Bottle of lenalidomide

Photo courtesy of Celgene

Updated trial results support continuous treatment with lenalidomide and low-dose dexamethasone (Rd) as a standard of care for patients of all ages who have newly diagnosed multiple myeloma (MM) and are ineligible for stem cell transplant, according to researchers.

In this phase 3 trial, patients who received continuous Rd (until disease progression) had better progression-free survival (PFS) and overall survival (OS) than patients who received 18 cycles of Rd (Rd18) or a combination of melphalan, prednisone, and thalidomide (MPT).

Updated results from this study, known as the FIRST trial, were published in the Journal of Clinical Oncology.

Results were previously published in NEJM in 2014. The study was supported by Intergroupe Francophone du Myélome and Celgene Corporation, the makers of lenalidomide.

Thierry Facon, MD, of Centre Hospitalier Regional Universitaire de Lille in France, and his colleagues enrolled 1623 patients on this trial. They were newly diagnosed with MM and not eligible for stem cell transplant.

Patients were randomized to receive Rd in 28-day cycles until disease progression (n=535), Rd18 for 72 weeks (n=541), or MPT for 72 weeks (n=547).

Response

In the intent-to-treat population, the overall response rate was 81% for the continuous Rd group, 79% for the Rd18 group, and 67% in the MPT group. The complete response rates were 21%, 20%, and 12%, respectively.

The median duration of response was 32 months (range, 26-37) in the continuous Rd group, 22 months (range, 19-23) in the Rd18 group, and 22 months (range, 20-25) in the MPT group.

PFS and OS

The median PFS was 26.0 months in the continuous Rd group, 21.0 months in the Rd18 group, and 21.9 months in the MPT group. At 4 years, the PFS rate was 33%, 14%, and 13%, respectively.

The hazard ratio (HR) for continuous Rd vs MPT was 0.69. The HR for continuous Rd vs Rd18 was 0.71. And the HR for Rd18 vs MPT was 0.99.

The median OS was 58.9 months in the continuous Rd group, 56.7 months in the Rd18 group, and 48.5 months in the MPT group. At 4 years, the OS rate was 60%, 57%, and 51%, respectively.

The HR for continuous Rd vs MPT was 0.75. The HR for continuous Rd vs Rd18 was 0.91. And the HR for Rd18 vs MPT was 0.83.

Safety

The most frequent grade 3/4 hematologic treatment-emergent adverse events were neutropenia and anemia. The rate of grade 3/4 neutropenia was higher in the MPT group than the continuous Rd or Rd18 groups.

Infections were the most common grade 3/4 non-hematologic treatment-emergent adverse events. The rate of grade 3/4 infections was higher in the Rd groups than the MPT group.

Grade 3/4 peripheral sensory neuropathy was less frequent in the continuous Rd and Rd18 groups than the MPT group.

The incidence of invasive second primary malignancy was 4% in the continuous Rd group, 6% in the Rd18 group, and 6% in the MPT group.

Bottle of lenalidomide

Photo courtesy of Celgene

Updated trial results support continuous treatment with lenalidomide and low-dose dexamethasone (Rd) as a standard of care for patients of all ages who have newly diagnosed multiple myeloma (MM) and are ineligible for stem cell transplant, according to researchers.

In this phase 3 trial, patients who received continuous Rd (until disease progression) had better progression-free survival (PFS) and overall survival (OS) than patients who received 18 cycles of Rd (Rd18) or a combination of melphalan, prednisone, and thalidomide (MPT).

Updated results from this study, known as the FIRST trial, were published in the Journal of Clinical Oncology.

Results were previously published in NEJM in 2014. The study was supported by Intergroupe Francophone du Myélome and Celgene Corporation, the makers of lenalidomide.

Thierry Facon, MD, of Centre Hospitalier Regional Universitaire de Lille in France, and his colleagues enrolled 1623 patients on this trial. They were newly diagnosed with MM and not eligible for stem cell transplant.

Patients were randomized to receive Rd in 28-day cycles until disease progression (n=535), Rd18 for 72 weeks (n=541), or MPT for 72 weeks (n=547).

Response

In the intent-to-treat population, the overall response rate was 81% for the continuous Rd group, 79% for the Rd18 group, and 67% in the MPT group. The complete response rates were 21%, 20%, and 12%, respectively.

The median duration of response was 32 months (range, 26-37) in the continuous Rd group, 22 months (range, 19-23) in the Rd18 group, and 22 months (range, 20-25) in the MPT group.

PFS and OS

The median PFS was 26.0 months in the continuous Rd group, 21.0 months in the Rd18 group, and 21.9 months in the MPT group. At 4 years, the PFS rate was 33%, 14%, and 13%, respectively.

The hazard ratio (HR) for continuous Rd vs MPT was 0.69. The HR for continuous Rd vs Rd18 was 0.71. And the HR for Rd18 vs MPT was 0.99.

The median OS was 58.9 months in the continuous Rd group, 56.7 months in the Rd18 group, and 48.5 months in the MPT group. At 4 years, the OS rate was 60%, 57%, and 51%, respectively.

The HR for continuous Rd vs MPT was 0.75. The HR for continuous Rd vs Rd18 was 0.91. And the HR for Rd18 vs MPT was 0.83.

Safety

The most frequent grade 3/4 hematologic treatment-emergent adverse events were neutropenia and anemia. The rate of grade 3/4 neutropenia was higher in the MPT group than the continuous Rd or Rd18 groups.

Infections were the most common grade 3/4 non-hematologic treatment-emergent adverse events. The rate of grade 3/4 infections was higher in the Rd groups than the MPT group.

Grade 3/4 peripheral sensory neuropathy was less frequent in the continuous Rd and Rd18 groups than the MPT group.

The incidence of invasive second primary malignancy was 4% in the continuous Rd group, 6% in the Rd18 group, and 6% in the MPT group.

Bottle of lenalidomide

Photo courtesy of Celgene

Updated trial results support continuous treatment with lenalidomide and low-dose dexamethasone (Rd) as a standard of care for patients of all ages who have newly diagnosed multiple myeloma (MM) and are ineligible for stem cell transplant, according to researchers.

In this phase 3 trial, patients who received continuous Rd (until disease progression) had better progression-free survival (PFS) and overall survival (OS) than patients who received 18 cycles of Rd (Rd18) or a combination of melphalan, prednisone, and thalidomide (MPT).

Updated results from this study, known as the FIRST trial, were published in the Journal of Clinical Oncology.

Results were previously published in NEJM in 2014. The study was supported by Intergroupe Francophone du Myélome and Celgene Corporation, the makers of lenalidomide.

Thierry Facon, MD, of Centre Hospitalier Regional Universitaire de Lille in France, and his colleagues enrolled 1623 patients on this trial. They were newly diagnosed with MM and not eligible for stem cell transplant.

Patients were randomized to receive Rd in 28-day cycles until disease progression (n=535), Rd18 for 72 weeks (n=541), or MPT for 72 weeks (n=547).

Response

In the intent-to-treat population, the overall response rate was 81% for the continuous Rd group, 79% for the Rd18 group, and 67% in the MPT group. The complete response rates were 21%, 20%, and 12%, respectively.

The median duration of response was 32 months (range, 26-37) in the continuous Rd group, 22 months (range, 19-23) in the Rd18 group, and 22 months (range, 20-25) in the MPT group.

PFS and OS

The median PFS was 26.0 months in the continuous Rd group, 21.0 months in the Rd18 group, and 21.9 months in the MPT group. At 4 years, the PFS rate was 33%, 14%, and 13%, respectively.

The hazard ratio (HR) for continuous Rd vs MPT was 0.69. The HR for continuous Rd vs Rd18 was 0.71. And the HR for Rd18 vs MPT was 0.99.

The median OS was 58.9 months in the continuous Rd group, 56.7 months in the Rd18 group, and 48.5 months in the MPT group. At 4 years, the OS rate was 60%, 57%, and 51%, respectively.

The HR for continuous Rd vs MPT was 0.75. The HR for continuous Rd vs Rd18 was 0.91. And the HR for Rd18 vs MPT was 0.83.

Safety

The most frequent grade 3/4 hematologic treatment-emergent adverse events were neutropenia and anemia. The rate of grade 3/4 neutropenia was higher in the MPT group than the continuous Rd or Rd18 groups.

Infections were the most common grade 3/4 non-hematologic treatment-emergent adverse events. The rate of grade 3/4 infections was higher in the Rd groups than the MPT group.

Grade 3/4 peripheral sensory neuropathy was less frequent in the continuous Rd and Rd18 groups than the MPT group.

The incidence of invasive second primary malignancy was 4% in the continuous Rd group, 6% in the Rd18 group, and 6% in the MPT group.

Micrograph showing
CMV infection

A vaccine designed to control cytomegalovirus (CMV) has produced favorable results in a phase 1 trial of healthy volunteers.

Investigators said the vaccine, known as Triplex, was well-tolerated at multiple dose levels.

The vaccine also generated “robust” and “durable” virus-specific immunity in subjects who were previously infected with CMV and those who were not.
 
The results of this study were published in Blood.

Triplex is a universal (non-HLA-restricted), recombinant modified vaccinia ankara viral vector vaccine engineered to induce a virus-specific T-cell response to 3 immuno-dominant proteins (UL83 [pp65], UL123 [IE1], and UL122 [IE2]) linked to CMV complications in the post-transplant setting.

Helocyte Inc. is developing the vaccine for control of CMV in recipients of allogeneic hematopoietic stem cell transplant (HSCT) and solid organ transplant.

This study was not funded by Helocyte. However, investigator Don J. Diamond, PhD, of City of Hope Comprehensive Cancer Center in Duarte, California is chair of Helocyte’s scientific advisory board and receives personal service fees from the company.

In this trial, Dr Diamond and his colleagues studied the response to Triplex in 24 healthy volunteers.

Subjects were divided into 3 groups of 8 receiving 3 different doses of the vaccine. The first dose level was 10xE7 plaque-forming units (pfu), the second was 5x10E7 pfu, and the third was 5x10E8 pfu.

The subjects received the vaccine in a volume of 1 mL by intramuscular injection in the upper arm and an identical booster injection 28 days later.

Safety

The investigators said Triplex was well tolerated in most subjects at all dose levels. There were no dose-limiting toxicities and no serious adverse events attributed to the vaccine.

One subject experienced a grade 3 injection site adverse event (erythema), which resolved in 1 day without treatment. In addition, there were 3 mild-to-moderate cutaneous reactions.

The investigators said the most common systemic reaction was mild-to-moderate flu-like symptoms. Most subjects in the highest dose group experienced these symptoms, as did a few subjects from the lower dose groups. All of these events were transient, self-limiting, and resolved.

Immunogenicity

The investigators reported “robust, functional, and durable” expansion of CMV-specific T cells after Triplex vaccination, in subjects with and without prior CMV infection.

At day 42, subjects had experienced a significant increase in pp65-specific T cells from baseline. The P values were 0.0003 for pp65-specific CD137+ CD8+ T cells and 0.001 for CD137+ CD4+ T cells.

Expansion remained above baseline levels until at least day 360 for pp65-specific CD137+ CD8+ T cells and at least until day 482 for pp65-specific CD137+ CD4+ T cells.

IE1-exon4- and IE2-exon5-specific T-cell expansions occurred as well, although the increase from baseline was not significant for IE1-exon4-specific T cells.

The median concentrations of IE2-exon5-specific T cells had increased significantly from baseline at day 42—for both CD137+ CD8+ T cells (P=0.014) and CD137+ CD4+ T cells (P=0.003).

The investigators noted that there was no significant difference in the responses to all 3 CMV libraries according to Triplex dose level, previous smallpox vaccination, or CMV-serostatus.

Next, the team found that Triplex vaccination induced significant expansion of pp65-specific IFN-γ+ CD8+ T cells. They said this suggests the vaccine was able to expand a functional subset of CMV-specific T cells, even in the absence of CMV viremia.

The median concentration of pp65-specific IFN-γ + CD8+ T cells increased significantly from baseline to day 28 (P=0.024), day 56 (P=0.003), day 100 (P=0.011), and day 360 (P=0.085).

There was no significant increase for pp65-specific IFN-γ + CD4+ T cells, IE1-exon4-specific IFN-γ+ T cells, or IE2-exon5-specific IFN-γ + T cells.

The investigators also said the Triplex vaccine induced significant vaccinia-specific T-cell increases by day 42 (P=0.0005), with an estimated decline to pre-vaccination levels at day 274.

These data supported the initiation of an ongoing phase 2 trial in which investigators are evaluating Triplex in patients undergoing allogeneic HSCT (NCT02506933).

“After years of work, it is very gratifying that we are making advancements in helping people worldwide achieve better health outcomes after a transplant procedure,” said Dr Diamond, who led the team that developed Triplex.

“Furthermore, Triplex’s favorable safety and immunogenicity may make the vaccine an ideal therapeutic platform to combat significant complications in many disease areas, like solid organ transplant and glioblastoma.”

Micrograph showing
CMV infection

A vaccine designed to control cytomegalovirus (CMV) has produced favorable results in a phase 1 trial of healthy volunteers.

Investigators said the vaccine, known as Triplex, was well-tolerated at multiple dose levels.

The vaccine also generated “robust” and “durable” virus-specific immunity in subjects who were previously infected with CMV and those who were not.
 
The results of this study were published in Blood.

Triplex is a universal (non-HLA-restricted), recombinant modified vaccinia ankara viral vector vaccine engineered to induce a virus-specific T-cell response to 3 immuno-dominant proteins (UL83 [pp65], UL123 [IE1], and UL122 [IE2]) linked to CMV complications in the post-transplant setting.

Helocyte Inc. is developing the vaccine for control of CMV in recipients of allogeneic hematopoietic stem cell transplant (HSCT) and solid organ transplant.

This study was not funded by Helocyte. However, investigator Don J. Diamond, PhD, of City of Hope Comprehensive Cancer Center in Duarte, California is chair of Helocyte’s scientific advisory board and receives personal service fees from the company.

In this trial, Dr Diamond and his colleagues studied the response to Triplex in 24 healthy volunteers.

Subjects were divided into 3 groups of 8 receiving 3 different doses of the vaccine. The first dose level was 10xE7 plaque-forming units (pfu), the second was 5x10E7 pfu, and the third was 5x10E8 pfu.

The subjects received the vaccine in a volume of 1 mL by intramuscular injection in the upper arm and an identical booster injection 28 days later.

Safety

The investigators said Triplex was well tolerated in most subjects at all dose levels. There were no dose-limiting toxicities and no serious adverse events attributed to the vaccine.

One subject experienced a grade 3 injection site adverse event (erythema), which resolved in 1 day without treatment. In addition, there were 3 mild-to-moderate cutaneous reactions.

The investigators said the most common systemic reaction was mild-to-moderate flu-like symptoms. Most subjects in the highest dose group experienced these symptoms, as did a few subjects from the lower dose groups. All of these events were transient, self-limiting, and resolved.

Immunogenicity

The investigators reported “robust, functional, and durable” expansion of CMV-specific T cells after Triplex vaccination, in subjects with and without prior CMV infection.

At day 42, subjects had experienced a significant increase in pp65-specific T cells from baseline. The P values were 0.0003 for pp65-specific CD137+ CD8+ T cells and 0.001 for CD137+ CD4+ T cells.

Expansion remained above baseline levels until at least day 360 for pp65-specific CD137+ CD8+ T cells and at least until day 482 for pp65-specific CD137+ CD4+ T cells.

IE1-exon4- and IE2-exon5-specific T-cell expansions occurred as well, although the increase from baseline was not significant for IE1-exon4-specific T cells.

The median concentrations of IE2-exon5-specific T cells had increased significantly from baseline at day 42—for both CD137+ CD8+ T cells (P=0.014) and CD137+ CD4+ T cells (P=0.003).

The investigators noted that there was no significant difference in the responses to all 3 CMV libraries according to Triplex dose level, previous smallpox vaccination, or CMV-serostatus.

Next, the team found that Triplex vaccination induced significant expansion of pp65-specific IFN-γ+ CD8+ T cells. They said this suggests the vaccine was able to expand a functional subset of CMV-specific T cells, even in the absence of CMV viremia.

The median concentration of pp65-specific IFN-γ + CD8+ T cells increased significantly from baseline to day 28 (P=0.024), day 56 (P=0.003), day 100 (P=0.011), and day 360 (P=0.085).

There was no significant increase for pp65-specific IFN-γ + CD4+ T cells, IE1-exon4-specific IFN-γ+ T cells, or IE2-exon5-specific IFN-γ + T cells.

The investigators also said the Triplex vaccine induced significant vaccinia-specific T-cell increases by day 42 (P=0.0005), with an estimated decline to pre-vaccination levels at day 274.

These data supported the initiation of an ongoing phase 2 trial in which investigators are evaluating Triplex in patients undergoing allogeneic HSCT (NCT02506933).

“After years of work, it is very gratifying that we are making advancements in helping people worldwide achieve better health outcomes after a transplant procedure,” said Dr Diamond, who led the team that developed Triplex.

“Furthermore, Triplex’s favorable safety and immunogenicity may make the vaccine an ideal therapeutic platform to combat significant complications in many disease areas, like solid organ transplant and glioblastoma.”

Micrograph showing
CMV infection

A vaccine designed to control cytomegalovirus (CMV) has produced favorable results in a phase 1 trial of healthy volunteers.

Investigators said the vaccine, known as Triplex, was well-tolerated at multiple dose levels.

The vaccine also generated “robust” and “durable” virus-specific immunity in subjects who were previously infected with CMV and those who were not.
 
The results of this study were published in Blood.

Triplex is a universal (non-HLA-restricted), recombinant modified vaccinia ankara viral vector vaccine engineered to induce a virus-specific T-cell response to 3 immuno-dominant proteins (UL83 [pp65], UL123 [IE1], and UL122 [IE2]) linked to CMV complications in the post-transplant setting.

Helocyte Inc. is developing the vaccine for control of CMV in recipients of allogeneic hematopoietic stem cell transplant (HSCT) and solid organ transplant.

This study was not funded by Helocyte. However, investigator Don J. Diamond, PhD, of City of Hope Comprehensive Cancer Center in Duarte, California is chair of Helocyte’s scientific advisory board and receives personal service fees from the company.

In this trial, Dr Diamond and his colleagues studied the response to Triplex in 24 healthy volunteers.

Subjects were divided into 3 groups of 8 receiving 3 different doses of the vaccine. The first dose level was 10xE7 plaque-forming units (pfu), the second was 5x10E7 pfu, and the third was 5x10E8 pfu.

The subjects received the vaccine in a volume of 1 mL by intramuscular injection in the upper arm and an identical booster injection 28 days later.

Safety

The investigators said Triplex was well tolerated in most subjects at all dose levels. There were no dose-limiting toxicities and no serious adverse events attributed to the vaccine.

One subject experienced a grade 3 injection site adverse event (erythema), which resolved in 1 day without treatment. In addition, there were 3 mild-to-moderate cutaneous reactions.

The investigators said the most common systemic reaction was mild-to-moderate flu-like symptoms. Most subjects in the highest dose group experienced these symptoms, as did a few subjects from the lower dose groups. All of these events were transient, self-limiting, and resolved.

Immunogenicity

The investigators reported “robust, functional, and durable” expansion of CMV-specific T cells after Triplex vaccination, in subjects with and without prior CMV infection.

At day 42, subjects had experienced a significant increase in pp65-specific T cells from baseline. The P values were 0.0003 for pp65-specific CD137+ CD8+ T cells and 0.001 for CD137+ CD4+ T cells.

