Depression

DENVER – Taking ozanimod for relapsing multiple sclerosis (MS) at the same time as taking antidepressants that increase serotonin levels does not appear to increase the risk for hypertension or any other adverse events related to serotonin toxicity, according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“Depression and anxiety are prevalent comorbidities occurring in up to 54% of patients with multiple sclerosis, and selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line treatments for depression and anxiety disorders,” Robert T. Naismith, MD, of Washington University in St. Louis, and his colleagues reported.

“Coadministration of ozanimod with drugs that increase serotonin could hypothetically lead to serotonin accumulation,” which can increase the likelihood of hypertension. U.S. prescribing information recommends that patients taking both ozanimod and medications that increase norepinephrine or serotonin be monitored for hypertension, an adverse reaction reported in 3.9% of patients receiving ozanimod in the phase 3 trials for relapsing MS.
 

Clarifying the risk

“It’s important to be aware of potential drug interactions and risks from MS disease modifying therapies,” Lauren Gluck, MD, an assistant professor and director of the division of multiple sclerosis at Montefiore Medical Center/Albert Einstein College of Medicine, New York, said in an interview. Dr. Gluck was not involved in this study but described some of the history that revealed the value of this type of research. For example, the first sphingosine-1-phosphate receptor (S1PR) modulator approved for MS, fingolimod (Gilenya), has a risk of cardiac conduction dysfunction with QTc prolongation, so people taking fingolimod with other medications that prolong QTc, such as SSRIs, need additional monitoring.

“Ozanimod is a newer, more selective S1PR modulator that initially raised concerns about interaction with serotonin-increasing drugs based on in vitro studies,” Dr. Gluck said. “This could mean that people on ozanimod and other serotonin-increasing medicine could be at risk for dangerous events like serotonin syndrome. However, in vitro studies do not always translate to how something affects the human body, so it is not clear how much risk truly exists.”
 

Examining open-label extension trial data

The researchers therefore evaluated the safety of taking ozanimod and SSRIs or SNRIs in a subset of patients with relapsing MS who participated in the DAYBREAK open-label extension trial. The phase 3 parent trials compared 30 mcg once weekly of intramuscular interferon beta-1a with 0.92 mg of once-daily oral ozanimod and 0.46 mg of once-daily oral ozanimod. In the DAYBREAK open-label extension, 2,256 participants underwent a dose escalation over one week until all reached 0.92 mg of ozanimod, where they remained for an average of just under 5 years of follow-up. Nearly all the participants (99.4%) were White, and two-thirds (66.5%) were female.

The researchers searched the study data for terms related to serotonin toxicity and compared the rates of adverse events related with those terms and the rates of hypertension in the 274 participants who were and the 2,032 participant who were not taking antidepressants at the same time as ozanimod.

They found that 13.9% of patients taking SSRIs or SNRIs experienced at least one treatment-emergent adverse event related to their search criteria, compared with 17.7% of patients not taking SSRIs or SNRIs. Similarly, 9.2% of trial participants not taking SSRIs or SNRIs had hypertension, compared with 4.7% of participants who were taking antidepressants. The authors further noted that “similar trends were observed when 6 weeks after the end date of concomitant SSRIs/SNRI use were included in the ‘on SSRI/SNRI’ analysis period.”

When the researchers searched specifically for three terms directly related to serotonin toxicity – “serotonin syndrome,” “neuroleptic malignant syndrome,” and “hyperthermia malignant” – they did not find any patients who had treatment-emergent adverse events related to those terms.

“SSRIs/SNRIs were freely allowed as concomitant medications in the DAYBREAK open-label extension, and among the patients from SUNBEAM or RADIANCE who were followed for up to 6 years, there have been no reported safety concerns during the concurrent administration of serotonergic antidepressants and ozanimod in patients with relapsing MS as of the data cutoff,” concluded the authors, though they also noted that the overall rate of SSRI and SNRI use was low in the extension trial.
 

A reassuring finding for clinicians and patients alike

“It is reassuring, if not unexpected, that there were no clinically significant rates of symptoms associated with excess serotonin in patients on ozanimod and SSRI/SNRIs,” Dr. Gluck commented. “These findings are important for both clinicians and patients – they can help [both] feel comfortable considering ozanimod if SSRI/SNRIs are already being used. There is also freedom to use SSRI/SNRIs for symptom management in patients already on ozanimod.”

The research was funded by Bristol Myers Squibb. Dr. Naismith reported consulting for Abata Therapeutics, Banner Life Sciences, BeiGene, Biogen, Bristol Myers Squibb, Celltrion, Genentech, Genzyme, GW Therapeutics, Janssen, Horizon Therapeutics, Lundbeck, NervGen, and TG Therapeutics. Six other authors reported disclosures for various pharmaceutical companies, and six other authors are employees and/or shareholders of Bristol Myers Squibb. Dr. Gluck has served on advisory boards with Genentech and EMD Serono.
 

DENVER – Taking ozanimod for relapsing multiple sclerosis (MS) at the same time as taking antidepressants that increase serotonin levels does not appear to increase the risk for hypertension or any other adverse events related to serotonin toxicity, according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“Depression and anxiety are prevalent comorbidities occurring in up to 54% of patients with multiple sclerosis, and selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line treatments for depression and anxiety disorders,” Robert T. Naismith, MD, of Washington University in St. Louis, and his colleagues reported.

“Coadministration of ozanimod with drugs that increase serotonin could hypothetically lead to serotonin accumulation,” which can increase the likelihood of hypertension. U.S. prescribing information recommends that patients taking both ozanimod and medications that increase norepinephrine or serotonin be monitored for hypertension, an adverse reaction reported in 3.9% of patients receiving ozanimod in the phase 3 trials for relapsing MS.
 

Clarifying the risk

“It’s important to be aware of potential drug interactions and risks from MS disease modifying therapies,” Lauren Gluck, MD, an assistant professor and director of the division of multiple sclerosis at Montefiore Medical Center/Albert Einstein College of Medicine, New York, said in an interview. Dr. Gluck was not involved in this study but described some of the history that revealed the value of this type of research. For example, the first sphingosine-1-phosphate receptor (S1PR) modulator approved for MS, fingolimod (Gilenya), has a risk of cardiac conduction dysfunction with QTc prolongation, so people taking fingolimod with other medications that prolong QTc, such as SSRIs, need additional monitoring.

“Ozanimod is a newer, more selective S1PR modulator that initially raised concerns about interaction with serotonin-increasing drugs based on in vitro studies,” Dr. Gluck said. “This could mean that people on ozanimod and other serotonin-increasing medicine could be at risk for dangerous events like serotonin syndrome. However, in vitro studies do not always translate to how something affects the human body, so it is not clear how much risk truly exists.”
 

Examining open-label extension trial data

The researchers therefore evaluated the safety of taking ozanimod and SSRIs or SNRIs in a subset of patients with relapsing MS who participated in the DAYBREAK open-label extension trial. The phase 3 parent trials compared 30 mcg once weekly of intramuscular interferon beta-1a with 0.92 mg of once-daily oral ozanimod and 0.46 mg of once-daily oral ozanimod. In the DAYBREAK open-label extension, 2,256 participants underwent a dose escalation over one week until all reached 0.92 mg of ozanimod, where they remained for an average of just under 5 years of follow-up. Nearly all the participants (99.4%) were White, and two-thirds (66.5%) were female.

The researchers searched the study data for terms related to serotonin toxicity and compared the rates of adverse events related with those terms and the rates of hypertension in the 274 participants who were and the 2,032 participant who were not taking antidepressants at the same time as ozanimod.

They found that 13.9% of patients taking SSRIs or SNRIs experienced at least one treatment-emergent adverse event related to their search criteria, compared with 17.7% of patients not taking SSRIs or SNRIs. Similarly, 9.2% of trial participants not taking SSRIs or SNRIs had hypertension, compared with 4.7% of participants who were taking antidepressants. The authors further noted that “similar trends were observed when 6 weeks after the end date of concomitant SSRIs/SNRI use were included in the ‘on SSRI/SNRI’ analysis period.”

When the researchers searched specifically for three terms directly related to serotonin toxicity – “serotonin syndrome,” “neuroleptic malignant syndrome,” and “hyperthermia malignant” – they did not find any patients who had treatment-emergent adverse events related to those terms.

“SSRIs/SNRIs were freely allowed as concomitant medications in the DAYBREAK open-label extension, and among the patients from SUNBEAM or RADIANCE who were followed for up to 6 years, there have been no reported safety concerns during the concurrent administration of serotonergic antidepressants and ozanimod in patients with relapsing MS as of the data cutoff,” concluded the authors, though they also noted that the overall rate of SSRI and SNRI use was low in the extension trial.
 

A reassuring finding for clinicians and patients alike

“It is reassuring, if not unexpected, that there were no clinically significant rates of symptoms associated with excess serotonin in patients on ozanimod and SSRI/SNRIs,” Dr. Gluck commented. “These findings are important for both clinicians and patients – they can help [both] feel comfortable considering ozanimod if SSRI/SNRIs are already being used. There is also freedom to use SSRI/SNRIs for symptom management in patients already on ozanimod.”

The research was funded by Bristol Myers Squibb. Dr. Naismith reported consulting for Abata Therapeutics, Banner Life Sciences, BeiGene, Biogen, Bristol Myers Squibb, Celltrion, Genentech, Genzyme, GW Therapeutics, Janssen, Horizon Therapeutics, Lundbeck, NervGen, and TG Therapeutics. Six other authors reported disclosures for various pharmaceutical companies, and six other authors are employees and/or shareholders of Bristol Myers Squibb. Dr. Gluck has served on advisory boards with Genentech and EMD Serono.
 

DENVER – Taking ozanimod for relapsing multiple sclerosis (MS) at the same time as taking antidepressants that increase serotonin levels does not appear to increase the risk for hypertension or any other adverse events related to serotonin toxicity, according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“Depression and anxiety are prevalent comorbidities occurring in up to 54% of patients with multiple sclerosis, and selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line treatments for depression and anxiety disorders,” Robert T. Naismith, MD, of Washington University in St. Louis, and his colleagues reported.

“Coadministration of ozanimod with drugs that increase serotonin could hypothetically lead to serotonin accumulation,” which can increase the likelihood of hypertension. U.S. prescribing information recommends that patients taking both ozanimod and medications that increase norepinephrine or serotonin be monitored for hypertension, an adverse reaction reported in 3.9% of patients receiving ozanimod in the phase 3 trials for relapsing MS.
 

Clarifying the risk

“It’s important to be aware of potential drug interactions and risks from MS disease modifying therapies,” Lauren Gluck, MD, an assistant professor and director of the division of multiple sclerosis at Montefiore Medical Center/Albert Einstein College of Medicine, New York, said in an interview. Dr. Gluck was not involved in this study but described some of the history that revealed the value of this type of research. For example, the first sphingosine-1-phosphate receptor (S1PR) modulator approved for MS, fingolimod (Gilenya), has a risk of cardiac conduction dysfunction with QTc prolongation, so people taking fingolimod with other medications that prolong QTc, such as SSRIs, need additional monitoring.

“Ozanimod is a newer, more selective S1PR modulator that initially raised concerns about interaction with serotonin-increasing drugs based on in vitro studies,” Dr. Gluck said. “This could mean that people on ozanimod and other serotonin-increasing medicine could be at risk for dangerous events like serotonin syndrome. However, in vitro studies do not always translate to how something affects the human body, so it is not clear how much risk truly exists.”
 

Examining open-label extension trial data

The researchers therefore evaluated the safety of taking ozanimod and SSRIs or SNRIs in a subset of patients with relapsing MS who participated in the DAYBREAK open-label extension trial. The phase 3 parent trials compared 30 mcg once weekly of intramuscular interferon beta-1a with 0.92 mg of once-daily oral ozanimod and 0.46 mg of once-daily oral ozanimod. In the DAYBREAK open-label extension, 2,256 participants underwent a dose escalation over one week until all reached 0.92 mg of ozanimod, where they remained for an average of just under 5 years of follow-up. Nearly all the participants (99.4%) were White, and two-thirds (66.5%) were female.

The researchers searched the study data for terms related to serotonin toxicity and compared the rates of adverse events related with those terms and the rates of hypertension in the 274 participants who were and the 2,032 participant who were not taking antidepressants at the same time as ozanimod.

They found that 13.9% of patients taking SSRIs or SNRIs experienced at least one treatment-emergent adverse event related to their search criteria, compared with 17.7% of patients not taking SSRIs or SNRIs. Similarly, 9.2% of trial participants not taking SSRIs or SNRIs had hypertension, compared with 4.7% of participants who were taking antidepressants. The authors further noted that “similar trends were observed when 6 weeks after the end date of concomitant SSRIs/SNRI use were included in the ‘on SSRI/SNRI’ analysis period.”

When the researchers searched specifically for three terms directly related to serotonin toxicity – “serotonin syndrome,” “neuroleptic malignant syndrome,” and “hyperthermia malignant” – they did not find any patients who had treatment-emergent adverse events related to those terms.

“SSRIs/SNRIs were freely allowed as concomitant medications in the DAYBREAK open-label extension, and among the patients from SUNBEAM or RADIANCE who were followed for up to 6 years, there have been no reported safety concerns during the concurrent administration of serotonergic antidepressants and ozanimod in patients with relapsing MS as of the data cutoff,” concluded the authors, though they also noted that the overall rate of SSRI and SNRI use was low in the extension trial.
 

A reassuring finding for clinicians and patients alike

“It is reassuring, if not unexpected, that there were no clinically significant rates of symptoms associated with excess serotonin in patients on ozanimod and SSRI/SNRIs,” Dr. Gluck commented. “These findings are important for both clinicians and patients – they can help [both] feel comfortable considering ozanimod if SSRI/SNRIs are already being used. There is also freedom to use SSRI/SNRIs for symptom management in patients already on ozanimod.”

The research was funded by Bristol Myers Squibb. Dr. Naismith reported consulting for Abata Therapeutics, Banner Life Sciences, BeiGene, Biogen, Bristol Myers Squibb, Celltrion, Genentech, Genzyme, GW Therapeutics, Janssen, Horizon Therapeutics, Lundbeck, NervGen, and TG Therapeutics. Six other authors reported disclosures for various pharmaceutical companies, and six other authors are employees and/or shareholders of Bristol Myers Squibb. Dr. Gluck has served on advisory boards with Genentech and EMD Serono.
 

TOPLINE

Alcohol dependence, but not consumption, at age 18 years increases the risk for depression at age 24 years.

METHODOLOGY

• The study included 3,902 mostly White adolescents, about 58% female, born in England from April 1991 to December 1992, who were part of the Avon Longitudinal Study of Parents and Children (ALSPAC) that examined genetic and environmental determinants of health and development.
• Participants completed the self-report Alcohol Use Disorders Identification Test (AUDIT) between the ages of 16 and 23 years, a period when average alcohol use increases rapidly.
• The primary outcome was probability for depression at age 24 years, using the Clinical Interview Schedule Revised (CIS-R), a self-administered computerized clinical assessment of common mental disorder symptoms during the past week.
• Researchers assessed frequency and quantity of alcohol consumption as well as alcohol dependence.
• Confounders included sex, housing type, maternal education and depressive symptoms, parents’ alcohol use, conduct problems at age 4 years, being bullied, and smoking status.

TAKEAWAYS

• After adjustments, alcohol dependence at age 18 years was associated with depression at age 24 years (unstandardized probit coefficient 0.13; 95% confidence interval, 0.02-0.25; P = .019)
• The relationship appeared to persist for alcohol dependence at each age of the growth curve (17-22 years).
• There was no evidence that frequency or quantity of alcohol consumption at age 18 was significantly associated with depression at age 24, suggesting these factors may not increase the risk for later depression unless there are also features of dependency.

IN PRACTICE

“Our findings suggest that preventing alcohol dependence during adolescence, or treating it early, could reduce the risk of depression,” which could have important public health implications, the researchers write.

STUDY DETAILS

The study was carried out by researchers at the University of Bristol; University College London; Critical Thinking Unit, Public Health Directorate, NHS; University of Nottingham, all in the United Kingdom. It was published online in Lancet Psychiatry

LIMITATIONS

There was substantial attrition in the ALSPAC cohort from birth to age 24 years. The sample was recruited from one U.K. region and most participants were White. Measures of alcohol consumption and dependence excluded some features of abuse. And as this is an observational study, the possibility of residual confounding can’t be excluded.

DISCLOSURES

The investigators report no relevant disclosures. The study received support from the UK Medical Research Council and Alcohol Research UK.

A version of this article first appeared on Medscape.com.

TOPLINE

Alcohol dependence, but not consumption, at age 18 years increases the risk for depression at age 24 years.

METHODOLOGY

• The study included 3,902 mostly White adolescents, about 58% female, born in England from April 1991 to December 1992, who were part of the Avon Longitudinal Study of Parents and Children (ALSPAC) that examined genetic and environmental determinants of health and development.
• Participants completed the self-report Alcohol Use Disorders Identification Test (AUDIT) between the ages of 16 and 23 years, a period when average alcohol use increases rapidly.
• The primary outcome was probability for depression at age 24 years, using the Clinical Interview Schedule Revised (CIS-R), a self-administered computerized clinical assessment of common mental disorder symptoms during the past week.
• Researchers assessed frequency and quantity of alcohol consumption as well as alcohol dependence.
• Confounders included sex, housing type, maternal education and depressive symptoms, parents’ alcohol use, conduct problems at age 4 years, being bullied, and smoking status.

TAKEAWAYS

• After adjustments, alcohol dependence at age 18 years was associated with depression at age 24 years (unstandardized probit coefficient 0.13; 95% confidence interval, 0.02-0.25; P = .019)
• The relationship appeared to persist for alcohol dependence at each age of the growth curve (17-22 years).
• There was no evidence that frequency or quantity of alcohol consumption at age 18 was significantly associated with depression at age 24, suggesting these factors may not increase the risk for later depression unless there are also features of dependency.

IN PRACTICE

“Our findings suggest that preventing alcohol dependence during adolescence, or treating it early, could reduce the risk of depression,” which could have important public health implications, the researchers write.

STUDY DETAILS

The study was carried out by researchers at the University of Bristol; University College London; Critical Thinking Unit, Public Health Directorate, NHS; University of Nottingham, all in the United Kingdom. It was published online in Lancet Psychiatry

LIMITATIONS

There was substantial attrition in the ALSPAC cohort from birth to age 24 years. The sample was recruited from one U.K. region and most participants were White. Measures of alcohol consumption and dependence excluded some features of abuse. And as this is an observational study, the possibility of residual confounding can’t be excluded.

