Major Depressive Disorder

Long-term antidepressant use is tied to an increased risk of adverse outcomes, including cardiovascular disease (CVD), cerebrovascular disease, coronary heart disease (CHD), and all-cause mortality, new research suggests.

The investigators drew on 10-year data from the UK Biobank on over 220,000 adults and compared the risk of developing adverse health outcomes among those taking antidepressants with the risk among those who were not taking antidepressants.

After adjusting for preexisting risk factors, they found that 10-year antidepressant use was associated with a twofold higher risk of CHD, an almost-twofold higher risk of CVD as well as CVD mortality, a higher risk of cerebrovascular disease, and more than double the risk of all-cause mortality.

On the other hand, at 10 years, antidepressant use was associated with a 23% lower risk of developing hypertension and a 32% lower risk of diabetes.

The main culprits were mirtazapine, venlafaxine, duloxetine, and trazodone, although SSRIs were also tied to increased risk.

“Our message for clinicians is that prescribing of antidepressants in the long term may not be harm free [and] we hope that this study will help doctors and patients have more informed conversations when they weigh up the potential risks and benefits of treatments for depression,” study investigator Narinder Bansal, MD, honorary research fellow, Centre for Academic Health and Centre for Academic Primary Care, University of Bristol (England), said in a news release.

“Regardless of whether the drugs are the underlying cause of these problems, our findings emphasize the importance of proactive cardiovascular monitoring and prevention in patients who have depression and are on antidepressants, given that both have been associated with higher risks,” she added.

The study was published online in the British Journal of Psychiatry Open.
 

Monitoring of CVD risk ‘critical’

Antidepressants are among the most widely prescribed drugs; 70 million prescriptions were dispensed in 2018 alone, representing a doubling of prescriptions for these agents in a decade, the investigators noted. “This striking rise in prescribing is attributed to long-term treatment rather than an increased incidence of depression.”

Most trials that have assessed antidepressant efficacy have been “poorly suited to examining adverse outcomes.” One reason for this is that many of the trials are short-term studies. Since depression is “strongly associated” with CVD risk factors, “careful assessment of the long-term cardiometabolic effects of antidepressant treatment is critical.”

Moreover, information about “a wide range of prospectively measured confounders ... is needed to provide robust estimates of the risks associated with long-term antidepressant use,” the authors noted.

The researchers examined the association between antidepressant use and four cardiometabolic morbidity outcomes – diabetes, hypertension, cerebrovascular disease, and CHD. In addition, they assessed two mortality outcomes – CVD mortality and all-cause mortality. Participants were divided into cohorts on the basis of outcome of interest.

The dataset contains detailed information on socioeconomic status, demographics, anthropometric, behavioral, and biochemical risk factors, disability, and health status and is linked to datasets of primary care records and deaths.

The study included 222,121 participants whose data had been linked to primary care records during 2018 (median age of participants, 56-57 years). About half were women, and 96% were of White ethnicity.

Participants were excluded if they had been prescribed antidepressants 12 months or less before baseline, if they had previously been diagnosed for the outcome of interest, if they had been previously prescribed psychotropic drugs, if they used cardiometabolic drugs at baseline, or if they had undergone treatment with antidepressant polytherapy.

Potential confounders included age, gender, body mass index, waist/hip ratio, smoking and alcohol intake status, physical activity, parental history of outcome, biochemical and hematologic biomarkers, socioeconomic status, and long-term illness, disability, or infirmity.
 

Mechanism unclear

By the end of the 5- and 10-year follow-up periods, an average of 8% and 6% of participants in each cohort, respectively, had been prescribed an antidepressant. SSRIs constituted the most commonly prescribed class (80%-82%), and citalopram was the most commonly prescribed SSRI (46%-47%). Mirtazapine was the most frequently prescribed non-SSRI antidepressant (44%-46%).

At 5 years, any antidepressant use was associated with an increased risk for diabetes, CHD, and all-cause mortality, but the findings were attenuated after further adjustment for confounders. In fact, SSRIs were associated with a reduced risk of diabetes at 5 years (hazard ratio, 0.64; 95% confidence interval, 0.49-0.83).

At 10 years, SSRIs were associated with an increased risk of cerebrovascular disease, CVD mortality, and all-cause mortality; non-SSRIs were associated with an increased risk of CHD, CVD, and all-cause mortality.

On the other hand, SSRIs were associated with a decrease in risk of diabetes and hypertension at 10 years (HR, 0.68; 95% CI, 0.53-0.87; and HR, 0.77; 95% CI, 0.66-0.89, respectively).

“While we have taken into account a wide range of pre-existing risk factors for cardiovascular disease, including those that are linked to depression such as excess weight, smoking, and low physical activity, it is difficult to fully control for the effects of depression in this kind of study, partly because there is considerable variability in the recording of depression severity in primary care,” said Dr. Bansal.

“This is important because many people taking antidepressants such as mirtazapine, venlafaxine, duloxetine and trazodone may have a more severe depression. This makes it difficult to fully separate the effects of the depression from the effects of medication,” she said.

Further research “is needed to assess whether the associations we have seen are genuinely due to the drugs; and, if so, why this might be,” she added.
 

Strengths, limitations

Commenting on the study, Roger McIntyre, MD, professor of psychiatry and pharmacology and head of the mood disorders psychopharmacology unit at the University of Toronto,, discussed the strengths and weaknesses of the study.

The UK Biobank is a “well-described, well-phenotyped dataset of good quality,” said Dr. McIntyre, chairperson and executive director of the Brain and Cognitive Discover Foundation, Toronto, who was not involved with the study. Another strength is the “impressive number of variables the database contains, which enabled the authors to go much deeper into the topics.”

A “significant limitation” is the confounding that is inherent to the disorder itself – “people with depression have a much higher intrinsic risk of CVD, [cerebrovascular disease], and cardiovascular mortality,” Dr. McIntyre noted.

The researchers did not adjust for trauma or childhood maltreatment, “which are the biggest risk factors for both depression and CVD; and drug and alcohol misuse were also not accounted for.”

Additionally, “to determine whether something is an association or potentially causative, it must satisfy the Bradford-Hill criteria,” said Dr. McIntyre. “Since we’re moving more toward using these big databases and because we depend on them to give us long-term perspectives, we would want to see coherent, compelling Bradford-Hill criteria regarding causation. If you don’t have any, that’s fine too, but then it’s important to make clear that there is no clear causative line, just an association.”

The research was funded by the National Institute of Health Research School for Primary Care Research and was supported by the NI Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. Dr. McIntyre has received research grant support from CI/GACD/National Natural Science Foundation of China and the Milken Institute and speaker/consultation fees from numerous companies. Dr. McIntyre is a CEO of Braxia Scientific.

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

Long-term antidepressant use is tied to an increased risk of adverse outcomes, including cardiovascular disease (CVD), cerebrovascular disease, coronary heart disease (CHD), and all-cause mortality, new research suggests.

The investigators drew on 10-year data from the UK Biobank on over 220,000 adults and compared the risk of developing adverse health outcomes among those taking antidepressants with the risk among those who were not taking antidepressants.

After adjusting for preexisting risk factors, they found that 10-year antidepressant use was associated with a twofold higher risk of CHD, an almost-twofold higher risk of CVD as well as CVD mortality, a higher risk of cerebrovascular disease, and more than double the risk of all-cause mortality.

On the other hand, at 10 years, antidepressant use was associated with a 23% lower risk of developing hypertension and a 32% lower risk of diabetes.

The main culprits were mirtazapine, venlafaxine, duloxetine, and trazodone, although SSRIs were also tied to increased risk.

“Our message for clinicians is that prescribing of antidepressants in the long term may not be harm free [and] we hope that this study will help doctors and patients have more informed conversations when they weigh up the potential risks and benefits of treatments for depression,” study investigator Narinder Bansal, MD, honorary research fellow, Centre for Academic Health and Centre for Academic Primary Care, University of Bristol (England), said in a news release.

“Regardless of whether the drugs are the underlying cause of these problems, our findings emphasize the importance of proactive cardiovascular monitoring and prevention in patients who have depression and are on antidepressants, given that both have been associated with higher risks,” she added.

The study was published online in the British Journal of Psychiatry Open.
 

Monitoring of CVD risk ‘critical’

Antidepressants are among the most widely prescribed drugs; 70 million prescriptions were dispensed in 2018 alone, representing a doubling of prescriptions for these agents in a decade, the investigators noted. “This striking rise in prescribing is attributed to long-term treatment rather than an increased incidence of depression.”

Most trials that have assessed antidepressant efficacy have been “poorly suited to examining adverse outcomes.” One reason for this is that many of the trials are short-term studies. Since depression is “strongly associated” with CVD risk factors, “careful assessment of the long-term cardiometabolic effects of antidepressant treatment is critical.”

Moreover, information about “a wide range of prospectively measured confounders ... is needed to provide robust estimates of the risks associated with long-term antidepressant use,” the authors noted.

The researchers examined the association between antidepressant use and four cardiometabolic morbidity outcomes – diabetes, hypertension, cerebrovascular disease, and CHD. In addition, they assessed two mortality outcomes – CVD mortality and all-cause mortality. Participants were divided into cohorts on the basis of outcome of interest.

The dataset contains detailed information on socioeconomic status, demographics, anthropometric, behavioral, and biochemical risk factors, disability, and health status and is linked to datasets of primary care records and deaths.

The study included 222,121 participants whose data had been linked to primary care records during 2018 (median age of participants, 56-57 years). About half were women, and 96% were of White ethnicity.

Participants were excluded if they had been prescribed antidepressants 12 months or less before baseline, if they had previously been diagnosed for the outcome of interest, if they had been previously prescribed psychotropic drugs, if they used cardiometabolic drugs at baseline, or if they had undergone treatment with antidepressant polytherapy.

Potential confounders included age, gender, body mass index, waist/hip ratio, smoking and alcohol intake status, physical activity, parental history of outcome, biochemical and hematologic biomarkers, socioeconomic status, and long-term illness, disability, or infirmity.
 

Mechanism unclear

By the end of the 5- and 10-year follow-up periods, an average of 8% and 6% of participants in each cohort, respectively, had been prescribed an antidepressant. SSRIs constituted the most commonly prescribed class (80%-82%), and citalopram was the most commonly prescribed SSRI (46%-47%). Mirtazapine was the most frequently prescribed non-SSRI antidepressant (44%-46%).

At 5 years, any antidepressant use was associated with an increased risk for diabetes, CHD, and all-cause mortality, but the findings were attenuated after further adjustment for confounders. In fact, SSRIs were associated with a reduced risk of diabetes at 5 years (hazard ratio, 0.64; 95% confidence interval, 0.49-0.83).

At 10 years, SSRIs were associated with an increased risk of cerebrovascular disease, CVD mortality, and all-cause mortality; non-SSRIs were associated with an increased risk of CHD, CVD, and all-cause mortality.

On the other hand, SSRIs were associated with a decrease in risk of diabetes and hypertension at 10 years (HR, 0.68; 95% CI, 0.53-0.87; and HR, 0.77; 95% CI, 0.66-0.89, respectively).

“While we have taken into account a wide range of pre-existing risk factors for cardiovascular disease, including those that are linked to depression such as excess weight, smoking, and low physical activity, it is difficult to fully control for the effects of depression in this kind of study, partly because there is considerable variability in the recording of depression severity in primary care,” said Dr. Bansal.

“This is important because many people taking antidepressants such as mirtazapine, venlafaxine, duloxetine and trazodone may have a more severe depression. This makes it difficult to fully separate the effects of the depression from the effects of medication,” she said.

Further research “is needed to assess whether the associations we have seen are genuinely due to the drugs; and, if so, why this might be,” she added.
 

Strengths, limitations

Commenting on the study, Roger McIntyre, MD, professor of psychiatry and pharmacology and head of the mood disorders psychopharmacology unit at the University of Toronto,, discussed the strengths and weaknesses of the study.

The UK Biobank is a “well-described, well-phenotyped dataset of good quality,” said Dr. McIntyre, chairperson and executive director of the Brain and Cognitive Discover Foundation, Toronto, who was not involved with the study. Another strength is the “impressive number of variables the database contains, which enabled the authors to go much deeper into the topics.”

A “significant limitation” is the confounding that is inherent to the disorder itself – “people with depression have a much higher intrinsic risk of CVD, [cerebrovascular disease], and cardiovascular mortality,” Dr. McIntyre noted.

The researchers did not adjust for trauma or childhood maltreatment, “which are the biggest risk factors for both depression and CVD; and drug and alcohol misuse were also not accounted for.”

Additionally, “to determine whether something is an association or potentially causative, it must satisfy the Bradford-Hill criteria,” said Dr. McIntyre. “Since we’re moving more toward using these big databases and because we depend on them to give us long-term perspectives, we would want to see coherent, compelling Bradford-Hill criteria regarding causation. If you don’t have any, that’s fine too, but then it’s important to make clear that there is no clear causative line, just an association.”

The research was funded by the National Institute of Health Research School for Primary Care Research and was supported by the NI Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. Dr. McIntyre has received research grant support from CI/GACD/National Natural Science Foundation of China and the Milken Institute and speaker/consultation fees from numerous companies. Dr. McIntyre is a CEO of Braxia Scientific.

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

Long-term antidepressant use is tied to an increased risk of adverse outcomes, including cardiovascular disease (CVD), cerebrovascular disease, coronary heart disease (CHD), and all-cause mortality, new research suggests.

The investigators drew on 10-year data from the UK Biobank on over 220,000 adults and compared the risk of developing adverse health outcomes among those taking antidepressants with the risk among those who were not taking antidepressants.

After adjusting for preexisting risk factors, they found that 10-year antidepressant use was associated with a twofold higher risk of CHD, an almost-twofold higher risk of CVD as well as CVD mortality, a higher risk of cerebrovascular disease, and more than double the risk of all-cause mortality.

On the other hand, at 10 years, antidepressant use was associated with a 23% lower risk of developing hypertension and a 32% lower risk of diabetes.

The main culprits were mirtazapine, venlafaxine, duloxetine, and trazodone, although SSRIs were also tied to increased risk.

“Our message for clinicians is that prescribing of antidepressants in the long term may not be harm free [and] we hope that this study will help doctors and patients have more informed conversations when they weigh up the potential risks and benefits of treatments for depression,” study investigator Narinder Bansal, MD, honorary research fellow, Centre for Academic Health and Centre for Academic Primary Care, University of Bristol (England), said in a news release.

“Regardless of whether the drugs are the underlying cause of these problems, our findings emphasize the importance of proactive cardiovascular monitoring and prevention in patients who have depression and are on antidepressants, given that both have been associated with higher risks,” she added.

The study was published online in the British Journal of Psychiatry Open.
 

Monitoring of CVD risk ‘critical’

Antidepressants are among the most widely prescribed drugs; 70 million prescriptions were dispensed in 2018 alone, representing a doubling of prescriptions for these agents in a decade, the investigators noted. “This striking rise in prescribing is attributed to long-term treatment rather than an increased incidence of depression.”

Most trials that have assessed antidepressant efficacy have been “poorly suited to examining adverse outcomes.” One reason for this is that many of the trials are short-term studies. Since depression is “strongly associated” with CVD risk factors, “careful assessment of the long-term cardiometabolic effects of antidepressant treatment is critical.”

Moreover, information about “a wide range of prospectively measured confounders ... is needed to provide robust estimates of the risks associated with long-term antidepressant use,” the authors noted.

