosomatic Medicine

Helping LGBTQ Youth During the Pandemic

Clinical Dilemmas: What’s Good for the Brain Is Good for the Heart

Serving the Needs of the Many: Identifying Strategies for Better Care

Addressing Obesity in Patients Taking Antipsychotics

Maternal Autoimmune Disease and ADHD Risk in Children

Gastrointestinal Symptoms During Depressive Episodes