DISCLOSURES

The investigators report no relevant disclosures. The study received support from the UK Medical Research Council and Alcohol Research UK.

A version of this article first appeared on Medscape.com.

TOPLINE

Alcohol dependence, but not consumption, at age 18 years increases the risk for depression at age 24 years.

METHODOLOGY

• The study included 3,902 mostly White adolescents, about 58% female, born in England from April 1991 to December 1992, who were part of the Avon Longitudinal Study of Parents and Children (ALSPAC) that examined genetic and environmental determinants of health and development.
• Participants completed the self-report Alcohol Use Disorders Identification Test (AUDIT) between the ages of 16 and 23 years, a period when average alcohol use increases rapidly.
• The primary outcome was probability for depression at age 24 years, using the Clinical Interview Schedule Revised (CIS-R), a self-administered computerized clinical assessment of common mental disorder symptoms during the past week.
• Researchers assessed frequency and quantity of alcohol consumption as well as alcohol dependence.
• Confounders included sex, housing type, maternal education and depressive symptoms, parents’ alcohol use, conduct problems at age 4 years, being bullied, and smoking status.

TAKEAWAYS

• After adjustments, alcohol dependence at age 18 years was associated with depression at age 24 years (unstandardized probit coefficient 0.13; 95% confidence interval, 0.02-0.25; P = .019)
• The relationship appeared to persist for alcohol dependence at each age of the growth curve (17-22 years).
• There was no evidence that frequency or quantity of alcohol consumption at age 18 was significantly associated with depression at age 24, suggesting these factors may not increase the risk for later depression unless there are also features of dependency.

IN PRACTICE

“Our findings suggest that preventing alcohol dependence during adolescence, or treating it early, could reduce the risk of depression,” which could have important public health implications, the researchers write.

STUDY DETAILS

The study was carried out by researchers at the University of Bristol; University College London; Critical Thinking Unit, Public Health Directorate, NHS; University of Nottingham, all in the United Kingdom. It was published online in Lancet Psychiatry

LIMITATIONS

There was substantial attrition in the ALSPAC cohort from birth to age 24 years. The sample was recruited from one U.K. region and most participants were White. Measures of alcohol consumption and dependence excluded some features of abuse. And as this is an observational study, the possibility of residual confounding can’t be excluded.

DISCLOSURES

The investigators report no relevant disclosures. The study received support from the UK Medical Research Council and Alcohol Research UK.

A version of this article first appeared on Medscape.com.

The B vitamin, L-methylfolate (LMF) can be an effective adjunctive treatment for patients with major depressive disorder (MDD) with an inadequate response to antidepressants, new research suggests.

The investigators analyzed six studies and found support for adjunctive use of LMF with patients with MDD not responding to antidepressant monotherapy. Treatment response was highest in those with obesity and inflammatory biomarkers.

Vladimir Maletic

“If clinicians try LMF on their patients with treatment-resistant depression, the treatment is very robust in patients who have high BMI [body mass index] or inflammatory biomarkers, and it’s worth a try even in patients who don’t have these indicators, since it’s safe and well tolerated, with no downside,” study investigator Vladimir Maletic, MD, MS, clinical professor of psychiatry and behavioral science, University of South Carolina, Greenville, said in an interview.

The study was published online in the Journal of Clinical Psychiatry.
 

‘Shortcut’ to the brain

A considerable percentage of patients with MDD fail to achieve an adequate response to treatment, the authors wrote.

Previous research shows benefits of folate (vitamin B9) and other B vitamins in the pathophysiology and treatment of depression.

Folate is available in several forms, including LMF, which differs from dietary folate and synthetic folic acid supplements because it’s a reduced metabolite that readily crosses the blood-brain barrier.

“This is a ‘shortcut’ that gets directly to the brain, especially in those with higher BMI or inflammatory indicators, allowing their antidepressant to work better,” Dr. Maletic said.

LMF is available as a prescription medical food and approved for the clinical dietary management of patients with MDD.

The authors wanted to understand the potential role of LMF in treating patients with MDD with insufficient response to current antidepressant therapy.

They analyzed six studies:

• Two multicenter, randomized, double-blind, placebo-controlled sequential parallel trials for patients with SSRI-resistant MDD (n = 148 and n = 75).
• A 12-month open-label extension trial of the two randomized, controlled trials (n = 68).
• A retrospective cohort study evaluating patients previously prescribed LMF (n = 554).
• Two post hoc exploratory analyses of the second randomized, controlled trial, stratifying patients by specific biological and genetic markers (n = 74) and evaluating the effect of biomarkers on treatment effect (n = 74).

The primary endpoints were improvement on the 17-item Hamilton Depression Rating Scale (HDRS-17) or the Patient Health Questionnaire (PHQ-9).

Patients in all trials were treated with either 7.5 mg or 15 mg of LMF.

Both RCTs were divided into two 30-day phases, with patients assessed every 10 days. Response was defined as at least a 50% reduction in HDRS-17 score during treatment or a final score of 7 or less.
 

‘Salvage pathway’

In the RCTs, patients who received 7.5 mg of LMF did not achieve efficacy superior to placebo, while those receiving 15 mg/day of LMF for 30 days showed significantly greater reduction in HDRS-17 scores (–5.6 vs. –3.0; P = .05, respectively) and higher response rates (32.3% vs. 14.6%; P = .05, respectively).

The 12-month open extension trial showed that among patients who received the 15-mg dose, 61% achieved remission at any point, and 38% achieved recovery. Among initial nonresponders, 60% eventually achieved remission, with no serious adverse events.

“These results indicate that patients who respond well to shorter-term treatment are likely to maintain that response over the subsequent year and shows that those not adequately responding within the first 8 weeks of therapy may benefit from longer-term LMF treatments,” the investigators noted.

In the prospective observational study, the pooled mean change in PHQ-9 was –8.5, with response and remission rates of 67.9% and 45.7%, respectively.

“These outcomes suggest that the results seen in the controlled trial are likely to extend to patients in real-world practice,” the researchers wrote.

The post hoc analyses focusing on the findings of the two RCTs explored the differences in response to LMF, based on biomarker, BMI, and genotype.

Individuals with BMI less than 30 did not have a significant change from baseline with LMF treatment, in contrast to those with BMI of 30 or higher (pooled treatment effect, –4.66;95% CI, –7.22 to –1.98) – a difference the authors call “striking.”

Levels of inflammatory markers (tumor necrosis factor–alpha, interleukin-8, heart-specific C-reactive protein, and leptin) above the median value were associated with significantly greater treatment effect – a finding that remained significant even after adjustment for BMI.

Although BMI and cytokines all showed significant main effects, the “synergy” between them “suggests that these risk factors may interact with each other to influence response to LMF,” the authors wrote.

The mechanism by which LMF augments antidepressant treatment is tied to monoamine synthesis, since LMF promotes the synthesis of key monoamine neurotransmitters associated with MDD (serotonin, norepinephrine, and dopamine), Dr. Maletic explained.

High levels of inflammation (often tied to obesity) cause oxidative stress, which inhibits the synthesis of these neurotransmitters and depletes them more rapidly. LMF provides a “salvage pathway” that may prevent this from happening, thus increasing the antidepressant response of the monoamines, he said.
 

A ‘good addition’

In a comment, David Mischoulon, MD, PhD, Joyce R. Tedlow Professor of Psychiatry at Harvard Medical School and director of the depression clinical and research program at Massachusetts General Hospital, both in Boston, said the paper “does a good job of synthesizing what we know about LMF as an adjunctive treatment in major depression.” 

However, he recommended “caution” when interpreting the findings, since “relatively few” studies were reviewed. 

Dr. Mischoulon, who was not involved with the study, said that a “particularly interesting finding from these studies is individuals who are overweight and/or have elevation in inflammatory activity ... seemed to respond better to the addition of LMF.” This finding is similar to what his research team observed when investigating the potential role of fish oils in treating depression.

“These findings overall are not surprising, in view of the well-established multidirectional relationship between depression, inflammation, and overweight status,” he said. 

LMF “seems like a good addition to the pharmacological armamentarium for depression; and because it is safe and has minimal side effects, it can be added to the treatment regimen of patients who are depressed and not responding adequately to standard antidepressants,” he said.

This work was funded by Alfasigma USA. The authors did not receive payment for their participation. Dr. Maletic has received writing support from Alfasigma USA; consulting/advisory fees from AbbVie/Allergan, Acadia, Alfasigma USA, Alkermes, Eisai-Purdue, Intra-Cellular Therapies, Janssen, Lundbeck, Jazz, Noven, Otsuka America, Sage, Sunovion, Supernus, and Takeda; and honoraria for lectures from AbbVie, Acadia, Alkermes, Allergan, Eisai, Ironshore, Intra-Cellular, Janssen, Lundbeck, Otsuka America, Sunovion, Supernus, and Takeda. Dr. Mischoulon has received research support from Nordic Naturals and Heckel Medizintechnik. He has received honoraria for speaking from the Massachusetts General Hospital Psychiatry Academy, PeerPoint Medical Education Institute, and Harvard blog.

A version of this article first appeared on Medscape.com.

The B vitamin, L-methylfolate (LMF) can be an effective adjunctive treatment for patients with major depressive disorder (MDD) with an inadequate response to antidepressants, new research suggests.

The investigators analyzed six studies and found support for adjunctive use of LMF with patients with MDD not responding to antidepressant monotherapy. Treatment response was highest in those with obesity and inflammatory biomarkers.

Vladimir Maletic

“If clinicians try LMF on their patients with treatment-resistant depression, the treatment is very robust in patients who have high BMI [body mass index] or inflammatory biomarkers, and it’s worth a try even in patients who don’t have these indicators, since it’s safe and well tolerated, with no downside,” study investigator Vladimir Maletic, MD, MS, clinical professor of psychiatry and behavioral science, University of South Carolina, Greenville, said in an interview.

The study was published online in the Journal of Clinical Psychiatry.
 

‘Shortcut’ to the brain

A considerable percentage of patients with MDD fail to achieve an adequate response to treatment, the authors wrote.

Previous research shows benefits of folate (vitamin B9) and other B vitamins in the pathophysiology and treatment of depression.

Folate is available in several forms, including LMF, which differs from dietary folate and synthetic folic acid supplements because it’s a reduced metabolite that readily crosses the blood-brain barrier.

“This is a ‘shortcut’ that gets directly to the brain, especially in those with higher BMI or inflammatory indicators, allowing their antidepressant to work better,” Dr. Maletic said.

LMF is available as a prescription medical food and approved for the clinical dietary management of patients with MDD.

The authors wanted to understand the potential role of LMF in treating patients with MDD with insufficient response to current antidepressant therapy.

They analyzed six studies:

• Two multicenter, randomized, double-blind, placebo-controlled sequential parallel trials for patients with SSRI-resistant MDD (n = 148 and n = 75).
• A 12-month open-label extension trial of the two randomized, controlled trials (n = 68).
• A retrospective cohort study evaluating patients previously prescribed LMF (n = 554).
• Two post hoc exploratory analyses of the second randomized, controlled trial, stratifying patients by specific biological and genetic markers (n = 74) and evaluating the effect of biomarkers on treatment effect (n = 74).

The primary endpoints were improvement on the 17-item Hamilton Depression Rating Scale (HDRS-17) or the Patient Health Questionnaire (PHQ-9).

Patients in all trials were treated with either 7.5 mg or 15 mg of LMF.

Both RCTs were divided into two 30-day phases, with patients assessed every 10 days. Response was defined as at least a 50% reduction in HDRS-17 score during treatment or a final score of 7 or less.
 

‘Salvage pathway’

In the RCTs, patients who received 7.5 mg of LMF did not achieve efficacy superior to placebo, while those receiving 15 mg/day of LMF for 30 days showed significantly greater reduction in HDRS-17 scores (–5.6 vs. –3.0; P = .05, respectively) and higher response rates (32.3% vs. 14.6%; P = .05, respectively).

The 12-month open extension trial showed that among patients who received the 15-mg dose, 61% achieved remission at any point, and 38% achieved recovery. Among initial nonresponders, 60% eventually achieved remission, with no serious adverse events.

“These results indicate that patients who respond well to shorter-term treatment are likely to maintain that response over the subsequent year and shows that those not adequately responding within the first 8 weeks of therapy may benefit from longer-term LMF treatments,” the investigators noted.

In the prospective observational study, the pooled mean change in PHQ-9 was –8.5, with response and remission rates of 67.9% and 45.7%, respectively.

“These outcomes suggest that the results seen in the controlled trial are likely to extend to patients in real-world practice,” the researchers wrote.

The post hoc analyses focusing on the findings of the two RCTs explored the differences in response to LMF, based on biomarker, BMI, and genotype.

Individuals with BMI less than 30 did not have a significant change from baseline with LMF treatment, in contrast to those with BMI of 30 or higher (pooled treatment effect, –4.66;95% CI, –7.22 to –1.98) – a difference the authors call “striking.”

Levels of inflammatory markers (tumor necrosis factor–alpha, interleukin-8, heart-specific C-reactive protein, and leptin) above the median value were associated with significantly greater treatment effect – a finding that remained significant even after adjustment for BMI.

Although BMI and cytokines all showed significant main effects, the “synergy” between them “suggests that these risk factors may interact with each other to influence response to LMF,” the authors wrote.

The mechanism by which LMF augments antidepressant treatment is tied to monoamine synthesis, since LMF promotes the synthesis of key monoamine neurotransmitters associated with MDD (serotonin, norepinephrine, and dopamine), Dr. Maletic explained.

High levels of inflammation (often tied to obesity) cause oxidative stress, which inhibits the synthesis of these neurotransmitters and depletes them more rapidly. LMF provides a “salvage pathway” that may prevent this from happening, thus increasing the antidepressant response of the monoamines, he said.
 

A ‘good addition’

In a comment, David Mischoulon, MD, PhD, Joyce R. Tedlow Professor of Psychiatry at Harvard Medical School and director of the depression clinical and research program at Massachusetts General Hospital, both in Boston, said the paper “does a good job of synthesizing what we know about LMF as an adjunctive treatment in major depression.” 

However, he recommended “caution” when interpreting the findings, since “relatively few” studies were reviewed. 

Dr. Mischoulon, who was not involved with the study, said that a “particularly interesting finding from these studies is individuals who are overweight and/or have elevation in inflammatory activity ... seemed to respond better to the addition of LMF.” This finding is similar to what his research team observed when investigating the potential role of fish oils in treating depression.

“These findings overall are not surprising, in view of the well-established multidirectional relationship between depression, inflammation, and overweight status,” he said. 

LMF “seems like a good addition to the pharmacological armamentarium for depression; and because it is safe and has minimal side effects, it can be added to the treatment regimen of patients who are depressed and not responding adequately to standard antidepressants,” he said.

This work was funded by Alfasigma USA. The authors did not receive payment for their participation. Dr. Maletic has received writing support from Alfasigma USA; consulting/advisory fees from AbbVie/Allergan, Acadia, Alfasigma USA, Alkermes, Eisai-Purdue, Intra-Cellular Therapies, Janssen, Lundbeck, Jazz, Noven, Otsuka America, Sage, Sunovion, Supernus, and Takeda; and honoraria for lectures from AbbVie, Acadia, Alkermes, Allergan, Eisai, Ironshore, Intra-Cellular, Janssen, Lundbeck, Otsuka America, Sunovion, Supernus, and Takeda. Dr. Mischoulon has received research support from Nordic Naturals and Heckel Medizintechnik. He has received honoraria for speaking from the Massachusetts General Hospital Psychiatry Academy, PeerPoint Medical Education Institute, and Harvard blog.

A version of this article first appeared on Medscape.com.

The B vitamin, L-methylfolate (LMF) can be an effective adjunctive treatment for patients with major depressive disorder (MDD) with an inadequate response to antidepressants, new research suggests.

The investigators analyzed six studies and found support for adjunctive use of LMF with patients with MDD not responding to antidepressant monotherapy. Treatment response was highest in those with obesity and inflammatory biomarkers.

Vladimir Maletic

“If clinicians try LMF on their patients with treatment-resistant depression, the treatment is very robust in patients who have high BMI [body mass index] or inflammatory biomarkers, and it’s worth a try even in patients who don’t have these indicators, since it’s safe and well tolerated, with no downside,” study investigator Vladimir Maletic, MD, MS, clinical professor of psychiatry and behavioral science, University of South Carolina, Greenville, said in an interview.

The study was published online in the Journal of Clinical Psychiatry.
 

‘Shortcut’ to the brain

A considerable percentage of patients with MDD fail to achieve an adequate response to treatment, the authors wrote.

Previous research shows benefits of folate (vitamin B9) and other B vitamins in the pathophysiology and treatment of depression.

Folate is available in several forms, including LMF, which differs from dietary folate and synthetic folic acid supplements because it’s a reduced metabolite that readily crosses the blood-brain barrier.

“This is a ‘shortcut’ that gets directly to the brain, especially in those with higher BMI or inflammatory indicators, allowing their antidepressant to work better,” Dr. Maletic said.

LMF is available as a prescription medical food and approved for the clinical dietary management of patients with MDD.

The authors wanted to understand the potential role of LMF in treating patients with MDD with insufficient response to current antidepressant therapy.

They analyzed six studies:

• Two multicenter, randomized, double-blind, placebo-controlled sequential parallel trials for patients with SSRI-resistant MDD (n = 148 and n = 75).
• A 12-month open-label extension trial of the two randomized, controlled trials (n = 68).
• A retrospective cohort study evaluating patients previously prescribed LMF (n = 554).
• Two post hoc exploratory analyses of the second randomized, controlled trial, stratifying patients by specific biological and genetic markers (n = 74) and evaluating the effect of biomarkers on treatment effect (n = 74).

The primary endpoints were improvement on the 17-item Hamilton Depression Rating Scale (HDRS-17) or the Patient Health Questionnaire (PHQ-9).

Patients in all trials were treated with either 7.5 mg or 15 mg of LMF.

Both RCTs were divided into two 30-day phases, with patients assessed every 10 days. Response was defined as at least a 50% reduction in HDRS-17 score during treatment or a final score of 7 or less.
 

‘Salvage pathway’

In the RCTs, patients who received 7.5 mg of LMF did not achieve efficacy superior to placebo, while those receiving 15 mg/day of LMF for 30 days showed significantly greater reduction in HDRS-17 scores (–5.6 vs. –3.0; P = .05, respectively) and higher response rates (32.3% vs. 14.6%; P = .05, respectively).

The 12-month open extension trial showed that among patients who received the 15-mg dose, 61% achieved remission at any point, and 38% achieved recovery. Among initial nonresponders, 60% eventually achieved remission, with no serious adverse events.