Expansion remained above baseline levels until at least day 360 for pp65-specific CD137+ CD8+ T cells and at least until day 482 for pp65-specific CD137+ CD4+ T cells.

IE1-exon4- and IE2-exon5-specific T-cell expansions occurred as well, although the increase from baseline was not significant for IE1-exon4-specific T cells.

The median concentrations of IE2-exon5-specific T cells had increased significantly from baseline at day 42—for both CD137+ CD8+ T cells (P=0.014) and CD137+ CD4+ T cells (P=0.003).

The investigators noted that there was no significant difference in the responses to all 3 CMV libraries according to Triplex dose level, previous smallpox vaccination, or CMV-serostatus.

Next, the team found that Triplex vaccination induced significant expansion of pp65-specific IFN-γ+ CD8+ T cells. They said this suggests the vaccine was able to expand a functional subset of CMV-specific T cells, even in the absence of CMV viremia.

The median concentration of pp65-specific IFN-γ + CD8+ T cells increased significantly from baseline to day 28 (P=0.024), day 56 (P=0.003), day 100 (P=0.011), and day 360 (P=0.085).

There was no significant increase for pp65-specific IFN-γ + CD4+ T cells, IE1-exon4-specific IFN-γ+ T cells, or IE2-exon5-specific IFN-γ + T cells.

The investigators also said the Triplex vaccine induced significant vaccinia-specific T-cell increases by day 42 (P=0.0005), with an estimated decline to pre-vaccination levels at day 274.

These data supported the initiation of an ongoing phase 2 trial in which investigators are evaluating Triplex in patients undergoing allogeneic HSCT (NCT02506933).

“After years of work, it is very gratifying that we are making advancements in helping people worldwide achieve better health outcomes after a transplant procedure,” said Dr Diamond, who led the team that developed Triplex.

“Furthermore, Triplex’s favorable safety and immunogenicity may make the vaccine an ideal therapeutic platform to combat significant complications in many disease areas, like solid organ transplant and glioblastoma.”

CASE Anxious and self-injurious

A, age 6, is forcibly inserting her finger into her nose repeatedly until she bleeds profusely, as many as 20 times per day. She is not nose-picking but is jabbing her finger into her nose as far as possible in a repetitive ramming motion. Less frequently, she inserts her finger into her vagina, resulting in chronic urinary tract infections (UTIs). She has bedtime checking rituals; worries that her parents will die; has a fear of vomiting to the point where she stopped eating normally and lost 5 lb in 6 months; intense fear of storms; refusal to use public bathrooms; and involuntary throat clearing, facial grimacing, and lip twitches.

A’s symptoms began at age 3. There is no history of physical or sexual abuse. She does well in school, but these behaviors have had a significant impact on her social functioning. She is not taking any medications and has been in weekly cognitive-behavioral therapy (CBT) for the last year. A has had several UTIs but otherwise is physically healthy.

Which diagnosis best describes A’s condition?

a) non-suicidal self-injury (NSSI)
b) generalized anxiety disorder (GAD)
c) obsessive-compulsive disorder (OCD)
d) Tourette’s disorder (TD)

The authors’ observations

A is causing herself to bleed and says she wants to stop this behavior. Onset of NSSI typically is age 12 to 14 and could be accompanied by traits of cluster B personality disorders.¹ In A’s case, her age and absence of any stated desire to relieve stress or intense negative affective states rules out NSSI.

Because A has multiple and frequent fears, worries, and anxieties that have been present for years and have caused significant functional impairment, a diagnosis of GAD is warranted. Because she has had both motor and vocal tics for more than 1 year, she also meets diagnostic criteria for TD (Table 1).

Treatment options

A has been receiving CBT for more than 1 year but her symptoms were worsening, which prompted her parents to seek evaluation in our clinic. Because of the level of interference with daily functioning and significant distress, our priority was developing a treatment plan that has the best chance of quickly reducing symptom severity and frequency. The results of the large-scale Pediatric OCD Treatment Study (POTS), which evaluated children age 7 to 17, and the Child/Adolescent Multimodal Anxiety Study, which evaluated children age <12, indicated that the combination of CBT with a selective serotonin reuptake inhibitor (SSRI) reduced OCD symptoms more than either modality alone.^6,7 Considerations for using SSRIs in this age group include:

• the risk of behavioral activation
• poor tolerability
• lack of an evidence base for dosage optimization.

The American Academy of Child and Adolescent Psychiatry’s Preschool Psychopharmacology Working Group’s guidelines for treating anxiety in preschoolers state that pharmacotherapeutic intervention can be considered when symptoms are intolerable and adequate psychotherapy interventions have been tried.⁸ In A’s case, she had been receiving CBT for a year without improvement in symptoms; therefore, initiating medication was indicated, as well as an examination of therapeutic modalities being used.

Treatment Next steps

A is started on liquid fluoxetine, 20 mg/5 mL, 1 mL (4 mg) daily, because of her inability to swallow pills and her young age. According to her mother, a week later A is sleeping better and seems happier. The entire family seems less stressed. During the third week, A successfully goes on a camping trip with her family and is starting to eat better. Her finger-in-nose insertions still are occurring but, according to her mother, she is not putting her finger in her vagina. In session, she is not observed putting her finger in her nose or touching her nose, which she had done frequently during the initial evaluation. Fluoxetine seems to be well tolerated and the dosage is increased to 2 mL (8 mg) per day.

Although A has weekly scheduled appointments, she is not brought in again until a month later. At that time her mother reports an approximately 40% improvement in overall symptoms, including less frequent nose-insertion behaviors.

What type of psychotherapy would you employ for A?

a) CBT
b) behavioral therapy
c) habit reversal training (HRT)
d) pharmacotherapy alone

The authors’ observations

The treatment team planned to begin psychotherapy after A showed a decrease in anxiety and frequency of problem behaviors to a point where she could benefit. Evidence-based treatment for compulsions and tics is CBT and/or HRT.⁹ However, clinicians frequently encounter special challenges in helping young children (age 5 to 8) who have OCD. Factors such as family functioning, parental accommodation to the child’s symptoms, and the child’s ability to understand symptoms, exposure and response prevention, and willingness to tolerate discomfort should be considered if treatment is to be effective.

Research has shown that including parents when treating anxious children—especially young children—can facilitate gains and hasten positive outcomes.^10,11 The POTS Jr study showed the relative efficacy of a family-based CBT model for young children with OCD that emphasizes consistent involvement of parents in all phases of treatment.¹² In this case, A and her mother were seen together for psychotherapy, with an initial focus on learning more about the antecedents and consequences of the child’s behaviors.

OUTCOME Inconsistencies

Treatment was initiated during the summer. With the upcoming start of the school year, A begins to complain of daily headache, stomachache, and anxiety related to the start of school. Fluoxetine is increased to 3 mL/d (12 mg/d). After school starts, her mother stops going to work and begins attending school daily with A to relieve both her and the child’s anxiety.

The following week, the mother pages the psychiatrist, hysterical and crying because she thought the child was “pulling her hair out so much she looks like a cancer survivor.” Both parents blame the increase in fluoxetine for the heightened anxiety. At the next visit, the treatment team does not notice any evidence of unusual hair loss on the child. A has not attended school for several weeks, and her mother has not returned to work. Her parents report that the finger-to-nose behavior has increased, although it is not observed during the session, and fluoxetine is tapered as her parents requested.

At the next session, her mother notes a significant increase in finger-to-nose behavior and requests that the child be put back on fluoxetine, saying, “I would give anything to have the child I had on Prozac back.”

How would you proceed?

a) confront the mother’s inconsistencies
b) restart fluoxetine and continue psychotherapy
c) refer A to another clinic or therapist
d) refer A to inpatient care

The authors’ observations

The treatment team identified several barriers to successful treatment in our clinic. The level of functional interference caused by A’s symptoms indicated sessions more often than once a week, but the parents felt that the distance from our clinic to their home made this too difficult. The mother’s anxiety and obvious distress over her daughter’s symptoms precluded working closely with child. Parental anxiety is correlated with the child’s anxiety and can moderate treatment outcome.¹¹ In response to the suffering of their anxious children, especially young ones, parents often will become anxious and accommodate to the child’s symptoms, which we strongly suspected was happening with A’s mother.

Parents’ concerns about A’s symptoms and response to treatment were addressed during a family meeting. Recognizing that the level of care needed by this family was higher than could be provided in our clinic, we recommended referral to a specialty clinic. A was brought to another clinic, and treatment at our facility was terminated.

CASE Anxious and self-injurious

A, age 6, is forcibly inserting her finger into her nose repeatedly until she bleeds profusely, as many as 20 times per day. She is not nose-picking but is jabbing her finger into her nose as far as possible in a repetitive ramming motion. Less frequently, she inserts her finger into her vagina, resulting in chronic urinary tract infections (UTIs). She has bedtime checking rituals; worries that her parents will die; has a fear of vomiting to the point where she stopped eating normally and lost 5 lb in 6 months; intense fear of storms; refusal to use public bathrooms; and involuntary throat clearing, facial grimacing, and lip twitches.

A’s symptoms began at age 3. There is no history of physical or sexual abuse. She does well in school, but these behaviors have had a significant impact on her social functioning. She is not taking any medications and has been in weekly cognitive-behavioral therapy (CBT) for the last year. A has had several UTIs but otherwise is physically healthy.

Which diagnosis best describes A’s condition?

a) non-suicidal self-injury (NSSI)
b) generalized anxiety disorder (GAD)
c) obsessive-compulsive disorder (OCD)
d) Tourette’s disorder (TD)

The authors’ observations

A is causing herself to bleed and says she wants to stop this behavior. Onset of NSSI typically is age 12 to 14 and could be accompanied by traits of cluster B personality disorders.¹ In A’s case, her age and absence of any stated desire to relieve stress or intense negative affective states rules out NSSI.

Because A has multiple and frequent fears, worries, and anxieties that have been present for years and have caused significant functional impairment, a diagnosis of GAD is warranted. Because she has had both motor and vocal tics for more than 1 year, she also meets diagnostic criteria for TD (Table 1).

Treatment options

A has been receiving CBT for more than 1 year but her symptoms were worsening, which prompted her parents to seek evaluation in our clinic. Because of the level of interference with daily functioning and significant distress, our priority was developing a treatment plan that has the best chance of quickly reducing symptom severity and frequency. The results of the large-scale Pediatric OCD Treatment Study (POTS), which evaluated children age 7 to 17, and the Child/Adolescent Multimodal Anxiety Study, which evaluated children age <12, indicated that the combination of CBT with a selective serotonin reuptake inhibitor (SSRI) reduced OCD symptoms more than either modality alone.^6,7 Considerations for using SSRIs in this age group include:

• the risk of behavioral activation
• poor tolerability
• lack of an evidence base for dosage optimization.

The American Academy of Child and Adolescent Psychiatry’s Preschool Psychopharmacology Working Group’s guidelines for treating anxiety in preschoolers state that pharmacotherapeutic intervention can be considered when symptoms are intolerable and adequate psychotherapy interventions have been tried.⁸ In A’s case, she had been receiving CBT for a year without improvement in symptoms; therefore, initiating medication was indicated, as well as an examination of therapeutic modalities being used.

Treatment Next steps

A is started on liquid fluoxetine, 20 mg/5 mL, 1 mL (4 mg) daily, because of her inability to swallow pills and her young age. According to her mother, a week later A is sleeping better and seems happier. The entire family seems less stressed. During the third week, A successfully goes on a camping trip with her family and is starting to eat better. Her finger-in-nose insertions still are occurring but, according to her mother, she is not putting her finger in her vagina. In session, she is not observed putting her finger in her nose or touching her nose, which she had done frequently during the initial evaluation. Fluoxetine seems to be well tolerated and the dosage is increased to 2 mL (8 mg) per day.

Although A has weekly scheduled appointments, she is not brought in again until a month later. At that time her mother reports an approximately 40% improvement in overall symptoms, including less frequent nose-insertion behaviors.

What type of psychotherapy would you employ for A?

a) CBT
b) behavioral therapy
c) habit reversal training (HRT)
d) pharmacotherapy alone

The authors’ observations

The treatment team planned to begin psychotherapy after A showed a decrease in anxiety and frequency of problem behaviors to a point where she could benefit. Evidence-based treatment for compulsions and tics is CBT and/or HRT.⁹ However, clinicians frequently encounter special challenges in helping young children (age 5 to 8) who have OCD. Factors such as family functioning, parental accommodation to the child’s symptoms, and the child’s ability to understand symptoms, exposure and response prevention, and willingness to tolerate discomfort should be considered if treatment is to be effective.

Research has shown that including parents when treating anxious children—especially young children—can facilitate gains and hasten positive outcomes.^10,11 The POTS Jr study showed the relative efficacy of a family-based CBT model for young children with OCD that emphasizes consistent involvement of parents in all phases of treatment.¹² In this case, A and her mother were seen together for psychotherapy, with an initial focus on learning more about the antecedents and consequences of the child’s behaviors.

OUTCOME Inconsistencies

Treatment was initiated during the summer. With the upcoming start of the school year, A begins to complain of daily headache, stomachache, and anxiety related to the start of school. Fluoxetine is increased to 3 mL/d (12 mg/d). After school starts, her mother stops going to work and begins attending school daily with A to relieve both her and the child’s anxiety.

The following week, the mother pages the psychiatrist, hysterical and crying because she thought the child was “pulling her hair out so much she looks like a cancer survivor.” Both parents blame the increase in fluoxetine for the heightened anxiety. At the next visit, the treatment team does not notice any evidence of unusual hair loss on the child. A has not attended school for several weeks, and her mother has not returned to work. Her parents report that the finger-to-nose behavior has increased, although it is not observed during the session, and fluoxetine is tapered as her parents requested.

At the next session, her mother notes a significant increase in finger-to-nose behavior and requests that the child be put back on fluoxetine, saying, “I would give anything to have the child I had on Prozac back.”

How would you proceed?

a) confront the mother’s inconsistencies
b) restart fluoxetine and continue psychotherapy
c) refer A to another clinic or therapist
d) refer A to inpatient care

The authors’ observations

The treatment team identified several barriers to successful treatment in our clinic. The level of functional interference caused by A’s symptoms indicated sessions more often than once a week, but the parents felt that the distance from our clinic to their home made this too difficult. The mother’s anxiety and obvious distress over her daughter’s symptoms precluded working closely with child. Parental anxiety is correlated with the child’s anxiety and can moderate treatment outcome.¹¹ In response to the suffering of their anxious children, especially young ones, parents often will become anxious and accommodate to the child’s symptoms, which we strongly suspected was happening with A’s mother.

Parents’ concerns about A’s symptoms and response to treatment were addressed during a family meeting. Recognizing that the level of care needed by this family was higher than could be provided in our clinic, we recommended referral to a specialty clinic. A was brought to another clinic, and treatment at our facility was terminated.

CASE Anxious and self-injurious

A, age 6, is forcibly inserting her finger into her nose repeatedly until she bleeds profusely, as many as 20 times per day. She is not nose-picking but is jabbing her finger into her nose as far as possible in a repetitive ramming motion. Less frequently, she inserts her finger into her vagina, resulting in chronic urinary tract infections (UTIs). She has bedtime checking rituals; worries that her parents will die; has a fear of vomiting to the point where she stopped eating normally and lost 5 lb in 6 months; intense fear of storms; refusal to use public bathrooms; and involuntary throat clearing, facial grimacing, and lip twitches.

A’s symptoms began at age 3. There is no history of physical or sexual abuse. She does well in school, but these behaviors have had a significant impact on her social functioning. She is not taking any medications and has been in weekly cognitive-behavioral therapy (CBT) for the last year. A has had several UTIs but otherwise is physically healthy.

Which diagnosis best describes A’s condition?

a) non-suicidal self-injury (NSSI)
b) generalized anxiety disorder (GAD)
c) obsessive-compulsive disorder (OCD)
d) Tourette’s disorder (TD)

The authors’ observations

A is causing herself to bleed and says she wants to stop this behavior. Onset of NSSI typically is age 12 to 14 and could be accompanied by traits of cluster B personality disorders.¹ In A’s case, her age and absence of any stated desire to relieve stress or intense negative affective states rules out NSSI.

Because A has multiple and frequent fears, worries, and anxieties that have been present for years and have caused significant functional impairment, a diagnosis of GAD is warranted. Because she has had both motor and vocal tics for more than 1 year, she also meets diagnostic criteria for TD (Table 1).

Treatment options

A has been receiving CBT for more than 1 year but her symptoms were worsening, which prompted her parents to seek evaluation in our clinic. Because of the level of interference with daily functioning and significant distress, our priority was developing a treatment plan that has the best chance of quickly reducing symptom severity and frequency. The results of the large-scale Pediatric OCD Treatment Study (POTS), which evaluated children age 7 to 17, and the Child/Adolescent Multimodal Anxiety Study, which evaluated children age <12, indicated that the combination of CBT with a selective serotonin reuptake inhibitor (SSRI) reduced OCD symptoms more than either modality alone.^6,7 Considerations for using SSRIs in this age group include:

• the risk of behavioral activation
• poor tolerability
• lack of an evidence base for dosage optimization.

The American Academy of Child and Adolescent Psychiatry’s Preschool Psychopharmacology Working Group’s guidelines for treating anxiety in preschoolers state that pharmacotherapeutic intervention can be considered when symptoms are intolerable and adequate psychotherapy interventions have been tried.⁸ In A’s case, she had been receiving CBT for a year without improvement in symptoms; therefore, initiating medication was indicated, as well as an examination of therapeutic modalities being used.

Treatment Next steps

A is started on liquid fluoxetine, 20 mg/5 mL, 1 mL (4 mg) daily, because of her inability to swallow pills and her young age. According to her mother, a week later A is sleeping better and seems happier. The entire family seems less stressed. During the third week, A successfully goes on a camping trip with her family and is starting to eat better. Her finger-in-nose insertions still are occurring but, according to her mother, she is not putting her finger in her vagina. In session, she is not observed putting her finger in her nose or touching her nose, which she had done frequently during the initial evaluation. Fluoxetine seems to be well tolerated and the dosage is increased to 2 mL (8 mg) per day.

Although A has weekly scheduled appointments, she is not brought in again until a month later. At that time her mother reports an approximately 40% improvement in overall symptoms, including less frequent nose-insertion behaviors.

What type of psychotherapy would you employ for A?

a) CBT
b) behavioral therapy
c) habit reversal training (HRT)
d) pharmacotherapy alone

The authors’ observations

The treatment team planned to begin psychotherapy after A showed a decrease in anxiety and frequency of problem behaviors to a point where she could benefit. Evidence-based treatment for compulsions and tics is CBT and/or HRT.⁹ However, clinicians frequently encounter special challenges in helping young children (age 5 to 8) who have OCD. Factors such as family functioning, parental accommodation to the child’s symptoms, and the child’s ability to understand symptoms, exposure and response prevention, and willingness to tolerate discomfort should be considered if treatment is to be effective.

Research has shown that including parents when treating anxious children—especially young children—can facilitate gains and hasten positive outcomes.^10,11 The POTS Jr study showed the relative efficacy of a family-based CBT model for young children with OCD that emphasizes consistent involvement of parents in all phases of treatment.¹² In this case, A and her mother were seen together for psychotherapy, with an initial focus on learning more about the antecedents and consequences of the child’s behaviors.

OUTCOME Inconsistencies

Treatment was initiated during the summer. With the upcoming start of the school year, A begins to complain of daily headache, stomachache, and anxiety related to the start of school. Fluoxetine is increased to 3 mL/d (12 mg/d). After school starts, her mother stops going to work and begins attending school daily with A to relieve both her and the child’s anxiety.