The researchers examined the association between antidepressant use and four cardiometabolic morbidity outcomes – diabetes, hypertension, cerebrovascular disease, and CHD. In addition, they assessed two mortality outcomes – CVD mortality and all-cause mortality. Participants were divided into cohorts on the basis of outcome of interest.

The dataset contains detailed information on socioeconomic status, demographics, anthropometric, behavioral, and biochemical risk factors, disability, and health status and is linked to datasets of primary care records and deaths.

The study included 222,121 participants whose data had been linked to primary care records during 2018 (median age of participants, 56-57 years). About half were women, and 96% were of White ethnicity.

Participants were excluded if they had been prescribed antidepressants 12 months or less before baseline, if they had previously been diagnosed for the outcome of interest, if they had been previously prescribed psychotropic drugs, if they used cardiometabolic drugs at baseline, or if they had undergone treatment with antidepressant polytherapy.

Potential confounders included age, gender, body mass index, waist/hip ratio, smoking and alcohol intake status, physical activity, parental history of outcome, biochemical and hematologic biomarkers, socioeconomic status, and long-term illness, disability, or infirmity.
 

Mechanism unclear

By the end of the 5- and 10-year follow-up periods, an average of 8% and 6% of participants in each cohort, respectively, had been prescribed an antidepressant. SSRIs constituted the most commonly prescribed class (80%-82%), and citalopram was the most commonly prescribed SSRI (46%-47%). Mirtazapine was the most frequently prescribed non-SSRI antidepressant (44%-46%).

At 5 years, any antidepressant use was associated with an increased risk for diabetes, CHD, and all-cause mortality, but the findings were attenuated after further adjustment for confounders. In fact, SSRIs were associated with a reduced risk of diabetes at 5 years (hazard ratio, 0.64; 95% confidence interval, 0.49-0.83).

At 10 years, SSRIs were associated with an increased risk of cerebrovascular disease, CVD mortality, and all-cause mortality; non-SSRIs were associated with an increased risk of CHD, CVD, and all-cause mortality.

On the other hand, SSRIs were associated with a decrease in risk of diabetes and hypertension at 10 years (HR, 0.68; 95% CI, 0.53-0.87; and HR, 0.77; 95% CI, 0.66-0.89, respectively).

“While we have taken into account a wide range of pre-existing risk factors for cardiovascular disease, including those that are linked to depression such as excess weight, smoking, and low physical activity, it is difficult to fully control for the effects of depression in this kind of study, partly because there is considerable variability in the recording of depression severity in primary care,” said Dr. Bansal.

“This is important because many people taking antidepressants such as mirtazapine, venlafaxine, duloxetine and trazodone may have a more severe depression. This makes it difficult to fully separate the effects of the depression from the effects of medication,” she said.

Further research “is needed to assess whether the associations we have seen are genuinely due to the drugs; and, if so, why this might be,” she added.
 

Strengths, limitations

Commenting on the study, Roger McIntyre, MD, professor of psychiatry and pharmacology and head of the mood disorders psychopharmacology unit at the University of Toronto,, discussed the strengths and weaknesses of the study.

The UK Biobank is a “well-described, well-phenotyped dataset of good quality,” said Dr. McIntyre, chairperson and executive director of the Brain and Cognitive Discover Foundation, Toronto, who was not involved with the study. Another strength is the “impressive number of variables the database contains, which enabled the authors to go much deeper into the topics.”

A “significant limitation” is the confounding that is inherent to the disorder itself – “people with depression have a much higher intrinsic risk of CVD, [cerebrovascular disease], and cardiovascular mortality,” Dr. McIntyre noted.

The researchers did not adjust for trauma or childhood maltreatment, “which are the biggest risk factors for both depression and CVD; and drug and alcohol misuse were also not accounted for.”

Additionally, “to determine whether something is an association or potentially causative, it must satisfy the Bradford-Hill criteria,” said Dr. McIntyre. “Since we’re moving more toward using these big databases and because we depend on them to give us long-term perspectives, we would want to see coherent, compelling Bradford-Hill criteria regarding causation. If you don’t have any, that’s fine too, but then it’s important to make clear that there is no clear causative line, just an association.”

The research was funded by the National Institute of Health Research School for Primary Care Research and was supported by the NI Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. Dr. McIntyre has received research grant support from CI/GACD/National Natural Science Foundation of China and the Milken Institute and speaker/consultation fees from numerous companies. Dr. McIntyre is a CEO of Braxia Scientific.

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

Despite a higher symptom burden, patients with major depressive disorder (MDD) and a history of childhood trauma (CT) can achieve significant recovery following treatment with a combination of pharmacotherapy and psychotherapy, new research suggests.
 

Results from a meta-analysis of 29 studies from 1966 to 2019, which included almost 7,000 adults with MDD, showed that more than 60% reported a history of CT. But despite having more severe depression at baseline, those with CT benefited from active treatment. Effect sizes were comparable, and dropout rates were similar to those of their counterparts without CT.

“Evidence-based psychotherapy and pharmacotherapy should be offered to depressed patients, regardless of their childhood trauma status,” lead author Erika Kuzminskaite, MSc, a PhD candidate at Amsterdam UMC department of psychiatry, the Netherlands, told this news organization.

“Screening for childhood trauma is important to identify individuals at risk for more severe course of the disorder and post-treatment residual symptoms,” she added.

The study was published online in the Lancet Psychiatry.
 

Common and potent risk factor

The researchers note that CT is common and is a potent risk factor for depression. Previous studies have “consistently indicated significantly higher severity and persistence of depressive symptoms in adult patients with depression and a history of childhood trauma.”

Previous individual and meta-analytic studies “indicated poorer response to first-line depression treatments in patients with childhood trauma, compared to those without trauma, suggesting the need for new personalized treatments for depressed patients with childhood trauma history,” Ms. Kuzminskaite said.

“However, the evidence on poorer treatment outcomes has not been definitive, and a comprehensive meta-analysis of available findings has been lacking,” she added.

The previous meta-analyses showed high between-study heterogeneity, and some primary studies reported similar or even superior improvement for patients with CT, compared with those without such history, following treatment with evidence-based psychotherapy or pharmacotherapy.

Previous studies also did not investigate the “relative contribution of different childhood trauma types.”

To address this gap, investigators in the Childhood Trauma Meta-Analysis Study Group conducted the “largest and most comprehensive study of available evidence examining the effects of childhood trauma on the efficacy and effectiveness of first-line treatments for adults with MDD.”

To be included, a study had to focus on adults over 18 years old who had received a primary diagnosis of depression. The study had to have included an available assessment of childhood trauma, and patients were required to have undergone psychotherapy and/or pharmacotherapy for depression alone or in combination with other guideline-recommended treatments. Studies were also required to have a comparator group, when applicable, and to have reported depression severity before and after the acute treatment phase.

Of 10,505 publications, 54 trials met inclusion criteria; of these, 29 (20 randomized controlled trials and 9 open trials), encompassing 6,830 participants aged 18-85 years, included data that had been made available by authors of the various studies and were included in the current analysis.

Most studies focused on MDD; 11 trials focused on patients with chronic or treatment-resistant depression.

The primary outcome was “depression severity change from baseline to the end of the acute treatment phase” (expressed as standardized effect size – Hedges’ g).
 

Greater treatment motivation?

Of the included patients, 62% reported a history of CT. They were found to have more severe depression at baseline, compared with those without CT (g = .202; 95% confidence interval, 0.145-0.258; I² = 0%).

The benefits from active treatment obtained by these patients with CT were similar to the benefits obtained by their counterparts without CT (between-group treatment effect difference: g = .016; 95% CI, –0.094-0.125; I² = 44.3%).

No significant difference in active treatment effects (in comparison with control condition) was found between individuals with and those without CT (g = .605; 95% CI, 0.294-0.916; I² = 58.0%; and g = .178; 95% CI, –0.195-0.552; I² = 67.5%, respectively; between-group difference P = .051).

Dropout rates were similar for the participants with and those without CT (risk ratio, 1.063; 95% CI, 0.945-1.195; I² = 0%).

“Findings did not significantly differ by childhood trauma type, study design, depression diagnosis, assessment method of childhood trauma, study quality, year, or treatment type or length,” the authors report.

The findings did, however, differ by country, with North American studies showing larger treatment effects for patients with CT, compared with studies conducted in Asian-Pacific countries (g = 0.150; 95% CI, 0.030-0.269; vs. g = 0.255; 95% CI, –0.508- –0.002, respectively; corrected false discovery rate, 0.0080). “However, because of limited power, these findings should be interpreted with caution,” the authors warn.

“It could be a chance finding and is certainly not causal,” Ms. Kuzminskaite suggested.

Most studies (21 of the 29) had a “moderate to high risk of bias.” But when the researchers conducted a sensitivity analysis in the low-bias studies, they found that results were similar to those of the primary analysis that included all the studies.

“Treatments were similarly effective for patients with and without childhood trauma, with slightly larger active treatment (vs. control condition – placebo, wait list, care-as-usual) effects for patients with childhood trauma history,” Ms. Kuzminskaite said.

“Some evidence suggests that patients with childhood trauma are characterized by greater treatment motivation,” she noted. Moreover, “they are also more severely depressed prior to treatment [and] thus have more room for improvement.”
 

‘Hopeful message’

Commenting for this news organization, Yvette Sheline, MD, McLure professor of psychiatry, radiology, and neurology and director of the center for neuromodulation in depression and Stress, University of Pennsylvania, Philadelphia, called it a “well-executed” and “straightforward” study “with clear-cut findings.”

Dr. Sheline, the director of the section on mood, anxiety, and trauma, who was not involved with the study, agrees with the authors’ conclusions – “to use evidence-based treatments for depression in all patients,” with or without a history of CT.

In an accompanying editorial, Antoine Yrondi, MD, PhD, of Université de Toulouse (France), called the findings “important and encouraging” but cautioned that CT could be associated with conditions other than depression, which could make MDD “more difficult to treat.”

Nevertheless, the meta-analysis “delivers a hopeful message to patients with childhood trauma that evidence-based psychotherapy and pharmacotherapy could improve depressive symptoms,” Dr. Yrondi said.

Dr. Yrondi encouraged physicians not to neglect CT in patients with MDD. “For this, it is important that physicians are trained to evaluate childhood trauma and to take it into account in their daily practice.”

No source of funding for the study was listed. The authors and Dr. Sheline have disclosed no relevant financial relationships. Dr. Yrondi has received speaker’s honoraria from AstraZeneca, Janssen, Lundbeck, Otsuka, and Jazz and has carried out clinical studies in relation to the development of a medicine for Janssen and Lundbeck that are unrelated to this work.

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

Despite a higher symptom burden, patients with major depressive disorder (MDD) and a history of childhood trauma (CT) can achieve significant recovery following treatment with a combination of pharmacotherapy and psychotherapy, new research suggests.
 

Results from a meta-analysis of 29 studies from 1966 to 2019, which included almost 7,000 adults with MDD, showed that more than 60% reported a history of CT. But despite having more severe depression at baseline, those with CT benefited from active treatment. Effect sizes were comparable, and dropout rates were similar to those of their counterparts without CT.

“Evidence-based psychotherapy and pharmacotherapy should be offered to depressed patients, regardless of their childhood trauma status,” lead author Erika Kuzminskaite, MSc, a PhD candidate at Amsterdam UMC department of psychiatry, the Netherlands, told this news organization.

“Screening for childhood trauma is important to identify individuals at risk for more severe course of the disorder and post-treatment residual symptoms,” she added.

The study was published online in the Lancet Psychiatry.
 

Common and potent risk factor

The researchers note that CT is common and is a potent risk factor for depression. Previous studies have “consistently indicated significantly higher severity and persistence of depressive symptoms in adult patients with depression and a history of childhood trauma.”

Previous individual and meta-analytic studies “indicated poorer response to first-line depression treatments in patients with childhood trauma, compared to those without trauma, suggesting the need for new personalized treatments for depressed patients with childhood trauma history,” Ms. Kuzminskaite said.

“However, the evidence on poorer treatment outcomes has not been definitive, and a comprehensive meta-analysis of available findings has been lacking,” she added.

The previous meta-analyses showed high between-study heterogeneity, and some primary studies reported similar or even superior improvement for patients with CT, compared with those without such history, following treatment with evidence-based psychotherapy or pharmacotherapy.

Previous studies also did not investigate the “relative contribution of different childhood trauma types.”

To address this gap, investigators in the Childhood Trauma Meta-Analysis Study Group conducted the “largest and most comprehensive study of available evidence examining the effects of childhood trauma on the efficacy and effectiveness of first-line treatments for adults with MDD.”

To be included, a study had to focus on adults over 18 years old who had received a primary diagnosis of depression. The study had to have included an available assessment of childhood trauma, and patients were required to have undergone psychotherapy and/or pharmacotherapy for depression alone or in combination with other guideline-recommended treatments. Studies were also required to have a comparator group, when applicable, and to have reported depression severity before and after the acute treatment phase.

Of 10,505 publications, 54 trials met inclusion criteria; of these, 29 (20 randomized controlled trials and 9 open trials), encompassing 6,830 participants aged 18-85 years, included data that had been made available by authors of the various studies and were included in the current analysis.

Most studies focused on MDD; 11 trials focused on patients with chronic or treatment-resistant depression.

The primary outcome was “depression severity change from baseline to the end of the acute treatment phase” (expressed as standardized effect size – Hedges’ g).
 

Greater treatment motivation?

Of the included patients, 62% reported a history of CT. They were found to have more severe depression at baseline, compared with those without CT (g = .202; 95% confidence interval, 0.145-0.258; I² = 0%).

The benefits from active treatment obtained by these patients with CT were similar to the benefits obtained by their counterparts without CT (between-group treatment effect difference: g = .016; 95% CI, –0.094-0.125; I² = 44.3%).

No significant difference in active treatment effects (in comparison with control condition) was found between individuals with and those without CT (g = .605; 95% CI, 0.294-0.916; I² = 58.0%; and g = .178; 95% CI, –0.195-0.552; I² = 67.5%, respectively; between-group difference P = .051).

Dropout rates were similar for the participants with and those without CT (risk ratio, 1.063; 95% CI, 0.945-1.195; I² = 0%).

“Findings did not significantly differ by childhood trauma type, study design, depression diagnosis, assessment method of childhood trauma, study quality, year, or treatment type or length,” the authors report.

The findings did, however, differ by country, with North American studies showing larger treatment effects for patients with CT, compared with studies conducted in Asian-Pacific countries (g = 0.150; 95% CI, 0.030-0.269; vs. g = 0.255; 95% CI, –0.508- –0.002, respectively; corrected false discovery rate, 0.0080). “However, because of limited power, these findings should be interpreted with caution,” the authors warn.

“It could be a chance finding and is certainly not causal,” Ms. Kuzminskaite suggested.

Most studies (21 of the 29) had a “moderate to high risk of bias.” But when the researchers conducted a sensitivity analysis in the low-bias studies, they found that results were similar to those of the primary analysis that included all the studies.

“Treatments were similarly effective for patients with and without childhood trauma, with slightly larger active treatment (vs. control condition – placebo, wait list, care-as-usual) effects for patients with childhood trauma history,” Ms. Kuzminskaite said.

“Some evidence suggests that patients with childhood trauma are characterized by greater treatment motivation,” she noted. Moreover, “they are also more severely depressed prior to treatment [and] thus have more room for improvement.”
 