“These results indicate that patients who respond well to shorter-term treatment are likely to maintain that response over the subsequent year and shows that those not adequately responding within the first 8 weeks of therapy may benefit from longer-term LMF treatments,” the investigators noted.

In the prospective observational study, the pooled mean change in PHQ-9 was –8.5, with response and remission rates of 67.9% and 45.7%, respectively.

“These outcomes suggest that the results seen in the controlled trial are likely to extend to patients in real-world practice,” the researchers wrote.

The post hoc analyses focusing on the findings of the two RCTs explored the differences in response to LMF, based on biomarker, BMI, and genotype.

Individuals with BMI less than 30 did not have a significant change from baseline with LMF treatment, in contrast to those with BMI of 30 or higher (pooled treatment effect, –4.66;95% CI, –7.22 to –1.98) – a difference the authors call “striking.”

Levels of inflammatory markers (tumor necrosis factor–alpha, interleukin-8, heart-specific C-reactive protein, and leptin) above the median value were associated with significantly greater treatment effect – a finding that remained significant even after adjustment for BMI.

Although BMI and cytokines all showed significant main effects, the “synergy” between them “suggests that these risk factors may interact with each other to influence response to LMF,” the authors wrote.

The mechanism by which LMF augments antidepressant treatment is tied to monoamine synthesis, since LMF promotes the synthesis of key monoamine neurotransmitters associated with MDD (serotonin, norepinephrine, and dopamine), Dr. Maletic explained.

High levels of inflammation (often tied to obesity) cause oxidative stress, which inhibits the synthesis of these neurotransmitters and depletes them more rapidly. LMF provides a “salvage pathway” that may prevent this from happening, thus increasing the antidepressant response of the monoamines, he said.
 

A ‘good addition’

In a comment, David Mischoulon, MD, PhD, Joyce R. Tedlow Professor of Psychiatry at Harvard Medical School and director of the depression clinical and research program at Massachusetts General Hospital, both in Boston, said the paper “does a good job of synthesizing what we know about LMF as an adjunctive treatment in major depression.” 

However, he recommended “caution” when interpreting the findings, since “relatively few” studies were reviewed. 

Dr. Mischoulon, who was not involved with the study, said that a “particularly interesting finding from these studies is individuals who are overweight and/or have elevation in inflammatory activity ... seemed to respond better to the addition of LMF.” This finding is similar to what his research team observed when investigating the potential role of fish oils in treating depression.

“These findings overall are not surprising, in view of the well-established multidirectional relationship between depression, inflammation, and overweight status,” he said. 

LMF “seems like a good addition to the pharmacological armamentarium for depression; and because it is safe and has minimal side effects, it can be added to the treatment regimen of patients who are depressed and not responding adequately to standard antidepressants,” he said.

This work was funded by Alfasigma USA. The authors did not receive payment for their participation. Dr. Maletic has received writing support from Alfasigma USA; consulting/advisory fees from AbbVie/Allergan, Acadia, Alfasigma USA, Alkermes, Eisai-Purdue, Intra-Cellular Therapies, Janssen, Lundbeck, Jazz, Noven, Otsuka America, Sage, Sunovion, Supernus, and Takeda; and honoraria for lectures from AbbVie, Acadia, Alkermes, Allergan, Eisai, Ironshore, Intra-Cellular, Janssen, Lundbeck, Otsuka America, Sunovion, Supernus, and Takeda. Dr. Mischoulon has received research support from Nordic Naturals and Heckel Medizintechnik. He has received honoraria for speaking from the Massachusetts General Hospital Psychiatry Academy, PeerPoint Medical Education Institute, and Harvard blog.

A version of this article first appeared on Medscape.com.

Anxiety, depression, and COVID-19 can be a bad combination for your brain – and your long-term health.

Having anxiety and depression before a COVID infection increases the risk of developing long COVID, researchers have found. 

Those with long COVID who develop anxiety and depression after an infection may have brain shrinkage in areas that regulate memory, emotion, and other functions as well as disruption of brain connectivity. 

While many questions remain about these intertwined relationships, the associations aren’t a complete surprise. Experts already know that depression and anxiety are associated with inflammation and immune dysfunction, perhaps helping to explain the link between these mental health conditions, the risk of long COVID, and the changes in the brain.

Brain changes accompanying a COVID infection have concerned researchers since earlier in the pandemic, when U.K. Biobank researchers found brain atrophy, loss of grey matter, and decline in cognition in those infected with COVID, compared with those not infected.
 

Common conditions

The ramifications of the research linking anxiety, depression, and long COVID are far-reaching. According to the Centers for Disease Control and Prevention, 12.5% of U.S. adults have regular feelings of anxiety (as well as nervousness and worry), and the latest Gallup Poll found that nearly 18% of adults currently have or are being treated for depression. 

As of May 8, 10% of infected adults in the United States have long COVID, according to the CDC, and among U.S. adults ever infected, 27% have reported long COVID. Long COVID has been defined by the CDC as symptoms such as fatigue, brain fog, and cough that persist longer than 4 weeks and by the World Health Organization as symptoms persisting for 3 months or more. 

Here’s a roundup of what the research shows about mental health and long COVID risk – along with other research finding that paying attention to health habits may reduce that risk. 
 

Pre-existing depression, anxiety, and long COVID risk

A history of mental health issues – including depression, anxiety, worry, perceived stress, and loneliness – raises the risk of long COVID if infection occurs, Harvard researchers have found.

The researchers evaluated data from three large, ongoing studies including nearly 55,000 participants to determine the effects of high levels of psychological distress before a COVID infection. 

“Our study was purely survey based,” said Siwen Wang, MD, the study’s lead author and a research fellow at Harvard School of Public Health, Boston.

At the start of the survey in April 2020, none of the participants reported a current or previous COVID infection. They answered surveys about psychological distress at the start of the study, at 6 monthly time points, then quarterly until November 2021.

Over the follow up, 3,193 people reported a positive COVID test and 43% of those, or 1,403, developed long COVID. That number may seem high, but 38% of the 55,000 were active health care workers. On the final questionnaire, they reported whether their symptoms persisted for 4 weeks or longer and thus had long COVID by the standard CDC definition.

Dr. Wang’s team then looked at the infected participants’ psychological status. Anxiety raised the risk of long COVID by 42%, depression by 32%, worry about COVID by 37%, perceived stress, 46%, and loneliness, 32%.

COVID patients with a history of depression or anxiety are also more likely than others to report trouble with cognition in the weeks after a COVID infection and to develop brain fog and long COVID, UCLA researchers found. They evaluated 766 people with a confirmed COVID infection; 36% said their thinking was affected within 4 weeks of the infection. Those with anxiety and depression were more likely to report those difficulties.
 

Long COVID, then anxiety, depression, brain changes

Even mild cases of COVID infection can lead to long COVID and brain changes in those who suffer anxiety or depression after the infection, according to Clarissa Yasuda, MD, PhD, assistant professor of neurology at the University of Campinas in Sao Paulo. She has researched long COVID’s effects on the brain, even as she is coping with being a long COVID patient.

In one of her studies, presented at the 2023 annual meeting of the American Academy of Neurology, she found brain changes in people with anxiety, depression, and COVID but not in those infected who did not have either mental health issue. She evaluated 254 people, median age 41, after about 82 days from their positive PCR test for COVID.  Everyone completed a standard questionnaire for depression (the Beck Depression Inventory) and another for anxiety (the Beck Anxiety Inventory). She further divided them into two groups – the 102 with symptoms and the 152 who had no symptoms of either depression or anxiety. 

Brain scans showed those with COVID who also had anxiety and depression had shrinkage in the limbic area of the brain (which helps process emotion and memory), while those infected who didn’t have anxiety or depression did not. The researchers then scanned the brains of 148 healthy people without COVID and found no shrinkage.

The atrophy, Dr. Yasuda said, “is not something you can see with your eyes. It was only detected with computer analysis. Visualization on an MRI is normal.”

The number of people in this study with mental health issues was surprisingly high, Dr. Yasuda said. “It was intriguing for us that we noticed many individuals have both symptoms, anxiety and depression. We were not expecting it at that proportion.”

The researchers found a pattern of change not only in brain structure but in brain communication. They found those changes by using specialized software to analyze brain networks in some of the participants. Those with anxiety and depression had widespread functional changes in each of 12 networks tested. The participants without mental health symptoms showed changes in just five networks. These changes are enough to lead to problems with thinking skills and memory, Dr. Yasuda said.
 

Explaining the links

Several ideas have been proposed to explain the link between psychological distress and long COVID risk, Dr. Wang said. “The first and most mainstream mechanism for long COVID is chronic inflammation and immune dysregulation. Several mental health conditions, such as anxiety and depression, are associated with inflammation and dysfunction and that might be the link between depression, anxiety, and long COVID.”

Another less mainstream hypothesis, she said, is that “those with long COVID have more autoantibodies and they are more likely to have blood clotting issues. These have also been found in people with anxiety, depression, or other psychological distress.”

Other researchers are looking more broadly at how COVID infections affect the brain. When German researchers evaluated the brain and other body parts of 20 patients who died from non-COVID causes but had documented COVID infections, they found that 12 had accumulations of the SARS-CoV-2 spike protein in the brain tissue as well as the skull and meninges, the membranes that line the skull and spinal cord. Healthy controls did not. 

The findings suggest the persistence of the spike protein may contribute to the long-term neurologic symptoms of long COVID and may also lead to understanding of the molecular mechanisms as well as therapies for long COVID, the researchers said in their preprint report, which has not yet been peer reviewed. 

In another recent study, researchers from Germany performed neuroimaging and neuropsychological assessments of 223 people who were not vaccinated and recovered from mild to moderate COVID infections, comparing them with 223 matched healthy controls who had the same testing. In those infected, they found alterations in the cerebral white matter but no worse cognitive function in the first year after recovering. They conclude that the infection triggers a prolonged neuroinflammatory response. 

Can the brain changes reverse? “We don’t have an answer right now, but we are working on that,” Dr. Yasuda said. For now, she speculates about the return of brain volume: “I think for most it will. But I think we need to treat the symptoms. We can’t disregard the symptoms of long COVID. People are suffering a lot, and this suffering is causing some brain damage.”
 

Lifestyle habits and risk of long COVID

Meanwhile, healthy lifestyle habits in those infected can reduce the risk of long COVID, research by Dr. Wang and colleagues found. They followed nearly 2,000 women with a positive COVID test over 19 months. Of these, 44%, or 871, developed long COVID. Compared with women who followed none of the healthy lifestyle habits evaluated, those with five to six of the habits had a 49% lower risk of long COVID.

The habits included: a healthy body mass index (18.5-24.9 kg/m²), never smoking, at least 150 minutes weekly of moderate to vigorous physical activity, moderate alcohol intake (5-15 grams a day), high diet quality, and good sleep (7-9 hours nightly).
 

Long-term solutions 

Dr. Yasuda hopes that mental health care – of those infected and those not – will be taken more seriously. In a commentary on her own long COVID experience, she wrote, in part: “I fear for the numerous survivors of COVID-19 who do not have access to medical attention for their post-COVID symptoms. ... The mental health system needs to become prepared to receive survivors with different neuropsychiatric symptoms, including anxiety and depression.” 

A version of this article originally appeared on Medscape.com.

Anxiety, depression, and COVID-19 can be a bad combination for your brain – and your long-term health.

Having anxiety and depression before a COVID infection increases the risk of developing long COVID, researchers have found. 

Those with long COVID who develop anxiety and depression after an infection may have brain shrinkage in areas that regulate memory, emotion, and other functions as well as disruption of brain connectivity. 

While many questions remain about these intertwined relationships, the associations aren’t a complete surprise. Experts already know that depression and anxiety are associated with inflammation and immune dysfunction, perhaps helping to explain the link between these mental health conditions, the risk of long COVID, and the changes in the brain.

Brain changes accompanying a COVID infection have concerned researchers since earlier in the pandemic, when U.K. Biobank researchers found brain atrophy, loss of grey matter, and decline in cognition in those infected with COVID, compared with those not infected.
 

Common conditions

The ramifications of the research linking anxiety, depression, and long COVID are far-reaching. According to the Centers for Disease Control and Prevention, 12.5% of U.S. adults have regular feelings of anxiety (as well as nervousness and worry), and the latest Gallup Poll found that nearly 18% of adults currently have or are being treated for depression. 

As of May 8, 10% of infected adults in the United States have long COVID, according to the CDC, and among U.S. adults ever infected, 27% have reported long COVID. Long COVID has been defined by the CDC as symptoms such as fatigue, brain fog, and cough that persist longer than 4 weeks and by the World Health Organization as symptoms persisting for 3 months or more. 

Here’s a roundup of what the research shows about mental health and long COVID risk – along with other research finding that paying attention to health habits may reduce that risk. 
 

Pre-existing depression, anxiety, and long COVID risk

A history of mental health issues – including depression, anxiety, worry, perceived stress, and loneliness – raises the risk of long COVID if infection occurs, Harvard researchers have found.

The researchers evaluated data from three large, ongoing studies including nearly 55,000 participants to determine the effects of high levels of psychological distress before a COVID infection. 

“Our study was purely survey based,” said Siwen Wang, MD, the study’s lead author and a research fellow at Harvard School of Public Health, Boston.

At the start of the survey in April 2020, none of the participants reported a current or previous COVID infection. They answered surveys about psychological distress at the start of the study, at 6 monthly time points, then quarterly until November 2021.

Over the follow up, 3,193 people reported a positive COVID test and 43% of those, or 1,403, developed long COVID. That number may seem high, but 38% of the 55,000 were active health care workers. On the final questionnaire, they reported whether their symptoms persisted for 4 weeks or longer and thus had long COVID by the standard CDC definition.

Dr. Wang’s team then looked at the infected participants’ psychological status. Anxiety raised the risk of long COVID by 42%, depression by 32%, worry about COVID by 37%, perceived stress, 46%, and loneliness, 32%.

COVID patients with a history of depression or anxiety are also more likely than others to report trouble with cognition in the weeks after a COVID infection and to develop brain fog and long COVID, UCLA researchers found. They evaluated 766 people with a confirmed COVID infection; 36% said their thinking was affected within 4 weeks of the infection. Those with anxiety and depression were more likely to report those difficulties.
 

Long COVID, then anxiety, depression, brain changes

Even mild cases of COVID infection can lead to long COVID and brain changes in those who suffer anxiety or depression after the infection, according to Clarissa Yasuda, MD, PhD, assistant professor of neurology at the University of Campinas in Sao Paulo. She has researched long COVID’s effects on the brain, even as she is coping with being a long COVID patient.

In one of her studies, presented at the 2023 annual meeting of the American Academy of Neurology, she found brain changes in people with anxiety, depression, and COVID but not in those infected who did not have either mental health issue. She evaluated 254 people, median age 41, after about 82 days from their positive PCR test for COVID.  Everyone completed a standard questionnaire for depression (the Beck Depression Inventory) and another for anxiety (the Beck Anxiety Inventory). She further divided them into two groups – the 102 with symptoms and the 152 who had no symptoms of either depression or anxiety. 

Brain scans showed those with COVID who also had anxiety and depression had shrinkage in the limbic area of the brain (which helps process emotion and memory), while those infected who didn’t have anxiety or depression did not. The researchers then scanned the brains of 148 healthy people without COVID and found no shrinkage.

The atrophy, Dr. Yasuda said, “is not something you can see with your eyes. It was only detected with computer analysis. Visualization on an MRI is normal.”

The number of people in this study with mental health issues was surprisingly high, Dr. Yasuda said. “It was intriguing for us that we noticed many individuals have both symptoms, anxiety and depression. We were not expecting it at that proportion.”

The researchers found a pattern of change not only in brain structure but in brain communication. They found those changes by using specialized software to analyze brain networks in some of the participants. Those with anxiety and depression had widespread functional changes in each of 12 networks tested. The participants without mental health symptoms showed changes in just five networks. These changes are enough to lead to problems with thinking skills and memory, Dr. Yasuda said.
 

Explaining the links

Several ideas have been proposed to explain the link between psychological distress and long COVID risk, Dr. Wang said. “The first and most mainstream mechanism for long COVID is chronic inflammation and immune dysregulation. Several mental health conditions, such as anxiety and depression, are associated with inflammation and dysfunction and that might be the link between depression, anxiety, and long COVID.”

Another less mainstream hypothesis, she said, is that “those with long COVID have more autoantibodies and they are more likely to have blood clotting issues. These have also been found in people with anxiety, depression, or other psychological distress.”

Other researchers are looking more broadly at how COVID infections affect the brain. When German researchers evaluated the brain and other body parts of 20 patients who died from non-COVID causes but had documented COVID infections, they found that 12 had accumulations of the SARS-CoV-2 spike protein in the brain tissue as well as the skull and meninges, the membranes that line the skull and spinal cord. Healthy controls did not. 

The findings suggest the persistence of the spike protein may contribute to the long-term neurologic symptoms of long COVID and may also lead to understanding of the molecular mechanisms as well as therapies for long COVID, the researchers said in their preprint report, which has not yet been peer reviewed. 

In another recent study, researchers from Germany performed neuroimaging and neuropsychological assessments of 223 people who were not vaccinated and recovered from mild to moderate COVID infections, comparing them with 223 matched healthy controls who had the same testing. In those infected, they found alterations in the cerebral white matter but no worse cognitive function in the first year after recovering. They conclude that the infection triggers a prolonged neuroinflammatory response. 

Can the brain changes reverse? “We don’t have an answer right now, but we are working on that,” Dr. Yasuda said. For now, she speculates about the return of brain volume: “I think for most it will. But I think we need to treat the symptoms. We can’t disregard the symptoms of long COVID. People are suffering a lot, and this suffering is causing some brain damage.”
 

Lifestyle habits and risk of long COVID

Meanwhile, healthy lifestyle habits in those infected can reduce the risk of long COVID, research by Dr. Wang and colleagues found. They followed nearly 2,000 women with a positive COVID test over 19 months. Of these, 44%, or 871, developed long COVID. Compared with women who followed none of the healthy lifestyle habits evaluated, those with five to six of the habits had a 49% lower risk of long COVID.

The habits included: a healthy body mass index (18.5-24.9 kg/m²), never smoking, at least 150 minutes weekly of moderate to vigorous physical activity, moderate alcohol intake (5-15 grams a day), high diet quality, and good sleep (7-9 hours nightly).
 

Long-term solutions 

Dr. Yasuda hopes that mental health care – of those infected and those not – will be taken more seriously. In a commentary on her own long COVID experience, she wrote, in part: “I fear for the numerous survivors of COVID-19 who do not have access to medical attention for their post-COVID symptoms. ... The mental health system needs to become prepared to receive survivors with different neuropsychiatric symptoms, including anxiety and depression.” 