The following week, the mother pages the psychiatrist, hysterical and crying because she thought the child was “pulling her hair out so much she looks like a cancer survivor.” Both parents blame the increase in fluoxetine for the heightened anxiety. At the next visit, the treatment team does not notice any evidence of unusual hair loss on the child. A has not attended school for several weeks, and her mother has not returned to work. Her parents report that the finger-to-nose behavior has increased, although it is not observed during the session, and fluoxetine is tapered as her parents requested.

At the next session, her mother notes a significant increase in finger-to-nose behavior and requests that the child be put back on fluoxetine, saying, “I would give anything to have the child I had on Prozac back.”

How would you proceed?

a) confront the mother’s inconsistencies
b) restart fluoxetine and continue psychotherapy
c) refer A to another clinic or therapist
d) refer A to inpatient care

The authors’ observations

The treatment team identified several barriers to successful treatment in our clinic. The level of functional interference caused by A’s symptoms indicated sessions more often than once a week, but the parents felt that the distance from our clinic to their home made this too difficult. The mother’s anxiety and obvious distress over her daughter’s symptoms precluded working closely with child. Parental anxiety is correlated with the child’s anxiety and can moderate treatment outcome.¹¹ In response to the suffering of their anxious children, especially young ones, parents often will become anxious and accommodate to the child’s symptoms, which we strongly suspected was happening with A’s mother.

Parents’ concerns about A’s symptoms and response to treatment were addressed during a family meeting. Recognizing that the level of care needed by this family was higher than could be provided in our clinic, we recommended referral to a specialty clinic. A was brought to another clinic, and treatment at our facility was terminated.

Healthy first-degree relatives of children and adolescents with inflammatory bowel disease had intestinal dysbiosis and an altered intestinal metabolome that correlated with one another and with the disease state, researchers reported in the November issue of Cellular and Molecular Gastroenterology and Hepatology.

These findings suggest the existence of a “high-risk microbiome/metabolome” that may increase susceptibility to inflammatory bowel disease (IBD), Jonathan Jacobs, MD, of the University of California, Los Angeles, reported with his associates. Among the healthy relatives with dysbiosis, nearly one-third also had elevated levels of fecal calprotectin, a marker of intestinal inflammation that has been previously reported in family members of patients with ulcerative colitis, the researchers noted. “If validated, prospective identification of [high-risk individuals] creates the opportunity to prevent disease development by targeting the dysbiosis and/or its metabolic consequences in the intestine,” they wrote.

selvanegra/thinkstockphotos.com

Healthy first-degree relatives of children and adolescents with inflammatory bowel disease had intestinal dysbiosis and an altered intestinal metabolome that correlated with one another and with the disease state, researchers reported in the November issue of Cellular and Molecular Gastroenterology and Hepatology.

These findings suggest the existence of a “high-risk microbiome/metabolome” that may increase susceptibility to inflammatory bowel disease (IBD), Jonathan Jacobs, MD, of the University of California, Los Angeles, reported with his associates. Among the healthy relatives with dysbiosis, nearly one-third also had elevated levels of fecal calprotectin, a marker of intestinal inflammation that has been previously reported in family members of patients with ulcerative colitis, the researchers noted. “If validated, prospective identification of [high-risk individuals] creates the opportunity to prevent disease development by targeting the dysbiosis and/or its metabolic consequences in the intestine,” they wrote.

selvanegra/thinkstockphotos.com

Healthy first-degree relatives of children and adolescents with inflammatory bowel disease had intestinal dysbiosis and an altered intestinal metabolome that correlated with one another and with the disease state, researchers reported in the November issue of Cellular and Molecular Gastroenterology and Hepatology.

These findings suggest the existence of a “high-risk microbiome/metabolome” that may increase susceptibility to inflammatory bowel disease (IBD), Jonathan Jacobs, MD, of the University of California, Los Angeles, reported with his associates. Among the healthy relatives with dysbiosis, nearly one-third also had elevated levels of fecal calprotectin, a marker of intestinal inflammation that has been previously reported in family members of patients with ulcerative colitis, the researchers noted. “If validated, prospective identification of [high-risk individuals] creates the opportunity to prevent disease development by targeting the dysbiosis and/or its metabolic consequences in the intestine,” they wrote.

selvanegra/thinkstockphotos.com

Interferon-free direct-acting antiviral (DAA) regimens for chronic hepatitis C virus (HCV) infection can cause reactivation of herpesvirus, said the authors of a multicenter case series published in the November issue of Clinical Gastroenterology and Hepatology.

Reactivation occurred in 10 of 576 (2%) patients treated at three hospitals in Spain, reported Dr. Christie Perello of Puerta de Hierro University Hospital in Madrid, together with her associates. Clinicians who treat HCV should maintain a high degree of clinical suspicion for latent herpesvirus infection, particularly when patients are older or have undergone liver transplantation, and should consider varicella zoster virus vaccination before beginning DAA therapy in nontransplant patients, they said.

Yale Rosen/Wikimedia Commons/Creative Commons Attribution-Share Alike 2.0 Generic

[email protected]

Interferon-free direct-acting antiviral (DAA) regimens for chronic hepatitis C virus (HCV) infection can cause reactivation of herpesvirus, said the authors of a multicenter case series published in the November issue of Clinical Gastroenterology and Hepatology.

Reactivation occurred in 10 of 576 (2%) patients treated at three hospitals in Spain, reported Dr. Christie Perello of Puerta de Hierro University Hospital in Madrid, together with her associates. Clinicians who treat HCV should maintain a high degree of clinical suspicion for latent herpesvirus infection, particularly when patients are older or have undergone liver transplantation, and should consider varicella zoster virus vaccination before beginning DAA therapy in nontransplant patients, they said.

Yale Rosen/Wikimedia Commons/Creative Commons Attribution-Share Alike 2.0 Generic

[email protected]

Interferon-free direct-acting antiviral (DAA) regimens for chronic hepatitis C virus (HCV) infection can cause reactivation of herpesvirus, said the authors of a multicenter case series published in the November issue of Clinical Gastroenterology and Hepatology.

Reactivation occurred in 10 of 576 (2%) patients treated at three hospitals in Spain, reported Dr. Christie Perello of Puerta de Hierro University Hospital in Madrid, together with her associates. Clinicians who treat HCV should maintain a high degree of clinical suspicion for latent herpesvirus infection, particularly when patients are older or have undergone liver transplantation, and should consider varicella zoster virus vaccination before beginning DAA therapy in nontransplant patients, they said.

Yale Rosen/Wikimedia Commons/Creative Commons Attribution-Share Alike 2.0 Generic

[email protected]

Long-term care (LTC) services provide health care to >8 million people in approximately 30,000 nursing homes and assisted living/residential care communities in the United States.¹ One-half of older adults in LTC have neurocognitive disorders (NCDs), and one-third have depressive syndromes.² Common reasons for psychiatric consultation include these 2 major diagnoses, as well as delirium, behavioral and psychological symptoms of dementia (BPSD), bipolar disorder, anxiety, sleep disorders, and pain management.

Psychiatric assessment of individuals in LTC can be challenging because of atypical presentations, cognitive impairment, and multiple comorbidities. Establishing a management plan involves eliciting a careful history from both the patient and caretakers, examining previous records and medications, and selecting appropriate screening tools and laboratory tests (Table 1 and Table 2).

• assessment tools for psychiatric symptoms in LTC
• potentially inappropriate medication use in older adults
• antipsychotic use for agitation and psychosis with dementia
• nonpharmacologic interventions to help prevent cognitive decline
• antipsychotic review in reducing antipsychotic use and mortality.

Delirium

Delirium is an important topic in LTC because it is highly prevalent, poorly recognized, and can be difficult to manage. Common causes of delirium in LTC include infection (often urinary), dehydration, medications, long-standing constipation, and urinary retention (Table 3).³ Early recognition is key because delirium has been associated with cognitive decline, decreased functional status, increased caregiver burden, and increased mortality.^4,5

The Confusion Assessment Method (CAM) is a quick tool with 4 features to differentiate delirium from other forms of cognitive impairment.⁶ The 2 core features are an acute change or fluctuating course of mental status and inattention. Family members or caregivers can provide information about an acute change. To assess inattention, ask the patient to say the days of the week backward or spell the word “world” backward. The 2 other features of delirium—one of which must be present when using the CAM—are disorganized thinking and altered level of consciousness.

Individuals with delirium may present with hyperactive or hypoactive psychomotor activity. Hypoactive delirium’s features, such as sluggishness and lethargy, could be confused with depression.⁷ A careful history to determine symptom onset and fluctuation in course can help differentiate between the 2.

Management. Delirium management always should begin by addressing underlying causes and implementing psychosocial and environmental interventions. Pharmacologic interventions have not demonstrated consistent benefit for delirium in well-designed trials and are not recommended as first-line treatment.⁸ The American Geriatrics Society (AGS) Beers Criteria for Potentially Inappropriate Medication Use in Older Adults recommends avoiding benzodiazepines in this population.⁹ Antipsychotics could be used in patients with severe agitation who pose harm to themselves or others. Nonpharmacologic approaches to delirium in LTC include:

• frequent reorientation (clocks, daily schedule)
• one-on-one monitoring by staff or family members
• use of hearing aids and eye-glasses, if needed
• maintaining an appropriate sleep-wake cycle by encouraging exposure to bright light during the day and avoiding night-time interruptions.

Restraints should not be used; they appear to worsen delirium severity, and their removal does not increase the rate of falls or fall-related injury.¹⁰

Various methods for managing a patient with delirium have been proposed, such as the TADA approach (tolerate, anticipate, and don’t agitate).^5,11,12 For example, if a patient’s agitation worsens with attempted reorientation, distraction or playing along with the disorientation could be more beneficial.¹²

Keep in mind delirium’s overlapping presentation with Lewy body dementia (LBD). Patients with LBD demonstrate a progressive decline in cognitive functioning associated with fluctuating cognition, visual hallucinations, and parkinsonism features. Consider LBD when no cause for delirium-like symptoms is found. These patients may show increased sensitivity to neuroleptics and extrapyramidal side effects.

Neurocognitive disorders

Reversible causes. Although most individuals with major NCDs are diagnosed before entering LTC, the consulting psychiatrist’s review of potentially reversible causes of neurocognitive symptoms can lead to dramatically different treatment regimens (Table 4³). For example, anticholinergic medications can harm the aging brain and have been linked to delirium, increased brain atrophy, and lower scores on tests of cognitive functioning.¹³ Given the prevalence of polypharmacy in older adults, be aware of unexpected anticholinergic properties of many common drugs, as rated by the Aging Brain Care initiative.¹⁴

The randomized, double-blind Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability provides convincing data that a nonpharmacologic approach could benefit older adults at risk for a major NCD. A 2-year intervention of nutritional advice, aerobic and strength training, cognitive training, social activities, and blood pressure and weight monitoring was more effective in improving or maintaining cognitive function in individuals age 60 to 77, compared with general health advice given to a control group.¹⁵

Behavioral and psychological symptoms. Psychiatrists are likely to be consulted in LTC when a person with a major NCD presents with an acute episode of increased confusion and cognitive worsening, often accompanied by behavioral symptoms. BPSD may include agitation, aggression, apathy, depression, sleep problems, socially inappropriate behaviors, and psychosis. One study of patients with Alzheimer’s disease (AD) reported a cumulative 51% incidence of new-onset hallucinations and delusions at 4 years.¹⁶

Increased vulnerability to stressors, unmet needs, over- or under-stimulation, or lack of routines may predispose individuals with major NCDs to developing BPSD.¹⁷ Nonpharmacologic approaches usually are tried first, although supporting evidence is not substantial.¹⁸ Changes in environment, behavioral redirection, sensory interventions, or music therapy may reduce disruptive behaviors.¹⁹ Patients with increased confusion and agitation in late afternoon and evening (“sundowning”) may benefit from short naps after lunch, light therapy, calming activities in late afternoon, and reduced noise (such as from dishes, loud speakers, staff conversations).²⁰

Antipsychotics. The drugs most commonly used to manage BPSD are antipsychotics, antidepressants, mood stabilizers/anticonvulsants, ChEIs, and the N-methyl-d-aspartate receptor antagonist memantine. Antipsychotics often are used despite their uncertain efficacy²¹ and serious safety concerns. Atypical antipsychotics are generally preferred for their side effect profiles, but both atypical and typical classes carry a “black-box” warning of increased risk of mortality in older patients with major NCDs. Other potential adverse events include anticholinergic effects, orthostatic hypotension, prolonged QT interval, and extrapyramidal symptoms (EPS).

When nonpharmacotherapeutic interventions are not successful, most guidelines agree that using an atypical antipsychotic is warranted in AD patients with severe agitation and/or psychosis that pose a risk to the patient or others or severely impair their quality of life.^9,22,23

Antipsychotic review. Recent guidelines from the American Psychiatric Association (APA) recommend that attempts to taper and withdraw antipsychotic drugs be made within 4 months of initiating treatment in patients with dementia who display an adequate response.²³ In a recent nursing home study, antipsychotic review was found to reduce antipsychotic use by 50% and, when combined with a social intervention, to reduce mortality compared with a group receiving neither intervention.²⁴

Interestingly, patients receiving antipsychotic review alone showed an increase in overall neuropsychiatric symptoms.²⁴ A previous study of patients with AD whose psychosis or agitation responded to risperidone also found an increased risk of relapse when risperidone was discontinued.²⁵ These results highlight the importance of making patient-centered decisions, frequent re-assessments, and adding non-pharmacologic interventions (eg, positive social interactions or exercise) when attempting to discontinue antipsychotics.

Other treatment options. Because patients with LBD often display increased sensitivity to neuroleptics, agents such as quetiapine or aripiprazole (with a lower risk of EPS) are preferred when managing severe psychosis/aggression. ChEIs may show some benefit for behavioral disturbances in patients with LBD.²⁶

In patients with AD, ChEIs have shown inconsistent results in benefiting neuropsychiatric symptoms. Preliminary data suggest some benefit with citalopram (also associated with prolonged QTc)²⁷ and the dextromethorphan/quinidine combination FDA-approved for pseudobulbar affect, but more studies are needed.²⁸ Pimavanserin, a 5-HT2A receptor inverse agonist, recently was approved for treating hallucinations and delusions associated with Parkinson’s disease psychosis and currently is in clinical trials for Alzheimer’s disease psychosis.

Electroconvulsive therapy (ECT) may be a therapeutic option for agitation and aggression in people with dementia.²⁹ ECT has no absolute contraindications and can be safely performed in individuals with pacemakers or implantable cardioverter defibrillators. Common adverse effects include transient changes in blood pressure or heart rate, headache, and nausea. Cognitive adverse effects from ECT may include:

• anterograde amnesia, which typically resolves after a few weeks
• retrograde amnesia, which typically manifests as loss of impersonal memories occurring in the past few months.

Depression

The prevalence of depression in nursing home residents is an estimated 3 to 4 times that of community-dwelling older adults.³⁰ Assessing for depression is particularly important in people with mild cognitive impairment, as depressive symptoms have been associated with progression to AD.³¹ Quick screening tools (Table 2) include short forms of the Patient Health Questionnaire (PHQ-2 or PHQ-9)³² or the Saint Louis University Appetite, Mood, Sleep, Activity, and thoughts of Death (SLU “AM SAD”) scale.³³ The Cornell Scale for Depression in Dementia is useful for individuals with major NCDs because it relies on interviews with the patient and nursing staff or family.³⁴

To test for other causes of depression, order a complete blood count for anemia, serum glucose, thyroid-stimulating hormone for hypothyroidism or hyperthyroidism, B12 and folate levels, and a cognitive screen such as the Saint Louis University Mental Status examination.³⁵

Treatment. Antidepressants are generally considered effective in older patients with depression. Selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line treatments because of safety concerns with tricyclic antidepressants. All 3 classes have shown similar efficacy in comparison trials in geriatric populations.

When initiating these agents, take care in the first few days and weeks to monitor for potential serious adverse effects, such as nausea and vomiting, which may be associated with substantial morbidity in patients with comorbidities. For monitoring treatment response, the PHQ-9 can effectively distinguish patients with persistent major depression, partial remission, or full remission.³⁶

The optimal duration of a short-term antidepressant trial before switching to a different agent is unclear, although a good therapeutic trial typically is 4 to 12 weeks. In one study of older adults with depression, 4 weeks was enough to reliably identify those likely to benefit from a change in treatment plan.³⁷

Cognitive-behavioral therapy (CBT) can be used in older adults not wishing to pursue pharmacotherapy or as an adjunct to antidepressants. Randomized controlled trials have shown some benefit for those with depression, anxiety, and insomnia.³⁸ Individuals with significant cognitive deficits or those not motivated to apply CBT strategies might not benefit.

ECT may be appropriate for treating depression in older adults with:

• urgent need of a therapeutic response (eg, suicidal ideation or nutritional compromise)
• lack of response to antidepressant medication
• major depressive disorder with psychotic or catatonic features.

Evidence regarding ECT’s efficacy for late-life depression is derived primarily from clinical experience and open-label trials.³⁹

Bipolar disorder

Most individuals with bipolar disorder present before age 50, although 9% of first manic episodes occur after age 60.⁴⁰ Earlier age of onset appears to predict poor outcomes, and early-onset bipolar disorder may worsen with advanced age related to increased comorbidities and difficulty in medical management.⁴¹ Compared with younger patients, features of bipolar disorder in older adults include increased prominence of rapid cycling, more time spent in a depressed state than in manic state, and less severe manic and psychotic symptoms.⁴²

When older patients present with depression, always evaluate for clinical features more consistent with late-onset bipolar disorder than with major depressive disorder: hypomania, family history of bipolar disorder, higher number of prior depressive episodes, and higher levels of fear and inner tension.⁴³ The differential diagnosis for new-onset manic symptoms in older adults includes:

• general medical conditions (stroke, brain tumors, hyperthyroidism, neurosyphilis)
• medications (corticosteroids, dopaminergic drugs, St. John’s wort)
• substance use.

Hyperthyroidism deserves special attention because it can present in older adults with either manic-like symptoms and hyperkinesis or features of apathy, depression, and somnolence. Given that older age and bipolar disorder both are associated with increased suicide risk, monitor these individuals for signs of hopelessness and statements of suicide.⁴⁴

Treatment. Managing bipolar disorder in older adults often requires complex medication regimens. Acute treatment options for geriatric mania and hypomania with the most supporting evidence include lithium, valproate, quetiapine, and olanzapine.^45-47 The therapeutic index of lithium is small, and older individuals are more vulnerable to adverse effects related to physiologic changes (eg, decreased glomerular filtration rate or low volume of distribution) that impair lithium clearance. Lithium also interacts with many drugs commonly used by older patients, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and diuretics. Common adverse events associated with lithium include memory impairment, diarrhea, falls, and tremors.

Maintenance treatment for bipolar disorder is generally the same medication used to induce remission. The evidence for maintenance treatment of bipolar disorder in older adults is limited mostly to subgroup analyses. In one retrospective analysis of patients age ≥55 in 2 randomized trials, lamotrigine and lithium were effective and well-tolerated in delaying time to intervention.⁴⁸

Anxiety disorders

Anxiety among LTC residents may manifest as irritability, insomnia, restlessness, and verbal and/or physical agitation/aggression.⁴⁹ Typical causes include:

• primary anxiety disorders
• anxiety symptoms during depressive episodes or bereavement
• adverse effects of medications
• complications of major NCDs or delirium.