‘Hopeful message’

Commenting for this news organization, Yvette Sheline, MD, McLure professor of psychiatry, radiology, and neurology and director of the center for neuromodulation in depression and Stress, University of Pennsylvania, Philadelphia, called it a “well-executed” and “straightforward” study “with clear-cut findings.”

Dr. Sheline, the director of the section on mood, anxiety, and trauma, who was not involved with the study, agrees with the authors’ conclusions – “to use evidence-based treatments for depression in all patients,” with or without a history of CT.

In an accompanying editorial, Antoine Yrondi, MD, PhD, of Université de Toulouse (France), called the findings “important and encouraging” but cautioned that CT could be associated with conditions other than depression, which could make MDD “more difficult to treat.”

Nevertheless, the meta-analysis “delivers a hopeful message to patients with childhood trauma that evidence-based psychotherapy and pharmacotherapy could improve depressive symptoms,” Dr. Yrondi said.

Dr. Yrondi encouraged physicians not to neglect CT in patients with MDD. “For this, it is important that physicians are trained to evaluate childhood trauma and to take it into account in their daily practice.”

No source of funding for the study was listed. The authors and Dr. Sheline have disclosed no relevant financial relationships. Dr. Yrondi has received speaker’s honoraria from AstraZeneca, Janssen, Lundbeck, Otsuka, and Jazz and has carried out clinical studies in relation to the development of a medicine for Janssen and Lundbeck that are unrelated to this work.

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

Despite a higher symptom burden, patients with major depressive disorder (MDD) and a history of childhood trauma (CT) can achieve significant recovery following treatment with a combination of pharmacotherapy and psychotherapy, new research suggests.
 

Results from a meta-analysis of 29 studies from 1966 to 2019, which included almost 7,000 adults with MDD, showed that more than 60% reported a history of CT. But despite having more severe depression at baseline, those with CT benefited from active treatment. Effect sizes were comparable, and dropout rates were similar to those of their counterparts without CT.

“Evidence-based psychotherapy and pharmacotherapy should be offered to depressed patients, regardless of their childhood trauma status,” lead author Erika Kuzminskaite, MSc, a PhD candidate at Amsterdam UMC department of psychiatry, the Netherlands, told this news organization.

“Screening for childhood trauma is important to identify individuals at risk for more severe course of the disorder and post-treatment residual symptoms,” she added.

The study was published online in the Lancet Psychiatry.
 

Common and potent risk factor

The researchers note that CT is common and is a potent risk factor for depression. Previous studies have “consistently indicated significantly higher severity and persistence of depressive symptoms in adult patients with depression and a history of childhood trauma.”

Previous individual and meta-analytic studies “indicated poorer response to first-line depression treatments in patients with childhood trauma, compared to those without trauma, suggesting the need for new personalized treatments for depressed patients with childhood trauma history,” Ms. Kuzminskaite said.

“However, the evidence on poorer treatment outcomes has not been definitive, and a comprehensive meta-analysis of available findings has been lacking,” she added.

The previous meta-analyses showed high between-study heterogeneity, and some primary studies reported similar or even superior improvement for patients with CT, compared with those without such history, following treatment with evidence-based psychotherapy or pharmacotherapy.

Previous studies also did not investigate the “relative contribution of different childhood trauma types.”

To address this gap, investigators in the Childhood Trauma Meta-Analysis Study Group conducted the “largest and most comprehensive study of available evidence examining the effects of childhood trauma on the efficacy and effectiveness of first-line treatments for adults with MDD.”

To be included, a study had to focus on adults over 18 years old who had received a primary diagnosis of depression. The study had to have included an available assessment of childhood trauma, and patients were required to have undergone psychotherapy and/or pharmacotherapy for depression alone or in combination with other guideline-recommended treatments. Studies were also required to have a comparator group, when applicable, and to have reported depression severity before and after the acute treatment phase.

Of 10,505 publications, 54 trials met inclusion criteria; of these, 29 (20 randomized controlled trials and 9 open trials), encompassing 6,830 participants aged 18-85 years, included data that had been made available by authors of the various studies and were included in the current analysis.

Most studies focused on MDD; 11 trials focused on patients with chronic or treatment-resistant depression.

The primary outcome was “depression severity change from baseline to the end of the acute treatment phase” (expressed as standardized effect size – Hedges’ g).
 

Greater treatment motivation?

Of the included patients, 62% reported a history of CT. They were found to have more severe depression at baseline, compared with those without CT (g = .202; 95% confidence interval, 0.145-0.258; I² = 0%).

The benefits from active treatment obtained by these patients with CT were similar to the benefits obtained by their counterparts without CT (between-group treatment effect difference: g = .016; 95% CI, –0.094-0.125; I² = 44.3%).

No significant difference in active treatment effects (in comparison with control condition) was found between individuals with and those without CT (g = .605; 95% CI, 0.294-0.916; I² = 58.0%; and g = .178; 95% CI, –0.195-0.552; I² = 67.5%, respectively; between-group difference P = .051).

Dropout rates were similar for the participants with and those without CT (risk ratio, 1.063; 95% CI, 0.945-1.195; I² = 0%).

“Findings did not significantly differ by childhood trauma type, study design, depression diagnosis, assessment method of childhood trauma, study quality, year, or treatment type or length,” the authors report.

The findings did, however, differ by country, with North American studies showing larger treatment effects for patients with CT, compared with studies conducted in Asian-Pacific countries (g = 0.150; 95% CI, 0.030-0.269; vs. g = 0.255; 95% CI, –0.508- –0.002, respectively; corrected false discovery rate, 0.0080). “However, because of limited power, these findings should be interpreted with caution,” the authors warn.

“It could be a chance finding and is certainly not causal,” Ms. Kuzminskaite suggested.

Most studies (21 of the 29) had a “moderate to high risk of bias.” But when the researchers conducted a sensitivity analysis in the low-bias studies, they found that results were similar to those of the primary analysis that included all the studies.

“Treatments were similarly effective for patients with and without childhood trauma, with slightly larger active treatment (vs. control condition – placebo, wait list, care-as-usual) effects for patients with childhood trauma history,” Ms. Kuzminskaite said.

“Some evidence suggests that patients with childhood trauma are characterized by greater treatment motivation,” she noted. Moreover, “they are also more severely depressed prior to treatment [and] thus have more room for improvement.”
 

‘Hopeful message’

Commenting for this news organization, Yvette Sheline, MD, McLure professor of psychiatry, radiology, and neurology and director of the center for neuromodulation in depression and Stress, University of Pennsylvania, Philadelphia, called it a “well-executed” and “straightforward” study “with clear-cut findings.”

Dr. Sheline, the director of the section on mood, anxiety, and trauma, who was not involved with the study, agrees with the authors’ conclusions – “to use evidence-based treatments for depression in all patients,” with or without a history of CT.

In an accompanying editorial, Antoine Yrondi, MD, PhD, of Université de Toulouse (France), called the findings “important and encouraging” but cautioned that CT could be associated with conditions other than depression, which could make MDD “more difficult to treat.”

Nevertheless, the meta-analysis “delivers a hopeful message to patients with childhood trauma that evidence-based psychotherapy and pharmacotherapy could improve depressive symptoms,” Dr. Yrondi said.

Dr. Yrondi encouraged physicians not to neglect CT in patients with MDD. “For this, it is important that physicians are trained to evaluate childhood trauma and to take it into account in their daily practice.”

No source of funding for the study was listed. The authors and Dr. Sheline have disclosed no relevant financial relationships. Dr. Yrondi has received speaker’s honoraria from AstraZeneca, Janssen, Lundbeck, Otsuka, and Jazz and has carried out clinical studies in relation to the development of a medicine for Janssen and Lundbeck that are unrelated to this work.

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

Individuals with depression who had high levels of C-reactive protein responded poorly to selected serotonin reuptake inhibitors compared to those with lower CRP levels, based on data from more than 900 patients.

C-reactive protein (CRP) has been shown to predict antidepressant treatment outcomes in depressed patients, but previous studies have been small and under restricted conditions, and data from large, real-world studies are lacking, wrote Yuqian Pan of First Affiliated Hospital of Zhengzhou University, Henan, China, and colleagues.

In a study published in the Journal of Affective Disorders , the researchers identified depressed patients aged 12-60 years who had tested CRP levels. The participants were followed through outpatient visits or telephone interviews to collect information on medication use and assess efficacy based on the Clinical Global Impressions–Improvement scale.

CRP was separated into the low CRP group of 709 patients (CRP < 1 mg/L) and a high CRP group of 209 patients (CRP ≥ 1 mg/L). The primary outcome was efficacy defined as effective and ineffective for high and low CRP levels in patients using different medications: Selected serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors, (SNRIs), melatonin receptor agonists (MTs), and norepinephrinergic and specific serotonergic antidepressants (NaSSAs).

The researchers compared efficacy in different groups according to CRP levels.

Overall, patients with low CRP showed significantly greater efficacy with SSRIs than did those with high CRP (hazard ratio [HR], 1.257, P = .047). SNRIs were more effective than SSRIs for treating patients with high CRP levels (HR, 1.652, P = .037).

A possible reason for the difference in efficacy is the correlation between CRP and body mass index; previous studies have shown that SSRIs may be less effective in obese individuals, the researchers said.

“Another possible explanation is that at high levels of inflammation, neurons, microglia, and macrophages respond to inflammatory challenges at the cellular level by activating metabolic pathways,” they said.

No significant changes in CRP levels were observed before and after starting medication use, which supports the stability of CRP as a biomarker under normal circumstances.

No difference in efficacy appeared between SSRIs and SNRIs in patients with low CRP, “which may indicate that SNRIs have stronger anti-inflammatory effects than SSRIs,” a finding consistent with previous studies, they said.

The study findings were limited by several factors including the small number of patients taking MT and NaSSA, the irregular time intervals for before and after SSRI treatment in 90 patients, the lack of classification by antidepressant type, and the potential for recall bias, the researchers noted.

However, the results suggest that CRP could predict the efficacy of SSRIs in depressed patients in a real-world setting, which may inform treatment decisions, they said.

The study received no outside funding. The researchers had no financial conflicts to disclose.

Individuals with depression who had high levels of C-reactive protein responded poorly to selected serotonin reuptake inhibitors compared to those with lower CRP levels, based on data from more than 900 patients.

C-reactive protein (CRP) has been shown to predict antidepressant treatment outcomes in depressed patients, but previous studies have been small and under restricted conditions, and data from large, real-world studies are lacking, wrote Yuqian Pan of First Affiliated Hospital of Zhengzhou University, Henan, China, and colleagues.

In a study published in the Journal of Affective Disorders , the researchers identified depressed patients aged 12-60 years who had tested CRP levels. The participants were followed through outpatient visits or telephone interviews to collect information on medication use and assess efficacy based on the Clinical Global Impressions–Improvement scale.

CRP was separated into the low CRP group of 709 patients (CRP < 1 mg/L) and a high CRP group of 209 patients (CRP ≥ 1 mg/L). The primary outcome was efficacy defined as effective and ineffective for high and low CRP levels in patients using different medications: Selected serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors, (SNRIs), melatonin receptor agonists (MTs), and norepinephrinergic and specific serotonergic antidepressants (NaSSAs).

The researchers compared efficacy in different groups according to CRP levels.

Overall, patients with low CRP showed significantly greater efficacy with SSRIs than did those with high CRP (hazard ratio [HR], 1.257, P = .047). SNRIs were more effective than SSRIs for treating patients with high CRP levels (HR, 1.652, P = .037).

A possible reason for the difference in efficacy is the correlation between CRP and body mass index; previous studies have shown that SSRIs may be less effective in obese individuals, the researchers said.

“Another possible explanation is that at high levels of inflammation, neurons, microglia, and macrophages respond to inflammatory challenges at the cellular level by activating metabolic pathways,” they said.

No significant changes in CRP levels were observed before and after starting medication use, which supports the stability of CRP as a biomarker under normal circumstances.

No difference in efficacy appeared between SSRIs and SNRIs in patients with low CRP, “which may indicate that SNRIs have stronger anti-inflammatory effects than SSRIs,” a finding consistent with previous studies, they said.

The study findings were limited by several factors including the small number of patients taking MT and NaSSA, the irregular time intervals for before and after SSRI treatment in 90 patients, the lack of classification by antidepressant type, and the potential for recall bias, the researchers noted.

However, the results suggest that CRP could predict the efficacy of SSRIs in depressed patients in a real-world setting, which may inform treatment decisions, they said.

The study received no outside funding. The researchers had no financial conflicts to disclose.

Individuals with depression who had high levels of C-reactive protein responded poorly to selected serotonin reuptake inhibitors compared to those with lower CRP levels, based on data from more than 900 patients.

C-reactive protein (CRP) has been shown to predict antidepressant treatment outcomes in depressed patients, but previous studies have been small and under restricted conditions, and data from large, real-world studies are lacking, wrote Yuqian Pan of First Affiliated Hospital of Zhengzhou University, Henan, China, and colleagues.

In a study published in the Journal of Affective Disorders , the researchers identified depressed patients aged 12-60 years who had tested CRP levels. The participants were followed through outpatient visits or telephone interviews to collect information on medication use and assess efficacy based on the Clinical Global Impressions–Improvement scale.

CRP was separated into the low CRP group of 709 patients (CRP < 1 mg/L) and a high CRP group of 209 patients (CRP ≥ 1 mg/L). The primary outcome was efficacy defined as effective and ineffective for high and low CRP levels in patients using different medications: Selected serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors, (SNRIs), melatonin receptor agonists (MTs), and norepinephrinergic and specific serotonergic antidepressants (NaSSAs).

The researchers compared efficacy in different groups according to CRP levels.

Overall, patients with low CRP showed significantly greater efficacy with SSRIs than did those with high CRP (hazard ratio [HR], 1.257, P = .047). SNRIs were more effective than SSRIs for treating patients with high CRP levels (HR, 1.652, P = .037).

A possible reason for the difference in efficacy is the correlation between CRP and body mass index; previous studies have shown that SSRIs may be less effective in obese individuals, the researchers said.

“Another possible explanation is that at high levels of inflammation, neurons, microglia, and macrophages respond to inflammatory challenges at the cellular level by activating metabolic pathways,” they said.

No significant changes in CRP levels were observed before and after starting medication use, which supports the stability of CRP as a biomarker under normal circumstances.

No difference in efficacy appeared between SSRIs and SNRIs in patients with low CRP, “which may indicate that SNRIs have stronger anti-inflammatory effects than SSRIs,” a finding consistent with previous studies, they said.

The study findings were limited by several factors including the small number of patients taking MT and NaSSA, the irregular time intervals for before and after SSRI treatment in 90 patients, the lack of classification by antidepressant type, and the potential for recall bias, the researchers noted.

However, the results suggest that CRP could predict the efficacy of SSRIs in depressed patients in a real-world setting, which may inform treatment decisions, they said.

The study received no outside funding. The researchers had no financial conflicts to disclose.

The broad-spectrum antibiotic minocycline (multiple brands) is not effective when added to standard antidepressant therapy, the largest randomized, controlled trial of minocycline in treatment-resistant depression (TRD) shows.

In the MinoTRD trial, 6 weeks of minocycline 200 mg daily added to stable antidepressant therapy did not show a statistically significant advantage over placebo on the overall course of depressive symptoms.

“The failure of minocycline treatment to reduce depressive symptoms in a naturalistic sample of patients with TRD is a setback for anti-inflammatory treatment strategies in this clinical population,” Julian Hellmann-Regen, MD, department of psychiatry and neurosciences, Charité – Universitätsmedizin Berlin, and colleagues wrote.  