A version of this article originally appeared on Medscape.com.

Anxiety, depression, and COVID-19 can be a bad combination for your brain – and your long-term health.

Having anxiety and depression before a COVID infection increases the risk of developing long COVID, researchers have found. 

Those with long COVID who develop anxiety and depression after an infection may have brain shrinkage in areas that regulate memory, emotion, and other functions as well as disruption of brain connectivity. 

While many questions remain about these intertwined relationships, the associations aren’t a complete surprise. Experts already know that depression and anxiety are associated with inflammation and immune dysfunction, perhaps helping to explain the link between these mental health conditions, the risk of long COVID, and the changes in the brain.

Brain changes accompanying a COVID infection have concerned researchers since earlier in the pandemic, when U.K. Biobank researchers found brain atrophy, loss of grey matter, and decline in cognition in those infected with COVID, compared with those not infected.
 

Common conditions

The ramifications of the research linking anxiety, depression, and long COVID are far-reaching. According to the Centers for Disease Control and Prevention, 12.5% of U.S. adults have regular feelings of anxiety (as well as nervousness and worry), and the latest Gallup Poll found that nearly 18% of adults currently have or are being treated for depression. 

As of May 8, 10% of infected adults in the United States have long COVID, according to the CDC, and among U.S. adults ever infected, 27% have reported long COVID. Long COVID has been defined by the CDC as symptoms such as fatigue, brain fog, and cough that persist longer than 4 weeks and by the World Health Organization as symptoms persisting for 3 months or more. 

Here’s a roundup of what the research shows about mental health and long COVID risk – along with other research finding that paying attention to health habits may reduce that risk. 
 

Pre-existing depression, anxiety, and long COVID risk

A history of mental health issues – including depression, anxiety, worry, perceived stress, and loneliness – raises the risk of long COVID if infection occurs, Harvard researchers have found.

The researchers evaluated data from three large, ongoing studies including nearly 55,000 participants to determine the effects of high levels of psychological distress before a COVID infection. 

“Our study was purely survey based,” said Siwen Wang, MD, the study’s lead author and a research fellow at Harvard School of Public Health, Boston.

At the start of the survey in April 2020, none of the participants reported a current or previous COVID infection. They answered surveys about psychological distress at the start of the study, at 6 monthly time points, then quarterly until November 2021.

Over the follow up, 3,193 people reported a positive COVID test and 43% of those, or 1,403, developed long COVID. That number may seem high, but 38% of the 55,000 were active health care workers. On the final questionnaire, they reported whether their symptoms persisted for 4 weeks or longer and thus had long COVID by the standard CDC definition.

Dr. Wang’s team then looked at the infected participants’ psychological status. Anxiety raised the risk of long COVID by 42%, depression by 32%, worry about COVID by 37%, perceived stress, 46%, and loneliness, 32%.

COVID patients with a history of depression or anxiety are also more likely than others to report trouble with cognition in the weeks after a COVID infection and to develop brain fog and long COVID, UCLA researchers found. They evaluated 766 people with a confirmed COVID infection; 36% said their thinking was affected within 4 weeks of the infection. Those with anxiety and depression were more likely to report those difficulties.
 

Long COVID, then anxiety, depression, brain changes

Even mild cases of COVID infection can lead to long COVID and brain changes in those who suffer anxiety or depression after the infection, according to Clarissa Yasuda, MD, PhD, assistant professor of neurology at the University of Campinas in Sao Paulo. She has researched long COVID’s effects on the brain, even as she is coping with being a long COVID patient.

In one of her studies, presented at the 2023 annual meeting of the American Academy of Neurology, she found brain changes in people with anxiety, depression, and COVID but not in those infected who did not have either mental health issue. She evaluated 254 people, median age 41, after about 82 days from their positive PCR test for COVID.  Everyone completed a standard questionnaire for depression (the Beck Depression Inventory) and another for anxiety (the Beck Anxiety Inventory). She further divided them into two groups – the 102 with symptoms and the 152 who had no symptoms of either depression or anxiety. 

Brain scans showed those with COVID who also had anxiety and depression had shrinkage in the limbic area of the brain (which helps process emotion and memory), while those infected who didn’t have anxiety or depression did not. The researchers then scanned the brains of 148 healthy people without COVID and found no shrinkage.

The atrophy, Dr. Yasuda said, “is not something you can see with your eyes. It was only detected with computer analysis. Visualization on an MRI is normal.”

The number of people in this study with mental health issues was surprisingly high, Dr. Yasuda said. “It was intriguing for us that we noticed many individuals have both symptoms, anxiety and depression. We were not expecting it at that proportion.”

The researchers found a pattern of change not only in brain structure but in brain communication. They found those changes by using specialized software to analyze brain networks in some of the participants. Those with anxiety and depression had widespread functional changes in each of 12 networks tested. The participants without mental health symptoms showed changes in just five networks. These changes are enough to lead to problems with thinking skills and memory, Dr. Yasuda said.
 

Explaining the links

Several ideas have been proposed to explain the link between psychological distress and long COVID risk, Dr. Wang said. “The first and most mainstream mechanism for long COVID is chronic inflammation and immune dysregulation. Several mental health conditions, such as anxiety and depression, are associated with inflammation and dysfunction and that might be the link between depression, anxiety, and long COVID.”

Another less mainstream hypothesis, she said, is that “those with long COVID have more autoantibodies and they are more likely to have blood clotting issues. These have also been found in people with anxiety, depression, or other psychological distress.”

Other researchers are looking more broadly at how COVID infections affect the brain. When German researchers evaluated the brain and other body parts of 20 patients who died from non-COVID causes but had documented COVID infections, they found that 12 had accumulations of the SARS-CoV-2 spike protein in the brain tissue as well as the skull and meninges, the membranes that line the skull and spinal cord. Healthy controls did not. 

The findings suggest the persistence of the spike protein may contribute to the long-term neurologic symptoms of long COVID and may also lead to understanding of the molecular mechanisms as well as therapies for long COVID, the researchers said in their preprint report, which has not yet been peer reviewed. 

In another recent study, researchers from Germany performed neuroimaging and neuropsychological assessments of 223 people who were not vaccinated and recovered from mild to moderate COVID infections, comparing them with 223 matched healthy controls who had the same testing. In those infected, they found alterations in the cerebral white matter but no worse cognitive function in the first year after recovering. They conclude that the infection triggers a prolonged neuroinflammatory response. 

Can the brain changes reverse? “We don’t have an answer right now, but we are working on that,” Dr. Yasuda said. For now, she speculates about the return of brain volume: “I think for most it will. But I think we need to treat the symptoms. We can’t disregard the symptoms of long COVID. People are suffering a lot, and this suffering is causing some brain damage.”
 

Lifestyle habits and risk of long COVID

Meanwhile, healthy lifestyle habits in those infected can reduce the risk of long COVID, research by Dr. Wang and colleagues found. They followed nearly 2,000 women with a positive COVID test over 19 months. Of these, 44%, or 871, developed long COVID. Compared with women who followed none of the healthy lifestyle habits evaluated, those with five to six of the habits had a 49% lower risk of long COVID.

The habits included: a healthy body mass index (18.5-24.9 kg/m²), never smoking, at least 150 minutes weekly of moderate to vigorous physical activity, moderate alcohol intake (5-15 grams a day), high diet quality, and good sleep (7-9 hours nightly).
 

Long-term solutions 

Dr. Yasuda hopes that mental health care – of those infected and those not – will be taken more seriously. In a commentary on her own long COVID experience, she wrote, in part: “I fear for the numerous survivors of COVID-19 who do not have access to medical attention for their post-COVID symptoms. ... The mental health system needs to become prepared to receive survivors with different neuropsychiatric symptoms, including anxiety and depression.” 

A version of this article originally appeared on Medscape.com.

Six distinct microribonucleic acids were down-regulated in adults with major depressive disorder (MDD), compared with healthy controls, based on data from 120 individuals.

National University Health System, Singapore

“Given the multifaceted nature of MDD, the multiple small but dynamic genetic alterations in biomolecular pathways, which are modulated by epigenetic modifications, could contribute to a better understanding of the underlying aetiology and pathophysiology of this disorder,” wrote Cyrus Su Hui Ho, MD, of National University Health System, Singapore, and colleagues. However, studies of biomarkers in psychiatry are limited, and the predictive potential of microribonucleic acids (miRNAs) has not been examined, they said.

In a study published in Comprehensive Psychiatry, the researchers identified 60 adults with depression and 60 healthy controls. Depression severity was assessed with the Hamilton Depression Rating Scale. Other demographic and clinical characteristics were similar between the patients and controls; 10 patients were unmedicated.

The researchers used QUIAGEN Ingenuity Pathway Analysis to identify the specific depression-related biological pathways affected by various miRNAs.

A total of six miRNAs (miR-542-3p, miR-181b-3p, miR-190a-5p, miR-33a-3p, miR-3690, and miR-6895-3p) were down-regulated in unmedicated depressed patients, compared with healthy controls.

In a receiver operating characteristic (ROC) analysis, a combination panel with three miRNAs (miR-542-3p, miR-181b-3p, and miR-3690) in whole blood yielded an area under the curve (AUC) of 0.67. This combination correctly classified 66.7% of MDD patients and 63.3% of healthy controls.

The ability of individual miRNAs to differentiate between MDD patients and controls in the current study was limited, the researchers wrote in their discussion. “However, when three miRNAs (miR-542b-3p, miR-181b-3p, and miR-3690) were combined as a panel, the AUC was enhanced to an almost acceptable degree (AUC of 0.67, approaching 0.7) and might have value in complementing clinical diagnoses,” they said.

The study findings were limited by several factors including the small sample size and the use of medications by most MDD patients, which resulted in an especially small number of unmedicated patients, the researchers noted. Other limitations included the use of study population from a single center, and the inability to explain the link between blood and brain miRNA expression, they said.

However, the study is the first clinical trial in Singapore to examine the role of miRNA in depression and to identify miRNAs as potential biomarkers for MDD, they said.

Additional studies are needed to explore miRNA biomarkers for diagnosis, disease prognosis, and treatment response in MDD, they concluded.

The study was supported by the National University Health System Seed Fund. The researchers had no financial conflicts to disclose.

Six distinct microribonucleic acids were down-regulated in adults with major depressive disorder (MDD), compared with healthy controls, based on data from 120 individuals.

National University Health System, Singapore

“Given the multifaceted nature of MDD, the multiple small but dynamic genetic alterations in biomolecular pathways, which are modulated by epigenetic modifications, could contribute to a better understanding of the underlying aetiology and pathophysiology of this disorder,” wrote Cyrus Su Hui Ho, MD, of National University Health System, Singapore, and colleagues. However, studies of biomarkers in psychiatry are limited, and the predictive potential of microribonucleic acids (miRNAs) has not been examined, they said.

In a study published in Comprehensive Psychiatry, the researchers identified 60 adults with depression and 60 healthy controls. Depression severity was assessed with the Hamilton Depression Rating Scale. Other demographic and clinical characteristics were similar between the patients and controls; 10 patients were unmedicated.

The researchers used QUIAGEN Ingenuity Pathway Analysis to identify the specific depression-related biological pathways affected by various miRNAs.

A total of six miRNAs (miR-542-3p, miR-181b-3p, miR-190a-5p, miR-33a-3p, miR-3690, and miR-6895-3p) were down-regulated in unmedicated depressed patients, compared with healthy controls.

In a receiver operating characteristic (ROC) analysis, a combination panel with three miRNAs (miR-542-3p, miR-181b-3p, and miR-3690) in whole blood yielded an area under the curve (AUC) of 0.67. This combination correctly classified 66.7% of MDD patients and 63.3% of healthy controls.

The ability of individual miRNAs to differentiate between MDD patients and controls in the current study was limited, the researchers wrote in their discussion. “However, when three miRNAs (miR-542b-3p, miR-181b-3p, and miR-3690) were combined as a panel, the AUC was enhanced to an almost acceptable degree (AUC of 0.67, approaching 0.7) and might have value in complementing clinical diagnoses,” they said.

The study findings were limited by several factors including the small sample size and the use of medications by most MDD patients, which resulted in an especially small number of unmedicated patients, the researchers noted. Other limitations included the use of study population from a single center, and the inability to explain the link between blood and brain miRNA expression, they said.

However, the study is the first clinical trial in Singapore to examine the role of miRNA in depression and to identify miRNAs as potential biomarkers for MDD, they said.

Additional studies are needed to explore miRNA biomarkers for diagnosis, disease prognosis, and treatment response in MDD, they concluded.

The study was supported by the National University Health System Seed Fund. The researchers had no financial conflicts to disclose.

Six distinct microribonucleic acids were down-regulated in adults with major depressive disorder (MDD), compared with healthy controls, based on data from 120 individuals.

National University Health System, Singapore

“Given the multifaceted nature of MDD, the multiple small but dynamic genetic alterations in biomolecular pathways, which are modulated by epigenetic modifications, could contribute to a better understanding of the underlying aetiology and pathophysiology of this disorder,” wrote Cyrus Su Hui Ho, MD, of National University Health System, Singapore, and colleagues. However, studies of biomarkers in psychiatry are limited, and the predictive potential of microribonucleic acids (miRNAs) has not been examined, they said.

In a study published in Comprehensive Psychiatry, the researchers identified 60 adults with depression and 60 healthy controls. Depression severity was assessed with the Hamilton Depression Rating Scale. Other demographic and clinical characteristics were similar between the patients and controls; 10 patients were unmedicated.

The researchers used QUIAGEN Ingenuity Pathway Analysis to identify the specific depression-related biological pathways affected by various miRNAs.

A total of six miRNAs (miR-542-3p, miR-181b-3p, miR-190a-5p, miR-33a-3p, miR-3690, and miR-6895-3p) were down-regulated in unmedicated depressed patients, compared with healthy controls.

In a receiver operating characteristic (ROC) analysis, a combination panel with three miRNAs (miR-542-3p, miR-181b-3p, and miR-3690) in whole blood yielded an area under the curve (AUC) of 0.67. This combination correctly classified 66.7% of MDD patients and 63.3% of healthy controls.

The ability of individual miRNAs to differentiate between MDD patients and controls in the current study was limited, the researchers wrote in their discussion. “However, when three miRNAs (miR-542b-3p, miR-181b-3p, and miR-3690) were combined as a panel, the AUC was enhanced to an almost acceptable degree (AUC of 0.67, approaching 0.7) and might have value in complementing clinical diagnoses,” they said.

The study findings were limited by several factors including the small sample size and the use of medications by most MDD patients, which resulted in an especially small number of unmedicated patients, the researchers noted. Other limitations included the use of study population from a single center, and the inability to explain the link between blood and brain miRNA expression, they said.

However, the study is the first clinical trial in Singapore to examine the role of miRNA in depression and to identify miRNAs as potential biomarkers for MDD, they said.

Additional studies are needed to explore miRNA biomarkers for diagnosis, disease prognosis, and treatment response in MDD, they concluded.

The study was supported by the National University Health System Seed Fund. The researchers had no financial conflicts to disclose.

Suicide risk in young people appears to follow a diurnal pattern, increasing at night, new research shows.

Investigators found that suicidal ideation and attempts were lowest in the mornings and highest in the evenings, particularly among youth with higher levels of self-critical rumination.

“These are preliminary findings, and there is a need for more data, but they signal potentially that there’s a need for support, particularly at nighttime, and that there might be a potential of targeting self-critical rumination in daily lives of youth,” said lead researcher Anastacia Kudinova, PhD, with the department of psychiatry and human behavior, Alpert Medical School of Brown University, Providence, R.I.

The findings were presented at the late-breaker session at the annual meeting of the Associated Professional Sleep Societies.
 

Urgent need

Suicidal ideation (SI) is a “robust” predictor of suicidal behavior and, “alarmingly,” both suicidal ideation and suicidal behavior have been increasing, Dr. Kudinova said.

“There is an urgent need to describe proximal time-period risk factors for suicide so that we can identify who is at a greater suicide risk on the time scale of weeks, days, or even hours,” she told attendees.

The researchers asked 165 psychiatrically hospitalized youth aged 11-18 (72% female) about the time of day of their most recent suicide attempt.

More than half (58%) said it occurred in the evenings and nights, followed by daytime (35%) and mornings (7%).

They also assessed the timing of suicidal ideation at home in 61 youth aged 12-15 (61% female) who were discharged after a partial hospitalization program.

They did this using ecological momentary assessments (EMAs) three times a day over 2 weeks. EMAs study people’s thoughts and behavior in their daily lives by repeatedly collecting data in an individual’s normal environment at or close to the time they carry out that behavior.

As in the other sample, youth in this sample also experienced significantly more frequent suicidal ideation later in the day (P < .01).

There was also a significant moderating effect of self-criticism (P < .01), such that more self-critical youth evidenced the highest levels of suicidal ideation later in the day.
 

True variation or mechanics?

Reached for comment, Paul Nestadt, MD, with Johns Hopkins Bloomberg School of Public Health, Baltimore, noted that EMA is becoming “an interesting way to track high-resolution temporal variation in suicidal ideation and other psych symptoms.”

Dr. Nestadt, who was not involved in the study, said that “it’s not surprising” that the majority of youth attempted suicide in evenings and nights, “as adolescents are generally being supervised in a school setting during daytime hours. It may not be the fluctuation in suicidality that impacts attempt timing so much as the mechanics – it is very hard to attempt suicide in math class.”

The same may be true for the youth in the second sample who were in the partial hospital program. “During the day, they were in therapy groups where feelings of suicidal ideation would have been solicited and addressed in real time,” Dr. Nestadt noted.

“Again, suicidal ideation later in the day may be a practical effect of how they are occupied in the partial hospital program, as opposed to some inherent suicidal ideation increase linked to something endogenous, such as circadian rhythm or cortisol level rises. That said, we do often see more attempts in the evenings in adults as well,” he added.
 

A vulnerable time

Also weighing in, Casey O’Brien, PsyD, a psychologist in the department of psychiatry at Columbia University Irving Medical Center, New York, said the findings in this study “track” with what she sees in the clinic.

Teens often report in session that the “unstructured time of night – especially the time when they usually should be getting to bed but are kind of staying up – tends to be a very vulnerable time for them,” Dr. O’Brien said in an interview.

“It’s really nice to have research confirm a lot of what we see reported anecdotally from the teens we work with,” said Dr. O’Brien.

Dr. O’Brien heads the intensive adolescent dialectical behavior therapy (DBT) program at Columbia for young people struggling with mental health issues.