Anxiety disorders and subsyndromal anxiety have been associated with poorer quality of life, decreased sleep, and increased distress and impairment.⁵⁰

Assessment begins with a self-report of symptoms, although this may be difficult in people with major NCDs. Factors that may differentiate true anxiety from major NCDs include restlessness, irritability, muscle tension, fears, and respiratory symptoms in addition to excessive anxiety and worry.⁵¹ The Geriatric Anxiety Inventory is a useful screening tool.⁵² The newer Brief Anxiety and Depression Scale may identify and differentiate patients with major depressive episodes and generalized anxiety disorder (GAD).⁵³ Potential instruments for patients with comorbid anxiety and major NCDs include the Neuropsychiatric Inventory, Rating Anxiety in Dementia scale,⁵⁴ and the Anxiety in Cognitive Impairment and Dementia scale.⁵⁵ Because medications can cause akathisia that may mimic anxiety symptoms, screen for the recent addition of antidepressants, antipsychotics, sympathomimetics, thyroid supplements, and corticosteroids.

Treatment of anxiety disorders—such as panic disorder, social phobia, or GAD—generally starts with SSRIs or SNRIs. Although benzodiazepines are commonly used for anxiety in older adults,⁵⁶ these drugs are associated with a high rate of adverse effects: increased risk of agitation, falls, impaired cognition, and possibly dementia.⁵⁷ In general, reserve benzodiazepines for treating acute episodes of severe anxiety in this population.

A particularly prevalent source of anxiety in LTC is fear of falling, which may affect up to 50% of residents and cause them to restrict their activities.⁵⁸ Interventions such as CBT, exercise, or tai chi may be beneficial, although supporting evidence is lacking.

Pain and sleep management

Addressing pain. Age-related changes in pain perception and difficulty in reporting pain likely contribute to under-recognition of pain in LTC residents. Two useful methods to recognize their pain are to:

• observe for pain behaviors, such as facial expressions (grimacing and brow lowering), vocalizations, and body movements (clenched fists)
• solicit reports from nurses and other caregivers.⁵⁹

Self-report may be a reliable indicator of pain for individuals with mild-to-moderate NCDs. Observational pain scales, such as the Pain Assessment Checklist for Seniors with Limited Ability to Communicate, may be useful in severe NCDs.⁶⁰

The AGS recommends acetaminophen as initial pharmacotherapy to manage persistent pain.⁶¹ NSAIDs may be another option, but caution is warranted for patients with acid-peptic disease or chronic kidney disease. Opioids may be considered for severe pain, but otherwise avoid using them.

Sleep disturbances are common in LTC because of physiologic changes associated with aging (altered circadian rhythm), comorbidities (depression), and environmental factors.⁶² A strong association appears to exist between insomnia and use of sedative-hypnotic drugs, and the AGS Beers Criteria recommend avoiding non-benzodiazepine receptor agonists and benzodiazepines when treating insomnia in older adults.⁹

Assess factors that may contribute to sleep disturbances, including medications and use of caffeine or alcohol. Have the resident or caregiver document sleep patterns in a sleep diary.

Consider administrating medications at different times (eg, switch donepezil from bedtime to morning) or replace with alternatives (switch from the more anticholinergic amitriptyline to nortriptyline). Ensure that residents engage in physical activity and have at least 30 minutes daily exposure to sunlight.

In addition to behavioral interventions and CBT, treatment in older adults can involve melatonin—which has mixed evidence—or sedating antidepressants, such as mirtazapine or trazodone, in patients with comorbid depression.

Long-term care (LTC) services provide health care to >8 million people in approximately 30,000 nursing homes and assisted living/residential care communities in the United States.¹ One-half of older adults in LTC have neurocognitive disorders (NCDs), and one-third have depressive syndromes.² Common reasons for psychiatric consultation include these 2 major diagnoses, as well as delirium, behavioral and psychological symptoms of dementia (BPSD), bipolar disorder, anxiety, sleep disorders, and pain management.

Psychiatric assessment of individuals in LTC can be challenging because of atypical presentations, cognitive impairment, and multiple comorbidities. Establishing a management plan involves eliciting a careful history from both the patient and caretakers, examining previous records and medications, and selecting appropriate screening tools and laboratory tests (Table 1 and Table 2).

• assessment tools for psychiatric symptoms in LTC
• potentially inappropriate medication use in older adults
• antipsychotic use for agitation and psychosis with dementia
• nonpharmacologic interventions to help prevent cognitive decline
• antipsychotic review in reducing antipsychotic use and mortality.

Delirium

Delirium is an important topic in LTC because it is highly prevalent, poorly recognized, and can be difficult to manage. Common causes of delirium in LTC include infection (often urinary), dehydration, medications, long-standing constipation, and urinary retention (Table 3).³ Early recognition is key because delirium has been associated with cognitive decline, decreased functional status, increased caregiver burden, and increased mortality.^4,5

The Confusion Assessment Method (CAM) is a quick tool with 4 features to differentiate delirium from other forms of cognitive impairment.⁶ The 2 core features are an acute change or fluctuating course of mental status and inattention. Family members or caregivers can provide information about an acute change. To assess inattention, ask the patient to say the days of the week backward or spell the word “world” backward. The 2 other features of delirium—one of which must be present when using the CAM—are disorganized thinking and altered level of consciousness.

Individuals with delirium may present with hyperactive or hypoactive psychomotor activity. Hypoactive delirium’s features, such as sluggishness and lethargy, could be confused with depression.⁷ A careful history to determine symptom onset and fluctuation in course can help differentiate between the 2.

Management. Delirium management always should begin by addressing underlying causes and implementing psychosocial and environmental interventions. Pharmacologic interventions have not demonstrated consistent benefit for delirium in well-designed trials and are not recommended as first-line treatment.⁸ The American Geriatrics Society (AGS) Beers Criteria for Potentially Inappropriate Medication Use in Older Adults recommends avoiding benzodiazepines in this population.⁹ Antipsychotics could be used in patients with severe agitation who pose harm to themselves or others. Nonpharmacologic approaches to delirium in LTC include:

• frequent reorientation (clocks, daily schedule)
• one-on-one monitoring by staff or family members
• use of hearing aids and eye-glasses, if needed
• maintaining an appropriate sleep-wake cycle by encouraging exposure to bright light during the day and avoiding night-time interruptions.

Restraints should not be used; they appear to worsen delirium severity, and their removal does not increase the rate of falls or fall-related injury.¹⁰

Various methods for managing a patient with delirium have been proposed, such as the TADA approach (tolerate, anticipate, and don’t agitate).^5,11,12 For example, if a patient’s agitation worsens with attempted reorientation, distraction or playing along with the disorientation could be more beneficial.¹²

Keep in mind delirium’s overlapping presentation with Lewy body dementia (LBD). Patients with LBD demonstrate a progressive decline in cognitive functioning associated with fluctuating cognition, visual hallucinations, and parkinsonism features. Consider LBD when no cause for delirium-like symptoms is found. These patients may show increased sensitivity to neuroleptics and extrapyramidal side effects.

Neurocognitive disorders

Reversible causes. Although most individuals with major NCDs are diagnosed before entering LTC, the consulting psychiatrist’s review of potentially reversible causes of neurocognitive symptoms can lead to dramatically different treatment regimens (Table 4³). For example, anticholinergic medications can harm the aging brain and have been linked to delirium, increased brain atrophy, and lower scores on tests of cognitive functioning.¹³ Given the prevalence of polypharmacy in older adults, be aware of unexpected anticholinergic properties of many common drugs, as rated by the Aging Brain Care initiative.¹⁴

The randomized, double-blind Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability provides convincing data that a nonpharmacologic approach could benefit older adults at risk for a major NCD. A 2-year intervention of nutritional advice, aerobic and strength training, cognitive training, social activities, and blood pressure and weight monitoring was more effective in improving or maintaining cognitive function in individuals age 60 to 77, compared with general health advice given to a control group.¹⁵

Behavioral and psychological symptoms. Psychiatrists are likely to be consulted in LTC when a person with a major NCD presents with an acute episode of increased confusion and cognitive worsening, often accompanied by behavioral symptoms. BPSD may include agitation, aggression, apathy, depression, sleep problems, socially inappropriate behaviors, and psychosis. One study of patients with Alzheimer’s disease (AD) reported a cumulative 51% incidence of new-onset hallucinations and delusions at 4 years.¹⁶

Increased vulnerability to stressors, unmet needs, over- or under-stimulation, or lack of routines may predispose individuals with major NCDs to developing BPSD.¹⁷ Nonpharmacologic approaches usually are tried first, although supporting evidence is not substantial.¹⁸ Changes in environment, behavioral redirection, sensory interventions, or music therapy may reduce disruptive behaviors.¹⁹ Patients with increased confusion and agitation in late afternoon and evening (“sundowning”) may benefit from short naps after lunch, light therapy, calming activities in late afternoon, and reduced noise (such as from dishes, loud speakers, staff conversations).²⁰

Antipsychotics. The drugs most commonly used to manage BPSD are antipsychotics, antidepressants, mood stabilizers/anticonvulsants, ChEIs, and the N-methyl-d-aspartate receptor antagonist memantine. Antipsychotics often are used despite their uncertain efficacy²¹ and serious safety concerns. Atypical antipsychotics are generally preferred for their side effect profiles, but both atypical and typical classes carry a “black-box” warning of increased risk of mortality in older patients with major NCDs. Other potential adverse events include anticholinergic effects, orthostatic hypotension, prolonged QT interval, and extrapyramidal symptoms (EPS).

When nonpharmacotherapeutic interventions are not successful, most guidelines agree that using an atypical antipsychotic is warranted in AD patients with severe agitation and/or psychosis that pose a risk to the patient or others or severely impair their quality of life.^9,22,23

Antipsychotic review. Recent guidelines from the American Psychiatric Association (APA) recommend that attempts to taper and withdraw antipsychotic drugs be made within 4 months of initiating treatment in patients with dementia who display an adequate response.²³ In a recent nursing home study, antipsychotic review was found to reduce antipsychotic use by 50% and, when combined with a social intervention, to reduce mortality compared with a group receiving neither intervention.²⁴

Interestingly, patients receiving antipsychotic review alone showed an increase in overall neuropsychiatric symptoms.²⁴ A previous study of patients with AD whose psychosis or agitation responded to risperidone also found an increased risk of relapse when risperidone was discontinued.²⁵ These results highlight the importance of making patient-centered decisions, frequent re-assessments, and adding non-pharmacologic interventions (eg, positive social interactions or exercise) when attempting to discontinue antipsychotics.

Other treatment options. Because patients with LBD often display increased sensitivity to neuroleptics, agents such as quetiapine or aripiprazole (with a lower risk of EPS) are preferred when managing severe psychosis/aggression. ChEIs may show some benefit for behavioral disturbances in patients with LBD.²⁶

In patients with AD, ChEIs have shown inconsistent results in benefiting neuropsychiatric symptoms. Preliminary data suggest some benefit with citalopram (also associated with prolonged QTc)²⁷ and the dextromethorphan/quinidine combination FDA-approved for pseudobulbar affect, but more studies are needed.²⁸ Pimavanserin, a 5-HT2A receptor inverse agonist, recently was approved for treating hallucinations and delusions associated with Parkinson’s disease psychosis and currently is in clinical trials for Alzheimer’s disease psychosis.

Electroconvulsive therapy (ECT) may be a therapeutic option for agitation and aggression in people with dementia.²⁹ ECT has no absolute contraindications and can be safely performed in individuals with pacemakers or implantable cardioverter defibrillators. Common adverse effects include transient changes in blood pressure or heart rate, headache, and nausea. Cognitive adverse effects from ECT may include:

• anterograde amnesia, which typically resolves after a few weeks
• retrograde amnesia, which typically manifests as loss of impersonal memories occurring in the past few months.

Depression

The prevalence of depression in nursing home residents is an estimated 3 to 4 times that of community-dwelling older adults.³⁰ Assessing for depression is particularly important in people with mild cognitive impairment, as depressive symptoms have been associated with progression to AD.³¹ Quick screening tools (Table 2) include short forms of the Patient Health Questionnaire (PHQ-2 or PHQ-9)³² or the Saint Louis University Appetite, Mood, Sleep, Activity, and thoughts of Death (SLU “AM SAD”) scale.³³ The Cornell Scale for Depression in Dementia is useful for individuals with major NCDs because it relies on interviews with the patient and nursing staff or family.³⁴

To test for other causes of depression, order a complete blood count for anemia, serum glucose, thyroid-stimulating hormone for hypothyroidism or hyperthyroidism, B12 and folate levels, and a cognitive screen such as the Saint Louis University Mental Status examination.³⁵

Treatment. Antidepressants are generally considered effective in older patients with depression. Selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line treatments because of safety concerns with tricyclic antidepressants. All 3 classes have shown similar efficacy in comparison trials in geriatric populations.

When initiating these agents, take care in the first few days and weeks to monitor for potential serious adverse effects, such as nausea and vomiting, which may be associated with substantial morbidity in patients with comorbidities. For monitoring treatment response, the PHQ-9 can effectively distinguish patients with persistent major depression, partial remission, or full remission.³⁶

The optimal duration of a short-term antidepressant trial before switching to a different agent is unclear, although a good therapeutic trial typically is 4 to 12 weeks. In one study of older adults with depression, 4 weeks was enough to reliably identify those likely to benefit from a change in treatment plan.³⁷

Cognitive-behavioral therapy (CBT) can be used in older adults not wishing to pursue pharmacotherapy or as an adjunct to antidepressants. Randomized controlled trials have shown some benefit for those with depression, anxiety, and insomnia.³⁸ Individuals with significant cognitive deficits or those not motivated to apply CBT strategies might not benefit.

ECT may be appropriate for treating depression in older adults with:

• urgent need of a therapeutic response (eg, suicidal ideation or nutritional compromise)
• lack of response to antidepressant medication
• major depressive disorder with psychotic or catatonic features.

Evidence regarding ECT’s efficacy for late-life depression is derived primarily from clinical experience and open-label trials.³⁹

Bipolar disorder

Most individuals with bipolar disorder present before age 50, although 9% of first manic episodes occur after age 60.⁴⁰ Earlier age of onset appears to predict poor outcomes, and early-onset bipolar disorder may worsen with advanced age related to increased comorbidities and difficulty in medical management.⁴¹ Compared with younger patients, features of bipolar disorder in older adults include increased prominence of rapid cycling, more time spent in a depressed state than in manic state, and less severe manic and psychotic symptoms.⁴²

When older patients present with depression, always evaluate for clinical features more consistent with late-onset bipolar disorder than with major depressive disorder: hypomania, family history of bipolar disorder, higher number of prior depressive episodes, and higher levels of fear and inner tension.⁴³ The differential diagnosis for new-onset manic symptoms in older adults includes:

• general medical conditions (stroke, brain tumors, hyperthyroidism, neurosyphilis)
• medications (corticosteroids, dopaminergic drugs, St. John’s wort)
• substance use.

Hyperthyroidism deserves special attention because it can present in older adults with either manic-like symptoms and hyperkinesis or features of apathy, depression, and somnolence. Given that older age and bipolar disorder both are associated with increased suicide risk, monitor these individuals for signs of hopelessness and statements of suicide.⁴⁴

Treatment. Managing bipolar disorder in older adults often requires complex medication regimens. Acute treatment options for geriatric mania and hypomania with the most supporting evidence include lithium, valproate, quetiapine, and olanzapine.^45-47 The therapeutic index of lithium is small, and older individuals are more vulnerable to adverse effects related to physiologic changes (eg, decreased glomerular filtration rate or low volume of distribution) that impair lithium clearance. Lithium also interacts with many drugs commonly used by older patients, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and diuretics. Common adverse events associated with lithium include memory impairment, diarrhea, falls, and tremors.

Maintenance treatment for bipolar disorder is generally the same medication used to induce remission. The evidence for maintenance treatment of bipolar disorder in older adults is limited mostly to subgroup analyses. In one retrospective analysis of patients age ≥55 in 2 randomized trials, lamotrigine and lithium were effective and well-tolerated in delaying time to intervention.⁴⁸

Anxiety disorders

Anxiety among LTC residents may manifest as irritability, insomnia, restlessness, and verbal and/or physical agitation/aggression.⁴⁹ Typical causes include:

• primary anxiety disorders
• anxiety symptoms during depressive episodes or bereavement
• adverse effects of medications
• complications of major NCDs or delirium.

Anxiety disorders and subsyndromal anxiety have been associated with poorer quality of life, decreased sleep, and increased distress and impairment.⁵⁰

Assessment begins with a self-report of symptoms, although this may be difficult in people with major NCDs. Factors that may differentiate true anxiety from major NCDs include restlessness, irritability, muscle tension, fears, and respiratory symptoms in addition to excessive anxiety and worry.⁵¹ The Geriatric Anxiety Inventory is a useful screening tool.⁵² The newer Brief Anxiety and Depression Scale may identify and differentiate patients with major depressive episodes and generalized anxiety disorder (GAD).⁵³ Potential instruments for patients with comorbid anxiety and major NCDs include the Neuropsychiatric Inventory, Rating Anxiety in Dementia scale,⁵⁴ and the Anxiety in Cognitive Impairment and Dementia scale.⁵⁵ Because medications can cause akathisia that may mimic anxiety symptoms, screen for the recent addition of antidepressants, antipsychotics, sympathomimetics, thyroid supplements, and corticosteroids.

Treatment of anxiety disorders—such as panic disorder, social phobia, or GAD—generally starts with SSRIs or SNRIs. Although benzodiazepines are commonly used for anxiety in older adults,⁵⁶ these drugs are associated with a high rate of adverse effects: increased risk of agitation, falls, impaired cognition, and possibly dementia.⁵⁷ In general, reserve benzodiazepines for treating acute episodes of severe anxiety in this population.

A particularly prevalent source of anxiety in LTC is fear of falling, which may affect up to 50% of residents and cause them to restrict their activities.⁵⁸ Interventions such as CBT, exercise, or tai chi may be beneficial, although supporting evidence is lacking.

Pain and sleep management

Addressing pain. Age-related changes in pain perception and difficulty in reporting pain likely contribute to under-recognition of pain in LTC residents. Two useful methods to recognize their pain are to:

• observe for pain behaviors, such as facial expressions (grimacing and brow lowering), vocalizations, and body movements (clenched fists)
• solicit reports from nurses and other caregivers.⁵⁹

Self-report may be a reliable indicator of pain for individuals with mild-to-moderate NCDs. Observational pain scales, such as the Pain Assessment Checklist for Seniors with Limited Ability to Communicate, may be useful in severe NCDs.⁶⁰

The AGS recommends acetaminophen as initial pharmacotherapy to manage persistent pain.⁶¹ NSAIDs may be another option, but caution is warranted for patients with acid-peptic disease or chronic kidney disease. Opioids may be considered for severe pain, but otherwise avoid using them.

Sleep disturbances are common in LTC because of physiologic changes associated with aging (altered circadian rhythm), comorbidities (depression), and environmental factors.⁶² A strong association appears to exist between insomnia and use of sedative-hypnotic drugs, and the AGS Beers Criteria recommend avoiding non-benzodiazepine receptor agonists and benzodiazepines when treating insomnia in older adults.⁹

Assess factors that may contribute to sleep disturbances, including medications and use of caffeine or alcohol. Have the resident or caregiver document sleep patterns in a sleep diary.