The findings were published online in JAMA Network Open.
 

No additional benefit

The “inflammatory hypothesis” of depression maintains that depression arises from increased immune activation and neurotrophic mechanisms.

This view is supported by observations that depression is accompanied by increased levels of proinflammatory cytokines. In addition, low-grade inflammatory processes may interfere with response to typical antidepressant medications. 

Minocycline has been put forth as a novel antidepressant, and a few small trials have hinted at a benefit.

In the MinoTRD trial, 168 patients (mean age, 46 years; 53% men) with TRD were randomly allocated minocycline 200 mg/day or matching placebo in addition to usual antidepressant treatment for 6 weeks.

Results showed minocycline was well tolerated but was not superior to placebo in reducing depressive symptoms, the researchers report.

Overall, the mean Montgomery-Åsberg Depression Rating Scale (MADRS) score at baseline was 26.5. There was no significant between-group difference in mean change in MADRS score from baseline to 6 weeks, the primary outcome.

After 6 weeks of treatment, the mean reduction in MADRS score was 8.46 points in the minocycline group versus 8.01 points in the placebo group, and the difference of 1.46 points was not significant (P = .25).

Six weeks of minocycline treatment did not alter the course of depression severity, compared with placebo, the investigators noted.

Minocycline treatment also showed no statistically significant effect on secondary outcomes of response, remission, and various other clinical rating scales.
 

Caveats and cautionary notes

The researchers noted that one explanation for the null result of the MinoTRD trial could be that the 6-week treatment duration was not long enough to reveal detectable differences. They point to a small study that showed a strong effect of minocycline, compared with placebo by and after 8 weeks of treatment.

However, a closer look at that study suggests the overall effect in the minocycline group was caused by an almost-complete lack of improvement in the placebo group, “which is very unusual,” the investigators wrote.

In the MinoTRD trial, the magnitude of improvement for placebo was as expected from similar trials in TRD, they pointed out.

They also noted that, unlike some other trials, the MinoTRD trial purposely recruited a naturalistic population of TRD, assuming (but not confirming) elevated baseline inflammation as a potential underlying cause in at least a subgroup of the patients.

Post hoc stratification by baseline CRP levels in MinoTRD participants did not yield any results supporting the hypothesis of minocycline treatment possibly being more effective in participants with higher-grade baseline inflammation, the researchers reported.

“Our results from this large randomized controlled trial of a pleiotropic anti-inflammatory drug in this difficult-to-treat patient population are of great clinical importance, robustly demonstrating that minocycline add-on treatment does not outperform placebo, not even in those participants with elevated levels of CRP prior to treatment initiation,” they wrote.

The trial was funded by a grant from the German Federal Ministry of Education and Research within the Consortium Optimizing Treatment of Depression, as part of the Research Network for Psychiatric Disorders. Dr. Hellmann-Regen reported no relevant financial relationship.

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

The broad-spectrum antibiotic minocycline (multiple brands) is not effective when added to standard antidepressant therapy, the largest randomized, controlled trial of minocycline in treatment-resistant depression (TRD) shows.

In the MinoTRD trial, 6 weeks of minocycline 200 mg daily added to stable antidepressant therapy did not show a statistically significant advantage over placebo on the overall course of depressive symptoms.

“The failure of minocycline treatment to reduce depressive symptoms in a naturalistic sample of patients with TRD is a setback for anti-inflammatory treatment strategies in this clinical population,” Julian Hellmann-Regen, MD, department of psychiatry and neurosciences, Charité – Universitätsmedizin Berlin, and colleagues wrote.  

The findings were published online in JAMA Network Open.
 

No additional benefit

The “inflammatory hypothesis” of depression maintains that depression arises from increased immune activation and neurotrophic mechanisms.

This view is supported by observations that depression is accompanied by increased levels of proinflammatory cytokines. In addition, low-grade inflammatory processes may interfere with response to typical antidepressant medications. 

Minocycline has been put forth as a novel antidepressant, and a few small trials have hinted at a benefit.

In the MinoTRD trial, 168 patients (mean age, 46 years; 53% men) with TRD were randomly allocated minocycline 200 mg/day or matching placebo in addition to usual antidepressant treatment for 6 weeks.

Results showed minocycline was well tolerated but was not superior to placebo in reducing depressive symptoms, the researchers report.

Overall, the mean Montgomery-Åsberg Depression Rating Scale (MADRS) score at baseline was 26.5. There was no significant between-group difference in mean change in MADRS score from baseline to 6 weeks, the primary outcome.

After 6 weeks of treatment, the mean reduction in MADRS score was 8.46 points in the minocycline group versus 8.01 points in the placebo group, and the difference of 1.46 points was not significant (P = .25).

Six weeks of minocycline treatment did not alter the course of depression severity, compared with placebo, the investigators noted.

Minocycline treatment also showed no statistically significant effect on secondary outcomes of response, remission, and various other clinical rating scales.
 

Caveats and cautionary notes

The researchers noted that one explanation for the null result of the MinoTRD trial could be that the 6-week treatment duration was not long enough to reveal detectable differences. They point to a small study that showed a strong effect of minocycline, compared with placebo by and after 8 weeks of treatment.

However, a closer look at that study suggests the overall effect in the minocycline group was caused by an almost-complete lack of improvement in the placebo group, “which is very unusual,” the investigators wrote.

In the MinoTRD trial, the magnitude of improvement for placebo was as expected from similar trials in TRD, they pointed out.

They also noted that, unlike some other trials, the MinoTRD trial purposely recruited a naturalistic population of TRD, assuming (but not confirming) elevated baseline inflammation as a potential underlying cause in at least a subgroup of the patients.

Post hoc stratification by baseline CRP levels in MinoTRD participants did not yield any results supporting the hypothesis of minocycline treatment possibly being more effective in participants with higher-grade baseline inflammation, the researchers reported.

“Our results from this large randomized controlled trial of a pleiotropic anti-inflammatory drug in this difficult-to-treat patient population are of great clinical importance, robustly demonstrating that minocycline add-on treatment does not outperform placebo, not even in those participants with elevated levels of CRP prior to treatment initiation,” they wrote.

The trial was funded by a grant from the German Federal Ministry of Education and Research within the Consortium Optimizing Treatment of Depression, as part of the Research Network for Psychiatric Disorders. Dr. Hellmann-Regen reported no relevant financial relationship.

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

The broad-spectrum antibiotic minocycline (multiple brands) is not effective when added to standard antidepressant therapy, the largest randomized, controlled trial of minocycline in treatment-resistant depression (TRD) shows.

In the MinoTRD trial, 6 weeks of minocycline 200 mg daily added to stable antidepressant therapy did not show a statistically significant advantage over placebo on the overall course of depressive symptoms.

“The failure of minocycline treatment to reduce depressive symptoms in a naturalistic sample of patients with TRD is a setback for anti-inflammatory treatment strategies in this clinical population,” Julian Hellmann-Regen, MD, department of psychiatry and neurosciences, Charité – Universitätsmedizin Berlin, and colleagues wrote.  

The findings were published online in JAMA Network Open.
 

No additional benefit

The “inflammatory hypothesis” of depression maintains that depression arises from increased immune activation and neurotrophic mechanisms.

This view is supported by observations that depression is accompanied by increased levels of proinflammatory cytokines. In addition, low-grade inflammatory processes may interfere with response to typical antidepressant medications. 

Minocycline has been put forth as a novel antidepressant, and a few small trials have hinted at a benefit.

In the MinoTRD trial, 168 patients (mean age, 46 years; 53% men) with TRD were randomly allocated minocycline 200 mg/day or matching placebo in addition to usual antidepressant treatment for 6 weeks.

Results showed minocycline was well tolerated but was not superior to placebo in reducing depressive symptoms, the researchers report.

Overall, the mean Montgomery-Åsberg Depression Rating Scale (MADRS) score at baseline was 26.5. There was no significant between-group difference in mean change in MADRS score from baseline to 6 weeks, the primary outcome.

After 6 weeks of treatment, the mean reduction in MADRS score was 8.46 points in the minocycline group versus 8.01 points in the placebo group, and the difference of 1.46 points was not significant (P = .25).

Six weeks of minocycline treatment did not alter the course of depression severity, compared with placebo, the investigators noted.

Minocycline treatment also showed no statistically significant effect on secondary outcomes of response, remission, and various other clinical rating scales.
 

Caveats and cautionary notes

The researchers noted that one explanation for the null result of the MinoTRD trial could be that the 6-week treatment duration was not long enough to reveal detectable differences. They point to a small study that showed a strong effect of minocycline, compared with placebo by and after 8 weeks of treatment.

However, a closer look at that study suggests the overall effect in the minocycline group was caused by an almost-complete lack of improvement in the placebo group, “which is very unusual,” the investigators wrote.

In the MinoTRD trial, the magnitude of improvement for placebo was as expected from similar trials in TRD, they pointed out.

They also noted that, unlike some other trials, the MinoTRD trial purposely recruited a naturalistic population of TRD, assuming (but not confirming) elevated baseline inflammation as a potential underlying cause in at least a subgroup of the patients.

Post hoc stratification by baseline CRP levels in MinoTRD participants did not yield any results supporting the hypothesis of minocycline treatment possibly being more effective in participants with higher-grade baseline inflammation, the researchers reported.

“Our results from this large randomized controlled trial of a pleiotropic anti-inflammatory drug in this difficult-to-treat patient population are of great clinical importance, robustly demonstrating that minocycline add-on treatment does not outperform placebo, not even in those participants with elevated levels of CRP prior to treatment initiation,” they wrote.

The trial was funded by a grant from the German Federal Ministry of Education and Research within the Consortium Optimizing Treatment of Depression, as part of the Research Network for Psychiatric Disorders. Dr. Hellmann-Regen reported no relevant financial relationship.

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

More than 80% of U.S. maternal deaths across a 2-year period were due to preventable causes, according to a new CDC report.

Black mothers made up about a third of deaths, and more than 90% of deaths among Indigenous mothers were preventable.

“It’s significant. It’s staggering. It’s heartbreaking,” Allison Bryant, MD, a high-risk pregnancy specialist and senior medical director for health equity at Massachusetts General Hospital, told USA Today.

“It just means that we have so much work to do,” she said.

In the report, CDC researchers looked at pregnancy-related deaths between 2017 to 2019 based on numbers from maternal mortality review committees, which are multidisciplinary groups in 36 states that investigate the circumstances around maternal deaths.

Of the 1,018 deaths during the 2-year period, 839 occurred up to a year after delivery. About 22% of deaths happened during pregnancy, and 25% happened on the day of delivery or within a week after delivery. But 53% occurred more than 7 days after delivery.

Mental health conditions, such as overdoses and deaths by suicide, were the top underlying cause, followed by hemorrhage, or extreme bleeding. About a quarter of deaths were due to mental health conditions, followed by 14% due to hemorrhage and 13% due to heart problems. The rest were related to infection, embolism, cardiomyopathy, and high blood pressure-related disorders.

The analysis included a section on maternal deaths for American Indian and Alaska Native mothers, who are more than twice as likely as White mothers to die but are often undercounted in health data due to misclassification. More than 90% of their deaths were preventable between 2017 to 2019, with most due to mental health conditions and hemorrhage.

“It’s incredibly distressful,” Brian Thompson, MD, of the Oneida Nation and assistant professor of obstetrics and gynecology at Upstate Medical University, New York, told USA Today.

Dr. Thompson is working with the National Indian Health Board to create the first national tribal review committee for maternal deaths.

“It really needs to be looked at and examined why that is the case if essentially all of them are preventable,” he said.

Black mothers were also three times as likely as White mothers to die and more likely to die from heart problems. Hispanic mothers, who made up 14% of deaths, were more likely to die from mental health conditions.

Some of the deaths, such as hemorrhage, should be highly preventable. Existing toolkits for clinicians provide evidence-based guidelines to prevent and treat excessive bleeding.

“No pregnant person should be passing away from a hemorrhage,” Andrea Jackson, MD, division chief of obstetrics and gynecology at the University of California, San Francisco, told USA Today.

“We have the tools in the United States, and we know how to deal with it,” she said. “That was really disheartening to see.”

What’s more, the new CDC report highlights the need for more mental health resources during pregnancy and the postpartum period – up to a year or more after delivery – including improvements in access to care, diagnosis, and treatment.

“These are things that need to happen systemically,” LeThenia Baker, MD, an obstetrician and gynecologist at Wellstar Health, Georgia, told USA Today.

“It can’t just be a few practices here or there who are adopting best practices,” she said. “It has to be a systemic change.”

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

More than 80% of U.S. maternal deaths across a 2-year period were due to preventable causes, according to a new CDC report.

Black mothers made up about a third of deaths, and more than 90% of deaths among Indigenous mothers were preventable.

“It’s significant. It’s staggering. It’s heartbreaking,” Allison Bryant, MD, a high-risk pregnancy specialist and senior medical director for health equity at Massachusetts General Hospital, told USA Today.

“It just means that we have so much work to do,” she said.

In the report, CDC researchers looked at pregnancy-related deaths between 2017 to 2019 based on numbers from maternal mortality review committees, which are multidisciplinary groups in 36 states that investigate the circumstances around maternal deaths.

Of the 1,018 deaths during the 2-year period, 839 occurred up to a year after delivery. About 22% of deaths happened during pregnancy, and 25% happened on the day of delivery or within a week after delivery. But 53% occurred more than 7 days after delivery.

Mental health conditions, such as overdoses and deaths by suicide, were the top underlying cause, followed by hemorrhage, or extreme bleeding. About a quarter of deaths were due to mental health conditions, followed by 14% due to hemorrhage and 13% due to heart problems. The rest were related to infection, embolism, cardiomyopathy, and high blood pressure-related disorders.

The analysis included a section on maternal deaths for American Indian and Alaska Native mothers, who are more than twice as likely as White mothers to die but are often undercounted in health data due to misclassification. More than 90% of their deaths were preventable between 2017 to 2019, with most due to mental health conditions and hemorrhage.

“It’s incredibly distressful,” Brian Thompson, MD, of the Oneida Nation and assistant professor of obstetrics and gynecology at Upstate Medical University, New York, told USA Today.

Dr. Thompson is working with the National Indian Health Board to create the first national tribal review committee for maternal deaths.

“It really needs to be looked at and examined why that is the case if essentially all of them are preventable,” he said.

Black mothers were also three times as likely as White mothers to die and more likely to die from heart problems. Hispanic mothers, who made up 14% of deaths, were more likely to die from mental health conditions.

Some of the deaths, such as hemorrhage, should be highly preventable. Existing toolkits for clinicians provide evidence-based guidelines to prevent and treat excessive bleeding.

“No pregnant person should be passing away from a hemorrhage,” Andrea Jackson, MD, division chief of obstetrics and gynecology at the University of California, San Francisco, told USA Today.

“We have the tools in the United States, and we know how to deal with it,” she said. “That was really disheartening to see.”

What’s more, the new CDC report highlights the need for more mental health resources during pregnancy and the postpartum period – up to a year or more after delivery – including improvements in access to care, diagnosis, and treatment.

“These are things that need to happen systemically,” LeThenia Baker, MD, an obstetrician and gynecologist at Wellstar Health, Georgia, told USA Today.

“It can’t just be a few practices here or there who are adopting best practices,” she said. “It has to be a systemic change.”

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

More than 80% of U.S. maternal deaths across a 2-year period were due to preventable causes, according to a new CDC report.

Black mothers made up about a third of deaths, and more than 90% of deaths among Indigenous mothers were preventable.