“Within the DBT framework, we try to really focus on accepting that this is a vulnerable time and then planning ahead for what the strategies are that they can use to help them transition to bed quickly and smoothly,” Dr. O’Brien said.

These strategies may include spending time with their parents before bed, reading, or building into their bedtime routines things that they find soothing and comforting, like taking a longer shower or having comfortable pajamas to change into, she explained.

“We also work a lot on sleep hygiene strategies to help develop a regular bedtime and have a consistent sleep-wake cycle. We also will plan ahead for using distress tolerance skills during times of emotional vulnerability,” Dr. O’Brien said.

The Columbia DBT program also offers phone coaching “so teens can reach out to a therapist for help using skills outside of a therapeutic hour, and we do find that we get more coaching calls closer to around bedtime,” Dr. O’Brien said.

Support for the study was provided by the National Institute of Mental Health and Bradley Hospital COBRE Center. Dr. Kudinova, Dr. Nestadt, and Dr. O’Brien have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Suicide risk in young people appears to follow a diurnal pattern, increasing at night, new research shows.

Investigators found that suicidal ideation and attempts were lowest in the mornings and highest in the evenings, particularly among youth with higher levels of self-critical rumination.

“These are preliminary findings, and there is a need for more data, but they signal potentially that there’s a need for support, particularly at nighttime, and that there might be a potential of targeting self-critical rumination in daily lives of youth,” said lead researcher Anastacia Kudinova, PhD, with the department of psychiatry and human behavior, Alpert Medical School of Brown University, Providence, R.I.

The findings were presented at the late-breaker session at the annual meeting of the Associated Professional Sleep Societies.
 

Urgent need

Suicidal ideation (SI) is a “robust” predictor of suicidal behavior and, “alarmingly,” both suicidal ideation and suicidal behavior have been increasing, Dr. Kudinova said.

“There is an urgent need to describe proximal time-period risk factors for suicide so that we can identify who is at a greater suicide risk on the time scale of weeks, days, or even hours,” she told attendees.

The researchers asked 165 psychiatrically hospitalized youth aged 11-18 (72% female) about the time of day of their most recent suicide attempt.

More than half (58%) said it occurred in the evenings and nights, followed by daytime (35%) and mornings (7%).

They also assessed the timing of suicidal ideation at home in 61 youth aged 12-15 (61% female) who were discharged after a partial hospitalization program.

They did this using ecological momentary assessments (EMAs) three times a day over 2 weeks. EMAs study people’s thoughts and behavior in their daily lives by repeatedly collecting data in an individual’s normal environment at or close to the time they carry out that behavior.

As in the other sample, youth in this sample also experienced significantly more frequent suicidal ideation later in the day (P < .01).

There was also a significant moderating effect of self-criticism (P < .01), such that more self-critical youth evidenced the highest levels of suicidal ideation later in the day.
 

True variation or mechanics?

Reached for comment, Paul Nestadt, MD, with Johns Hopkins Bloomberg School of Public Health, Baltimore, noted that EMA is becoming “an interesting way to track high-resolution temporal variation in suicidal ideation and other psych symptoms.”

Dr. Nestadt, who was not involved in the study, said that “it’s not surprising” that the majority of youth attempted suicide in evenings and nights, “as adolescents are generally being supervised in a school setting during daytime hours. It may not be the fluctuation in suicidality that impacts attempt timing so much as the mechanics – it is very hard to attempt suicide in math class.”

The same may be true for the youth in the second sample who were in the partial hospital program. “During the day, they were in therapy groups where feelings of suicidal ideation would have been solicited and addressed in real time,” Dr. Nestadt noted.

“Again, suicidal ideation later in the day may be a practical effect of how they are occupied in the partial hospital program, as opposed to some inherent suicidal ideation increase linked to something endogenous, such as circadian rhythm or cortisol level rises. That said, we do often see more attempts in the evenings in adults as well,” he added.
 

A vulnerable time

Also weighing in, Casey O’Brien, PsyD, a psychologist in the department of psychiatry at Columbia University Irving Medical Center, New York, said the findings in this study “track” with what she sees in the clinic.

Teens often report in session that the “unstructured time of night – especially the time when they usually should be getting to bed but are kind of staying up – tends to be a very vulnerable time for them,” Dr. O’Brien said in an interview.

“It’s really nice to have research confirm a lot of what we see reported anecdotally from the teens we work with,” said Dr. O’Brien.

Dr. O’Brien heads the intensive adolescent dialectical behavior therapy (DBT) program at Columbia for young people struggling with mental health issues.

“Within the DBT framework, we try to really focus on accepting that this is a vulnerable time and then planning ahead for what the strategies are that they can use to help them transition to bed quickly and smoothly,” Dr. O’Brien said.

These strategies may include spending time with their parents before bed, reading, or building into their bedtime routines things that they find soothing and comforting, like taking a longer shower or having comfortable pajamas to change into, she explained.

“We also work a lot on sleep hygiene strategies to help develop a regular bedtime and have a consistent sleep-wake cycle. We also will plan ahead for using distress tolerance skills during times of emotional vulnerability,” Dr. O’Brien said.

The Columbia DBT program also offers phone coaching “so teens can reach out to a therapist for help using skills outside of a therapeutic hour, and we do find that we get more coaching calls closer to around bedtime,” Dr. O’Brien said.

Support for the study was provided by the National Institute of Mental Health and Bradley Hospital COBRE Center. Dr. Kudinova, Dr. Nestadt, and Dr. O’Brien have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Suicide risk in young people appears to follow a diurnal pattern, increasing at night, new research shows.

Investigators found that suicidal ideation and attempts were lowest in the mornings and highest in the evenings, particularly among youth with higher levels of self-critical rumination.

“These are preliminary findings, and there is a need for more data, but they signal potentially that there’s a need for support, particularly at nighttime, and that there might be a potential of targeting self-critical rumination in daily lives of youth,” said lead researcher Anastacia Kudinova, PhD, with the department of psychiatry and human behavior, Alpert Medical School of Brown University, Providence, R.I.

The findings were presented at the late-breaker session at the annual meeting of the Associated Professional Sleep Societies.
 

Urgent need

Suicidal ideation (SI) is a “robust” predictor of suicidal behavior and, “alarmingly,” both suicidal ideation and suicidal behavior have been increasing, Dr. Kudinova said.

“There is an urgent need to describe proximal time-period risk factors for suicide so that we can identify who is at a greater suicide risk on the time scale of weeks, days, or even hours,” she told attendees.

The researchers asked 165 psychiatrically hospitalized youth aged 11-18 (72% female) about the time of day of their most recent suicide attempt.

More than half (58%) said it occurred in the evenings and nights, followed by daytime (35%) and mornings (7%).

They also assessed the timing of suicidal ideation at home in 61 youth aged 12-15 (61% female) who were discharged after a partial hospitalization program.

They did this using ecological momentary assessments (EMAs) three times a day over 2 weeks. EMAs study people’s thoughts and behavior in their daily lives by repeatedly collecting data in an individual’s normal environment at or close to the time they carry out that behavior.

As in the other sample, youth in this sample also experienced significantly more frequent suicidal ideation later in the day (P < .01).

There was also a significant moderating effect of self-criticism (P < .01), such that more self-critical youth evidenced the highest levels of suicidal ideation later in the day.
 

True variation or mechanics?

Reached for comment, Paul Nestadt, MD, with Johns Hopkins Bloomberg School of Public Health, Baltimore, noted that EMA is becoming “an interesting way to track high-resolution temporal variation in suicidal ideation and other psych symptoms.”

Dr. Nestadt, who was not involved in the study, said that “it’s not surprising” that the majority of youth attempted suicide in evenings and nights, “as adolescents are generally being supervised in a school setting during daytime hours. It may not be the fluctuation in suicidality that impacts attempt timing so much as the mechanics – it is very hard to attempt suicide in math class.”

The same may be true for the youth in the second sample who were in the partial hospital program. “During the day, they were in therapy groups where feelings of suicidal ideation would have been solicited and addressed in real time,” Dr. Nestadt noted.

“Again, suicidal ideation later in the day may be a practical effect of how they are occupied in the partial hospital program, as opposed to some inherent suicidal ideation increase linked to something endogenous, such as circadian rhythm or cortisol level rises. That said, we do often see more attempts in the evenings in adults as well,” he added.
 

A vulnerable time

Also weighing in, Casey O’Brien, PsyD, a psychologist in the department of psychiatry at Columbia University Irving Medical Center, New York, said the findings in this study “track” with what she sees in the clinic.

Teens often report in session that the “unstructured time of night – especially the time when they usually should be getting to bed but are kind of staying up – tends to be a very vulnerable time for them,” Dr. O’Brien said in an interview.

“It’s really nice to have research confirm a lot of what we see reported anecdotally from the teens we work with,” said Dr. O’Brien.

Dr. O’Brien heads the intensive adolescent dialectical behavior therapy (DBT) program at Columbia for young people struggling with mental health issues.

“Within the DBT framework, we try to really focus on accepting that this is a vulnerable time and then planning ahead for what the strategies are that they can use to help them transition to bed quickly and smoothly,” Dr. O’Brien said.

These strategies may include spending time with their parents before bed, reading, or building into their bedtime routines things that they find soothing and comforting, like taking a longer shower or having comfortable pajamas to change into, she explained.

“We also work a lot on sleep hygiene strategies to help develop a regular bedtime and have a consistent sleep-wake cycle. We also will plan ahead for using distress tolerance skills during times of emotional vulnerability,” Dr. O’Brien said.

The Columbia DBT program also offers phone coaching “so teens can reach out to a therapist for help using skills outside of a therapeutic hour, and we do find that we get more coaching calls closer to around bedtime,” Dr. O’Brien said.

Support for the study was provided by the National Institute of Mental Health and Bradley Hospital COBRE Center. Dr. Kudinova, Dr. Nestadt, and Dr. O’Brien have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Electroconvulsive therapy (ECT) is the standard treatment for resistant depression, but results of a new randomized, head-to-head trial suggest intravenous ketamine is at least as effective and has fewer side effects.

“The take-home message right now is that if somebody is being referred for ECT, the treating clinician should think of offering ketamine first,” study investigator Amit Anand, MD, professor of psychiatry, Harvard Medical School, Boston, said in an interview.

The study was published online in the New England Journal of Medicine.
 

‘Preferred treatment’

More than one-third of cases of depression are treatment resistant, said Dr. Anand, who is also director of Psychiatry Translational Clinical Trials at Mass General Brigham. He noted that ECT has been the “gold standard for treating severe depression for over 80 years.”

Julia Hiebaum/Alamy

He added that although ECT is very effective and is fast acting, “it requires anesthesia, can be socially stigmatizing, and is associated with memory problems following the treatment.”

An anesthetic agent, ketamine has been shown to have rapid antidepressant effects and does not cause memory loss or carry the stigma associated with ECT, he added. For these reasons, the investigators examined whether it may be a viable alternative to ECT.

To date, no large, head-to-head trials have compared ECT to intravenous ketamine. A recent meta-analysis showed that ECT was superior to ketamine for major depression, but the total number of patients included in the analysis was small, Dr. Anand said.

In addition, most of the participants in that trial were drawn from a single center. Approximately 95 patients were enrolled in each arm of the trial, which included some participants with features of psychosis. “ECT is very effective for depression associated with psychotic features, which may be one reason ECT had a better response in that trial,” said Dr. Anand.

The investigators compared ECT to ketamine in a larger sample that excluded patients with psychosis. They randomly assigned 403 patients at five clinical sites in a 1:1 ratio to receive either ketamine or ECT (n = 200 and 203, respectively; 53% and 49.3% women, respectively; aged 45.6 ± 14.8 and 47.1 ± 14.1 years, respectively).

Patients were required to have had an unsatisfactory response to two or more adequate trials of antidepressant treatment.

Prior to initiation of the assigned treatment, 38 patients withdrew, leaving 195 in the ketamine group and 170 in the ECT group.

Treatment was administered over a 3-week period, during which patients received either ECT three times per week or ketamine (0.5 mg/kg of body weight) twice per week.

The primary outcome was treatment response, defined as a decrease of 50% or more from baseline in the16-item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR-16). Secondary outcomes included scores on memory tests and patient-reported quality of life.

Patients who had a response were followed for 6 months after the initial treatment phase.
 

More research needed

Following the 3-week treatment period, a total of 55.4% patients who received ketamine and 41.2% of patients who underwent ECT responded to treatment, which translates into a difference of 14.2 percentage points (95% confidence interval, 3.9-24.2; P < .001) – a finding that fell within the noninferiority threshold set by the investigators.

ECT was associated with decreased memory recall after the 3 weeks of treatment, with a mean (standard deviation) decrease in the T-score for delayed recall on the Hopkins Verbal Learning Test–Revised of –0.9 (1.1) in the ketamine group vs. –9.7 (1.2) in the ECT group (difference, –1.8 points [–2.8 to –0.8]).

Remission, determined on the basis of QIDS-SR-16 score, occurred in 32% of the ketamine group and in 20% in the ECT group. Similar findings were seen on the Montgomery-Åsberg Depression Rating Scale.

Both groups showed significant improvements in quality of life, with changes of 12.3 and 12.9 points, respectively, on the 16-item Quality of Life Scale.

“ECT was associated with musculoskeletal adverse events, whereas ketamine was associated with dissociation,” the investigators note.

During the 6-month follow-up period, there were differences in relapse rates between the groups (defined as QIDS-SRS-16 score > 11). At 1 month, the rates were 19.0% for those receiving ketamine and 35.4% for those receiving ECT. At 3 months, the rates were 25.0% and 50.9%, respectively; at 6 months, the rates were 34.5% and 56.3%, respectively.

ECT has been shown to be effective for older adults, patients with MDD and psychosis, and in inpatient and research settings. Future studies are needed to determine the comparative effectiveness of ketamine in these populations, the authors note.
 

Not life-changing

In a comment, Dan Iosifescu, MD, professor of psychiatry, NYU Langone Health, New York, called it an “extraordinarily important and clinically relevant study, large, well-designed, and well-conducted.”

Dr. Iosifescu, director of the clinical research division, Nathan Kline Institute, Orangeburg, N.Y., who was not involved with the study, noted that the study wasn’t powered to determine whether one treatment was superior to the other, but rather it assessed noninferiority.

“The main point of this study is that the two treatments are largely equivalent, although numerically, ketamine was slightly associated with more beneficial outcomes and fewer cognitive side effects,” he said.

The findings suggest “that people who have no contraindications and are candidates for both ketamine and ECT – which is the vast majority of people with treatment-resistant depression – should consider getting ketamine first because it is somewhat easier in terms of side effects and logistics and consider ECT afterwards if the ketamine doesn’t work.”

In an accompanying editorial, Robert Freedman, MD, clinical professor, University of Colorado at Denver, Aurora, noted that although “3 weeks of lightened mood is undoubtedly a gift ... the results of this current trial suggests that the 3-week treatment was not life-changing,” since effects had largely worn off by 6 months in both groups.

Longer-term treatment with ketamine “increases the likelihood of both drug dependence and cognitive adverse effects, including dissociation, paranoia, and other psychotic symptoms,” Dr. Freedman said.

He recommends that informed consent documents be used to caution patients and clinicians considering ketamine “that temporary relief may come with longer-term costs.”

The study was supported by a grant from PCORI to Dr. Anand. Dr. Freedman has disclosed no relevant financial relationships. In the past 2 years, Dr. Iosifescu has been a consultant for Axsome, Allergan, Biogen, Clexio, Jazz, Neumora, Relmada, and Sage. He has also received a research grant from Otsuka.

A version of this article first appeared on Medscape.com.

Electroconvulsive therapy (ECT) is the standard treatment for resistant depression, but results of a new randomized, head-to-head trial suggest intravenous ketamine is at least as effective and has fewer side effects.

“The take-home message right now is that if somebody is being referred for ECT, the treating clinician should think of offering ketamine first,” study investigator Amit Anand, MD, professor of psychiatry, Harvard Medical School, Boston, said in an interview.

The study was published online in the New England Journal of Medicine.
 

‘Preferred treatment’

More than one-third of cases of depression are treatment resistant, said Dr. Anand, who is also director of Psychiatry Translational Clinical Trials at Mass General Brigham. He noted that ECT has been the “gold standard for treating severe depression for over 80 years.”

Julia Hiebaum/Alamy

He added that although ECT is very effective and is fast acting, “it requires anesthesia, can be socially stigmatizing, and is associated with memory problems following the treatment.”

An anesthetic agent, ketamine has been shown to have rapid antidepressant effects and does not cause memory loss or carry the stigma associated with ECT, he added. For these reasons, the investigators examined whether it may be a viable alternative to ECT.

To date, no large, head-to-head trials have compared ECT to intravenous ketamine. A recent meta-analysis showed that ECT was superior to ketamine for major depression, but the total number of patients included in the analysis was small, Dr. Anand said.

In addition, most of the participants in that trial were drawn from a single center. Approximately 95 patients were enrolled in each arm of the trial, which included some participants with features of psychosis. “ECT is very effective for depression associated with psychotic features, which may be one reason ECT had a better response in that trial,” said Dr. Anand.

The investigators compared ECT to ketamine in a larger sample that excluded patients with psychosis. They randomly assigned 403 patients at five clinical sites in a 1:1 ratio to receive either ketamine or ECT (n = 200 and 203, respectively; 53% and 49.3% women, respectively; aged 45.6 ± 14.8 and 47.1 ± 14.1 years, respectively).

Patients were required to have had an unsatisfactory response to two or more adequate trials of antidepressant treatment.

Prior to initiation of the assigned treatment, 38 patients withdrew, leaving 195 in the ketamine group and 170 in the ECT group.

Treatment was administered over a 3-week period, during which patients received either ECT three times per week or ketamine (0.5 mg/kg of body weight) twice per week.

The primary outcome was treatment response, defined as a decrease of 50% or more from baseline in the16-item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR-16). Secondary outcomes included scores on memory tests and patient-reported quality of life.

Patients who had a response were followed for 6 months after the initial treatment phase.
 

More research needed

Following the 3-week treatment period, a total of 55.4% patients who received ketamine and 41.2% of patients who underwent ECT responded to treatment, which translates into a difference of 14.2 percentage points (95% confidence interval, 3.9-24.2; P < .001) – a finding that fell within the noninferiority threshold set by the investigators.

ECT was associated with decreased memory recall after the 3 weeks of treatment, with a mean (standard deviation) decrease in the T-score for delayed recall on the Hopkins Verbal Learning Test–Revised of –0.9 (1.1) in the ketamine group vs. –9.7 (1.2) in the ECT group (difference, –1.8 points [–2.8 to –0.8]).