Consider administrating medications at different times (eg, switch donepezil from bedtime to morning) or replace with alternatives (switch from the more anticholinergic amitriptyline to nortriptyline). Ensure that residents engage in physical activity and have at least 30 minutes daily exposure to sunlight.

In addition to behavioral interventions and CBT, treatment in older adults can involve melatonin—which has mixed evidence—or sedating antidepressants, such as mirtazapine or trazodone, in patients with comorbid depression.

Long-term care (LTC) services provide health care to >8 million people in approximately 30,000 nursing homes and assisted living/residential care communities in the United States.¹ One-half of older adults in LTC have neurocognitive disorders (NCDs), and one-third have depressive syndromes.² Common reasons for psychiatric consultation include these 2 major diagnoses, as well as delirium, behavioral and psychological symptoms of dementia (BPSD), bipolar disorder, anxiety, sleep disorders, and pain management.

Psychiatric assessment of individuals in LTC can be challenging because of atypical presentations, cognitive impairment, and multiple comorbidities. Establishing a management plan involves eliciting a careful history from both the patient and caretakers, examining previous records and medications, and selecting appropriate screening tools and laboratory tests (Table 1 and Table 2).

• assessment tools for psychiatric symptoms in LTC
• potentially inappropriate medication use in older adults
• antipsychotic use for agitation and psychosis with dementia
• nonpharmacologic interventions to help prevent cognitive decline
• antipsychotic review in reducing antipsychotic use and mortality.

Delirium

Delirium is an important topic in LTC because it is highly prevalent, poorly recognized, and can be difficult to manage. Common causes of delirium in LTC include infection (often urinary), dehydration, medications, long-standing constipation, and urinary retention (Table 3).³ Early recognition is key because delirium has been associated with cognitive decline, decreased functional status, increased caregiver burden, and increased mortality.^4,5

The Confusion Assessment Method (CAM) is a quick tool with 4 features to differentiate delirium from other forms of cognitive impairment.⁶ The 2 core features are an acute change or fluctuating course of mental status and inattention. Family members or caregivers can provide information about an acute change. To assess inattention, ask the patient to say the days of the week backward or spell the word “world” backward. The 2 other features of delirium—one of which must be present when using the CAM—are disorganized thinking and altered level of consciousness.

Individuals with delirium may present with hyperactive or hypoactive psychomotor activity. Hypoactive delirium’s features, such as sluggishness and lethargy, could be confused with depression.⁷ A careful history to determine symptom onset and fluctuation in course can help differentiate between the 2.

Management. Delirium management always should begin by addressing underlying causes and implementing psychosocial and environmental interventions. Pharmacologic interventions have not demonstrated consistent benefit for delirium in well-designed trials and are not recommended as first-line treatment.⁸ The American Geriatrics Society (AGS) Beers Criteria for Potentially Inappropriate Medication Use in Older Adults recommends avoiding benzodiazepines in this population.⁹ Antipsychotics could be used in patients with severe agitation who pose harm to themselves or others. Nonpharmacologic approaches to delirium in LTC include:

• frequent reorientation (clocks, daily schedule)
• one-on-one monitoring by staff or family members
• use of hearing aids and eye-glasses, if needed
• maintaining an appropriate sleep-wake cycle by encouraging exposure to bright light during the day and avoiding night-time interruptions.

Restraints should not be used; they appear to worsen delirium severity, and their removal does not increase the rate of falls or fall-related injury.¹⁰

Various methods for managing a patient with delirium have been proposed, such as the TADA approach (tolerate, anticipate, and don’t agitate).^5,11,12 For example, if a patient’s agitation worsens with attempted reorientation, distraction or playing along with the disorientation could be more beneficial.¹²

Keep in mind delirium’s overlapping presentation with Lewy body dementia (LBD). Patients with LBD demonstrate a progressive decline in cognitive functioning associated with fluctuating cognition, visual hallucinations, and parkinsonism features. Consider LBD when no cause for delirium-like symptoms is found. These patients may show increased sensitivity to neuroleptics and extrapyramidal side effects.

Neurocognitive disorders

Reversible causes. Although most individuals with major NCDs are diagnosed before entering LTC, the consulting psychiatrist’s review of potentially reversible causes of neurocognitive symptoms can lead to dramatically different treatment regimens (Table 4³). For example, anticholinergic medications can harm the aging brain and have been linked to delirium, increased brain atrophy, and lower scores on tests of cognitive functioning.¹³ Given the prevalence of polypharmacy in older adults, be aware of unexpected anticholinergic properties of many common drugs, as rated by the Aging Brain Care initiative.¹⁴

The randomized, double-blind Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability provides convincing data that a nonpharmacologic approach could benefit older adults at risk for a major NCD. A 2-year intervention of nutritional advice, aerobic and strength training, cognitive training, social activities, and blood pressure and weight monitoring was more effective in improving or maintaining cognitive function in individuals age 60 to 77, compared with general health advice given to a control group.¹⁵

Behavioral and psychological symptoms. Psychiatrists are likely to be consulted in LTC when a person with a major NCD presents with an acute episode of increased confusion and cognitive worsening, often accompanied by behavioral symptoms. BPSD may include agitation, aggression, apathy, depression, sleep problems, socially inappropriate behaviors, and psychosis. One study of patients with Alzheimer’s disease (AD) reported a cumulative 51% incidence of new-onset hallucinations and delusions at 4 years.¹⁶

Increased vulnerability to stressors, unmet needs, over- or under-stimulation, or lack of routines may predispose individuals with major NCDs to developing BPSD.¹⁷ Nonpharmacologic approaches usually are tried first, although supporting evidence is not substantial.¹⁸ Changes in environment, behavioral redirection, sensory interventions, or music therapy may reduce disruptive behaviors.¹⁹ Patients with increased confusion and agitation in late afternoon and evening (“sundowning”) may benefit from short naps after lunch, light therapy, calming activities in late afternoon, and reduced noise (such as from dishes, loud speakers, staff conversations).²⁰

Antipsychotics. The drugs most commonly used to manage BPSD are antipsychotics, antidepressants, mood stabilizers/anticonvulsants, ChEIs, and the N-methyl-d-aspartate receptor antagonist memantine. Antipsychotics often are used despite their uncertain efficacy²¹ and serious safety concerns. Atypical antipsychotics are generally preferred for their side effect profiles, but both atypical and typical classes carry a “black-box” warning of increased risk of mortality in older patients with major NCDs. Other potential adverse events include anticholinergic effects, orthostatic hypotension, prolonged QT interval, and extrapyramidal symptoms (EPS).

When nonpharmacotherapeutic interventions are not successful, most guidelines agree that using an atypical antipsychotic is warranted in AD patients with severe agitation and/or psychosis that pose a risk to the patient or others or severely impair their quality of life.^9,22,23

Antipsychotic review. Recent guidelines from the American Psychiatric Association (APA) recommend that attempts to taper and withdraw antipsychotic drugs be made within 4 months of initiating treatment in patients with dementia who display an adequate response.²³ In a recent nursing home study, antipsychotic review was found to reduce antipsychotic use by 50% and, when combined with a social intervention, to reduce mortality compared with a group receiving neither intervention.²⁴

Interestingly, patients receiving antipsychotic review alone showed an increase in overall neuropsychiatric symptoms.²⁴ A previous study of patients with AD whose psychosis or agitation responded to risperidone also found an increased risk of relapse when risperidone was discontinued.²⁵ These results highlight the importance of making patient-centered decisions, frequent re-assessments, and adding non-pharmacologic interventions (eg, positive social interactions or exercise) when attempting to discontinue antipsychotics.

Other treatment options. Because patients with LBD often display increased sensitivity to neuroleptics, agents such as quetiapine or aripiprazole (with a lower risk of EPS) are preferred when managing severe psychosis/aggression. ChEIs may show some benefit for behavioral disturbances in patients with LBD.²⁶

In patients with AD, ChEIs have shown inconsistent results in benefiting neuropsychiatric symptoms. Preliminary data suggest some benefit with citalopram (also associated with prolonged QTc)²⁷ and the dextromethorphan/quinidine combination FDA-approved for pseudobulbar affect, but more studies are needed.²⁸ Pimavanserin, a 5-HT2A receptor inverse agonist, recently was approved for treating hallucinations and delusions associated with Parkinson’s disease psychosis and currently is in clinical trials for Alzheimer’s disease psychosis.

Electroconvulsive therapy (ECT) may be a therapeutic option for agitation and aggression in people with dementia.²⁹ ECT has no absolute contraindications and can be safely performed in individuals with pacemakers or implantable cardioverter defibrillators. Common adverse effects include transient changes in blood pressure or heart rate, headache, and nausea. Cognitive adverse effects from ECT may include:

• anterograde amnesia, which typically resolves after a few weeks
• retrograde amnesia, which typically manifests as loss of impersonal memories occurring in the past few months.

Depression

The prevalence of depression in nursing home residents is an estimated 3 to 4 times that of community-dwelling older adults.³⁰ Assessing for depression is particularly important in people with mild cognitive impairment, as depressive symptoms have been associated with progression to AD.³¹ Quick screening tools (Table 2) include short forms of the Patient Health Questionnaire (PHQ-2 or PHQ-9)³² or the Saint Louis University Appetite, Mood, Sleep, Activity, and thoughts of Death (SLU “AM SAD”) scale.³³ The Cornell Scale for Depression in Dementia is useful for individuals with major NCDs because it relies on interviews with the patient and nursing staff or family.³⁴

To test for other causes of depression, order a complete blood count for anemia, serum glucose, thyroid-stimulating hormone for hypothyroidism or hyperthyroidism, B12 and folate levels, and a cognitive screen such as the Saint Louis University Mental Status examination.³⁵

Treatment. Antidepressants are generally considered effective in older patients with depression. Selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line treatments because of safety concerns with tricyclic antidepressants. All 3 classes have shown similar efficacy in comparison trials in geriatric populations.

When initiating these agents, take care in the first few days and weeks to monitor for potential serious adverse effects, such as nausea and vomiting, which may be associated with substantial morbidity in patients with comorbidities. For monitoring treatment response, the PHQ-9 can effectively distinguish patients with persistent major depression, partial remission, or full remission.³⁶

The optimal duration of a short-term antidepressant trial before switching to a different agent is unclear, although a good therapeutic trial typically is 4 to 12 weeks. In one study of older adults with depression, 4 weeks was enough to reliably identify those likely to benefit from a change in treatment plan.³⁷

Cognitive-behavioral therapy (CBT) can be used in older adults not wishing to pursue pharmacotherapy or as an adjunct to antidepressants. Randomized controlled trials have shown some benefit for those with depression, anxiety, and insomnia.³⁸ Individuals with significant cognitive deficits or those not motivated to apply CBT strategies might not benefit.

ECT may be appropriate for treating depression in older adults with:

• urgent need of a therapeutic response (eg, suicidal ideation or nutritional compromise)
• lack of response to antidepressant medication
• major depressive disorder with psychotic or catatonic features.

Evidence regarding ECT’s efficacy for late-life depression is derived primarily from clinical experience and open-label trials.³⁹

Bipolar disorder

Most individuals with bipolar disorder present before age 50, although 9% of first manic episodes occur after age 60.⁴⁰ Earlier age of onset appears to predict poor outcomes, and early-onset bipolar disorder may worsen with advanced age related to increased comorbidities and difficulty in medical management.⁴¹ Compared with younger patients, features of bipolar disorder in older adults include increased prominence of rapid cycling, more time spent in a depressed state than in manic state, and less severe manic and psychotic symptoms.⁴²

When older patients present with depression, always evaluate for clinical features more consistent with late-onset bipolar disorder than with major depressive disorder: hypomania, family history of bipolar disorder, higher number of prior depressive episodes, and higher levels of fear and inner tension.⁴³ The differential diagnosis for new-onset manic symptoms in older adults includes:

• general medical conditions (stroke, brain tumors, hyperthyroidism, neurosyphilis)
• medications (corticosteroids, dopaminergic drugs, St. John’s wort)
• substance use.

Hyperthyroidism deserves special attention because it can present in older adults with either manic-like symptoms and hyperkinesis or features of apathy, depression, and somnolence. Given that older age and bipolar disorder both are associated with increased suicide risk, monitor these individuals for signs of hopelessness and statements of suicide.⁴⁴

Treatment. Managing bipolar disorder in older adults often requires complex medication regimens. Acute treatment options for geriatric mania and hypomania with the most supporting evidence include lithium, valproate, quetiapine, and olanzapine.^45-47 The therapeutic index of lithium is small, and older individuals are more vulnerable to adverse effects related to physiologic changes (eg, decreased glomerular filtration rate or low volume of distribution) that impair lithium clearance. Lithium also interacts with many drugs commonly used by older patients, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and diuretics. Common adverse events associated with lithium include memory impairment, diarrhea, falls, and tremors.

Maintenance treatment for bipolar disorder is generally the same medication used to induce remission. The evidence for maintenance treatment of bipolar disorder in older adults is limited mostly to subgroup analyses. In one retrospective analysis of patients age ≥55 in 2 randomized trials, lamotrigine and lithium were effective and well-tolerated in delaying time to intervention.⁴⁸

Anxiety disorders

Anxiety among LTC residents may manifest as irritability, insomnia, restlessness, and verbal and/or physical agitation/aggression.⁴⁹ Typical causes include:

• primary anxiety disorders
• anxiety symptoms during depressive episodes or bereavement
• adverse effects of medications
• complications of major NCDs or delirium.

Anxiety disorders and subsyndromal anxiety have been associated with poorer quality of life, decreased sleep, and increased distress and impairment.⁵⁰

Assessment begins with a self-report of symptoms, although this may be difficult in people with major NCDs. Factors that may differentiate true anxiety from major NCDs include restlessness, irritability, muscle tension, fears, and respiratory symptoms in addition to excessive anxiety and worry.⁵¹ The Geriatric Anxiety Inventory is a useful screening tool.⁵² The newer Brief Anxiety and Depression Scale may identify and differentiate patients with major depressive episodes and generalized anxiety disorder (GAD).⁵³ Potential instruments for patients with comorbid anxiety and major NCDs include the Neuropsychiatric Inventory, Rating Anxiety in Dementia scale,⁵⁴ and the Anxiety in Cognitive Impairment and Dementia scale.⁵⁵ Because medications can cause akathisia that may mimic anxiety symptoms, screen for the recent addition of antidepressants, antipsychotics, sympathomimetics, thyroid supplements, and corticosteroids.

Treatment of anxiety disorders—such as panic disorder, social phobia, or GAD—generally starts with SSRIs or SNRIs. Although benzodiazepines are commonly used for anxiety in older adults,⁵⁶ these drugs are associated with a high rate of adverse effects: increased risk of agitation, falls, impaired cognition, and possibly dementia.⁵⁷ In general, reserve benzodiazepines for treating acute episodes of severe anxiety in this population.

A particularly prevalent source of anxiety in LTC is fear of falling, which may affect up to 50% of residents and cause them to restrict their activities.⁵⁸ Interventions such as CBT, exercise, or tai chi may be beneficial, although supporting evidence is lacking.

Pain and sleep management

Addressing pain. Age-related changes in pain perception and difficulty in reporting pain likely contribute to under-recognition of pain in LTC residents. Two useful methods to recognize their pain are to:

• observe for pain behaviors, such as facial expressions (grimacing and brow lowering), vocalizations, and body movements (clenched fists)
• solicit reports from nurses and other caregivers.⁵⁹

Self-report may be a reliable indicator of pain for individuals with mild-to-moderate NCDs. Observational pain scales, such as the Pain Assessment Checklist for Seniors with Limited Ability to Communicate, may be useful in severe NCDs.⁶⁰

The AGS recommends acetaminophen as initial pharmacotherapy to manage persistent pain.⁶¹ NSAIDs may be another option, but caution is warranted for patients with acid-peptic disease or chronic kidney disease. Opioids may be considered for severe pain, but otherwise avoid using them.

Sleep disturbances are common in LTC because of physiologic changes associated with aging (altered circadian rhythm), comorbidities (depression), and environmental factors.⁶² A strong association appears to exist between insomnia and use of sedative-hypnotic drugs, and the AGS Beers Criteria recommend avoiding non-benzodiazepine receptor agonists and benzodiazepines when treating insomnia in older adults.⁹

Assess factors that may contribute to sleep disturbances, including medications and use of caffeine or alcohol. Have the resident or caregiver document sleep patterns in a sleep diary.

Consider administrating medications at different times (eg, switch donepezil from bedtime to morning) or replace with alternatives (switch from the more anticholinergic amitriptyline to nortriptyline). Ensure that residents engage in physical activity and have at least 30 minutes daily exposure to sunlight.

In addition to behavioral interventions and CBT, treatment in older adults can involve melatonin—which has mixed evidence—or sedating antidepressants, such as mirtazapine or trazodone, in patients with comorbid depression.

High serum cholesterol is a leading cause of heart attack and stroke,^1,2 yet remains one of the most under-screened and undertreated modifiable risk factors in persons with mental illness. Well tolerated and effective treatments can considerably lower the risk of cardiovascular events, and should be offered to psychiatric patients who are at high risk, while considering possible adverse effects and potential interactions between psychotropics and medications used to lower cholesterol.

Systematic lowering of total cholesterol and, particularly, atherogenic low-density lipoprotein (LDL) and non-high density lipoprotein (HDL) cholesterol, results in consistent and significant reduction in risk of cardiovascular events in persons at risk for developing cardiovascular disease (CVD) and in preventing reoccurrence of these events.^1,3,4 Even individuals who have relatively lower levels of total cholesterol but are at high risk (such as if a cardiovascular event has occurred) could reduce their CVD risk (known as secondary prevention) through lipid lowering therapies.^5,6

Adults with psychiatric illness shoulder a disproportionate burden of CVD morbidity and mortality, especially those with severe mental illness (SMI, schizophrenia, schizoaffective disorder, bipolar disorder, treatment-resistant depression).^7-9 Among modifiable CVD risk factors, dyslipidemia has the highest rates of missed screenings and treatment within psychiatric populations. In one analysis, up to 90% of adults with SMI and identified lipid disorders did not receive treatment.¹⁰ Persons with SMI generally do not receive guideline-concordant, systematic quality preventive care, which contributes to a widening mortality gap for this population.^11,12

This review aims to provide clinicians with practical guidance on the assessment and management of high cholesterol to improve recognition and treatment, lower CVD risk, and reduce this observed mortality gap.

Screening and diagnosis

In 2013, the American College of Cardiology (ACC) and the American Heart Association (AHA) released updated guidelines on diagnosing and managing high cholesterol to reduce CVD risk.¹ These guidelines focus on updated 10-year CVD risk assessment models with treatment goals reliant on adherence to statin therapy rather than pre-specified cholesterol targets listed in previous guidelines.¹³

Updates to assessment and treatment guidelines have removed some barriers to screening and diagnosing high cholesterol—namely, fasting lipid panels are no longer required to determine 10-year CVD risk and initiate treatment.¹⁴ For adults taking a second-generation antipsychotic that is associated with weight gain and metabolic syndrome, experts generally recommend yearly non-fasting lipid panels.^6,14

The United States Preventive Services Task Force recommends screening:

• men age ≥35 at average risk for CVD every 5 years
• women age ≥45 every 5 years¹⁵
• adults as young as age 20 who have accelerated risk factors, such as cigarette smoking and hypertension
• adults with a family history of heart attack or stroke in male first-degree relative age ≥50 and female first-degree relatives age ≥60.

Many adults receiving care in behavioral health settings, regardless of their medication regimen, qualify for screening at least every 5 years, if not more frequently. Although statin treatment before age 40 is less beneficial and likely not necessary for primary prevention, monitoring could help identify alternative therapies and prioritize more intensive diet and lifestyle modifications.