“It’s significant. It’s staggering. It’s heartbreaking,” Allison Bryant, MD, a high-risk pregnancy specialist and senior medical director for health equity at Massachusetts General Hospital, told USA Today.

“It just means that we have so much work to do,” she said.

In the report, CDC researchers looked at pregnancy-related deaths between 2017 to 2019 based on numbers from maternal mortality review committees, which are multidisciplinary groups in 36 states that investigate the circumstances around maternal deaths.

Of the 1,018 deaths during the 2-year period, 839 occurred up to a year after delivery. About 22% of deaths happened during pregnancy, and 25% happened on the day of delivery or within a week after delivery. But 53% occurred more than 7 days after delivery.

Mental health conditions, such as overdoses and deaths by suicide, were the top underlying cause, followed by hemorrhage, or extreme bleeding. About a quarter of deaths were due to mental health conditions, followed by 14% due to hemorrhage and 13% due to heart problems. The rest were related to infection, embolism, cardiomyopathy, and high blood pressure-related disorders.

The analysis included a section on maternal deaths for American Indian and Alaska Native mothers, who are more than twice as likely as White mothers to die but are often undercounted in health data due to misclassification. More than 90% of their deaths were preventable between 2017 to 2019, with most due to mental health conditions and hemorrhage.

“It’s incredibly distressful,” Brian Thompson, MD, of the Oneida Nation and assistant professor of obstetrics and gynecology at Upstate Medical University, New York, told USA Today.

Dr. Thompson is working with the National Indian Health Board to create the first national tribal review committee for maternal deaths.

“It really needs to be looked at and examined why that is the case if essentially all of them are preventable,” he said.

Black mothers were also three times as likely as White mothers to die and more likely to die from heart problems. Hispanic mothers, who made up 14% of deaths, were more likely to die from mental health conditions.

Some of the deaths, such as hemorrhage, should be highly preventable. Existing toolkits for clinicians provide evidence-based guidelines to prevent and treat excessive bleeding.

“No pregnant person should be passing away from a hemorrhage,” Andrea Jackson, MD, division chief of obstetrics and gynecology at the University of California, San Francisco, told USA Today.

“We have the tools in the United States, and we know how to deal with it,” she said. “That was really disheartening to see.”

What’s more, the new CDC report highlights the need for more mental health resources during pregnancy and the postpartum period – up to a year or more after delivery – including improvements in access to care, diagnosis, and treatment.

“These are things that need to happen systemically,” LeThenia Baker, MD, an obstetrician and gynecologist at Wellstar Health, Georgia, told USA Today.

“It can’t just be a few practices here or there who are adopting best practices,” she said. “It has to be a systemic change.”

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

Ketamine infusions can help reduce symptoms of suicidal ideation, depression, and anxiety in patients with treatment-resistant depression (TRD), new research suggests.

MindPeace Clinics

Results from a retrospective chart review analysis, which included more than 400 participants with TRD, illustrate that ketamine is a safe and rapid treatment in a real-world patient population, lead author Patrick A. Oliver, MD, founder and medical director, MindPeace Clinics, Richmond, Va., told this news organization.

The effect was perhaps most notable for reducing suicidal ideation, he said.

“In 2 weeks, we can take somebody from being suicidal to nonsuicidal. It’s a total game changer,” Dr. Oliver added.

Every year in the United States, about 12 million individuals think about suicide, 3.2 million make a plan to kill themselves, and more than 46,000 succeed, the investigators note.

The findings were published online in the Journal of Clinical Psychiatry.
 

Molecule mixture

Primarily used as an anesthetic in hospitals, ketamine is also taken illegally as a recreational drug. Users may aim for an intense high or feeling of dissociation, or an out-of-body–type experience.

Ketamine is a mixture of two mirror-image molecules. An intranasal version of one of these molecules (esketamine) is approved by the U.S. Food and Drug Administration for TRD. Both esketamine and ketamine are believed to increase neurotrophic signaling that affects synaptic function.

The study included 424 patients (mean age, 41.7 years) with major depressive disorder or another mood disorder and who received at least one ketamine infusion at a specialty clinic. Most participants had failed prior medication trials.

Patients in the study were typically started on 0.5 mg/kg of ketamine, with the dose titrated to achieve symptoms of partial dissociation. The median dose administered after titration was 0.93 mg/kg over 40 minutes.

The main treatment course of at least six infusions within 21 days was completed by 70% of the patients.

At each clinic visit, all participants completed the Patient Health Questionnaire-9 (PHQ-9) and the Generalized Anxiety Disorder-7 (GAD-7).

The primary outcome was PHQ-9 total scores, for which researchers looked at seven time periods: 1 week, 2-3 weeks, 4-6 weeks, 7-12 weeks, 13-24 weeks, 25-51 weeks, and 52+ weeks.
 

‘Blows it out of the water’

Results showed PHQ-9 total scores declined by 50% throughout the course of treatment, with much of the improvement gained within 4-6 weeks. There was a significant difference between week 1 and all later time periods (all P values < .001) and between weeks 2 and 3 and all later periods (all P values < .001).

Other measures included treatment response, defined as at least a 50% improvement on the PHQ-9, and depression remission, defined as a PHQ-9 score of less than 5. After three infusions, 14% of the patients responded and 7% were in remission. After 10 infusions, 72% responded and 38% were in remission.

These results compare favorably to other depression treatments, said Dr. Oliver. “Truthfully, with the exception of ECT [electroconvulsive therapy], this blows it all out of the water,” he added.

Dr. Oliver noted that the success rate for repetitive transcranial magnetic stimulation is 40%-60% depending on the modality; and for selective serotonin reuptake inhibitors, the success rate “is somewhere between the mid-20s and low-30s percent range.”

Another outcome measure was the self-harm/suicidal ideation item of the PHQ-9 questionnaire, which asks about “thoughts that you would be better off dead, or of hurting yourself in some way.” About 22% of the study participants no longer reported suicidal ideation after 3 infusions, 50% by 6 infusions, and 75% by 10 infusions.

By 15 infusions, 85% no longer reported these thoughts. “Nothing else has shown that, ever,” said Dr. Oliver.

Symptoms of generalized anxiety were also substantially improved. There was about a 30% reduction in the GAD-7 score during treatment and, again, most of the response occurred by 4-6 weeks.
 

Study limitations

Sex, age, and other demographic characteristics did not predict response or remission, but suicide planning trended toward higher response rates (P = .083). This suggests that a more depressed subgroup can achieve greater benefit from the treatment than can less symptomatic patients, the investigators note.

A history of psychosis also trended toward better response to treatment (P = .086) but not remission.

The researchers note that study limitations include that it was retrospective, lacked a control group, and did not require patients to be hospitalized – so the study sample may have been less severely ill than in other studies.

In addition, most patients paid out of pocket for the treatment at $495 per infusion, and they self-reported their symptoms.

As well, the researchers did not assess adverse events, although nurses made follow-up calls to patients. Dr. Oliver noted the most common side effects of ketamine are nausea, vomiting, and anxiety.

Previous research has suggested that ketamine therapy is not linked to long-term side effects, such as sexual dysfunction, weight gain, lethargy, or cognitive issues, said Dr. Oliver.

The investigators point out another study limitation was lack of detailed demographic information, such as race, income, and education, which might affect its generalizability.
 

Concerns and questions

Pouya Movahed Rad, MD, PhD, senior consultant and researcher in psychiatry, Lund (Sweden) University, noted several concerns, including that the clinics treating the study participants with ketamine profited from it.

He also speculated about who can afford the treatment because only a few patients in the study were reimbursed through insurance.

Dr. Movahed Rad was not involved with the current research but was principal investigator for a recent study  that compared intravenous ketamine to ECT.

He questioned whether the patient population in the new study really was “real world.” Well-designed randomized controlled trials have been carried out in a “naturalistic setting, [which] get closer to real-life patients,” he said.

He also noted that the median dose after clinician titration (0.93 mg/kg over 40 minutes) “may be considered very high.”

With regard to doses being titrated to achieve symptoms of partial dissociation, “there is no obvious evidence to my knowledge that patients need to develop dissociative symptoms in order to have antidepressant effect,” said Dr. Movahed Rad.

Finally, he noted that the finding that 28% of the participants were using illegal drugs “is worrying” and wondered what drugs they were taking; he also questioned why 81% of the study population needed to take antidepressants.

The study did not receive outside funding. Dr. Oliver is the founder of MindPeace Clinics, which specialize in ketamine therapeutics. Dr. Movahed Rad has reported no relevant financial relationships.

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

Ketamine infusions can help reduce symptoms of suicidal ideation, depression, and anxiety in patients with treatment-resistant depression (TRD), new research suggests.

MindPeace Clinics

Results from a retrospective chart review analysis, which included more than 400 participants with TRD, illustrate that ketamine is a safe and rapid treatment in a real-world patient population, lead author Patrick A. Oliver, MD, founder and medical director, MindPeace Clinics, Richmond, Va., told this news organization.

The effect was perhaps most notable for reducing suicidal ideation, he said.

“In 2 weeks, we can take somebody from being suicidal to nonsuicidal. It’s a total game changer,” Dr. Oliver added.

Every year in the United States, about 12 million individuals think about suicide, 3.2 million make a plan to kill themselves, and more than 46,000 succeed, the investigators note.

The findings were published online in the Journal of Clinical Psychiatry.
 

Molecule mixture

Primarily used as an anesthetic in hospitals, ketamine is also taken illegally as a recreational drug. Users may aim for an intense high or feeling of dissociation, or an out-of-body–type experience.

Ketamine is a mixture of two mirror-image molecules. An intranasal version of one of these molecules (esketamine) is approved by the U.S. Food and Drug Administration for TRD. Both esketamine and ketamine are believed to increase neurotrophic signaling that affects synaptic function.

The study included 424 patients (mean age, 41.7 years) with major depressive disorder or another mood disorder and who received at least one ketamine infusion at a specialty clinic. Most participants had failed prior medication trials.

Patients in the study were typically started on 0.5 mg/kg of ketamine, with the dose titrated to achieve symptoms of partial dissociation. The median dose administered after titration was 0.93 mg/kg over 40 minutes.

The main treatment course of at least six infusions within 21 days was completed by 70% of the patients.

At each clinic visit, all participants completed the Patient Health Questionnaire-9 (PHQ-9) and the Generalized Anxiety Disorder-7 (GAD-7).

The primary outcome was PHQ-9 total scores, for which researchers looked at seven time periods: 1 week, 2-3 weeks, 4-6 weeks, 7-12 weeks, 13-24 weeks, 25-51 weeks, and 52+ weeks.
 

‘Blows it out of the water’

Results showed PHQ-9 total scores declined by 50% throughout the course of treatment, with much of the improvement gained within 4-6 weeks. There was a significant difference between week 1 and all later time periods (all P values < .001) and between weeks 2 and 3 and all later periods (all P values < .001).

Other measures included treatment response, defined as at least a 50% improvement on the PHQ-9, and depression remission, defined as a PHQ-9 score of less than 5. After three infusions, 14% of the patients responded and 7% were in remission. After 10 infusions, 72% responded and 38% were in remission.

These results compare favorably to other depression treatments, said Dr. Oliver. “Truthfully, with the exception of ECT [electroconvulsive therapy], this blows it all out of the water,” he added.

Dr. Oliver noted that the success rate for repetitive transcranial magnetic stimulation is 40%-60% depending on the modality; and for selective serotonin reuptake inhibitors, the success rate “is somewhere between the mid-20s and low-30s percent range.”

Another outcome measure was the self-harm/suicidal ideation item of the PHQ-9 questionnaire, which asks about “thoughts that you would be better off dead, or of hurting yourself in some way.” About 22% of the study participants no longer reported suicidal ideation after 3 infusions, 50% by 6 infusions, and 75% by 10 infusions.

By 15 infusions, 85% no longer reported these thoughts. “Nothing else has shown that, ever,” said Dr. Oliver.

Symptoms of generalized anxiety were also substantially improved. There was about a 30% reduction in the GAD-7 score during treatment and, again, most of the response occurred by 4-6 weeks.
 

Study limitations

Sex, age, and other demographic characteristics did not predict response or remission, but suicide planning trended toward higher response rates (P = .083). This suggests that a more depressed subgroup can achieve greater benefit from the treatment than can less symptomatic patients, the investigators note.

A history of psychosis also trended toward better response to treatment (P = .086) but not remission.

The researchers note that study limitations include that it was retrospective, lacked a control group, and did not require patients to be hospitalized – so the study sample may have been less severely ill than in other studies.

In addition, most patients paid out of pocket for the treatment at $495 per infusion, and they self-reported their symptoms.

As well, the researchers did not assess adverse events, although nurses made follow-up calls to patients. Dr. Oliver noted the most common side effects of ketamine are nausea, vomiting, and anxiety.

Previous research has suggested that ketamine therapy is not linked to long-term side effects, such as sexual dysfunction, weight gain, lethargy, or cognitive issues, said Dr. Oliver.

The investigators point out another study limitation was lack of detailed demographic information, such as race, income, and education, which might affect its generalizability.
 

Concerns and questions

Pouya Movahed Rad, MD, PhD, senior consultant and researcher in psychiatry, Lund (Sweden) University, noted several concerns, including that the clinics treating the study participants with ketamine profited from it.

He also speculated about who can afford the treatment because only a few patients in the study were reimbursed through insurance.

Dr. Movahed Rad was not involved with the current research but was principal investigator for a recent study  that compared intravenous ketamine to ECT.

He questioned whether the patient population in the new study really was “real world.” Well-designed randomized controlled trials have been carried out in a “naturalistic setting, [which] get closer to real-life patients,” he said.

He also noted that the median dose after clinician titration (0.93 mg/kg over 40 minutes) “may be considered very high.”

With regard to doses being titrated to achieve symptoms of partial dissociation, “there is no obvious evidence to my knowledge that patients need to develop dissociative symptoms in order to have antidepressant effect,” said Dr. Movahed Rad.

Finally, he noted that the finding that 28% of the participants were using illegal drugs “is worrying” and wondered what drugs they were taking; he also questioned why 81% of the study population needed to take antidepressants.

The study did not receive outside funding. Dr. Oliver is the founder of MindPeace Clinics, which specialize in ketamine therapeutics. Dr. Movahed Rad has reported no relevant financial relationships.

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

Ketamine infusions can help reduce symptoms of suicidal ideation, depression, and anxiety in patients with treatment-resistant depression (TRD), new research suggests.

MindPeace Clinics

Results from a retrospective chart review analysis, which included more than 400 participants with TRD, illustrate that ketamine is a safe and rapid treatment in a real-world patient population, lead author Patrick A. Oliver, MD, founder and medical director, MindPeace Clinics, Richmond, Va., told this news organization.

The effect was perhaps most notable for reducing suicidal ideation, he said.

“In 2 weeks, we can take somebody from being suicidal to nonsuicidal. It’s a total game changer,” Dr. Oliver added.

Every year in the United States, about 12 million individuals think about suicide, 3.2 million make a plan to kill themselves, and more than 46,000 succeed, the investigators note.

The findings were published online in the Journal of Clinical Psychiatry.
 

Molecule mixture

Primarily used as an anesthetic in hospitals, ketamine is also taken illegally as a recreational drug. Users may aim for an intense high or feeling of dissociation, or an out-of-body–type experience.

Ketamine is a mixture of two mirror-image molecules. An intranasal version of one of these molecules (esketamine) is approved by the U.S. Food and Drug Administration for TRD. Both esketamine and ketamine are believed to increase neurotrophic signaling that affects synaptic function.