Remission, determined on the basis of QIDS-SR-16 score, occurred in 32% of the ketamine group and in 20% in the ECT group. Similar findings were seen on the Montgomery-Åsberg Depression Rating Scale.

Both groups showed significant improvements in quality of life, with changes of 12.3 and 12.9 points, respectively, on the 16-item Quality of Life Scale.

“ECT was associated with musculoskeletal adverse events, whereas ketamine was associated with dissociation,” the investigators note.

During the 6-month follow-up period, there were differences in relapse rates between the groups (defined as QIDS-SRS-16 score > 11). At 1 month, the rates were 19.0% for those receiving ketamine and 35.4% for those receiving ECT. At 3 months, the rates were 25.0% and 50.9%, respectively; at 6 months, the rates were 34.5% and 56.3%, respectively.

ECT has been shown to be effective for older adults, patients with MDD and psychosis, and in inpatient and research settings. Future studies are needed to determine the comparative effectiveness of ketamine in these populations, the authors note.
 

Not life-changing

In a comment, Dan Iosifescu, MD, professor of psychiatry, NYU Langone Health, New York, called it an “extraordinarily important and clinically relevant study, large, well-designed, and well-conducted.”

Dr. Iosifescu, director of the clinical research division, Nathan Kline Institute, Orangeburg, N.Y., who was not involved with the study, noted that the study wasn’t powered to determine whether one treatment was superior to the other, but rather it assessed noninferiority.

“The main point of this study is that the two treatments are largely equivalent, although numerically, ketamine was slightly associated with more beneficial outcomes and fewer cognitive side effects,” he said.

The findings suggest “that people who have no contraindications and are candidates for both ketamine and ECT – which is the vast majority of people with treatment-resistant depression – should consider getting ketamine first because it is somewhat easier in terms of side effects and logistics and consider ECT afterwards if the ketamine doesn’t work.”

In an accompanying editorial, Robert Freedman, MD, clinical professor, University of Colorado at Denver, Aurora, noted that although “3 weeks of lightened mood is undoubtedly a gift ... the results of this current trial suggests that the 3-week treatment was not life-changing,” since effects had largely worn off by 6 months in both groups.

Longer-term treatment with ketamine “increases the likelihood of both drug dependence and cognitive adverse effects, including dissociation, paranoia, and other psychotic symptoms,” Dr. Freedman said.

He recommends that informed consent documents be used to caution patients and clinicians considering ketamine “that temporary relief may come with longer-term costs.”

The study was supported by a grant from PCORI to Dr. Anand. Dr. Freedman has disclosed no relevant financial relationships. In the past 2 years, Dr. Iosifescu has been a consultant for Axsome, Allergan, Biogen, Clexio, Jazz, Neumora, Relmada, and Sage. He has also received a research grant from Otsuka.

A version of this article first appeared on Medscape.com.

Electroconvulsive therapy (ECT) is the standard treatment for resistant depression, but results of a new randomized, head-to-head trial suggest intravenous ketamine is at least as effective and has fewer side effects.

“The take-home message right now is that if somebody is being referred for ECT, the treating clinician should think of offering ketamine first,” study investigator Amit Anand, MD, professor of psychiatry, Harvard Medical School, Boston, said in an interview.

The study was published online in the New England Journal of Medicine.
 

‘Preferred treatment’

More than one-third of cases of depression are treatment resistant, said Dr. Anand, who is also director of Psychiatry Translational Clinical Trials at Mass General Brigham. He noted that ECT has been the “gold standard for treating severe depression for over 80 years.”

Julia Hiebaum/Alamy

He added that although ECT is very effective and is fast acting, “it requires anesthesia, can be socially stigmatizing, and is associated with memory problems following the treatment.”

An anesthetic agent, ketamine has been shown to have rapid antidepressant effects and does not cause memory loss or carry the stigma associated with ECT, he added. For these reasons, the investigators examined whether it may be a viable alternative to ECT.

To date, no large, head-to-head trials have compared ECT to intravenous ketamine. A recent meta-analysis showed that ECT was superior to ketamine for major depression, but the total number of patients included in the analysis was small, Dr. Anand said.

In addition, most of the participants in that trial were drawn from a single center. Approximately 95 patients were enrolled in each arm of the trial, which included some participants with features of psychosis. “ECT is very effective for depression associated with psychotic features, which may be one reason ECT had a better response in that trial,” said Dr. Anand.

The investigators compared ECT to ketamine in a larger sample that excluded patients with psychosis. They randomly assigned 403 patients at five clinical sites in a 1:1 ratio to receive either ketamine or ECT (n = 200 and 203, respectively; 53% and 49.3% women, respectively; aged 45.6 ± 14.8 and 47.1 ± 14.1 years, respectively).

Patients were required to have had an unsatisfactory response to two or more adequate trials of antidepressant treatment.

Prior to initiation of the assigned treatment, 38 patients withdrew, leaving 195 in the ketamine group and 170 in the ECT group.

Treatment was administered over a 3-week period, during which patients received either ECT three times per week or ketamine (0.5 mg/kg of body weight) twice per week.

The primary outcome was treatment response, defined as a decrease of 50% or more from baseline in the16-item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR-16). Secondary outcomes included scores on memory tests and patient-reported quality of life.

Patients who had a response were followed for 6 months after the initial treatment phase.
 

More research needed

Following the 3-week treatment period, a total of 55.4% patients who received ketamine and 41.2% of patients who underwent ECT responded to treatment, which translates into a difference of 14.2 percentage points (95% confidence interval, 3.9-24.2; P < .001) – a finding that fell within the noninferiority threshold set by the investigators.

ECT was associated with decreased memory recall after the 3 weeks of treatment, with a mean (standard deviation) decrease in the T-score for delayed recall on the Hopkins Verbal Learning Test–Revised of –0.9 (1.1) in the ketamine group vs. –9.7 (1.2) in the ECT group (difference, –1.8 points [–2.8 to –0.8]).

Remission, determined on the basis of QIDS-SR-16 score, occurred in 32% of the ketamine group and in 20% in the ECT group. Similar findings were seen on the Montgomery-Åsberg Depression Rating Scale.

Both groups showed significant improvements in quality of life, with changes of 12.3 and 12.9 points, respectively, on the 16-item Quality of Life Scale.

“ECT was associated with musculoskeletal adverse events, whereas ketamine was associated with dissociation,” the investigators note.

During the 6-month follow-up period, there were differences in relapse rates between the groups (defined as QIDS-SRS-16 score > 11). At 1 month, the rates were 19.0% for those receiving ketamine and 35.4% for those receiving ECT. At 3 months, the rates were 25.0% and 50.9%, respectively; at 6 months, the rates were 34.5% and 56.3%, respectively.

ECT has been shown to be effective for older adults, patients with MDD and psychosis, and in inpatient and research settings. Future studies are needed to determine the comparative effectiveness of ketamine in these populations, the authors note.
 

Not life-changing

In a comment, Dan Iosifescu, MD, professor of psychiatry, NYU Langone Health, New York, called it an “extraordinarily important and clinically relevant study, large, well-designed, and well-conducted.”

Dr. Iosifescu, director of the clinical research division, Nathan Kline Institute, Orangeburg, N.Y., who was not involved with the study, noted that the study wasn’t powered to determine whether one treatment was superior to the other, but rather it assessed noninferiority.

“The main point of this study is that the two treatments are largely equivalent, although numerically, ketamine was slightly associated with more beneficial outcomes and fewer cognitive side effects,” he said.

The findings suggest “that people who have no contraindications and are candidates for both ketamine and ECT – which is the vast majority of people with treatment-resistant depression – should consider getting ketamine first because it is somewhat easier in terms of side effects and logistics and consider ECT afterwards if the ketamine doesn’t work.”

In an accompanying editorial, Robert Freedman, MD, clinical professor, University of Colorado at Denver, Aurora, noted that although “3 weeks of lightened mood is undoubtedly a gift ... the results of this current trial suggests that the 3-week treatment was not life-changing,” since effects had largely worn off by 6 months in both groups.

Longer-term treatment with ketamine “increases the likelihood of both drug dependence and cognitive adverse effects, including dissociation, paranoia, and other psychotic symptoms,” Dr. Freedman said.

He recommends that informed consent documents be used to caution patients and clinicians considering ketamine “that temporary relief may come with longer-term costs.”

The study was supported by a grant from PCORI to Dr. Anand. Dr. Freedman has disclosed no relevant financial relationships. In the past 2 years, Dr. Iosifescu has been a consultant for Axsome, Allergan, Biogen, Clexio, Jazz, Neumora, Relmada, and Sage. He has also received a research grant from Otsuka.

A version of this article first appeared on Medscape.com.

SAN FRANCISCO – University of California, San Diego, psychiatrist Stephen M. Stahl, MD, PhD, has heard the scary stories about monoamine oxidase inhibitors (MAOIs): Patients supposedly need to be on restrictive diets free of culinary joys like cheese, beer, and wine; they can’t take cold medicines; and they can just forget about anesthesia for dental work or surgery.

Waketonay via Creative Commons (https://creativecommons.org/licenses/by-sa/4.0/legalcode)

Wrong, wrong, and wrong, Dr. Stahl told an audience at the annual meeting of the American Psychiatric Association. While the venerable antidepressants can transform the lives of patients with treatment-resistant depression, he said, MAOIs are plagued by myths that exaggerate their risks.

“These are good options,” he said. “Everybody who prescribes these today, without exception, has seen patients respond after nothing else has – including ECT (electroconvulsive therapy).”

Still, MAOIs, which were first developed in the 1950s, remain little-used in the United States. While an average of six selective serotonin reuptake inhibitors (SSRIs) are prescribed every second in the United States each day, Dr. Stahl said, “there are only a few hundred MAOI prescribers for a few thousand patients.”

The main barrier to the use of the drugs is unfamiliarity, he said. Despite their low profile, they’re appropriate to use after failures of monotherapy with SSRIs/serotonin and norepinephrine reuptake inhibitors (SNRIs) and augmentation with atypical antipsychotics. And they can be used in conjunction with ketamine/esketamine and ECT, which are other options for treatment-resistant depression, he said.

As for the myths about MAOIs, Dr. Stahl said the drugs can indeed interact with tyramine, which is found in foods like cheese, beer, and wine. The interaction can lead to potentially fatal hypertensive crises, Dr. Stahl said, noting that patients should avoid aged cheeses, tap and unpasteurized beer, soy products, and certain other foods. (Patients taking 6 mg transdermal or low-dose oral selegiline can ignore these restrictions.)

But canned beer, certain wines, yogurt, fresh American cheese, mozzarella/pizza chain cheese, cream cheese, and fresh or processed meat/poultry/fish are fine, he said. “Selectively, you can have a pretty high tyramine diet,” he added, although it’s a good idea for patients to have a blood pressure monitor at home.

As for cold medicines, sympathomimetic decongestants and stimulants should be used cautiously with blood pressure monitoring or not at all, he said, but those with codeine or expectorants are OK. Dextromethorphan, a weak serotonin reuptake inhibitor in some cough medicine, should be avoided. However, antihistamines other than chlorpheniramine/brompheniramine are OK to use, he added, and they may be the ideal choice for cold relief.

As for anesthesia, he cautioned that local anesthetics with epinephrine and general anesthesia can disrupt blood pressure. Choose a local anesthetic that does not contain vasoconstrictors, he said, and if surgery with general anesthesia is needed, “you can wash [the MAOI] out if you want” ahead of time.

Benzodiazepines, mivacurium, rapacuronium, morphine, or codeine can be used cautiously, he said, in urgent or elective surgery in a patient on an MAOI.

As for other myths, he said tricyclic antidepressants and related drugs aren’t as troublesome as psychiatrists may assume. Clomipramine and imipramine should be avoided. But other tricyclic antidepressants can be used with caution.

As for painkillers, he said it’s not true that they must be avoided, although MAIOs shouldn’t be taken with meperidine, fentanyl, methadone, tramadol, or tapentadol. Other painkillers, including over-the-counter products like aspirin, NSAIDs, and acetaminophen, should be used with caution, he said. And expert guidance is advised for use of hydromorphone, morphine, oxycodone, or oxymorphone.

In the big picture, he noted, myths are so prevalent “that you have more calls from patients – and other doctors, dentists, and anesthesiologists – about MAO inhibitors then you will ever have about any other drug there.”

Columbia University, New York, psychiatrist Jonathan W. Stewart, MD, also spoke at the presentation on MAIOs at the APA conference. He recommended that colleagues consider the drugs if two or more antidepressants that work in different ways fail to provide relief after 4 weeks at a sufficient dose. Start low with one pill a day, he recommended, and seek full remission – no depressed mood – instead of simply “better.”

Ultimately, he said, “we do patients a disservice” if MAOIs aren’t considered in the appropriate patients.

Dr. Stahl discloses grant/research support (Acadia, Allergan/AbbVie, Avanir, Boehringer Ingelheim Braeburn, Daiichi Sankyo-Brazil Eisai, Eli Lilly, Harmony, Indivior, Intra-Cellular Therapies, Ironshore, Neurocrine, Otsuka, Pear Therapeutics, Sage, Shire Sunovion, Supernus, and Torrent), consultant/advisor support (Acadia, Alkermes, Allergan, AbbVie, Axsome, Clearview, Done, Eisai Pharmaceuticals, Gedeon Richter, Intra-Cellular Therapies, Karuna, Levo, Lundbeck, Neurocrine, Neurawell, Otsuka, Relmada, Sage, Sunovion, Supernus, Taliaz, Teva, Tris Pharma, and VistaGen), speakers bureau payments (Acadia, Lundbeck, Neurocrine, Otsuka, Servier, Sunovion, and Teva), and options in Genomind, Lipidio, Neurawell and Delix. Dr. Stewart discloses unspecified relationships with Eli Lilly, Pfizer, Merck, Boeringer- Ingleheim, Bristol-Myers, Sinolfi-Aventis, Amilyn, Novartis, Organon, GlaxoSmithKlein, Shire, and Somerset.

SAN FRANCISCO – University of California, San Diego, psychiatrist Stephen M. Stahl, MD, PhD, has heard the scary stories about monoamine oxidase inhibitors (MAOIs): Patients supposedly need to be on restrictive diets free of culinary joys like cheese, beer, and wine; they can’t take cold medicines; and they can just forget about anesthesia for dental work or surgery.

Waketonay via Creative Commons (https://creativecommons.org/licenses/by-sa/4.0/legalcode)

Wrong, wrong, and wrong, Dr. Stahl told an audience at the annual meeting of the American Psychiatric Association. While the venerable antidepressants can transform the lives of patients with treatment-resistant depression, he said, MAOIs are plagued by myths that exaggerate their risks.

“These are good options,” he said. “Everybody who prescribes these today, without exception, has seen patients respond after nothing else has – including ECT (electroconvulsive therapy).”

Still, MAOIs, which were first developed in the 1950s, remain little-used in the United States. While an average of six selective serotonin reuptake inhibitors (SSRIs) are prescribed every second in the United States each day, Dr. Stahl said, “there are only a few hundred MAOI prescribers for a few thousand patients.”

The main barrier to the use of the drugs is unfamiliarity, he said. Despite their low profile, they’re appropriate to use after failures of monotherapy with SSRIs/serotonin and norepinephrine reuptake inhibitors (SNRIs) and augmentation with atypical antipsychotics. And they can be used in conjunction with ketamine/esketamine and ECT, which are other options for treatment-resistant depression, he said.

As for the myths about MAOIs, Dr. Stahl said the drugs can indeed interact with tyramine, which is found in foods like cheese, beer, and wine. The interaction can lead to potentially fatal hypertensive crises, Dr. Stahl said, noting that patients should avoid aged cheeses, tap and unpasteurized beer, soy products, and certain other foods. (Patients taking 6 mg transdermal or low-dose oral selegiline can ignore these restrictions.)

But canned beer, certain wines, yogurt, fresh American cheese, mozzarella/pizza chain cheese, cream cheese, and fresh or processed meat/poultry/fish are fine, he said. “Selectively, you can have a pretty high tyramine diet,” he added, although it’s a good idea for patients to have a blood pressure monitor at home.

As for cold medicines, sympathomimetic decongestants and stimulants should be used cautiously with blood pressure monitoring or not at all, he said, but those with codeine or expectorants are OK. Dextromethorphan, a weak serotonin reuptake inhibitor in some cough medicine, should be avoided. However, antihistamines other than chlorpheniramine/brompheniramine are OK to use, he added, and they may be the ideal choice for cold relief.

As for anesthesia, he cautioned that local anesthetics with epinephrine and general anesthesia can disrupt blood pressure. Choose a local anesthetic that does not contain vasoconstrictors, he said, and if surgery with general anesthesia is needed, “you can wash [the MAOI] out if you want” ahead of time.

Benzodiazepines, mivacurium, rapacuronium, morphine, or codeine can be used cautiously, he said, in urgent or elective surgery in a patient on an MAOI.

As for other myths, he said tricyclic antidepressants and related drugs aren’t as troublesome as psychiatrists may assume. Clomipramine and imipramine should be avoided. But other tricyclic antidepressants can be used with caution.

As for painkillers, he said it’s not true that they must be avoided, although MAIOs shouldn’t be taken with meperidine, fentanyl, methadone, tramadol, or tapentadol. Other painkillers, including over-the-counter products like aspirin, NSAIDs, and acetaminophen, should be used with caution, he said. And expert guidance is advised for use of hydromorphone, morphine, oxycodone, or oxymorphone.

In the big picture, he noted, myths are so prevalent “that you have more calls from patients – and other doctors, dentists, and anesthesiologists – about MAO inhibitors then you will ever have about any other drug there.”

Columbia University, New York, psychiatrist Jonathan W. Stewart, MD, also spoke at the presentation on MAIOs at the APA conference. He recommended that colleagues consider the drugs if two or more antidepressants that work in different ways fail to provide relief after 4 weeks at a sufficient dose. Start low with one pill a day, he recommended, and seek full remission – no depressed mood – instead of simply “better.”

Ultimately, he said, “we do patients a disservice” if MAOIs aren’t considered in the appropriate patients.