Treatment and management

Dietary modification and lifestyle changes (exercise, quitting smoking), lowering high cholesterol with medications, and switching from highly metabolically active drugs to less metabolically active ones can help lower total cholesterol in patients at risk of CVD.

Statins

HMG-CoA reductase inhibitors (statins) consistently reduce total cholesterol and non-HDL cholesterol by 30% to 50%, depending on drug and dosage (potency, listed as low, medium, and high). Not all statins are equally effective at lowering cholesterol; some are more potent than others (Table 2).¹⁶

Individuals are eligible for statin therapy based on their level of CVD risk. Persons at higher risk generally benefit from greater intensity statin treatment and cholesterol reduction; highest intensity statin regimens can lower total cholesterol by approximately 50%.

There are 4 statin eligibility classes (Table 3). Most adults fall into category 4: 10-year risk of >7.5% and needing primary prevention. In addition to removing specific LDL targets as therapy goals, calculation of this risk percentage and the specific cut-off values have been the most controversial aspects of the new cholesterol guidelines. Most experts agree that, in adults age 40 to 75, 10-year risk >10% indicates daily statin use as tolerated for primary prevention, and 10-year risk <5% does not warrant statin use. Recent large studies have validated these new techniques for calculating risk, and found them to be beneficial in potential for cost savings and risk classification.^17,18

Considerations in psychiatric patients. Statins have been associated with depression in case series, but larger analyses have not confirmed this association.¹⁹ Emerging evidence has identified a potential correlation between statin use and accelerated onset of T2DM, but the absolute risk is relatively low and most experts continue to recommend statin therapy despite this potential risk.¹³ Many statins, including atorvastatin, are available as a generic and can be taken once daily. Some, such as simvastatin, have notable interactions with commonly prescribed psychotropics including risperidone and quetiapine. Pravastatin is dually excreted by the liver and kidneys and may have fewer drug-drug interactions in patients with psychiatric illness taking common psychotropic therapies, but is not considered a high-potency statin and might not confer adequate benefits in CVD risk reduction.

Contraindications. Statins are pregnancy category X, and generally should not be prescribed for women of childbearing age without intensive counseling. The most notable adverse effects for statins include muscle aches and cramps (myalgia), but generally are not severe. If encountered, consider checking a serum creatinine kinase (CK) level, and if significantly elevated above 10 times the upper limit, stopping statin therapy would be advised. If the CK is only mildly elevated, consider lowering the dosage or switching to a lower potency agent. Lovastatin and pravastatin generally are better tolerated than atorvastatin and are considered lower potency (Table 2).

Statins can be safely used in the presence of liver conditions, such as hepatitis C and alcohol use, although periodic monitoring of transaminase levels is recommended. For adults in the general population without liver disease, regular monitoring of transaminase levels is not necessary.

Alternate lipid-lowering pharmacotherapies unfortunately have fallen out of favor. Fibrates, niacin, ezetimibe, and omega-3 fatty acids once were recommended to lower triglycerides or raise HDL cholesterol levels, but since have been shown to have little effect on cardiovascular morbidity or mortality. Adding further medications, other than statins, to lower cholesterol values to pre-defined targets is not the current standard of care.

High triglyceride concentrations traditionally have been addressed directly, but failure to improve CVD mortality or morbidity by treating triglycerides alone has resulted in refocusing clinical efforts in dyslipidemia management on atherogenic cholesterol, including LDL and non-HDL fractions.²⁰ Non-fasting triglycerides >500 mg/dL should be retested when fasting, and levels that remain >500 mg/dL could place the patient at risk for pancreatitis and might warrant intervention with fibrates at that time. This scenario is not common, and referral to a primary care physician or endocrinologist may be warranted.

Lifestyle changes

With or without statin therapies, diet and lifestyle changes are the cornerstone of healthy living and should be encouraged in all patients. Most overweight or obese patients will benefit from exercise and dietary modifications. Such interventions have shown potential for reducing total cholesterol and non-HDL and HDL cholesterol, but rarely are these interventions sustained long enough to produce meaningful reduction in CVD risk through lipid lowering. Diets rich in isocaloric tree nuts and red-yeast rice extract—a form of a statin—have shown promise in reducing cholesterol, but typically take excessive personal resources and are not sustained to the degree necessary to reduce CVD risk over time.²¹ Similarly, regular exercise routines can help lower overall cholesterol numbers, but rarely reduce total cholesterol by >10%.

Because individuals with SMI smoke at a higher rate than the general population, it should be noted that smoking cessation is associated with a reduction in total cholesterol and a trial of smoking cessation therapy is warranted before initiating a statin medication for primary prevention of CVD. Many patients would discover that their 10-year ASCVD risk would fall under the level needed for statin therapy if they could successfully stop smoking.

Switching pharmacotherapies

Switching antipsychotic agents from highly metabolically risky compounds, such as risperidone and olanzapine, to less metabolically active compounds, such as aripiprazole, ziprasidone, or haloperidol, have been associated with improvements in lipid profiles.^22-24 Clinicians must weigh the potential benefits of switching therapies against the risk of psychiatric destabilization and long-term adherence, keeping in mind that changes in lipids seen with switching could be mild (approximately 10% reduction in total cholesterol).

Summing up

Cholesterol management is considered part of a program to systematically lower CVD risk. Statin therapy usually is indicated for life, or until the age of 75, at which point treatment risks and benefits change because of life expectancy. Other components of CVD risk reduction include a focus on blood pressure control, smoking cessation, T2DM management, and weight loss. Tracking lipid profiles over time to ensure broad targets of 30% to 50% reduction in total cholesterol, approximately 3 months after initiation and yearly thereafter, can help ensure adherence to therapy. With systematic lowering of modifiable CVD risk factors, we can hope to gradually improve the quality of life for our patients with mental illnesses (see the Box for a case example illustrating successful use of these strategies).

High serum cholesterol is a leading cause of heart attack and stroke,^1,2 yet remains one of the most under-screened and undertreated modifiable risk factors in persons with mental illness. Well tolerated and effective treatments can considerably lower the risk of cardiovascular events, and should be offered to psychiatric patients who are at high risk, while considering possible adverse effects and potential interactions between psychotropics and medications used to lower cholesterol.

Systematic lowering of total cholesterol and, particularly, atherogenic low-density lipoprotein (LDL) and non-high density lipoprotein (HDL) cholesterol, results in consistent and significant reduction in risk of cardiovascular events in persons at risk for developing cardiovascular disease (CVD) and in preventing reoccurrence of these events.^1,3,4 Even individuals who have relatively lower levels of total cholesterol but are at high risk (such as if a cardiovascular event has occurred) could reduce their CVD risk (known as secondary prevention) through lipid lowering therapies.^5,6

Adults with psychiatric illness shoulder a disproportionate burden of CVD morbidity and mortality, especially those with severe mental illness (SMI, schizophrenia, schizoaffective disorder, bipolar disorder, treatment-resistant depression).^7-9 Among modifiable CVD risk factors, dyslipidemia has the highest rates of missed screenings and treatment within psychiatric populations. In one analysis, up to 90% of adults with SMI and identified lipid disorders did not receive treatment.¹⁰ Persons with SMI generally do not receive guideline-concordant, systematic quality preventive care, which contributes to a widening mortality gap for this population.^11,12

This review aims to provide clinicians with practical guidance on the assessment and management of high cholesterol to improve recognition and treatment, lower CVD risk, and reduce this observed mortality gap.

Screening and diagnosis

In 2013, the American College of Cardiology (ACC) and the American Heart Association (AHA) released updated guidelines on diagnosing and managing high cholesterol to reduce CVD risk.¹ These guidelines focus on updated 10-year CVD risk assessment models with treatment goals reliant on adherence to statin therapy rather than pre-specified cholesterol targets listed in previous guidelines.¹³

Updates to assessment and treatment guidelines have removed some barriers to screening and diagnosing high cholesterol—namely, fasting lipid panels are no longer required to determine 10-year CVD risk and initiate treatment.¹⁴ For adults taking a second-generation antipsychotic that is associated with weight gain and metabolic syndrome, experts generally recommend yearly non-fasting lipid panels.^6,14

The United States Preventive Services Task Force recommends screening:

• men age ≥35 at average risk for CVD every 5 years
• women age ≥45 every 5 years¹⁵
• adults as young as age 20 who have accelerated risk factors, such as cigarette smoking and hypertension
• adults with a family history of heart attack or stroke in male first-degree relative age ≥50 and female first-degree relatives age ≥60.

Many adults receiving care in behavioral health settings, regardless of their medication regimen, qualify for screening at least every 5 years, if not more frequently. Although statin treatment before age 40 is less beneficial and likely not necessary for primary prevention, monitoring could help identify alternative therapies and prioritize more intensive diet and lifestyle modifications.

Treatment and management

Dietary modification and lifestyle changes (exercise, quitting smoking), lowering high cholesterol with medications, and switching from highly metabolically active drugs to less metabolically active ones can help lower total cholesterol in patients at risk of CVD.

Statins

HMG-CoA reductase inhibitors (statins) consistently reduce total cholesterol and non-HDL cholesterol by 30% to 50%, depending on drug and dosage (potency, listed as low, medium, and high). Not all statins are equally effective at lowering cholesterol; some are more potent than others (Table 2).¹⁶

Individuals are eligible for statin therapy based on their level of CVD risk. Persons at higher risk generally benefit from greater intensity statin treatment and cholesterol reduction; highest intensity statin regimens can lower total cholesterol by approximately 50%.

There are 4 statin eligibility classes (Table 3). Most adults fall into category 4: 10-year risk of >7.5% and needing primary prevention. In addition to removing specific LDL targets as therapy goals, calculation of this risk percentage and the specific cut-off values have been the most controversial aspects of the new cholesterol guidelines. Most experts agree that, in adults age 40 to 75, 10-year risk >10% indicates daily statin use as tolerated for primary prevention, and 10-year risk <5% does not warrant statin use. Recent large studies have validated these new techniques for calculating risk, and found them to be beneficial in potential for cost savings and risk classification.^17,18

Considerations in psychiatric patients. Statins have been associated with depression in case series, but larger analyses have not confirmed this association.¹⁹ Emerging evidence has identified a potential correlation between statin use and accelerated onset of T2DM, but the absolute risk is relatively low and most experts continue to recommend statin therapy despite this potential risk.¹³ Many statins, including atorvastatin, are available as a generic and can be taken once daily. Some, such as simvastatin, have notable interactions with commonly prescribed psychotropics including risperidone and quetiapine. Pravastatin is dually excreted by the liver and kidneys and may have fewer drug-drug interactions in patients with psychiatric illness taking common psychotropic therapies, but is not considered a high-potency statin and might not confer adequate benefits in CVD risk reduction.

Contraindications. Statins are pregnancy category X, and generally should not be prescribed for women of childbearing age without intensive counseling. The most notable adverse effects for statins include muscle aches and cramps (myalgia), but generally are not severe. If encountered, consider checking a serum creatinine kinase (CK) level, and if significantly elevated above 10 times the upper limit, stopping statin therapy would be advised. If the CK is only mildly elevated, consider lowering the dosage or switching to a lower potency agent. Lovastatin and pravastatin generally are better tolerated than atorvastatin and are considered lower potency (Table 2).

Statins can be safely used in the presence of liver conditions, such as hepatitis C and alcohol use, although periodic monitoring of transaminase levels is recommended. For adults in the general population without liver disease, regular monitoring of transaminase levels is not necessary.

Alternate lipid-lowering pharmacotherapies unfortunately have fallen out of favor. Fibrates, niacin, ezetimibe, and omega-3 fatty acids once were recommended to lower triglycerides or raise HDL cholesterol levels, but since have been shown to have little effect on cardiovascular morbidity or mortality. Adding further medications, other than statins, to lower cholesterol values to pre-defined targets is not the current standard of care.

High triglyceride concentrations traditionally have been addressed directly, but failure to improve CVD mortality or morbidity by treating triglycerides alone has resulted in refocusing clinical efforts in dyslipidemia management on atherogenic cholesterol, including LDL and non-HDL fractions.²⁰ Non-fasting triglycerides >500 mg/dL should be retested when fasting, and levels that remain >500 mg/dL could place the patient at risk for pancreatitis and might warrant intervention with fibrates at that time. This scenario is not common, and referral to a primary care physician or endocrinologist may be warranted.

Lifestyle changes

With or without statin therapies, diet and lifestyle changes are the cornerstone of healthy living and should be encouraged in all patients. Most overweight or obese patients will benefit from exercise and dietary modifications. Such interventions have shown potential for reducing total cholesterol and non-HDL and HDL cholesterol, but rarely are these interventions sustained long enough to produce meaningful reduction in CVD risk through lipid lowering. Diets rich in isocaloric tree nuts and red-yeast rice extract—a form of a statin—have shown promise in reducing cholesterol, but typically take excessive personal resources and are not sustained to the degree necessary to reduce CVD risk over time.²¹ Similarly, regular exercise routines can help lower overall cholesterol numbers, but rarely reduce total cholesterol by >10%.

Because individuals with SMI smoke at a higher rate than the general population, it should be noted that smoking cessation is associated with a reduction in total cholesterol and a trial of smoking cessation therapy is warranted before initiating a statin medication for primary prevention of CVD. Many patients would discover that their 10-year ASCVD risk would fall under the level needed for statin therapy if they could successfully stop smoking.

Switching pharmacotherapies

Switching antipsychotic agents from highly metabolically risky compounds, such as risperidone and olanzapine, to less metabolically active compounds, such as aripiprazole, ziprasidone, or haloperidol, have been associated with improvements in lipid profiles.^22-24 Clinicians must weigh the potential benefits of switching therapies against the risk of psychiatric destabilization and long-term adherence, keeping in mind that changes in lipids seen with switching could be mild (approximately 10% reduction in total cholesterol).

Summing up

Cholesterol management is considered part of a program to systematically lower CVD risk. Statin therapy usually is indicated for life, or until the age of 75, at which point treatment risks and benefits change because of life expectancy. Other components of CVD risk reduction include a focus on blood pressure control, smoking cessation, T2DM management, and weight loss. Tracking lipid profiles over time to ensure broad targets of 30% to 50% reduction in total cholesterol, approximately 3 months after initiation and yearly thereafter, can help ensure adherence to therapy. With systematic lowering of modifiable CVD risk factors, we can hope to gradually improve the quality of life for our patients with mental illnesses (see the Box for a case example illustrating successful use of these strategies).

High serum cholesterol is a leading cause of heart attack and stroke,^1,2 yet remains one of the most under-screened and undertreated modifiable risk factors in persons with mental illness. Well tolerated and effective treatments can considerably lower the risk of cardiovascular events, and should be offered to psychiatric patients who are at high risk, while considering possible adverse effects and potential interactions between psychotropics and medications used to lower cholesterol.

Systematic lowering of total cholesterol and, particularly, atherogenic low-density lipoprotein (LDL) and non-high density lipoprotein (HDL) cholesterol, results in consistent and significant reduction in risk of cardiovascular events in persons at risk for developing cardiovascular disease (CVD) and in preventing reoccurrence of these events.^1,3,4 Even individuals who have relatively lower levels of total cholesterol but are at high risk (such as if a cardiovascular event has occurred) could reduce their CVD risk (known as secondary prevention) through lipid lowering therapies.^5,6

Adults with psychiatric illness shoulder a disproportionate burden of CVD morbidity and mortality, especially those with severe mental illness (SMI, schizophrenia, schizoaffective disorder, bipolar disorder, treatment-resistant depression).^7-9 Among modifiable CVD risk factors, dyslipidemia has the highest rates of missed screenings and treatment within psychiatric populations. In one analysis, up to 90% of adults with SMI and identified lipid disorders did not receive treatment.¹⁰ Persons with SMI generally do not receive guideline-concordant, systematic quality preventive care, which contributes to a widening mortality gap for this population.^11,12

This review aims to provide clinicians with practical guidance on the assessment and management of high cholesterol to improve recognition and treatment, lower CVD risk, and reduce this observed mortality gap.

Screening and diagnosis

In 2013, the American College of Cardiology (ACC) and the American Heart Association (AHA) released updated guidelines on diagnosing and managing high cholesterol to reduce CVD risk.¹ These guidelines focus on updated 10-year CVD risk assessment models with treatment goals reliant on adherence to statin therapy rather than pre-specified cholesterol targets listed in previous guidelines.¹³

Updates to assessment and treatment guidelines have removed some barriers to screening and diagnosing high cholesterol—namely, fasting lipid panels are no longer required to determine 10-year CVD risk and initiate treatment.¹⁴ For adults taking a second-generation antipsychotic that is associated with weight gain and metabolic syndrome, experts generally recommend yearly non-fasting lipid panels.^6,14

The United States Preventive Services Task Force recommends screening:

• men age ≥35 at average risk for CVD every 5 years
• women age ≥45 every 5 years¹⁵
• adults as young as age 20 who have accelerated risk factors, such as cigarette smoking and hypertension
• adults with a family history of heart attack or stroke in male first-degree relative age ≥50 and female first-degree relatives age ≥60.

Many adults receiving care in behavioral health settings, regardless of their medication regimen, qualify for screening at least every 5 years, if not more frequently. Although statin treatment before age 40 is less beneficial and likely not necessary for primary prevention, monitoring could help identify alternative therapies and prioritize more intensive diet and lifestyle modifications.

Treatment and management

Dietary modification and lifestyle changes (exercise, quitting smoking), lowering high cholesterol with medications, and switching from highly metabolically active drugs to less metabolically active ones can help lower total cholesterol in patients at risk of CVD.

Statins

HMG-CoA reductase inhibitors (statins) consistently reduce total cholesterol and non-HDL cholesterol by 30% to 50%, depending on drug and dosage (potency, listed as low, medium, and high). Not all statins are equally effective at lowering cholesterol; some are more potent than others (Table 2).¹⁶

Individuals are eligible for statin therapy based on their level of CVD risk. Persons at higher risk generally benefit from greater intensity statin treatment and cholesterol reduction; highest intensity statin regimens can lower total cholesterol by approximately 50%.

There are 4 statin eligibility classes (Table 3). Most adults fall into category 4: 10-year risk of >7.5% and needing primary prevention. In addition to removing specific LDL targets as therapy goals, calculation of this risk percentage and the specific cut-off values have been the most controversial aspects of the new cholesterol guidelines. Most experts agree that, in adults age 40 to 75, 10-year risk >10% indicates daily statin use as tolerated for primary prevention, and 10-year risk <5% does not warrant statin use. Recent large studies have validated these new techniques for calculating risk, and found them to be beneficial in potential for cost savings and risk classification.^17,18

Considerations in psychiatric patients. Statins have been associated with depression in case series, but larger analyses have not confirmed this association.¹⁹ Emerging evidence has identified a potential correlation between statin use and accelerated onset of T2DM, but the absolute risk is relatively low and most experts continue to recommend statin therapy despite this potential risk.¹³ Many statins, including atorvastatin, are available as a generic and can be taken once daily. Some, such as simvastatin, have notable interactions with commonly prescribed psychotropics including risperidone and quetiapine. Pravastatin is dually excreted by the liver and kidneys and may have fewer drug-drug interactions in patients with psychiatric illness taking common psychotropic therapies, but is not considered a high-potency statin and might not confer adequate benefits in CVD risk reduction.