The study included 424 patients (mean age, 41.7 years) with major depressive disorder or another mood disorder and who received at least one ketamine infusion at a specialty clinic. Most participants had failed prior medication trials.

Patients in the study were typically started on 0.5 mg/kg of ketamine, with the dose titrated to achieve symptoms of partial dissociation. The median dose administered after titration was 0.93 mg/kg over 40 minutes.

The main treatment course of at least six infusions within 21 days was completed by 70% of the patients.

At each clinic visit, all participants completed the Patient Health Questionnaire-9 (PHQ-9) and the Generalized Anxiety Disorder-7 (GAD-7).

The primary outcome was PHQ-9 total scores, for which researchers looked at seven time periods: 1 week, 2-3 weeks, 4-6 weeks, 7-12 weeks, 13-24 weeks, 25-51 weeks, and 52+ weeks.
 

‘Blows it out of the water’

Results showed PHQ-9 total scores declined by 50% throughout the course of treatment, with much of the improvement gained within 4-6 weeks. There was a significant difference between week 1 and all later time periods (all P values < .001) and between weeks 2 and 3 and all later periods (all P values < .001).

Other measures included treatment response, defined as at least a 50% improvement on the PHQ-9, and depression remission, defined as a PHQ-9 score of less than 5. After three infusions, 14% of the patients responded and 7% were in remission. After 10 infusions, 72% responded and 38% were in remission.

These results compare favorably to other depression treatments, said Dr. Oliver. “Truthfully, with the exception of ECT [electroconvulsive therapy], this blows it all out of the water,” he added.

Dr. Oliver noted that the success rate for repetitive transcranial magnetic stimulation is 40%-60% depending on the modality; and for selective serotonin reuptake inhibitors, the success rate “is somewhere between the mid-20s and low-30s percent range.”

Another outcome measure was the self-harm/suicidal ideation item of the PHQ-9 questionnaire, which asks about “thoughts that you would be better off dead, or of hurting yourself in some way.” About 22% of the study participants no longer reported suicidal ideation after 3 infusions, 50% by 6 infusions, and 75% by 10 infusions.

By 15 infusions, 85% no longer reported these thoughts. “Nothing else has shown that, ever,” said Dr. Oliver.

Symptoms of generalized anxiety were also substantially improved. There was about a 30% reduction in the GAD-7 score during treatment and, again, most of the response occurred by 4-6 weeks.
 

Study limitations

Sex, age, and other demographic characteristics did not predict response or remission, but suicide planning trended toward higher response rates (P = .083). This suggests that a more depressed subgroup can achieve greater benefit from the treatment than can less symptomatic patients, the investigators note.

A history of psychosis also trended toward better response to treatment (P = .086) but not remission.

The researchers note that study limitations include that it was retrospective, lacked a control group, and did not require patients to be hospitalized – so the study sample may have been less severely ill than in other studies.

In addition, most patients paid out of pocket for the treatment at $495 per infusion, and they self-reported their symptoms.

As well, the researchers did not assess adverse events, although nurses made follow-up calls to patients. Dr. Oliver noted the most common side effects of ketamine are nausea, vomiting, and anxiety.

Previous research has suggested that ketamine therapy is not linked to long-term side effects, such as sexual dysfunction, weight gain, lethargy, or cognitive issues, said Dr. Oliver.

The investigators point out another study limitation was lack of detailed demographic information, such as race, income, and education, which might affect its generalizability.
 

Concerns and questions

Pouya Movahed Rad, MD, PhD, senior consultant and researcher in psychiatry, Lund (Sweden) University, noted several concerns, including that the clinics treating the study participants with ketamine profited from it.

He also speculated about who can afford the treatment because only a few patients in the study were reimbursed through insurance.

Dr. Movahed Rad was not involved with the current research but was principal investigator for a recent study  that compared intravenous ketamine to ECT.

He questioned whether the patient population in the new study really was “real world.” Well-designed randomized controlled trials have been carried out in a “naturalistic setting, [which] get closer to real-life patients,” he said.

He also noted that the median dose after clinician titration (0.93 mg/kg over 40 minutes) “may be considered very high.”

With regard to doses being titrated to achieve symptoms of partial dissociation, “there is no obvious evidence to my knowledge that patients need to develop dissociative symptoms in order to have antidepressant effect,” said Dr. Movahed Rad.

Finally, he noted that the finding that 28% of the participants were using illegal drugs “is worrying” and wondered what drugs they were taking; he also questioned why 81% of the study population needed to take antidepressants.

The study did not receive outside funding. Dr. Oliver is the founder of MindPeace Clinics, which specialize in ketamine therapeutics. Dr. Movahed Rad has reported no relevant financial relationships.

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

In 2020, there were 5,224 suicide deaths registered in England and Wales.¹ The Mental Health Foundation, a London-based charitable organization, reports that approximately 70% of such deaths are in patients with depression.² The number of attempted suicides is much higher – the South West London and St. George’s Mental Health Trust estimates that at least 140,000 people attempt suicide in England and Wales every year.³

In suicidal depression, the psychological pain is often unbearable and feels overwhelmingly incompatible with life. One is no longer living but merely surviving, and eventually the exhaustion will lead to decompensation. This is marked by suicide. The goal is to end the suffering permanently and this is achieved through death.

Depression, like all other physical and mental illnesses, runs a course. This is highly variable between individuals and can be the case even between separate relapse episodes in the same patient. Like many diagnoses, depression is known to lead to death in a significant number of people. Many suicidally depressed patients feel that death will be an inevitable result of the illness.

Suicide is often viewed as a symptom of severe depression, but what if we considered death as part of the disease process itself? Consequently, would it be justifiable to consider depression in these patients as a form of terminal illness, since without treatment, the condition would lead to death? Accordingly, could there be a place for palliative care in a small minority of suicidally depressed patients? Taking such a perspective would mean that instead of placing the focus on the prevention of deaths and prolonging of lifespan, the focus would be on making the patients comfortable as the disease progresses, maintaining their dignity, and promoting autonomy.
 

Suicidal depression and rights

Patients with psychiatric conditions are generally not given the same rights to make decisions regarding their mental health and treatment, particularly if they wish to decline treatment. The rationale for this is that psychiatric patients do not have the capacity to make such decisions in the acute setting, because of the direct effects of the unwell mind on their decision-making processes and cognitive faculties. While this may be true in some cases, there is limited evidence that this applies to all suicidally depressed patients in all cases.

Another argument against allowing suicidally depressed patients to decline treatment is the notion that the episode of depression can be successfully treated, and the patients can return to their normal level of functioning. However, in individuals with a previous history of severe depression, it is possible that they will relapse again at some point. In the same way, a cancer can be treated, and patients could return to their baseline level of functioning, only for the cancer to then return later in life. In both cases, these relapses are emotionally and physically exhausting and painful to get through. The difference is that a cancer patient can decline further treatment and opt for no treatment or for palliative treatment, knowing that the disease will shorten life expectancy. For suicidal depression, this is not an option. Such patients may be sectioned, admitted, and treated against their will. Suicide, which could be considered a natural endpoint of the depressive illness, is unacceptable.

Is it fair to confiscate one’s right to decline treatment, solely because that person suffers from a mental illness, as opposed to a physical one? Numerous studies have demonstrated clear structural, neurological, and neurochemical changes in suicidal depression. This is evidence that such a condition encompasses a clear physical property. Other conditions, such as dementia and chronic pain, have previously been accepted for euthanasia in certain countries. Pain is a subjective experience of nociceptive and neurochemical signaling. In the same way, depression is a subjective experience involving aberrant neurochemical signaling. The difference is that physical pain can often be localized. However, patients with suicidal depression often experience very severe and tangible pain that can be difficult to articulate and for others to understand if they have never experienced it themselves.

Like distinct forms of physical pain, suicidal depression creates a different form of pain, but it is pain, nonetheless. Is it therefore fair for suicidally depressed patients to be given lesser rights than those suffering from physical illnesses in determining their fate?
 

Suicidal depression and capacity

A patient is assumed to have capacity unless proven otherwise. This is often the reverse when managing psychiatric patients. However, if patients are able to fulfill all criteria required for demonstrating capacity (understanding the information, retaining, weighing up, and communicating the decision), surely they have demonstrated capacity to make their decisions, whether that is to receive or to refuse treatment.

For physical illnesses, adults with capacity are permitted to make decisions that their treating teams may not agree with, but this disagreement alone is generally insufficient to override the decisions. These patients, unlike in suicidal depression, have the right to refuse lifesaving or life-prolonging treatment.

An argument for this is that in terminal physical illnesses, death is a passive process and neither the patient nor the physician are actively causing it. However, in many palliative settings, patients can be given medications and treatment for symptomatic relief, even if these may hasten their death. The principle that makes this permissible is that the primary aim is to improve the symptoms and ensure comfort. The unintended effect includes side effects and hastened death. Similarly, in suicidal depression, one could argue that the patient should be permitted medications that may hasten or lead to death, so long as the primary aim is to improve the symptoms of the unbearable mental pain and suffering.

Let us consider an alternative scenario. What if previously suicidal patients are currently in remission from depression and make advanced directives? In their current healthy state, they assert that if, in the future, they were to relapse, they would not want any form of treatment. Instead, they wish for the disease to run its course, which may end in death through suicide.

In this case, the circumstances in which the statement was made would be entirely valid – the patients at that moment have capacity, are not under coercion, are able to articulate logical thought processes, and their reasoning would not be affected by a concurrent psychiatric pathology. Furthermore, they can demonstrate that suicide is not an impulsive decision and have considered the consequences of suicide on themselves and others. If the patients can demonstrate all the above, what would the ethical grounds be for refusing this advanced directive?
 

Medical ethics

Below, I consider this debate in the context of four pillars of medical ethics.
 

Non-maleficence

To determine whether an action is in line with non-maleficence, one must ask whether the proposed treatment will improve or resolve one’s condition. In the case of severe suicidal depression, the treatment may help patients in the short term, but what happens if or when they relapse? The treatment will likely prolong life, but also inadvertently prolong suffering. What if the patients do not wish to go through this again? The treatment regime can be profoundly taxing for the patients, the loved ones, and sometimes even for the treating team. Are we doing more harm by forcing these patients to stay alive against their will?

Beneficence

Beneficence is the moral duty to promote the action that is in the patient’s best interest. But who should determine what the patient’s best interests are if the patient and the doctor disagree? Usually, this decision is made by the treating doctor, who considers the patient’s past and present wishes, beliefs and values, and capacity assessment. Supposing that the law was not a restriction, could one’s psychiatrist ever agree on psychiatric grounds alone that it is indeed in the patient’s best interests to die?

Doctors play a central role in the duty of care. But care does not always mean active treatment. Caring encompasses physical, psychological, and spiritual welfare and includes considering an individual patient’s dignity, personal circumstances, and wishes. In certain circumstances, keeping patients with capacity alive against their wishes could be more harmful than caring.
 

Autonomy

Autonomy gives the patients ultimate decision-making responsibility for their own lives. It allows patients with capacity to decline treatment that is recommended by their physicians and to make decisions regarding their own death. However, in suicidally depressed patients, this autonomy is confiscated. Severely unwell patients, at high risk of committing suicide, are not permitted the autonomy to make the decision regarding their treatment, suicide, and death.

Justice

A justice-orientated and utilitarian view questions whether spending resources on these patients wastes time, resources, and expertise, and whether resources should instead be spent on patients who do want treatment.

For example, the British National Health Service holds an outstanding debt of £13.4 billion.⁴ The financial cost of treating mental illness in 2020/2021 was £14.31 billion.⁵ The NHS estimates that wider costs to national economy, including welfare benefits, housing support, social workers, community support, lost productivity at work, etc., amounts to approximately £77 billion annually.⁶ Many severely depressed patients are so unwell that their ability to contribute to society, financially, socially, and otherwise, is minimal. If patients with capacity genuinely want to die and society would benefit from a reduction in the pressures on health and social care services, would it not be in both their best interests to allow them to die? This way, resources could be redirected to service users who would appreciate and benefit from them the most.

A consequentialist view focuses on whether the action will benefit the patient overall; the action itself is not so relevant. According to this view, keeping suicidally depressed patients alive against their wishes would be ethical if the patients lack capacity. Keeping them safe and treating them until they are better would overall be in the patients’ best interests. However, if the patients do have capacity and wish to die, forcing them to stay alive and undergo treatment against their wishes would merely prolong their suffering and thus could be considered unethical.
 

When enough is enough

In suicidal treatment-resistant depression, where the patient has tried multiple treatments over time and carefully considered alternatives, when is it time to stop trying? For physical illness, patients can refuse treatment provided they can demonstrate capacity. In depression, they can refuse treatment only if they can demonstrate that they are not at serious risk to themselves or others. Most societies consider suicide as a serious risk to self and therefore unacceptable. However, if we considered suicide as a natural endpoint of the disease process, should the patient have the right to refuse treatment and allow the disease to progress to death?

The treatment regime can be a lengthy process and the repeated failures to improve can be physically and mentally exhausting and further compound the hopelessness. Treatments often have side effects, which further erode the patient’s physical and mental wellbeing. Is there a time when giving up and withdrawing active treatment is in the patient’s best interests, especially if that is what the patient wants?

Terminal diseases are incurable and likely to hasten one’s death. Severe suicidal treatment-resistant depression conforms to both conditions – it is unresponsive to treatment and has a high likelihood of precipitating premature death through suicide. Most terminal illnesses can be managed with palliative treatment. In the context of severe suicidal depression, euthanasia and assisted suicide could be considered as means of palliative care.

Palliative care involves managing the patient’s symptomatology, dignity, and comfort. Euthanasia and assisted suicide help to address all of these. Like palliative care, euthanasia and assisted suicide aim to improve symptoms of depression by alleviating pain and suffering, even if they may hasten death.
 

Euthanasia and assisted suicide in severe depression

Euthanasia and assisted suicide are legal in seven countries. Two countries (Belgium and the Netherlands) permit euthanasia for psychiatric illnesses. Passive euthanasia is practiced in most countries, e.g., withholding artificial life support. In suicidal depression, it could be considered that this withholding of treatment may directly lead to death by suicide.

In active euthanasia and assisted suicide, the patient is given a chemical that will directly lead to death. Euthanasia and assisted suicide allow individuals to die with dignity in a controlled and organized manner. It ends the patients’ suffering and allows them to finally find peace. The difficulties that led them to seek euthanasia/assisted suicide indicate a loss of control of the pain and suffering in life, and euthanasia allows them to regain this control and autonomy through death. It allows these individuals to properly say goodbye to their loved ones, and a chance to share their thoughts and feelings.

In contrast, suicide is often covert, clandestine, and planned in secret, and it frequently requires individuals to be dishonest with their closest loved ones. The suicide often comes as a shock to the loved ones and profound grief, questions, anger, pain, sorrow, and guilt follow. These are due to questions that have been left unanswered, thoughts that were never shared, regret that they had not done more to help, and anguish knowing that their loved one died alone, in unbearable mental agony, unable to speak to anyone about this final hurdle.

Euthanasia and assisted suicide provide a path to overcome all these issues. They encourage open conversations between the patients, their loved ones, and the treating team. They promote transparency, mutual support, and help prepare the loved ones for the death. In this way, euthanasia and assisted suicide can benefit both the patient and the loved ones.