Dr. Stahl discloses grant/research support (Acadia, Allergan/AbbVie, Avanir, Boehringer Ingelheim Braeburn, Daiichi Sankyo-Brazil Eisai, Eli Lilly, Harmony, Indivior, Intra-Cellular Therapies, Ironshore, Neurocrine, Otsuka, Pear Therapeutics, Sage, Shire Sunovion, Supernus, and Torrent), consultant/advisor support (Acadia, Alkermes, Allergan, AbbVie, Axsome, Clearview, Done, Eisai Pharmaceuticals, Gedeon Richter, Intra-Cellular Therapies, Karuna, Levo, Lundbeck, Neurocrine, Neurawell, Otsuka, Relmada, Sage, Sunovion, Supernus, Taliaz, Teva, Tris Pharma, and VistaGen), speakers bureau payments (Acadia, Lundbeck, Neurocrine, Otsuka, Servier, Sunovion, and Teva), and options in Genomind, Lipidio, Neurawell and Delix. Dr. Stewart discloses unspecified relationships with Eli Lilly, Pfizer, Merck, Boeringer- Ingleheim, Bristol-Myers, Sinolfi-Aventis, Amilyn, Novartis, Organon, GlaxoSmithKlein, Shire, and Somerset.

SAN FRANCISCO – University of California, San Diego, psychiatrist Stephen M. Stahl, MD, PhD, has heard the scary stories about monoamine oxidase inhibitors (MAOIs): Patients supposedly need to be on restrictive diets free of culinary joys like cheese, beer, and wine; they can’t take cold medicines; and they can just forget about anesthesia for dental work or surgery.

Waketonay via Creative Commons (https://creativecommons.org/licenses/by-sa/4.0/legalcode)

Wrong, wrong, and wrong, Dr. Stahl told an audience at the annual meeting of the American Psychiatric Association. While the venerable antidepressants can transform the lives of patients with treatment-resistant depression, he said, MAOIs are plagued by myths that exaggerate their risks.

“These are good options,” he said. “Everybody who prescribes these today, without exception, has seen patients respond after nothing else has – including ECT (electroconvulsive therapy).”

Still, MAOIs, which were first developed in the 1950s, remain little-used in the United States. While an average of six selective serotonin reuptake inhibitors (SSRIs) are prescribed every second in the United States each day, Dr. Stahl said, “there are only a few hundred MAOI prescribers for a few thousand patients.”

The main barrier to the use of the drugs is unfamiliarity, he said. Despite their low profile, they’re appropriate to use after failures of monotherapy with SSRIs/serotonin and norepinephrine reuptake inhibitors (SNRIs) and augmentation with atypical antipsychotics. And they can be used in conjunction with ketamine/esketamine and ECT, which are other options for treatment-resistant depression, he said.

As for the myths about MAOIs, Dr. Stahl said the drugs can indeed interact with tyramine, which is found in foods like cheese, beer, and wine. The interaction can lead to potentially fatal hypertensive crises, Dr. Stahl said, noting that patients should avoid aged cheeses, tap and unpasteurized beer, soy products, and certain other foods. (Patients taking 6 mg transdermal or low-dose oral selegiline can ignore these restrictions.)

But canned beer, certain wines, yogurt, fresh American cheese, mozzarella/pizza chain cheese, cream cheese, and fresh or processed meat/poultry/fish are fine, he said. “Selectively, you can have a pretty high tyramine diet,” he added, although it’s a good idea for patients to have a blood pressure monitor at home.

As for cold medicines, sympathomimetic decongestants and stimulants should be used cautiously with blood pressure monitoring or not at all, he said, but those with codeine or expectorants are OK. Dextromethorphan, a weak serotonin reuptake inhibitor in some cough medicine, should be avoided. However, antihistamines other than chlorpheniramine/brompheniramine are OK to use, he added, and they may be the ideal choice for cold relief.

As for anesthesia, he cautioned that local anesthetics with epinephrine and general anesthesia can disrupt blood pressure. Choose a local anesthetic that does not contain vasoconstrictors, he said, and if surgery with general anesthesia is needed, “you can wash [the MAOI] out if you want” ahead of time.

Benzodiazepines, mivacurium, rapacuronium, morphine, or codeine can be used cautiously, he said, in urgent or elective surgery in a patient on an MAOI.

As for other myths, he said tricyclic antidepressants and related drugs aren’t as troublesome as psychiatrists may assume. Clomipramine and imipramine should be avoided. But other tricyclic antidepressants can be used with caution.

As for painkillers, he said it’s not true that they must be avoided, although MAIOs shouldn’t be taken with meperidine, fentanyl, methadone, tramadol, or tapentadol. Other painkillers, including over-the-counter products like aspirin, NSAIDs, and acetaminophen, should be used with caution, he said. And expert guidance is advised for use of hydromorphone, morphine, oxycodone, or oxymorphone.

In the big picture, he noted, myths are so prevalent “that you have more calls from patients – and other doctors, dentists, and anesthesiologists – about MAO inhibitors then you will ever have about any other drug there.”

Columbia University, New York, psychiatrist Jonathan W. Stewart, MD, also spoke at the presentation on MAIOs at the APA conference. He recommended that colleagues consider the drugs if two or more antidepressants that work in different ways fail to provide relief after 4 weeks at a sufficient dose. Start low with one pill a day, he recommended, and seek full remission – no depressed mood – instead of simply “better.”

Ultimately, he said, “we do patients a disservice” if MAOIs aren’t considered in the appropriate patients.

Dr. Stahl discloses grant/research support (Acadia, Allergan/AbbVie, Avanir, Boehringer Ingelheim Braeburn, Daiichi Sankyo-Brazil Eisai, Eli Lilly, Harmony, Indivior, Intra-Cellular Therapies, Ironshore, Neurocrine, Otsuka, Pear Therapeutics, Sage, Shire Sunovion, Supernus, and Torrent), consultant/advisor support (Acadia, Alkermes, Allergan, AbbVie, Axsome, Clearview, Done, Eisai Pharmaceuticals, Gedeon Richter, Intra-Cellular Therapies, Karuna, Levo, Lundbeck, Neurocrine, Neurawell, Otsuka, Relmada, Sage, Sunovion, Supernus, Taliaz, Teva, Tris Pharma, and VistaGen), speakers bureau payments (Acadia, Lundbeck, Neurocrine, Otsuka, Servier, Sunovion, and Teva), and options in Genomind, Lipidio, Neurawell and Delix. Dr. Stewart discloses unspecified relationships with Eli Lilly, Pfizer, Merck, Boeringer- Ingleheim, Bristol-Myers, Sinolfi-Aventis, Amilyn, Novartis, Organon, GlaxoSmithKlein, Shire, and Somerset.

Suicidal ideation peaks during the winter but suicide attempts are most common in late spring and early summer in the early hours of the morning, new research shows.

In addition, the results from Harvard University’s Project Implicit Health also show that people are most likely to make an attempt at suicide between 4 and 6 a.m.

“No research has demonstrated a peak in suicidal ideation in winter until our paper,” study investigator Brian O’Shea, PhD, assistant professor of social psychology at the University of Nottingham, England, told this news organization.

“Most people incorrectly assume that suicide behaviours peak in winter and are surprised, as I was, when learning about this phenomenon, that suicide actually peaks in spring/early summer,” he added.

However, at least one expert cautioned that the database, which comprises mostly responses from younger women, doesn’t capture responses from those who are most likely to attempt suicide: older men with substance abuse.

The findings were published online in Translational Psychiatry.
 

New insight into suicide risk

Previous studies examining the seasonality of suicides and suicide attempts have reported a peak in spring and early summer, but there has been very little information about why this may be, the investigators noted.

Dr. O’Shea and his colleague from the University of Amsterdam, René Freichel, mined one of the databases from Project Implicit Health, which contains self-report measures on suicidal ideation, self-harm, and past suicide attempts, as well as respondents’ implicit biases on these topics.

The analysis included data from 10,000 respondents living in the United States, United Kingdom, and Canada provided between April 2012 and November 2018.

The sample was predominantly young and female, with 38% (3,247) of the sample reporting that they had made at least one suicide attempt.

The researchers found a peak in negative mood and desire to die occurring in December, especially among those who reported attempting suicide (P ≤ .001)

Suicidal ideation peaked approximately 3-4 months before the annual seasonal crest of suicide attempts in early spring and summer.

“Affected individuals may become severely depressed and experience a lack of energy throughout the winter months. Essentially, this period may put them below a threshold of severe suicide risk as the high level of suicidal ideation coincides with a low level of energy,” said Dr. O’Shea.

When the days get longer, brighter, and warmer, these changes likely improve an individuals’ mood, he explained. “Hence, the most at-risk individuals become slightly less depressed and may gain more energy to contemplate and plan their method to attempt suicide,” Dr. O’Shea noted.

A major limitation of the study is that all responses included in analysis were based on self-report.

To confirm the findings, future research should include ecological momentary assessment, which involves using a large community sample to question participants about suicidal intent at various time points, along with real-time monitoring of vital signs, said Dr. O’Shea.

Ideally, the investigators noted, the study’s findings will inform clinician assessments of patients who are at risk for suicide.
 

A research gap?

Commenting on the findings, Justin Shuster, MD, MPH, assistant professor of psychiatry at the University of Pittsburgh and medical director of two psychiatric units at Western Psychiatric Hospital, noted that the database used in the study did not include responses from those who were most likely to attempt or commit suicide: older men with a history of substance abuse, who require social supports, and who have a family history of suicide.

Though Dr. Shuster agreed with Dr. O’Shea about the possibility that spring brought energy to a desire to take one’s life, he had another theory.

“When people are depressed in the winter, they expect to feel better with the advent of the warmer weather in spring. When they don’t feel better, they may think to themselves, ‘If I’m going to feel like this forever, I may as well follow through with these plans,’ ” he said.

As for the early morning attempts, he noted that 4-6 a.m. is often when people are alone, and there are fewer distractions.

“The other thing I see a great deal of clinically is intoxication,” said Dr. Shuster. “Either intoxication with substances or alcohol, or the fact that intoxication is waning at those early morning hours, and people are becoming desperate as they face a new day,” he said.

The study was funded by a German Academic Exchange Service Scholarship and an EU Horizon 2020 Fellowship. Dr. O’Shea reports being an unpaid member of Project Implicit’s scientific advisory board and is on the executive committee of Project Implicit Health.

A version of this article first appeared on Medscape.com.

Suicidal ideation peaks during the winter but suicide attempts are most common in late spring and early summer in the early hours of the morning, new research shows.

In addition, the results from Harvard University’s Project Implicit Health also show that people are most likely to make an attempt at suicide between 4 and 6 a.m.

“No research has demonstrated a peak in suicidal ideation in winter until our paper,” study investigator Brian O’Shea, PhD, assistant professor of social psychology at the University of Nottingham, England, told this news organization.

“Most people incorrectly assume that suicide behaviours peak in winter and are surprised, as I was, when learning about this phenomenon, that suicide actually peaks in spring/early summer,” he added.

However, at least one expert cautioned that the database, which comprises mostly responses from younger women, doesn’t capture responses from those who are most likely to attempt suicide: older men with substance abuse.

The findings were published online in Translational Psychiatry.
 

New insight into suicide risk

Previous studies examining the seasonality of suicides and suicide attempts have reported a peak in spring and early summer, but there has been very little information about why this may be, the investigators noted.

Dr. O’Shea and his colleague from the University of Amsterdam, René Freichel, mined one of the databases from Project Implicit Health, which contains self-report measures on suicidal ideation, self-harm, and past suicide attempts, as well as respondents’ implicit biases on these topics.

The analysis included data from 10,000 respondents living in the United States, United Kingdom, and Canada provided between April 2012 and November 2018.

The sample was predominantly young and female, with 38% (3,247) of the sample reporting that they had made at least one suicide attempt.

The researchers found a peak in negative mood and desire to die occurring in December, especially among those who reported attempting suicide (P ≤ .001)

Suicidal ideation peaked approximately 3-4 months before the annual seasonal crest of suicide attempts in early spring and summer.

“Affected individuals may become severely depressed and experience a lack of energy throughout the winter months. Essentially, this period may put them below a threshold of severe suicide risk as the high level of suicidal ideation coincides with a low level of energy,” said Dr. O’Shea.

When the days get longer, brighter, and warmer, these changes likely improve an individuals’ mood, he explained. “Hence, the most at-risk individuals become slightly less depressed and may gain more energy to contemplate and plan their method to attempt suicide,” Dr. O’Shea noted.

A major limitation of the study is that all responses included in analysis were based on self-report.

To confirm the findings, future research should include ecological momentary assessment, which involves using a large community sample to question participants about suicidal intent at various time points, along with real-time monitoring of vital signs, said Dr. O’Shea.

Ideally, the investigators noted, the study’s findings will inform clinician assessments of patients who are at risk for suicide.
 

A research gap?

Commenting on the findings, Justin Shuster, MD, MPH, assistant professor of psychiatry at the University of Pittsburgh and medical director of two psychiatric units at Western Psychiatric Hospital, noted that the database used in the study did not include responses from those who were most likely to attempt or commit suicide: older men with a history of substance abuse, who require social supports, and who have a family history of suicide.

Though Dr. Shuster agreed with Dr. O’Shea about the possibility that spring brought energy to a desire to take one’s life, he had another theory.

“When people are depressed in the winter, they expect to feel better with the advent of the warmer weather in spring. When they don’t feel better, they may think to themselves, ‘If I’m going to feel like this forever, I may as well follow through with these plans,’ ” he said.

As for the early morning attempts, he noted that 4-6 a.m. is often when people are alone, and there are fewer distractions.

“The other thing I see a great deal of clinically is intoxication,” said Dr. Shuster. “Either intoxication with substances or alcohol, or the fact that intoxication is waning at those early morning hours, and people are becoming desperate as they face a new day,” he said.

The study was funded by a German Academic Exchange Service Scholarship and an EU Horizon 2020 Fellowship. Dr. O’Shea reports being an unpaid member of Project Implicit’s scientific advisory board and is on the executive committee of Project Implicit Health.

A version of this article first appeared on Medscape.com.

Suicidal ideation peaks during the winter but suicide attempts are most common in late spring and early summer in the early hours of the morning, new research shows.

In addition, the results from Harvard University’s Project Implicit Health also show that people are most likely to make an attempt at suicide between 4 and 6 a.m.

“No research has demonstrated a peak in suicidal ideation in winter until our paper,” study investigator Brian O’Shea, PhD, assistant professor of social psychology at the University of Nottingham, England, told this news organization.

“Most people incorrectly assume that suicide behaviours peak in winter and are surprised, as I was, when learning about this phenomenon, that suicide actually peaks in spring/early summer,” he added.

However, at least one expert cautioned that the database, which comprises mostly responses from younger women, doesn’t capture responses from those who are most likely to attempt suicide: older men with substance abuse.

The findings were published online in Translational Psychiatry.
 

New insight into suicide risk

Previous studies examining the seasonality of suicides and suicide attempts have reported a peak in spring and early summer, but there has been very little information about why this may be, the investigators noted.

Dr. O’Shea and his colleague from the University of Amsterdam, René Freichel, mined one of the databases from Project Implicit Health, which contains self-report measures on suicidal ideation, self-harm, and past suicide attempts, as well as respondents’ implicit biases on these topics.

The analysis included data from 10,000 respondents living in the United States, United Kingdom, and Canada provided between April 2012 and November 2018.

The sample was predominantly young and female, with 38% (3,247) of the sample reporting that they had made at least one suicide attempt.

The researchers found a peak in negative mood and desire to die occurring in December, especially among those who reported attempting suicide (P ≤ .001)

Suicidal ideation peaked approximately 3-4 months before the annual seasonal crest of suicide attempts in early spring and summer.

“Affected individuals may become severely depressed and experience a lack of energy throughout the winter months. Essentially, this period may put them below a threshold of severe suicide risk as the high level of suicidal ideation coincides with a low level of energy,” said Dr. O’Shea.

When the days get longer, brighter, and warmer, these changes likely improve an individuals’ mood, he explained. “Hence, the most at-risk individuals become slightly less depressed and may gain more energy to contemplate and plan their method to attempt suicide,” Dr. O’Shea noted.

A major limitation of the study is that all responses included in analysis were based on self-report.

To confirm the findings, future research should include ecological momentary assessment, which involves using a large community sample to question participants about suicidal intent at various time points, along with real-time monitoring of vital signs, said Dr. O’Shea.

Ideally, the investigators noted, the study’s findings will inform clinician assessments of patients who are at risk for suicide.
 

A research gap?

Commenting on the findings, Justin Shuster, MD, MPH, assistant professor of psychiatry at the University of Pittsburgh and medical director of two psychiatric units at Western Psychiatric Hospital, noted that the database used in the study did not include responses from those who were most likely to attempt or commit suicide: older men with a history of substance abuse, who require social supports, and who have a family history of suicide.

Though Dr. Shuster agreed with Dr. O’Shea about the possibility that spring brought energy to a desire to take one’s life, he had another theory.

“When people are depressed in the winter, they expect to feel better with the advent of the warmer weather in spring. When they don’t feel better, they may think to themselves, ‘If I’m going to feel like this forever, I may as well follow through with these plans,’ ” he said.

As for the early morning attempts, he noted that 4-6 a.m. is often when people are alone, and there are fewer distractions.

“The other thing I see a great deal of clinically is intoxication,” said Dr. Shuster. “Either intoxication with substances or alcohol, or the fact that intoxication is waning at those early morning hours, and people are becoming desperate as they face a new day,” he said.

The study was funded by a German Academic Exchange Service Scholarship and an EU Horizon 2020 Fellowship. Dr. O’Shea reports being an unpaid member of Project Implicit’s scientific advisory board and is on the executive committee of Project Implicit Health.

A version of this article first appeared on Medscape.com.

BALTIMORE – Poor prenatal sleep may increase the risk of postpartum depression, and prenatal depression may reduce the likelihood of mothers coming to their prenatal appointments, according to research presented at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.

Together, the two studies suggest that commonly overlooked experiences in the prenatal period can have negative effects down the line if clinicians aren’t asking patients about them and addressing the issue.

”I think the national conversation around mental health in general will hopefully carry us forward to better supporting the patients who are coming in with preexisting conditions,” lead author Minnie Jang, a 4th-year medical student at Johns Hopkins University, Baltimore, said in an interview.

Most of the attention on mood disorders of pregnancy focus on the postpartum period, but preexisting or new-onset depression during pregnancy deserves more attention, Ms. Jang told attendees. ACOG recommends that clinicians screen all patients at least once during the perinatal period, but that could be anywhere from early pregnancy to the postpartum period. Ms. Jang would like to see recommendations addressing both early pregnancy and the postpartum period.

“I think there’s this framing that postpartum depression is a distinct entity from other mental health conditions whereas it’s really part of a continuum,” Ms. Jang said in an interview.

She retrospectively analyzed the medical records of all pregnant women who completed the Edinburgh Postnatal Depression Scale (EPDS) during their first or second trimesters between 2002 and 2021 at Johns Hopkins Hospital. Among the 718 women who were screened in early pregnancy, 44.6% were Black or African American, 39.7% were white, and 15.7% were of a different race. Nearly all (94%) were not Hispanic/Latino.