Contraindications. Statins are pregnancy category X, and generally should not be prescribed for women of childbearing age without intensive counseling. The most notable adverse effects for statins include muscle aches and cramps (myalgia), but generally are not severe. If encountered, consider checking a serum creatinine kinase (CK) level, and if significantly elevated above 10 times the upper limit, stopping statin therapy would be advised. If the CK is only mildly elevated, consider lowering the dosage or switching to a lower potency agent. Lovastatin and pravastatin generally are better tolerated than atorvastatin and are considered lower potency (Table 2).

Statins can be safely used in the presence of liver conditions, such as hepatitis C and alcohol use, although periodic monitoring of transaminase levels is recommended. For adults in the general population without liver disease, regular monitoring of transaminase levels is not necessary.

Alternate lipid-lowering pharmacotherapies unfortunately have fallen out of favor. Fibrates, niacin, ezetimibe, and omega-3 fatty acids once were recommended to lower triglycerides or raise HDL cholesterol levels, but since have been shown to have little effect on cardiovascular morbidity or mortality. Adding further medications, other than statins, to lower cholesterol values to pre-defined targets is not the current standard of care.

High triglyceride concentrations traditionally have been addressed directly, but failure to improve CVD mortality or morbidity by treating triglycerides alone has resulted in refocusing clinical efforts in dyslipidemia management on atherogenic cholesterol, including LDL and non-HDL fractions.²⁰ Non-fasting triglycerides >500 mg/dL should be retested when fasting, and levels that remain >500 mg/dL could place the patient at risk for pancreatitis and might warrant intervention with fibrates at that time. This scenario is not common, and referral to a primary care physician or endocrinologist may be warranted.

Lifestyle changes

With or without statin therapies, diet and lifestyle changes are the cornerstone of healthy living and should be encouraged in all patients. Most overweight or obese patients will benefit from exercise and dietary modifications. Such interventions have shown potential for reducing total cholesterol and non-HDL and HDL cholesterol, but rarely are these interventions sustained long enough to produce meaningful reduction in CVD risk through lipid lowering. Diets rich in isocaloric tree nuts and red-yeast rice extract—a form of a statin—have shown promise in reducing cholesterol, but typically take excessive personal resources and are not sustained to the degree necessary to reduce CVD risk over time.²¹ Similarly, regular exercise routines can help lower overall cholesterol numbers, but rarely reduce total cholesterol by >10%.

Because individuals with SMI smoke at a higher rate than the general population, it should be noted that smoking cessation is associated with a reduction in total cholesterol and a trial of smoking cessation therapy is warranted before initiating a statin medication for primary prevention of CVD. Many patients would discover that their 10-year ASCVD risk would fall under the level needed for statin therapy if they could successfully stop smoking.

Switching pharmacotherapies

Switching antipsychotic agents from highly metabolically risky compounds, such as risperidone and olanzapine, to less metabolically active compounds, such as aripiprazole, ziprasidone, or haloperidol, have been associated with improvements in lipid profiles.^22-24 Clinicians must weigh the potential benefits of switching therapies against the risk of psychiatric destabilization and long-term adherence, keeping in mind that changes in lipids seen with switching could be mild (approximately 10% reduction in total cholesterol).

Summing up

Cholesterol management is considered part of a program to systematically lower CVD risk. Statin therapy usually is indicated for life, or until the age of 75, at which point treatment risks and benefits change because of life expectancy. Other components of CVD risk reduction include a focus on blood pressure control, smoking cessation, T2DM management, and weight loss. Tracking lipid profiles over time to ensure broad targets of 30% to 50% reduction in total cholesterol, approximately 3 months after initiation and yearly thereafter, can help ensure adherence to therapy. With systematic lowering of modifiable CVD risk factors, we can hope to gradually improve the quality of life for our patients with mental illnesses (see the Box for a case example illustrating successful use of these strategies).

Suicide is a staggering, tragic, and growing cause of death in the United States. One out of every 62 Americans will die from suicide, based on the national lifetime prevalence rate.¹ More than 42,000 Americans died from suicide in 2014, making suicide the second leading cause of death in individuals age 15 to 34, the fourth leading cause among those age 35 to 54, and the tenth leading cause of death in the country overall.² The incidence of suicide in the general population of the United States increased by 24% between 1999 and 2014.³ This tragedy obviously is not solving itself.

The proposal

U.S. Centers for Disease Control and Prevention (CDC) publishes statistics about the number of suicides, as well as demographic information, collected from coroners and medical examiners across the country. However, these sources do not provide a biological sample that could be used to gather data concerning DNA, RNA, and other potential blood markers, including those reflecting inflammatory and epigenetic processes. However, such biological samples are commonly collected by the U.S. medicolegal death investigation system. In 2003, this system investigated 450,000 unnatural and/or unexplained deaths (ie, approximately 20% of the 2.4 million deaths in the United States that year).⁴

Each unnatural or unexplained death is examined, often extensively, by a coroner or medical examiner. This examination system costs more than $600 million annually. Yet the data that are collected are handled on a case-by-case and often county-by-county basis, rather than in aggregate. The essence of the proposal presented here is to take the information and biological samples collected in this process and put them into a National Suicide Database (NSD), which then can serve as a resource for scientists to increase our understanding of the genetic, epigenetic, and other factors underlying death due to suicide. This increased understanding will result in the development more effective tools to detect to those at risk for suicide (ie, risk factor tests), to monitor treatment, and to develop new treatments based on a better understanding of the underlying pathophysiology and pathogenesis of suicide. These tools will reduce:

• the number of lives lost to suicide
• the pain and suffering of loved ones
• lost productivity to society, especially when one considers that suicide disproportionately affects individuals during the most productive period of their lives (ie, age 15 to 54).

The NSD will be organized as a government–private partnership, with the government represented by the National Institutes of Health (NIH) and/or the CDC. The goal will be to take the information that is currently being collected by the nation’s medicolegal death investigation system, including the biological samples, systematize it, enter it into a common database, and make it available to qualified researchers across the country. The administrative arm of the system will be responsible for ensuring systematic data collection, storage in a searchable and integrated database housed within the NIH and/or the CDC, and vetting researchers who will have access to the data, including those with expertise in genomics, molecular biology, suicide, epidemiology, and data-mining. (Currently, the CDC’s National Violent Death Reporting System, which is a state-based surveillance system, pools data on violent deaths from multiple sources into a usable, anonymous database. These sources include state and local medical examiners, coroners, law enforcement, crime labs, and vital statistics records, but they do not include any biological material even though it is collected [personal correspondence with the CDC, July 2016].)

Because information on suicides currently are handled primarily on a county-by-county basis, data concerning these deaths are not facilitating a better understanding of the causes and strategies for preventing suicide. Correcting this situation is the goal of this proposal, as modeled by the National Cancer Institute’s War on Cancer, which has transformed the treatment and the outcomes of cancer. If this proposal is enacted, the same type of transformation will occur and result in a reduction in the suicide rate and better outcomes for the psychiatric illnesses that underlie most instances of suicide.

The proposed NSD will address a major and common problem for researchers in this area—small sample sizes. When considered from the perspective of the size of samples feasible for most independent research teams to collect and study, suicide on an annual basis is rare—however, that is not the case when the incidence of suicide in the nation as a whole is considered. In contrast to the data concerning suicides that individual research teams can collect, the proposed genomic database will grow by approximately 40,000 individuals every year, until a meaningful reduction in deaths due to suicide is achieved.

From a research perspective, suicide, although tragic, is one of the few binary outcomes in psychiatry—that is, life or death. Although there may be >1 genetic and/or epigenetic contributor to suicide, within a relatively short period of time, the proposed database will amass—and continue to amass on an ongoing basis—data from a large population of suicide victims. Researchers then can compare the findings from this database with the normative human genome, looking for variants that are over-represented in the population of those who have died by suicide.

Environmental factors undoubtedly also contribute to the risk of suicide, given that the incidence of suicide increases with age, particularly among white males, and with the addition of psychiatric and medical comorbidities. Inflammatory processes also have been implicated in the pathophysiology of a number of psychiatric disorders, including major depression, which is the primary psychiatric risk factor for suicide. Therefore, consideration should be given to collecting whole blood samples if the time between death and autopsy is within an appropriate limit to obtain interpretable data concerning RNA (ie, gene expression) and even biomarkers of inflammatory and other processes at the time of the suicide. This approach has been used by Niculescu et al^5,6 for whole blood gene expression. The rationale for using samples of whole blood is that this strategy could be more easily adapted to clinical practice in contrast to using samples from the target organ (ie, brain) or cerebrospinal fluid.

Roadblocks to progress. In the absence of this proposed NSD, progress in this area has been stymied despite concerted governmental efforts (Box^7-10). One reason for the lack of progress has been that governmental efforts have focused on a public health model rather than also including a basic science model aimed at exploring the biological mechanisms underlying the risk of death from suicide. In the current decentralized system, individual researchers and even teams of researchers cannot easily collect data from a sufficiently large population of suicide victims to make inroads in gaining the needed understanding.

Because of the relatively small samples that individual research teams can collect in a reasonable period of time (ie, in terms of grant cycles), many investigators have studied suicide attempts as a surrogate for suicide itself, undoubtedly because suicide attempts are more numerous than suicides themselves, making it easier to collect data. However, there is evidence that these 2 populations—suicide attempters vs those who die by suicide—only partially overlap.

First, the frequency of suicide attempts is 10 to 20 times higher than actual suicides. Second, suicide attempters are 3 times more likely to be female whereas those who die by suicide are 4 times more likely to be male. Third, most individuals who die by suicide do so on their first or second attempt, whereas individuals who have made ≥4 attempts have an increased risk of future attempts rather than for completed suicide compared with the general population. Fourth, certain psychiatric illnesses are more often associated with death by suicide (particularly major depressive disorder, bipolar disorder, and schizophrenia in the first 5 years of an illness) whereas multiple suicide attempts are more often associated with other psychiatric diagnoses such as antisocial and borderline personality disorders.

Finally, in a study in men with a psychiatric disorder, Niculescu et al⁵ started with 412 candidate genes and found that 208 were associated with suicidal ideation but not suicide itself, whereas 76 genes were associated with both suicidal ideation and completion. Taken together, this evidence suggests that findings concerning suicide attempters, especially those who have made multiple (ie, >3) attempts, might not be extrapolatable to the population of actual suicides.

Is there evidence that this proposal could work?

Yes, research supports the potential utility of the proposed NSD, and this section highlights some of the major findings from these studies, although this review is not intended to be exhaustive.

First, considerable evidence exists for a biological basis for the risk of death due to suicide. The concordance rates for suicide are 10 times higher in monozygotic (“identical”) vs dizygotic (“fraternal”) twins (24.1% vs 2.8%) and 2 to 5 times higher in relatives of those who die by suicide than in the general population. Heritability estimates of fatal suicides and nonfatal suicide attempts in biological relatives of adoptees who die from suicide range from 17% to 45%.¹¹

Second, studies using information from small samples that was arduously collected by individual research groups have yielded important positive data. Most recently, in 2015, a multidisciplinary group led by Niculescu et al⁵ at Indiana University and other institutions described a test that could predict suicidality in men. This test was developed on the basis of a within-participant discovery approach to identify genes that change in expression between states of no suicidal ideation and high suicidal ideation, which was combined with clinical information assessed by 2 scales, the Convergent Functional Information for Suicidality and the Simplified Affective State Scale. Gene expression was measured in whole blood collected postmortem unless the method of suicide involved a medication overdose that could affect gene expression. These researchers identified 76 genes that likely were involved in suicidal ideation and suicide.

This report had a number of limitations.⁵ All of the individuals in these studies were being treated for psychiatric illness, were being closely followed by the investigators, and all were male. In addition, as noted above, suicides by overdose were eliminated from the analysis.

In a subsequent study published in 2016, the Niculescu group⁶ extended their work to women and identified 50 genes contributing to suicide risk in women. Underscoring the need for larger samples, only 3 of the top contributing genes were seen in both men and women, suggesting that there are likely significant sex differences in the biology of suicide completion. This important work needs to be replicated and extended.

In addition to these remarkable advances made in genetic understanding of the risk of suicide, recent research also has demonstrated a role for epigenetic and inflammatory processes as contributors to suicide risk.^12-15

There are likely many contributors, including genetic, epigenetic, and environmental factors such as inflammatory processes, that increase the risk of suicide. The goal of this article is not to provide an exhaustive or integrative review of research in this area but rather to argue for the establishment of a national initiative to study all of these factors and to begin that process by establishing the NSD.

What will be the foreseeable outcome of this initiative?

The establishment of the NSD is expected to lead to better identification of those who are genetically at increased risk of suicide as well as biological factors (eg, inflammatory or other processes) and environmental factors (eg, drug abuse), which can turn that genetic risk into reality. Using research results made possible by the implementation of this proposal, objective testing can be developed to monitor risk more effectively than is currently possible using clinical assessment alone.

Furthermore, this work also can provide targets for developing new treatments. For example, there is convergence between the work of Niculescu et al,^5,6 who identified genetic biomarkers for mechanistic target of rapamycin (mTOR) signaling as a risk factor in individuals who died by suicide and the work of Li et al and other researchers,^16-18 whose findings have implicated mTOR-dependent synapse formation as a mechanism underlying the rapid (ie, within hours to a couple of days) antidepressant effects of N-methyl-d-aspartate antagonists, such as ketamine, CP-101,606, and esketamine. In fact, the authors of a study presented earlier this year reported that esketamine—an active enantiomer of ketamine—rapidly reduced suicidal ideation as well as other depressive symptoms in individuals admitted to the hospital for suicidal ideation.¹⁹ (mTOR is a serine/threonine protein kinase that regulates a number of biological processes in addition to synaptogenesis, including cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and autophagy.^20,21)

In aggregate, establishment of this proposed database will facilitate identification of biological (and therefore pharmaceutical) mechanisms beyond those involving biogenic amines, which have been the exclusive biological targets for antidepressants for the past 50 years.²² The likely consequences of the findings generated from research made possible by the proposed NSD will open completely new vistas for helping people at risk for suicide and psychiatric illnesses.

What foreseeable obstacles will need to be addressed?

Of course, obstacles and problems will arise but these will not exceed those encountered by the War on Cancer and they can similarly be overcome with sufficient public support and cooperation. Potential obstacles include:

• need for incremental funding
• obtaining the cooperation of the offices of each county medical examiner or coroner in a process that includes uniform systematic data collection
• determining the situations (eg, time after death and means of death) that will allow for meaningful collection of data such as RNA and inflammatory biomarkers
• establishing how data and particularly biological samples will be transported and stored
• issues related to privacy of health information particularly for relatives of suicide victims
• ensuring the reliability, validity, and comparability of the data received from different medical examiners and coroners.

With regard to the last issue, because stigma is associated with death by suicide, some true suicides could be missed, which would compromise sensitivity but simultaneously increase specificity. Other obstacles or problems may arise; however, I am certain that all such issues are surmountable and that the resulting NSD will be much better than what we have now and will propel our understanding of the biological underpinnings of the loss of life to suicide. (The author proposed a similar but even more ambitious plan 25 years ago,²³ but he believes that this is an idea whose time has come.)

Acknowledgments

The author thanks Wayne C. Drevets, MD, Alexander Niculescu, MD, PhD, John Oldman, MD, and John Savitz, PhD, David Sheehan, MD, and Matthew Macaluso, DO for their review and suggestions concerning this proposal/manuscript, and Kaylee Hervey, MPH, from the Sedgwick County Health Department, Wichita, Kansas, for her input. The author also thanks Ruth Ross, as always, for her excellent editing and general assistance.

Suicide is a staggering, tragic, and growing cause of death in the United States. One out of every 62 Americans will die from suicide, based on the national lifetime prevalence rate.¹ More than 42,000 Americans died from suicide in 2014, making suicide the second leading cause of death in individuals age 15 to 34, the fourth leading cause among those age 35 to 54, and the tenth leading cause of death in the country overall.² The incidence of suicide in the general population of the United States increased by 24% between 1999 and 2014.³ This tragedy obviously is not solving itself.

The proposal

U.S. Centers for Disease Control and Prevention (CDC) publishes statistics about the number of suicides, as well as demographic information, collected from coroners and medical examiners across the country. However, these sources do not provide a biological sample that could be used to gather data concerning DNA, RNA, and other potential blood markers, including those reflecting inflammatory and epigenetic processes. However, such biological samples are commonly collected by the U.S. medicolegal death investigation system. In 2003, this system investigated 450,000 unnatural and/or unexplained deaths (ie, approximately 20% of the 2.4 million deaths in the United States that year).⁴

Each unnatural or unexplained death is examined, often extensively, by a coroner or medical examiner. This examination system costs more than $600 million annually. Yet the data that are collected are handled on a case-by-case and often county-by-county basis, rather than in aggregate. The essence of the proposal presented here is to take the information and biological samples collected in this process and put them into a National Suicide Database (NSD), which then can serve as a resource for scientists to increase our understanding of the genetic, epigenetic, and other factors underlying death due to suicide. This increased understanding will result in the development more effective tools to detect to those at risk for suicide (ie, risk factor tests), to monitor treatment, and to develop new treatments based on a better understanding of the underlying pathophysiology and pathogenesis of suicide. These tools will reduce:

• the number of lives lost to suicide
• the pain and suffering of loved ones
• lost productivity to society, especially when one considers that suicide disproportionately affects individuals during the most productive period of their lives (ie, age 15 to 54).

The NSD will be organized as a government–private partnership, with the government represented by the National Institutes of Health (NIH) and/or the CDC. The goal will be to take the information that is currently being collected by the nation’s medicolegal death investigation system, including the biological samples, systematize it, enter it into a common database, and make it available to qualified researchers across the country. The administrative arm of the system will be responsible for ensuring systematic data collection, storage in a searchable and integrated database housed within the NIH and/or the CDC, and vetting researchers who will have access to the data, including those with expertise in genomics, molecular biology, suicide, epidemiology, and data-mining. (Currently, the CDC’s National Violent Death Reporting System, which is a state-based surveillance system, pools data on violent deaths from multiple sources into a usable, anonymous database. These sources include state and local medical examiners, coroners, law enforcement, crime labs, and vital statistics records, but they do not include any biological material even though it is collected [personal correspondence with the CDC, July 2016].)

Because information on suicides currently are handled primarily on a county-by-county basis, data concerning these deaths are not facilitating a better understanding of the causes and strategies for preventing suicide. Correcting this situation is the goal of this proposal, as modeled by the National Cancer Institute’s War on Cancer, which has transformed the treatment and the outcomes of cancer. If this proposal is enacted, the same type of transformation will occur and result in a reduction in the suicide rate and better outcomes for the psychiatric illnesses that underlie most instances of suicide.

The proposed NSD will address a major and common problem for researchers in this area—small sample sizes. When considered from the perspective of the size of samples feasible for most independent research teams to collect and study, suicide on an annual basis is rare—however, that is not the case when the incidence of suicide in the nation as a whole is considered. In contrast to the data concerning suicides that individual research teams can collect, the proposed genomic database will grow by approximately 40,000 individuals every year, until a meaningful reduction in deaths due to suicide is achieved.

From a research perspective, suicide, although tragic, is one of the few binary outcomes in psychiatry—that is, life or death. Although there may be >1 genetic and/or epigenetic contributor to suicide, within a relatively short period of time, the proposed database will amass—and continue to amass on an ongoing basis—data from a large population of suicide victims. Researchers then can compare the findings from this database with the normative human genome, looking for variants that are over-represented in the population of those who have died by suicide.