A significant proportion of severely suicidally depressed patients will eventually go on to commit or attempt suicide. Thus, giving them the autonomy to choose euthanasia or assisted suicide could be considered a kind, fair, and compassionate course of action, as it respects their wishes, and allows them to escape their suffering and to die with dignity.
 

Conclusion

Depression has historically never been considered a terminal illness, but there is undeniable evidence that a significant number of deaths every year are directly caused by depression. Should we therefore shift the focus from lifesaving and life-prolonging treatment to ensuring comfort and maintaining dignity by exploring palliative options for extremely suicidally depressed patients with capacity, who are adamant on ending their lives?

Euthanasia and assisted suicide for depression pose a profound paradox when viewed through a deontological lens. According to this, the correct course of action directly corresponds to what the most “moral” action would be. The moral stance would be to help those who are suffering. But what exactly constitutes “help”? Are euthanasia and assisted suicide helping or harming? Likewise, is keeping patients with capacity alive against their wishes helping or harming? Many believe that euthanasia, assisted suicide, and suicide itself are intrinsically and morally wrong. But this poses another clear impasse. Who should be the ones to decide whether an action is moral or not? Should it be the individual? The treating physician? Or society?
 

Dr. Chang graduated from Imperial College London with an MBBS (medicine and surgery) and a BSc (gastroenterology and hepatology) degree.

References

1. Office for National Statistics. Suicides in England and Wales – Office for National Statistics, 2021.

2. Faulkner, A. Suicide and Deliberate Self Harm: The Fundamental Facts. Mental Health Foundation; 1997.

3. NHS. Suicide Factsheet. Southwest London and St. George’s Mental Health NHS Trust [ebook], 2022.

4. The King’s Fund. Financial debts and loans in the NHS. 2020.

5. NHS England. Mental Health Five Year Forward View Dashboard. 2018.

6. National Mental Health, Policy into Practice. The costs of mental ill health.

In 2020, there were 5,224 suicide deaths registered in England and Wales.¹ The Mental Health Foundation, a London-based charitable organization, reports that approximately 70% of such deaths are in patients with depression.² The number of attempted suicides is much higher – the South West London and St. George’s Mental Health Trust estimates that at least 140,000 people attempt suicide in England and Wales every year.³

In suicidal depression, the psychological pain is often unbearable and feels overwhelmingly incompatible with life. One is no longer living but merely surviving, and eventually the exhaustion will lead to decompensation. This is marked by suicide. The goal is to end the suffering permanently and this is achieved through death.

Depression, like all other physical and mental illnesses, runs a course. This is highly variable between individuals and can be the case even between separate relapse episodes in the same patient. Like many diagnoses, depression is known to lead to death in a significant number of people. Many suicidally depressed patients feel that death will be an inevitable result of the illness.

Suicide is often viewed as a symptom of severe depression, but what if we considered death as part of the disease process itself? Consequently, would it be justifiable to consider depression in these patients as a form of terminal illness, since without treatment, the condition would lead to death? Accordingly, could there be a place for palliative care in a small minority of suicidally depressed patients? Taking such a perspective would mean that instead of placing the focus on the prevention of deaths and prolonging of lifespan, the focus would be on making the patients comfortable as the disease progresses, maintaining their dignity, and promoting autonomy.
 

Suicidal depression and rights

Patients with psychiatric conditions are generally not given the same rights to make decisions regarding their mental health and treatment, particularly if they wish to decline treatment. The rationale for this is that psychiatric patients do not have the capacity to make such decisions in the acute setting, because of the direct effects of the unwell mind on their decision-making processes and cognitive faculties. While this may be true in some cases, there is limited evidence that this applies to all suicidally depressed patients in all cases.

Another argument against allowing suicidally depressed patients to decline treatment is the notion that the episode of depression can be successfully treated, and the patients can return to their normal level of functioning. However, in individuals with a previous history of severe depression, it is possible that they will relapse again at some point. In the same way, a cancer can be treated, and patients could return to their baseline level of functioning, only for the cancer to then return later in life. In both cases, these relapses are emotionally and physically exhausting and painful to get through. The difference is that a cancer patient can decline further treatment and opt for no treatment or for palliative treatment, knowing that the disease will shorten life expectancy. For suicidal depression, this is not an option. Such patients may be sectioned, admitted, and treated against their will. Suicide, which could be considered a natural endpoint of the depressive illness, is unacceptable.

Is it fair to confiscate one’s right to decline treatment, solely because that person suffers from a mental illness, as opposed to a physical one? Numerous studies have demonstrated clear structural, neurological, and neurochemical changes in suicidal depression. This is evidence that such a condition encompasses a clear physical property. Other conditions, such as dementia and chronic pain, have previously been accepted for euthanasia in certain countries. Pain is a subjective experience of nociceptive and neurochemical signaling. In the same way, depression is a subjective experience involving aberrant neurochemical signaling. The difference is that physical pain can often be localized. However, patients with suicidal depression often experience very severe and tangible pain that can be difficult to articulate and for others to understand if they have never experienced it themselves.

Like distinct forms of physical pain, suicidal depression creates a different form of pain, but it is pain, nonetheless. Is it therefore fair for suicidally depressed patients to be given lesser rights than those suffering from physical illnesses in determining their fate?
 

Suicidal depression and capacity

A patient is assumed to have capacity unless proven otherwise. This is often the reverse when managing psychiatric patients. However, if patients are able to fulfill all criteria required for demonstrating capacity (understanding the information, retaining, weighing up, and communicating the decision), surely they have demonstrated capacity to make their decisions, whether that is to receive or to refuse treatment.

For physical illnesses, adults with capacity are permitted to make decisions that their treating teams may not agree with, but this disagreement alone is generally insufficient to override the decisions. These patients, unlike in suicidal depression, have the right to refuse lifesaving or life-prolonging treatment.

An argument for this is that in terminal physical illnesses, death is a passive process and neither the patient nor the physician are actively causing it. However, in many palliative settings, patients can be given medications and treatment for symptomatic relief, even if these may hasten their death. The principle that makes this permissible is that the primary aim is to improve the symptoms and ensure comfort. The unintended effect includes side effects and hastened death. Similarly, in suicidal depression, one could argue that the patient should be permitted medications that may hasten or lead to death, so long as the primary aim is to improve the symptoms of the unbearable mental pain and suffering.

Let us consider an alternative scenario. What if previously suicidal patients are currently in remission from depression and make advanced directives? In their current healthy state, they assert that if, in the future, they were to relapse, they would not want any form of treatment. Instead, they wish for the disease to run its course, which may end in death through suicide.

In this case, the circumstances in which the statement was made would be entirely valid – the patients at that moment have capacity, are not under coercion, are able to articulate logical thought processes, and their reasoning would not be affected by a concurrent psychiatric pathology. Furthermore, they can demonstrate that suicide is not an impulsive decision and have considered the consequences of suicide on themselves and others. If the patients can demonstrate all the above, what would the ethical grounds be for refusing this advanced directive?
 

Medical ethics

Below, I consider this debate in the context of four pillars of medical ethics.
 

Non-maleficence

To determine whether an action is in line with non-maleficence, one must ask whether the proposed treatment will improve or resolve one’s condition. In the case of severe suicidal depression, the treatment may help patients in the short term, but what happens if or when they relapse? The treatment will likely prolong life, but also inadvertently prolong suffering. What if the patients do not wish to go through this again? The treatment regime can be profoundly taxing for the patients, the loved ones, and sometimes even for the treating team. Are we doing more harm by forcing these patients to stay alive against their will?

Beneficence

Beneficence is the moral duty to promote the action that is in the patient’s best interest. But who should determine what the patient’s best interests are if the patient and the doctor disagree? Usually, this decision is made by the treating doctor, who considers the patient’s past and present wishes, beliefs and values, and capacity assessment. Supposing that the law was not a restriction, could one’s psychiatrist ever agree on psychiatric grounds alone that it is indeed in the patient’s best interests to die?

Doctors play a central role in the duty of care. But care does not always mean active treatment. Caring encompasses physical, psychological, and spiritual welfare and includes considering an individual patient’s dignity, personal circumstances, and wishes. In certain circumstances, keeping patients with capacity alive against their wishes could be more harmful than caring.
 

Autonomy

Autonomy gives the patients ultimate decision-making responsibility for their own lives. It allows patients with capacity to decline treatment that is recommended by their physicians and to make decisions regarding their own death. However, in suicidally depressed patients, this autonomy is confiscated. Severely unwell patients, at high risk of committing suicide, are not permitted the autonomy to make the decision regarding their treatment, suicide, and death.

Justice

A justice-orientated and utilitarian view questions whether spending resources on these patients wastes time, resources, and expertise, and whether resources should instead be spent on patients who do want treatment.

For example, the British National Health Service holds an outstanding debt of £13.4 billion.⁴ The financial cost of treating mental illness in 2020/2021 was £14.31 billion.⁵ The NHS estimates that wider costs to national economy, including welfare benefits, housing support, social workers, community support, lost productivity at work, etc., amounts to approximately £77 billion annually.⁶ Many severely depressed patients are so unwell that their ability to contribute to society, financially, socially, and otherwise, is minimal. If patients with capacity genuinely want to die and society would benefit from a reduction in the pressures on health and social care services, would it not be in both their best interests to allow them to die? This way, resources could be redirected to service users who would appreciate and benefit from them the most.

A consequentialist view focuses on whether the action will benefit the patient overall; the action itself is not so relevant. According to this view, keeping suicidally depressed patients alive against their wishes would be ethical if the patients lack capacity. Keeping them safe and treating them until they are better would overall be in the patients’ best interests. However, if the patients do have capacity and wish to die, forcing them to stay alive and undergo treatment against their wishes would merely prolong their suffering and thus could be considered unethical.
 

When enough is enough

In suicidal treatment-resistant depression, where the patient has tried multiple treatments over time and carefully considered alternatives, when is it time to stop trying? For physical illness, patients can refuse treatment provided they can demonstrate capacity. In depression, they can refuse treatment only if they can demonstrate that they are not at serious risk to themselves or others. Most societies consider suicide as a serious risk to self and therefore unacceptable. However, if we considered suicide as a natural endpoint of the disease process, should the patient have the right to refuse treatment and allow the disease to progress to death?

The treatment regime can be a lengthy process and the repeated failures to improve can be physically and mentally exhausting and further compound the hopelessness. Treatments often have side effects, which further erode the patient’s physical and mental wellbeing. Is there a time when giving up and withdrawing active treatment is in the patient’s best interests, especially if that is what the patient wants?

Terminal diseases are incurable and likely to hasten one’s death. Severe suicidal treatment-resistant depression conforms to both conditions – it is unresponsive to treatment and has a high likelihood of precipitating premature death through suicide. Most terminal illnesses can be managed with palliative treatment. In the context of severe suicidal depression, euthanasia and assisted suicide could be considered as means of palliative care.

Palliative care involves managing the patient’s symptomatology, dignity, and comfort. Euthanasia and assisted suicide help to address all of these. Like palliative care, euthanasia and assisted suicide aim to improve symptoms of depression by alleviating pain and suffering, even if they may hasten death.
 

Euthanasia and assisted suicide in severe depression

Euthanasia and assisted suicide are legal in seven countries. Two countries (Belgium and the Netherlands) permit euthanasia for psychiatric illnesses. Passive euthanasia is practiced in most countries, e.g., withholding artificial life support. In suicidal depression, it could be considered that this withholding of treatment may directly lead to death by suicide.

In active euthanasia and assisted suicide, the patient is given a chemical that will directly lead to death. Euthanasia and assisted suicide allow individuals to die with dignity in a controlled and organized manner. It ends the patients’ suffering and allows them to finally find peace. The difficulties that led them to seek euthanasia/assisted suicide indicate a loss of control of the pain and suffering in life, and euthanasia allows them to regain this control and autonomy through death. It allows these individuals to properly say goodbye to their loved ones, and a chance to share their thoughts and feelings.

In contrast, suicide is often covert, clandestine, and planned in secret, and it frequently requires individuals to be dishonest with their closest loved ones. The suicide often comes as a shock to the loved ones and profound grief, questions, anger, pain, sorrow, and guilt follow. These are due to questions that have been left unanswered, thoughts that were never shared, regret that they had not done more to help, and anguish knowing that their loved one died alone, in unbearable mental agony, unable to speak to anyone about this final hurdle.

Euthanasia and assisted suicide provide a path to overcome all these issues. They encourage open conversations between the patients, their loved ones, and the treating team. They promote transparency, mutual support, and help prepare the loved ones for the death. In this way, euthanasia and assisted suicide can benefit both the patient and the loved ones.

A significant proportion of severely suicidally depressed patients will eventually go on to commit or attempt suicide. Thus, giving them the autonomy to choose euthanasia or assisted suicide could be considered a kind, fair, and compassionate course of action, as it respects their wishes, and allows them to escape their suffering and to die with dignity.
 

Conclusion

Depression has historically never been considered a terminal illness, but there is undeniable evidence that a significant number of deaths every year are directly caused by depression. Should we therefore shift the focus from lifesaving and life-prolonging treatment to ensuring comfort and maintaining dignity by exploring palliative options for extremely suicidally depressed patients with capacity, who are adamant on ending their lives?

Euthanasia and assisted suicide for depression pose a profound paradox when viewed through a deontological lens. According to this, the correct course of action directly corresponds to what the most “moral” action would be. The moral stance would be to help those who are suffering. But what exactly constitutes “help”? Are euthanasia and assisted suicide helping or harming? Likewise, is keeping patients with capacity alive against their wishes helping or harming? Many believe that euthanasia, assisted suicide, and suicide itself are intrinsically and morally wrong. But this poses another clear impasse. Who should be the ones to decide whether an action is moral or not? Should it be the individual? The treating physician? Or society?
 

Dr. Chang graduated from Imperial College London with an MBBS (medicine and surgery) and a BSc (gastroenterology and hepatology) degree.

References

1. Office for National Statistics. Suicides in England and Wales – Office for National Statistics, 2021.

2. Faulkner, A. Suicide and Deliberate Self Harm: The Fundamental Facts. Mental Health Foundation; 1997.

3. NHS. Suicide Factsheet. Southwest London and St. George’s Mental Health NHS Trust [ebook], 2022.

4. The King’s Fund. Financial debts and loans in the NHS. 2020.

5. NHS England. Mental Health Five Year Forward View Dashboard. 2018.

6. National Mental Health, Policy into Practice. The costs of mental ill health.

In 2020, there were 5,224 suicide deaths registered in England and Wales.¹ The Mental Health Foundation, a London-based charitable organization, reports that approximately 70% of such deaths are in patients with depression.² The number of attempted suicides is much higher – the South West London and St. George’s Mental Health Trust estimates that at least 140,000 people attempt suicide in England and Wales every year.³

In suicidal depression, the psychological pain is often unbearable and feels overwhelmingly incompatible with life. One is no longer living but merely surviving, and eventually the exhaustion will lead to decompensation. This is marked by suicide. The goal is to end the suffering permanently and this is achieved through death.

Depression, like all other physical and mental illnesses, runs a course. This is highly variable between individuals and can be the case even between separate relapse episodes in the same patient. Like many diagnoses, depression is known to lead to death in a significant number of people. Many suicidally depressed patients feel that death will be an inevitable result of the illness.

Suicide is often viewed as a symptom of severe depression, but what if we considered death as part of the disease process itself? Consequently, would it be justifiable to consider depression in these patients as a form of terminal illness, since without treatment, the condition would lead to death? Accordingly, could there be a place for palliative care in a small minority of suicidally depressed patients? Taking such a perspective would mean that instead of placing the focus on the prevention of deaths and prolonging of lifespan, the focus would be on making the patients comfortable as the disease progresses, maintaining their dignity, and promoting autonomy.
 