Most (59%) were partnered, employed (68%), and had private insurance (58%). Only 7% used tobacco while 11% used alcohol and 6% used illicit drugs.

Twelve percent of the patients scored positive for depression, with a score of at least 10 or an affirmative answer to question 10 regarding self-harm. These women tended to be younger (P = .034), with an median age of 28 at their first visit versus 31 for those who screened negative, and were more likely to be publicly insured (P = .013) and without a partner (P = .005).

Patients who screened positive were more likely to have a history of substance use or history of a previous psychiatric diagnosis (P < .0001 for both). In addition, more patients who screened positive (49%) than those who screened negative (26%) had fetal complications (P < .001).

”There are some interesting subgroups of patients who are screening positive for depressive symptoms early on in pregnancy,” Ms. Jang said. Some come into pregnancy with preexisting mental health conditions while others have situational depressive symptoms, such as the subgroup referred to social work who had diagnosed fetal complications, she said. “Then there’s a whole other group of patients who are developing new symptoms during pregnancy.”

Patients who screened positive tended to start prenatal care later, at a median 12.3 weeks gestational age, than patients who screened negative, at a median 10.7 weeks gestational age (P = .002), the analysis found.

The number of routine prenatal care visits did not significantly differ between those who screened positive and those who screened negative, but patients with positive depression screens were almost half as likely to complete glucose tolerance testing (odds ratio, 0.6) or group B streptococcus testing (OR, 0.56) after adjusting for insurance status, gravidity, and gestational age at the patient’s first visit.

The researchers also identified a significant positive association between higher EPDS scores and the number of labor and delivery triage visits (P = .006). There were no significant differences in the rates of Tdap vaccination or screening for sexually transmitted infections between the two groups.
 

Poor sleep linked to later depression

The other study was prospective, using data from the PATCH Prenatal Care and Maternal and Child Health Outcomes study, which initially “compared health outcomes and satisfaction with prenatal care between patients receiving Centering Pregnancy group prenatal care and patients receiving traditional prenatal care,” the authors explained. This secondary analysis looked at sleep problems and postpartum depression.

“We don’t routinely ask patients about sleep or screen patients for sleeping issues,” lead author Carolyn Sinow, MD, a 4th-year resident at Kaiser Permanente Santa Clara (Calif.) Medical Center, said in an interview. “I think that we need to take sleep complaints more seriously overall, especially in early pregnancy.” While sleep problems in the third trimester often have more to do with discomforts from pregnancy itself, better sleep “in the first and second trimester is something we can really target with good sleep hygiene,” she added.

The 336 pregnant participants were recruited from Health Connect as long as they had a singleton pregnancy, were receiving prenatal care from Kaiser Permanente Northern California, and completed baseline questionnaires about their sleep and depression and anxiety symptoms during their first trimester between August 2020 and April 2021. Those with clinical depression or a high-risk pregnancy were excluded. The participants then completed the questionnaires again between 4 and 8 weeks post partum.

After adjusting for baseline depression and potential confounders, patients with poor sleep quality, indicated by a score greater than 5 on the Pittsburgh Sleep Quality Index (PSQI), were 12% more likely to develop postpartum depression, indicated by a score on the Patient Health Questionnaire depression scale (PHQ-8) of 10 or greater (relative risk, 1.12; 95% confidence interval, 1.01-1.25).

The two aspects of sleep that specifically correlated with postpartum depression were sleep quality and sleep latency, or taking a long time to fall asleep. Those reporting poor sleep quality were twice as likely to develop postpartum depression (relative risk, 2.18; 95% CI, 1.22-3.91), and those who took a while to fall asleep were 52% more likely to develop postpartum depression (RR, 1.52; 95% CI, 1.06-2.17).

Though the study also found prenatal sleep problems correlated with higher postpartum anxiety scores on the General Anxiety Disorder scale (GAD-7), the results were not statistically significant.

Kathleen Morrell, MD, MPH, an ob.gyn. in New York, was not involved in the study and said she was surprised it wasn’t something that had been studied much before because it makes sense.

“I always like it when studies confirm what we think should make sense, so it’s nice to see it,” Dr. Morrell said in an interview. “I think anytime you put something out, research it, and define it with numbers for doctors, that sometimes allows us to [realize], ‘Oh, that’s probably something we should be paying more attention to, especially if we have available treatments for it,’” she added.

“The clinical takeaway is that we really need to be screening for sleep pattern disruptions early in pregnancy, because even though it makes logical sense, it might not be something on our radar to think about,” Dr. Morrell said. “If people aren’t sleeping, well, their mental health is negatively affected.”

The most promising therapy for sleep issues currently is cognitive-behavioral therapy, which can accessed through various apps, Dr. Sinow said in an interview. “There are also safe interventions, such as melatonin and Unisom, that are totally safe in pregnancy that we can use to target sleep in early pregnancy.”

Dr. Morrell added that vitamin B6, often taken for nausea and vomiting during pregnancy, can also sometimes help people sleep and is safe during pregnancy.

“We know that postpartum depression does not necessarily only have a negative effect on the mother, but also has a negative effect on the infant and the family dynamic as well,” Dr. Morrell said. “So, we should be looking and screening for it so that we can offer people potential treatment because we know it can have long-term effects.”

Ms. Jang and Dr. Sinow did not have any disclosures. Dr. Morrell has done training for Nexplanon. Neither study noted external funding.

BALTIMORE – Poor prenatal sleep may increase the risk of postpartum depression, and prenatal depression may reduce the likelihood of mothers coming to their prenatal appointments, according to research presented at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.

Together, the two studies suggest that commonly overlooked experiences in the prenatal period can have negative effects down the line if clinicians aren’t asking patients about them and addressing the issue.

”I think the national conversation around mental health in general will hopefully carry us forward to better supporting the patients who are coming in with preexisting conditions,” lead author Minnie Jang, a 4th-year medical student at Johns Hopkins University, Baltimore, said in an interview.

Most of the attention on mood disorders of pregnancy focus on the postpartum period, but preexisting or new-onset depression during pregnancy deserves more attention, Ms. Jang told attendees. ACOG recommends that clinicians screen all patients at least once during the perinatal period, but that could be anywhere from early pregnancy to the postpartum period. Ms. Jang would like to see recommendations addressing both early pregnancy and the postpartum period.

“I think there’s this framing that postpartum depression is a distinct entity from other mental health conditions whereas it’s really part of a continuum,” Ms. Jang said in an interview.

She retrospectively analyzed the medical records of all pregnant women who completed the Edinburgh Postnatal Depression Scale (EPDS) during their first or second trimesters between 2002 and 2021 at Johns Hopkins Hospital. Among the 718 women who were screened in early pregnancy, 44.6% were Black or African American, 39.7% were white, and 15.7% were of a different race. Nearly all (94%) were not Hispanic/Latino.

Most (59%) were partnered, employed (68%), and had private insurance (58%). Only 7% used tobacco while 11% used alcohol and 6% used illicit drugs.

Twelve percent of the patients scored positive for depression, with a score of at least 10 or an affirmative answer to question 10 regarding self-harm. These women tended to be younger (P = .034), with an median age of 28 at their first visit versus 31 for those who screened negative, and were more likely to be publicly insured (P = .013) and without a partner (P = .005).

Patients who screened positive were more likely to have a history of substance use or history of a previous psychiatric diagnosis (P < .0001 for both). In addition, more patients who screened positive (49%) than those who screened negative (26%) had fetal complications (P < .001).

”There are some interesting subgroups of patients who are screening positive for depressive symptoms early on in pregnancy,” Ms. Jang said. Some come into pregnancy with preexisting mental health conditions while others have situational depressive symptoms, such as the subgroup referred to social work who had diagnosed fetal complications, she said. “Then there’s a whole other group of patients who are developing new symptoms during pregnancy.”

Patients who screened positive tended to start prenatal care later, at a median 12.3 weeks gestational age, than patients who screened negative, at a median 10.7 weeks gestational age (P = .002), the analysis found.

The number of routine prenatal care visits did not significantly differ between those who screened positive and those who screened negative, but patients with positive depression screens were almost half as likely to complete glucose tolerance testing (odds ratio, 0.6) or group B streptococcus testing (OR, 0.56) after adjusting for insurance status, gravidity, and gestational age at the patient’s first visit.

The researchers also identified a significant positive association between higher EPDS scores and the number of labor and delivery triage visits (P = .006). There were no significant differences in the rates of Tdap vaccination or screening for sexually transmitted infections between the two groups.
 

Poor sleep linked to later depression

The other study was prospective, using data from the PATCH Prenatal Care and Maternal and Child Health Outcomes study, which initially “compared health outcomes and satisfaction with prenatal care between patients receiving Centering Pregnancy group prenatal care and patients receiving traditional prenatal care,” the authors explained. This secondary analysis looked at sleep problems and postpartum depression.

“We don’t routinely ask patients about sleep or screen patients for sleeping issues,” lead author Carolyn Sinow, MD, a 4th-year resident at Kaiser Permanente Santa Clara (Calif.) Medical Center, said in an interview. “I think that we need to take sleep complaints more seriously overall, especially in early pregnancy.” While sleep problems in the third trimester often have more to do with discomforts from pregnancy itself, better sleep “in the first and second trimester is something we can really target with good sleep hygiene,” she added.

The 336 pregnant participants were recruited from Health Connect as long as they had a singleton pregnancy, were receiving prenatal care from Kaiser Permanente Northern California, and completed baseline questionnaires about their sleep and depression and anxiety symptoms during their first trimester between August 2020 and April 2021. Those with clinical depression or a high-risk pregnancy were excluded. The participants then completed the questionnaires again between 4 and 8 weeks post partum.

After adjusting for baseline depression and potential confounders, patients with poor sleep quality, indicated by a score greater than 5 on the Pittsburgh Sleep Quality Index (PSQI), were 12% more likely to develop postpartum depression, indicated by a score on the Patient Health Questionnaire depression scale (PHQ-8) of 10 or greater (relative risk, 1.12; 95% confidence interval, 1.01-1.25).

The two aspects of sleep that specifically correlated with postpartum depression were sleep quality and sleep latency, or taking a long time to fall asleep. Those reporting poor sleep quality were twice as likely to develop postpartum depression (relative risk, 2.18; 95% CI, 1.22-3.91), and those who took a while to fall asleep were 52% more likely to develop postpartum depression (RR, 1.52; 95% CI, 1.06-2.17).

Though the study also found prenatal sleep problems correlated with higher postpartum anxiety scores on the General Anxiety Disorder scale (GAD-7), the results were not statistically significant.

Kathleen Morrell, MD, MPH, an ob.gyn. in New York, was not involved in the study and said she was surprised it wasn’t something that had been studied much before because it makes sense.

“I always like it when studies confirm what we think should make sense, so it’s nice to see it,” Dr. Morrell said in an interview. “I think anytime you put something out, research it, and define it with numbers for doctors, that sometimes allows us to [realize], ‘Oh, that’s probably something we should be paying more attention to, especially if we have available treatments for it,’” she added.

“The clinical takeaway is that we really need to be screening for sleep pattern disruptions early in pregnancy, because even though it makes logical sense, it might not be something on our radar to think about,” Dr. Morrell said. “If people aren’t sleeping, well, their mental health is negatively affected.”

The most promising therapy for sleep issues currently is cognitive-behavioral therapy, which can accessed through various apps, Dr. Sinow said in an interview. “There are also safe interventions, such as melatonin and Unisom, that are totally safe in pregnancy that we can use to target sleep in early pregnancy.”

Dr. Morrell added that vitamin B6, often taken for nausea and vomiting during pregnancy, can also sometimes help people sleep and is safe during pregnancy.

“We know that postpartum depression does not necessarily only have a negative effect on the mother, but also has a negative effect on the infant and the family dynamic as well,” Dr. Morrell said. “So, we should be looking and screening for it so that we can offer people potential treatment because we know it can have long-term effects.”

Ms. Jang and Dr. Sinow did not have any disclosures. Dr. Morrell has done training for Nexplanon. Neither study noted external funding.

BALTIMORE – Poor prenatal sleep may increase the risk of postpartum depression, and prenatal depression may reduce the likelihood of mothers coming to their prenatal appointments, according to research presented at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.

Together, the two studies suggest that commonly overlooked experiences in the prenatal period can have negative effects down the line if clinicians aren’t asking patients about them and addressing the issue.

”I think the national conversation around mental health in general will hopefully carry us forward to better supporting the patients who are coming in with preexisting conditions,” lead author Minnie Jang, a 4th-year medical student at Johns Hopkins University, Baltimore, said in an interview.

Most of the attention on mood disorders of pregnancy focus on the postpartum period, but preexisting or new-onset depression during pregnancy deserves more attention, Ms. Jang told attendees. ACOG recommends that clinicians screen all patients at least once during the perinatal period, but that could be anywhere from early pregnancy to the postpartum period. Ms. Jang would like to see recommendations addressing both early pregnancy and the postpartum period.

“I think there’s this framing that postpartum depression is a distinct entity from other mental health conditions whereas it’s really part of a continuum,” Ms. Jang said in an interview.

She retrospectively analyzed the medical records of all pregnant women who completed the Edinburgh Postnatal Depression Scale (EPDS) during their first or second trimesters between 2002 and 2021 at Johns Hopkins Hospital. Among the 718 women who were screened in early pregnancy, 44.6% were Black or African American, 39.7% were white, and 15.7% were of a different race. Nearly all (94%) were not Hispanic/Latino.

Most (59%) were partnered, employed (68%), and had private insurance (58%). Only 7% used tobacco while 11% used alcohol and 6% used illicit drugs.

Twelve percent of the patients scored positive for depression, with a score of at least 10 or an affirmative answer to question 10 regarding self-harm. These women tended to be younger (P = .034), with an median age of 28 at their first visit versus 31 for those who screened negative, and were more likely to be publicly insured (P = .013) and without a partner (P = .005).

Patients who screened positive were more likely to have a history of substance use or history of a previous psychiatric diagnosis (P < .0001 for both). In addition, more patients who screened positive (49%) than those who screened negative (26%) had fetal complications (P < .001).

”There are some interesting subgroups of patients who are screening positive for depressive symptoms early on in pregnancy,” Ms. Jang said. Some come into pregnancy with preexisting mental health conditions while others have situational depressive symptoms, such as the subgroup referred to social work who had diagnosed fetal complications, she said. “Then there’s a whole other group of patients who are developing new symptoms during pregnancy.”

Patients who screened positive tended to start prenatal care later, at a median 12.3 weeks gestational age, than patients who screened negative, at a median 10.7 weeks gestational age (P = .002), the analysis found.

The number of routine prenatal care visits did not significantly differ between those who screened positive and those who screened negative, but patients with positive depression screens were almost half as likely to complete glucose tolerance testing (odds ratio, 0.6) or group B streptococcus testing (OR, 0.56) after adjusting for insurance status, gravidity, and gestational age at the patient’s first visit.

The researchers also identified a significant positive association between higher EPDS scores and the number of labor and delivery triage visits (P = .006). There were no significant differences in the rates of Tdap vaccination or screening for sexually transmitted infections between the two groups.
 

Poor sleep linked to later depression

The other study was prospective, using data from the PATCH Prenatal Care and Maternal and Child Health Outcomes study, which initially “compared health outcomes and satisfaction with prenatal care between patients receiving Centering Pregnancy group prenatal care and patients receiving traditional prenatal care,” the authors explained. This secondary analysis looked at sleep problems and postpartum depression.

“We don’t routinely ask patients about sleep or screen patients for sleeping issues,” lead author Carolyn Sinow, MD, a 4th-year resident at Kaiser Permanente Santa Clara (Calif.) Medical Center, said in an interview. “I think that we need to take sleep complaints more seriously overall, especially in early pregnancy.” While sleep problems in the third trimester often have more to do with discomforts from pregnancy itself, better sleep “in the first and second trimester is something we can really target with good sleep hygiene,” she added.

The 336 pregnant participants were recruited from Health Connect as long as they had a singleton pregnancy, were receiving prenatal care from Kaiser Permanente Northern California, and completed baseline questionnaires about their sleep and depression and anxiety symptoms during their first trimester between August 2020 and April 2021. Those with clinical depression or a high-risk pregnancy were excluded. The participants then completed the questionnaires again between 4 and 8 weeks post partum.

After adjusting for baseline depression and potential confounders, patients with poor sleep quality, indicated by a score greater than 5 on the Pittsburgh Sleep Quality Index (PSQI), were 12% more likely to develop postpartum depression, indicated by a score on the Patient Health Questionnaire depression scale (PHQ-8) of 10 or greater (relative risk, 1.12; 95% confidence interval, 1.01-1.25).

The two aspects of sleep that specifically correlated with postpartum depression were sleep quality and sleep latency, or taking a long time to fall asleep. Those reporting poor sleep quality were twice as likely to develop postpartum depression (relative risk, 2.18; 95% CI, 1.22-3.91), and those who took a while to fall asleep were 52% more likely to develop postpartum depression (RR, 1.52; 95% CI, 1.06-2.17).

Though the study also found prenatal sleep problems correlated with higher postpartum anxiety scores on the General Anxiety Disorder scale (GAD-7), the results were not statistically significant.

Kathleen Morrell, MD, MPH, an ob.gyn. in New York, was not involved in the study and said she was surprised it wasn’t something that had been studied much before because it makes sense.

“I always like it when studies confirm what we think should make sense, so it’s nice to see it,” Dr. Morrell said in an interview. “I think anytime you put something out, research it, and define it with numbers for doctors, that sometimes allows us to [realize], ‘Oh, that’s probably something we should be paying more attention to, especially if we have available treatments for it,’” she added.

“The clinical takeaway is that we really need to be screening for sleep pattern disruptions early in pregnancy, because even though it makes logical sense, it might not be something on our radar to think about,” Dr. Morrell said. “If people aren’t sleeping, well, their mental health is negatively affected.”

The most promising therapy for sleep issues currently is cognitive-behavioral therapy, which can accessed through various apps, Dr. Sinow said in an interview. “There are also safe interventions, such as melatonin and Unisom, that are totally safe in pregnancy that we can use to target sleep in early pregnancy.”

Dr. Morrell added that vitamin B6, often taken for nausea and vomiting during pregnancy, can also sometimes help people sleep and is safe during pregnancy.

“We know that postpartum depression does not necessarily only have a negative effect on the mother, but also has a negative effect on the infant and the family dynamic as well,” Dr. Morrell said. “So, we should be looking and screening for it so that we can offer people potential treatment because we know it can have long-term effects.”

Ms. Jang and Dr. Sinow did not have any disclosures. Dr. Morrell has done training for Nexplanon. Neither study noted external funding.