Environmental factors undoubtedly also contribute to the risk of suicide, given that the incidence of suicide increases with age, particularly among white males, and with the addition of psychiatric and medical comorbidities. Inflammatory processes also have been implicated in the pathophysiology of a number of psychiatric disorders, including major depression, which is the primary psychiatric risk factor for suicide. Therefore, consideration should be given to collecting whole blood samples if the time between death and autopsy is within an appropriate limit to obtain interpretable data concerning RNA (ie, gene expression) and even biomarkers of inflammatory and other processes at the time of the suicide. This approach has been used by Niculescu et al^5,6 for whole blood gene expression. The rationale for using samples of whole blood is that this strategy could be more easily adapted to clinical practice in contrast to using samples from the target organ (ie, brain) or cerebrospinal fluid.

Roadblocks to progress. In the absence of this proposed NSD, progress in this area has been stymied despite concerted governmental efforts (Box^7-10). One reason for the lack of progress has been that governmental efforts have focused on a public health model rather than also including a basic science model aimed at exploring the biological mechanisms underlying the risk of death from suicide. In the current decentralized system, individual researchers and even teams of researchers cannot easily collect data from a sufficiently large population of suicide victims to make inroads in gaining the needed understanding.

Because of the relatively small samples that individual research teams can collect in a reasonable period of time (ie, in terms of grant cycles), many investigators have studied suicide attempts as a surrogate for suicide itself, undoubtedly because suicide attempts are more numerous than suicides themselves, making it easier to collect data. However, there is evidence that these 2 populations—suicide attempters vs those who die by suicide—only partially overlap.

First, the frequency of suicide attempts is 10 to 20 times higher than actual suicides. Second, suicide attempters are 3 times more likely to be female whereas those who die by suicide are 4 times more likely to be male. Third, most individuals who die by suicide do so on their first or second attempt, whereas individuals who have made ≥4 attempts have an increased risk of future attempts rather than for completed suicide compared with the general population. Fourth, certain psychiatric illnesses are more often associated with death by suicide (particularly major depressive disorder, bipolar disorder, and schizophrenia in the first 5 years of an illness) whereas multiple suicide attempts are more often associated with other psychiatric diagnoses such as antisocial and borderline personality disorders.

Finally, in a study in men with a psychiatric disorder, Niculescu et al⁵ started with 412 candidate genes and found that 208 were associated with suicidal ideation but not suicide itself, whereas 76 genes were associated with both suicidal ideation and completion. Taken together, this evidence suggests that findings concerning suicide attempters, especially those who have made multiple (ie, >3) attempts, might not be extrapolatable to the population of actual suicides.

Is there evidence that this proposal could work?

Yes, research supports the potential utility of the proposed NSD, and this section highlights some of the major findings from these studies, although this review is not intended to be exhaustive.

First, considerable evidence exists for a biological basis for the risk of death due to suicide. The concordance rates for suicide are 10 times higher in monozygotic (“identical”) vs dizygotic (“fraternal”) twins (24.1% vs 2.8%) and 2 to 5 times higher in relatives of those who die by suicide than in the general population. Heritability estimates of fatal suicides and nonfatal suicide attempts in biological relatives of adoptees who die from suicide range from 17% to 45%.¹¹

Second, studies using information from small samples that was arduously collected by individual research groups have yielded important positive data. Most recently, in 2015, a multidisciplinary group led by Niculescu et al⁵ at Indiana University and other institutions described a test that could predict suicidality in men. This test was developed on the basis of a within-participant discovery approach to identify genes that change in expression between states of no suicidal ideation and high suicidal ideation, which was combined with clinical information assessed by 2 scales, the Convergent Functional Information for Suicidality and the Simplified Affective State Scale. Gene expression was measured in whole blood collected postmortem unless the method of suicide involved a medication overdose that could affect gene expression. These researchers identified 76 genes that likely were involved in suicidal ideation and suicide.

This report had a number of limitations.⁵ All of the individuals in these studies were being treated for psychiatric illness, were being closely followed by the investigators, and all were male. In addition, as noted above, suicides by overdose were eliminated from the analysis.

In a subsequent study published in 2016, the Niculescu group⁶ extended their work to women and identified 50 genes contributing to suicide risk in women. Underscoring the need for larger samples, only 3 of the top contributing genes were seen in both men and women, suggesting that there are likely significant sex differences in the biology of suicide completion. This important work needs to be replicated and extended.

In addition to these remarkable advances made in genetic understanding of the risk of suicide, recent research also has demonstrated a role for epigenetic and inflammatory processes as contributors to suicide risk.^12-15

There are likely many contributors, including genetic, epigenetic, and environmental factors such as inflammatory processes, that increase the risk of suicide. The goal of this article is not to provide an exhaustive or integrative review of research in this area but rather to argue for the establishment of a national initiative to study all of these factors and to begin that process by establishing the NSD.

What will be the foreseeable outcome of this initiative?

The establishment of the NSD is expected to lead to better identification of those who are genetically at increased risk of suicide as well as biological factors (eg, inflammatory or other processes) and environmental factors (eg, drug abuse), which can turn that genetic risk into reality. Using research results made possible by the implementation of this proposal, objective testing can be developed to monitor risk more effectively than is currently possible using clinical assessment alone.

Furthermore, this work also can provide targets for developing new treatments. For example, there is convergence between the work of Niculescu et al,^5,6 who identified genetic biomarkers for mechanistic target of rapamycin (mTOR) signaling as a risk factor in individuals who died by suicide and the work of Li et al and other researchers,^16-18 whose findings have implicated mTOR-dependent synapse formation as a mechanism underlying the rapid (ie, within hours to a couple of days) antidepressant effects of N-methyl-d-aspartate antagonists, such as ketamine, CP-101,606, and esketamine. In fact, the authors of a study presented earlier this year reported that esketamine—an active enantiomer of ketamine—rapidly reduced suicidal ideation as well as other depressive symptoms in individuals admitted to the hospital for suicidal ideation.¹⁹ (mTOR is a serine/threonine protein kinase that regulates a number of biological processes in addition to synaptogenesis, including cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and autophagy.^20,21)

In aggregate, establishment of this proposed database will facilitate identification of biological (and therefore pharmaceutical) mechanisms beyond those involving biogenic amines, which have been the exclusive biological targets for antidepressants for the past 50 years.²² The likely consequences of the findings generated from research made possible by the proposed NSD will open completely new vistas for helping people at risk for suicide and psychiatric illnesses.

What foreseeable obstacles will need to be addressed?

Of course, obstacles and problems will arise but these will not exceed those encountered by the War on Cancer and they can similarly be overcome with sufficient public support and cooperation. Potential obstacles include:

• need for incremental funding
• obtaining the cooperation of the offices of each county medical examiner or coroner in a process that includes uniform systematic data collection
• determining the situations (eg, time after death and means of death) that will allow for meaningful collection of data such as RNA and inflammatory biomarkers
• establishing how data and particularly biological samples will be transported and stored
• issues related to privacy of health information particularly for relatives of suicide victims
• ensuring the reliability, validity, and comparability of the data received from different medical examiners and coroners.

With regard to the last issue, because stigma is associated with death by suicide, some true suicides could be missed, which would compromise sensitivity but simultaneously increase specificity. Other obstacles or problems may arise; however, I am certain that all such issues are surmountable and that the resulting NSD will be much better than what we have now and will propel our understanding of the biological underpinnings of the loss of life to suicide. (The author proposed a similar but even more ambitious plan 25 years ago,²³ but he believes that this is an idea whose time has come.)

Acknowledgments

The author thanks Wayne C. Drevets, MD, Alexander Niculescu, MD, PhD, John Oldman, MD, and John Savitz, PhD, David Sheehan, MD, and Matthew Macaluso, DO for their review and suggestions concerning this proposal/manuscript, and Kaylee Hervey, MPH, from the Sedgwick County Health Department, Wichita, Kansas, for her input. The author also thanks Ruth Ross, as always, for her excellent editing and general assistance.

Suicide is a staggering, tragic, and growing cause of death in the United States. One out of every 62 Americans will die from suicide, based on the national lifetime prevalence rate.¹ More than 42,000 Americans died from suicide in 2014, making suicide the second leading cause of death in individuals age 15 to 34, the fourth leading cause among those age 35 to 54, and the tenth leading cause of death in the country overall.² The incidence of suicide in the general population of the United States increased by 24% between 1999 and 2014.³ This tragedy obviously is not solving itself.

The proposal

U.S. Centers for Disease Control and Prevention (CDC) publishes statistics about the number of suicides, as well as demographic information, collected from coroners and medical examiners across the country. However, these sources do not provide a biological sample that could be used to gather data concerning DNA, RNA, and other potential blood markers, including those reflecting inflammatory and epigenetic processes. However, such biological samples are commonly collected by the U.S. medicolegal death investigation system. In 2003, this system investigated 450,000 unnatural and/or unexplained deaths (ie, approximately 20% of the 2.4 million deaths in the United States that year).⁴

Each unnatural or unexplained death is examined, often extensively, by a coroner or medical examiner. This examination system costs more than $600 million annually. Yet the data that are collected are handled on a case-by-case and often county-by-county basis, rather than in aggregate. The essence of the proposal presented here is to take the information and biological samples collected in this process and put them into a National Suicide Database (NSD), which then can serve as a resource for scientists to increase our understanding of the genetic, epigenetic, and other factors underlying death due to suicide. This increased understanding will result in the development more effective tools to detect to those at risk for suicide (ie, risk factor tests), to monitor treatment, and to develop new treatments based on a better understanding of the underlying pathophysiology and pathogenesis of suicide. These tools will reduce:

• the number of lives lost to suicide
• the pain and suffering of loved ones
• lost productivity to society, especially when one considers that suicide disproportionately affects individuals during the most productive period of their lives (ie, age 15 to 54).

The NSD will be organized as a government–private partnership, with the government represented by the National Institutes of Health (NIH) and/or the CDC. The goal will be to take the information that is currently being collected by the nation’s medicolegal death investigation system, including the biological samples, systematize it, enter it into a common database, and make it available to qualified researchers across the country. The administrative arm of the system will be responsible for ensuring systematic data collection, storage in a searchable and integrated database housed within the NIH and/or the CDC, and vetting researchers who will have access to the data, including those with expertise in genomics, molecular biology, suicide, epidemiology, and data-mining. (Currently, the CDC’s National Violent Death Reporting System, which is a state-based surveillance system, pools data on violent deaths from multiple sources into a usable, anonymous database. These sources include state and local medical examiners, coroners, law enforcement, crime labs, and vital statistics records, but they do not include any biological material even though it is collected [personal correspondence with the CDC, July 2016].)

Because information on suicides currently are handled primarily on a county-by-county basis, data concerning these deaths are not facilitating a better understanding of the causes and strategies for preventing suicide. Correcting this situation is the goal of this proposal, as modeled by the National Cancer Institute’s War on Cancer, which has transformed the treatment and the outcomes of cancer. If this proposal is enacted, the same type of transformation will occur and result in a reduction in the suicide rate and better outcomes for the psychiatric illnesses that underlie most instances of suicide.

The proposed NSD will address a major and common problem for researchers in this area—small sample sizes. When considered from the perspective of the size of samples feasible for most independent research teams to collect and study, suicide on an annual basis is rare—however, that is not the case when the incidence of suicide in the nation as a whole is considered. In contrast to the data concerning suicides that individual research teams can collect, the proposed genomic database will grow by approximately 40,000 individuals every year, until a meaningful reduction in deaths due to suicide is achieved.

From a research perspective, suicide, although tragic, is one of the few binary outcomes in psychiatry—that is, life or death. Although there may be >1 genetic and/or epigenetic contributor to suicide, within a relatively short period of time, the proposed database will amass—and continue to amass on an ongoing basis—data from a large population of suicide victims. Researchers then can compare the findings from this database with the normative human genome, looking for variants that are over-represented in the population of those who have died by suicide.

Environmental factors undoubtedly also contribute to the risk of suicide, given that the incidence of suicide increases with age, particularly among white males, and with the addition of psychiatric and medical comorbidities. Inflammatory processes also have been implicated in the pathophysiology of a number of psychiatric disorders, including major depression, which is the primary psychiatric risk factor for suicide. Therefore, consideration should be given to collecting whole blood samples if the time between death and autopsy is within an appropriate limit to obtain interpretable data concerning RNA (ie, gene expression) and even biomarkers of inflammatory and other processes at the time of the suicide. This approach has been used by Niculescu et al^5,6 for whole blood gene expression. The rationale for using samples of whole blood is that this strategy could be more easily adapted to clinical practice in contrast to using samples from the target organ (ie, brain) or cerebrospinal fluid.

Roadblocks to progress. In the absence of this proposed NSD, progress in this area has been stymied despite concerted governmental efforts (Box^7-10). One reason for the lack of progress has been that governmental efforts have focused on a public health model rather than also including a basic science model aimed at exploring the biological mechanisms underlying the risk of death from suicide. In the current decentralized system, individual researchers and even teams of researchers cannot easily collect data from a sufficiently large population of suicide victims to make inroads in gaining the needed understanding.

Because of the relatively small samples that individual research teams can collect in a reasonable period of time (ie, in terms of grant cycles), many investigators have studied suicide attempts as a surrogate for suicide itself, undoubtedly because suicide attempts are more numerous than suicides themselves, making it easier to collect data. However, there is evidence that these 2 populations—suicide attempters vs those who die by suicide—only partially overlap.

First, the frequency of suicide attempts is 10 to 20 times higher than actual suicides. Second, suicide attempters are 3 times more likely to be female whereas those who die by suicide are 4 times more likely to be male. Third, most individuals who die by suicide do so on their first or second attempt, whereas individuals who have made ≥4 attempts have an increased risk of future attempts rather than for completed suicide compared with the general population. Fourth, certain psychiatric illnesses are more often associated with death by suicide (particularly major depressive disorder, bipolar disorder, and schizophrenia in the first 5 years of an illness) whereas multiple suicide attempts are more often associated with other psychiatric diagnoses such as antisocial and borderline personality disorders.

Finally, in a study in men with a psychiatric disorder, Niculescu et al⁵ started with 412 candidate genes and found that 208 were associated with suicidal ideation but not suicide itself, whereas 76 genes were associated with both suicidal ideation and completion. Taken together, this evidence suggests that findings concerning suicide attempters, especially those who have made multiple (ie, >3) attempts, might not be extrapolatable to the population of actual suicides.

Is there evidence that this proposal could work?

Yes, research supports the potential utility of the proposed NSD, and this section highlights some of the major findings from these studies, although this review is not intended to be exhaustive.

First, considerable evidence exists for a biological basis for the risk of death due to suicide. The concordance rates for suicide are 10 times higher in monozygotic (“identical”) vs dizygotic (“fraternal”) twins (24.1% vs 2.8%) and 2 to 5 times higher in relatives of those who die by suicide than in the general population. Heritability estimates of fatal suicides and nonfatal suicide attempts in biological relatives of adoptees who die from suicide range from 17% to 45%.¹¹

Second, studies using information from small samples that was arduously collected by individual research groups have yielded important positive data. Most recently, in 2015, a multidisciplinary group led by Niculescu et al⁵ at Indiana University and other institutions described a test that could predict suicidality in men. This test was developed on the basis of a within-participant discovery approach to identify genes that change in expression between states of no suicidal ideation and high suicidal ideation, which was combined with clinical information assessed by 2 scales, the Convergent Functional Information for Suicidality and the Simplified Affective State Scale. Gene expression was measured in whole blood collected postmortem unless the method of suicide involved a medication overdose that could affect gene expression. These researchers identified 76 genes that likely were involved in suicidal ideation and suicide.

This report had a number of limitations.⁵ All of the individuals in these studies were being treated for psychiatric illness, were being closely followed by the investigators, and all were male. In addition, as noted above, suicides by overdose were eliminated from the analysis.

In a subsequent study published in 2016, the Niculescu group⁶ extended their work to women and identified 50 genes contributing to suicide risk in women. Underscoring the need for larger samples, only 3 of the top contributing genes were seen in both men and women, suggesting that there are likely significant sex differences in the biology of suicide completion. This important work needs to be replicated and extended.

In addition to these remarkable advances made in genetic understanding of the risk of suicide, recent research also has demonstrated a role for epigenetic and inflammatory processes as contributors to suicide risk.^12-15

There are likely many contributors, including genetic, epigenetic, and environmental factors such as inflammatory processes, that increase the risk of suicide. The goal of this article is not to provide an exhaustive or integrative review of research in this area but rather to argue for the establishment of a national initiative to study all of these factors and to begin that process by establishing the NSD.

What will be the foreseeable outcome of this initiative?

The establishment of the NSD is expected to lead to better identification of those who are genetically at increased risk of suicide as well as biological factors (eg, inflammatory or other processes) and environmental factors (eg, drug abuse), which can turn that genetic risk into reality. Using research results made possible by the implementation of this proposal, objective testing can be developed to monitor risk more effectively than is currently possible using clinical assessment alone.

Furthermore, this work also can provide targets for developing new treatments. For example, there is convergence between the work of Niculescu et al,^5,6 who identified genetic biomarkers for mechanistic target of rapamycin (mTOR) signaling as a risk factor in individuals who died by suicide and the work of Li et al and other researchers,^16-18 whose findings have implicated mTOR-dependent synapse formation as a mechanism underlying the rapid (ie, within hours to a couple of days) antidepressant effects of N-methyl-d-aspartate antagonists, such as ketamine, CP-101,606, and esketamine. In fact, the authors of a study presented earlier this year reported that esketamine—an active enantiomer of ketamine—rapidly reduced suicidal ideation as well as other depressive symptoms in individuals admitted to the hospital for suicidal ideation.¹⁹ (mTOR is a serine/threonine protein kinase that regulates a number of biological processes in addition to synaptogenesis, including cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and autophagy.^20,21)

In aggregate, establishment of this proposed database will facilitate identification of biological (and therefore pharmaceutical) mechanisms beyond those involving biogenic amines, which have been the exclusive biological targets for antidepressants for the past 50 years.²² The likely consequences of the findings generated from research made possible by the proposed NSD will open completely new vistas for helping people at risk for suicide and psychiatric illnesses.

What foreseeable obstacles will need to be addressed?

Of course, obstacles and problems will arise but these will not exceed those encountered by the War on Cancer and they can similarly be overcome with sufficient public support and cooperation. Potential obstacles include:

• need for incremental funding
• obtaining the cooperation of the offices of each county medical examiner or coroner in a process that includes uniform systematic data collection
• determining the situations (eg, time after death and means of death) that will allow for meaningful collection of data such as RNA and inflammatory biomarkers
• establishing how data and particularly biological samples will be transported and stored
• issues related to privacy of health information particularly for relatives of suicide victims
• ensuring the reliability, validity, and comparability of the data received from different medical examiners and coroners.

With regard to the last issue, because stigma is associated with death by suicide, some true suicides could be missed, which would compromise sensitivity but simultaneously increase specificity. Other obstacles or problems may arise; however, I am certain that all such issues are surmountable and that the resulting NSD will be much better than what we have now and will propel our understanding of the biological underpinnings of the loss of life to suicide. (The author proposed a similar but even more ambitious plan 25 years ago,²³ but he believes that this is an idea whose time has come.)

Acknowledgments

The author thanks Wayne C. Drevets, MD, Alexander Niculescu, MD, PhD, John Oldman, MD, and John Savitz, PhD, David Sheehan, MD, and Matthew Macaluso, DO for their review and suggestions concerning this proposal/manuscript, and Kaylee Hervey, MPH, from the Sedgwick County Health Department, Wichita, Kansas, for her input. The author also thanks Ruth Ross, as always, for her excellent editing and general assistance.