Suicidal depression and rights

Patients with psychiatric conditions are generally not given the same rights to make decisions regarding their mental health and treatment, particularly if they wish to decline treatment. The rationale for this is that psychiatric patients do not have the capacity to make such decisions in the acute setting, because of the direct effects of the unwell mind on their decision-making processes and cognitive faculties. While this may be true in some cases, there is limited evidence that this applies to all suicidally depressed patients in all cases.

Another argument against allowing suicidally depressed patients to decline treatment is the notion that the episode of depression can be successfully treated, and the patients can return to their normal level of functioning. However, in individuals with a previous history of severe depression, it is possible that they will relapse again at some point. In the same way, a cancer can be treated, and patients could return to their baseline level of functioning, only for the cancer to then return later in life. In both cases, these relapses are emotionally and physically exhausting and painful to get through. The difference is that a cancer patient can decline further treatment and opt for no treatment or for palliative treatment, knowing that the disease will shorten life expectancy. For suicidal depression, this is not an option. Such patients may be sectioned, admitted, and treated against their will. Suicide, which could be considered a natural endpoint of the depressive illness, is unacceptable.

Is it fair to confiscate one’s right to decline treatment, solely because that person suffers from a mental illness, as opposed to a physical one? Numerous studies have demonstrated clear structural, neurological, and neurochemical changes in suicidal depression. This is evidence that such a condition encompasses a clear physical property. Other conditions, such as dementia and chronic pain, have previously been accepted for euthanasia in certain countries. Pain is a subjective experience of nociceptive and neurochemical signaling. In the same way, depression is a subjective experience involving aberrant neurochemical signaling. The difference is that physical pain can often be localized. However, patients with suicidal depression often experience very severe and tangible pain that can be difficult to articulate and for others to understand if they have never experienced it themselves.

Like distinct forms of physical pain, suicidal depression creates a different form of pain, but it is pain, nonetheless. Is it therefore fair for suicidally depressed patients to be given lesser rights than those suffering from physical illnesses in determining their fate?
 

Suicidal depression and capacity

A patient is assumed to have capacity unless proven otherwise. This is often the reverse when managing psychiatric patients. However, if patients are able to fulfill all criteria required for demonstrating capacity (understanding the information, retaining, weighing up, and communicating the decision), surely they have demonstrated capacity to make their decisions, whether that is to receive or to refuse treatment.

For physical illnesses, adults with capacity are permitted to make decisions that their treating teams may not agree with, but this disagreement alone is generally insufficient to override the decisions. These patients, unlike in suicidal depression, have the right to refuse lifesaving or life-prolonging treatment.

An argument for this is that in terminal physical illnesses, death is a passive process and neither the patient nor the physician are actively causing it. However, in many palliative settings, patients can be given medications and treatment for symptomatic relief, even if these may hasten their death. The principle that makes this permissible is that the primary aim is to improve the symptoms and ensure comfort. The unintended effect includes side effects and hastened death. Similarly, in suicidal depression, one could argue that the patient should be permitted medications that may hasten or lead to death, so long as the primary aim is to improve the symptoms of the unbearable mental pain and suffering.

Let us consider an alternative scenario. What if previously suicidal patients are currently in remission from depression and make advanced directives? In their current healthy state, they assert that if, in the future, they were to relapse, they would not want any form of treatment. Instead, they wish for the disease to run its course, which may end in death through suicide.

In this case, the circumstances in which the statement was made would be entirely valid – the patients at that moment have capacity, are not under coercion, are able to articulate logical thought processes, and their reasoning would not be affected by a concurrent psychiatric pathology. Furthermore, they can demonstrate that suicide is not an impulsive decision and have considered the consequences of suicide on themselves and others. If the patients can demonstrate all the above, what would the ethical grounds be for refusing this advanced directive?
 

Medical ethics

Below, I consider this debate in the context of four pillars of medical ethics.
 

Non-maleficence

To determine whether an action is in line with non-maleficence, one must ask whether the proposed treatment will improve or resolve one’s condition. In the case of severe suicidal depression, the treatment may help patients in the short term, but what happens if or when they relapse? The treatment will likely prolong life, but also inadvertently prolong suffering. What if the patients do not wish to go through this again? The treatment regime can be profoundly taxing for the patients, the loved ones, and sometimes even for the treating team. Are we doing more harm by forcing these patients to stay alive against their will?

Beneficence

Beneficence is the moral duty to promote the action that is in the patient’s best interest. But who should determine what the patient’s best interests are if the patient and the doctor disagree? Usually, this decision is made by the treating doctor, who considers the patient’s past and present wishes, beliefs and values, and capacity assessment. Supposing that the law was not a restriction, could one’s psychiatrist ever agree on psychiatric grounds alone that it is indeed in the patient’s best interests to die?

Doctors play a central role in the duty of care. But care does not always mean active treatment. Caring encompasses physical, psychological, and spiritual welfare and includes considering an individual patient’s dignity, personal circumstances, and wishes. In certain circumstances, keeping patients with capacity alive against their wishes could be more harmful than caring.
 

Autonomy

Autonomy gives the patients ultimate decision-making responsibility for their own lives. It allows patients with capacity to decline treatment that is recommended by their physicians and to make decisions regarding their own death. However, in suicidally depressed patients, this autonomy is confiscated. Severely unwell patients, at high risk of committing suicide, are not permitted the autonomy to make the decision regarding their treatment, suicide, and death.

Justice

A justice-orientated and utilitarian view questions whether spending resources on these patients wastes time, resources, and expertise, and whether resources should instead be spent on patients who do want treatment.

For example, the British National Health Service holds an outstanding debt of £13.4 billion.⁴ The financial cost of treating mental illness in 2020/2021 was £14.31 billion.⁵ The NHS estimates that wider costs to national economy, including welfare benefits, housing support, social workers, community support, lost productivity at work, etc., amounts to approximately £77 billion annually.⁶ Many severely depressed patients are so unwell that their ability to contribute to society, financially, socially, and otherwise, is minimal. If patients with capacity genuinely want to die and society would benefit from a reduction in the pressures on health and social care services, would it not be in both their best interests to allow them to die? This way, resources could be redirected to service users who would appreciate and benefit from them the most.

A consequentialist view focuses on whether the action will benefit the patient overall; the action itself is not so relevant. According to this view, keeping suicidally depressed patients alive against their wishes would be ethical if the patients lack capacity. Keeping them safe and treating them until they are better would overall be in the patients’ best interests. However, if the patients do have capacity and wish to die, forcing them to stay alive and undergo treatment against their wishes would merely prolong their suffering and thus could be considered unethical.
 

When enough is enough

In suicidal treatment-resistant depression, where the patient has tried multiple treatments over time and carefully considered alternatives, when is it time to stop trying? For physical illness, patients can refuse treatment provided they can demonstrate capacity. In depression, they can refuse treatment only if they can demonstrate that they are not at serious risk to themselves or others. Most societies consider suicide as a serious risk to self and therefore unacceptable. However, if we considered suicide as a natural endpoint of the disease process, should the patient have the right to refuse treatment and allow the disease to progress to death?

The treatment regime can be a lengthy process and the repeated failures to improve can be physically and mentally exhausting and further compound the hopelessness. Treatments often have side effects, which further erode the patient’s physical and mental wellbeing. Is there a time when giving up and withdrawing active treatment is in the patient’s best interests, especially if that is what the patient wants?

Terminal diseases are incurable and likely to hasten one’s death. Severe suicidal treatment-resistant depression conforms to both conditions – it is unresponsive to treatment and has a high likelihood of precipitating premature death through suicide. Most terminal illnesses can be managed with palliative treatment. In the context of severe suicidal depression, euthanasia and assisted suicide could be considered as means of palliative care.

Palliative care involves managing the patient’s symptomatology, dignity, and comfort. Euthanasia and assisted suicide help to address all of these. Like palliative care, euthanasia and assisted suicide aim to improve symptoms of depression by alleviating pain and suffering, even if they may hasten death.
 

Euthanasia and assisted suicide in severe depression

Euthanasia and assisted suicide are legal in seven countries. Two countries (Belgium and the Netherlands) permit euthanasia for psychiatric illnesses. Passive euthanasia is practiced in most countries, e.g., withholding artificial life support. In suicidal depression, it could be considered that this withholding of treatment may directly lead to death by suicide.

In active euthanasia and assisted suicide, the patient is given a chemical that will directly lead to death. Euthanasia and assisted suicide allow individuals to die with dignity in a controlled and organized manner. It ends the patients’ suffering and allows them to finally find peace. The difficulties that led them to seek euthanasia/assisted suicide indicate a loss of control of the pain and suffering in life, and euthanasia allows them to regain this control and autonomy through death. It allows these individuals to properly say goodbye to their loved ones, and a chance to share their thoughts and feelings.

In contrast, suicide is often covert, clandestine, and planned in secret, and it frequently requires individuals to be dishonest with their closest loved ones. The suicide often comes as a shock to the loved ones and profound grief, questions, anger, pain, sorrow, and guilt follow. These are due to questions that have been left unanswered, thoughts that were never shared, regret that they had not done more to help, and anguish knowing that their loved one died alone, in unbearable mental agony, unable to speak to anyone about this final hurdle.

Euthanasia and assisted suicide provide a path to overcome all these issues. They encourage open conversations between the patients, their loved ones, and the treating team. They promote transparency, mutual support, and help prepare the loved ones for the death. In this way, euthanasia and assisted suicide can benefit both the patient and the loved ones.

A significant proportion of severely suicidally depressed patients will eventually go on to commit or attempt suicide. Thus, giving them the autonomy to choose euthanasia or assisted suicide could be considered a kind, fair, and compassionate course of action, as it respects their wishes, and allows them to escape their suffering and to die with dignity.
 

Conclusion

Depression has historically never been considered a terminal illness, but there is undeniable evidence that a significant number of deaths every year are directly caused by depression. Should we therefore shift the focus from lifesaving and life-prolonging treatment to ensuring comfort and maintaining dignity by exploring palliative options for extremely suicidally depressed patients with capacity, who are adamant on ending their lives?

Euthanasia and assisted suicide for depression pose a profound paradox when viewed through a deontological lens. According to this, the correct course of action directly corresponds to what the most “moral” action would be. The moral stance would be to help those who are suffering. But what exactly constitutes “help”? Are euthanasia and assisted suicide helping or harming? Likewise, is keeping patients with capacity alive against their wishes helping or harming? Many believe that euthanasia, assisted suicide, and suicide itself are intrinsically and morally wrong. But this poses another clear impasse. Who should be the ones to decide whether an action is moral or not? Should it be the individual? The treating physician? Or society?
 

Dr. Chang graduated from Imperial College London with an MBBS (medicine and surgery) and a BSc (gastroenterology and hepatology) degree.

References

1. Office for National Statistics. Suicides in England and Wales – Office for National Statistics, 2021.

2. Faulkner, A. Suicide and Deliberate Self Harm: The Fundamental Facts. Mental Health Foundation; 1997.

3. NHS. Suicide Factsheet. Southwest London and St. George’s Mental Health NHS Trust [ebook], 2022.

4. The King’s Fund. Financial debts and loans in the NHS. 2020.

5. NHS England. Mental Health Five Year Forward View Dashboard. 2018.

6. National Mental Health, Policy into Practice. The costs of mental ill health.

Borderline personality disorder was significantly associated with relapse after 6 months in adults with major depressive disorder who underwent electroconvulsive therapy (ECT), based on data from 109 individuals.

ECT has demonstrated effectiveness for treatment of unipolar and bipolar major depression, but relapses within 6 months are frequent, and potential factors affecting relapse have not been well studied, wrote Matthieu Hein, MD, PhD, of Erasme Hospital, Université Libre de Bruxelles, and colleagues.

Borderline personality disorder (BPD) is a common comorbidity among individuals with major depressive disorder, and previous research suggests a possible negative effect of BPD on ECT response in MDD patients, they wrote.

In a study published in Psychiatry Research, the researchers recruited 68 females and 41 males aged 18 years and older with diagnosed MDD who had partial or complete response to ECT after receiving treatment at a single center. Approximately two-thirds of the patients were aged 50 years and older, and 22 met criteria for BPD. The ECT consisted of three sessions per week; the total number of sessions ranged from 6 to 18.

The primary outcome was relapse at 6 months after ECT treatment. Relapse was defined as a score of 16 or higher on the Hamilton Depression Rating Scale in combination with a mean absolute increase of at least 10 points from the psychiatric interview at the end of the ECT.

Relapse rates at 6 months were 37.6% for the study population overall, but significantly higher for those with BPD, compared with those without BPD (72.7% vs. 28.7%; P < .001).

In a multivariate analysis, adjusting for age, gender, and mood stabilizer use after ECT, relapse was approximately four times more likely among individuals with BPD, compared with those without (hazard ratio, 4.14). No significant association appeared between increased relapse and other comorbid personality disorders, anxiety disorders, alcohol or substance use disorders, or hospitalization during the ECT treatment period.

Potential reasons for the increased relapse risk among individuals with MDD and BPD include the younger age of the individuals with BPD, which has been shown to increase MDD relapse risk; the direct negative impact of BPD on mental functioning; and the documented tendency to poor treatment adherence, the researchers wrote in their discussion.

“Given these different elements, it seems important to screen more systematically for BPD in major depressed individuals treated with ECT in order to allow the implementation of more effective prevention strategies for relapse within 6 months in this particular subpopulation,” they emphasized.

“The demonstration of this higher risk of relapse within 6 months associated with BPD in major depressed individuals treated with ECT could open new therapeutic perspectives to allow better maintenance of euthymia in this particular subpopulation,” they added.

The study findings were limited by several factors including the retrospective design and the focus on only BPD, which may not generalize to other personality disorders, the researchers noted.

However, the results support data from previous studies and highlight the need for more systematic BPD screening in MDD patients to prevent relapse after ECT, they said.

The study received no outside funding. The researchers had no financial conflicts to disclose.
 

Borderline personality disorder was significantly associated with relapse after 6 months in adults with major depressive disorder who underwent electroconvulsive therapy (ECT), based on data from 109 individuals.

ECT has demonstrated effectiveness for treatment of unipolar and bipolar major depression, but relapses within 6 months are frequent, and potential factors affecting relapse have not been well studied, wrote Matthieu Hein, MD, PhD, of Erasme Hospital, Université Libre de Bruxelles, and colleagues.

Borderline personality disorder (BPD) is a common comorbidity among individuals with major depressive disorder, and previous research suggests a possible negative effect of BPD on ECT response in MDD patients, they wrote.

In a study published in Psychiatry Research, the researchers recruited 68 females and 41 males aged 18 years and older with diagnosed MDD who had partial or complete response to ECT after receiving treatment at a single center. Approximately two-thirds of the patients were aged 50 years and older, and 22 met criteria for BPD. The ECT consisted of three sessions per week; the total number of sessions ranged from 6 to 18.

The primary outcome was relapse at 6 months after ECT treatment. Relapse was defined as a score of 16 or higher on the Hamilton Depression Rating Scale in combination with a mean absolute increase of at least 10 points from the psychiatric interview at the end of the ECT.

Relapse rates at 6 months were 37.6% for the study population overall, but significantly higher for those with BPD, compared with those without BPD (72.7% vs. 28.7%; P < .001).

In a multivariate analysis, adjusting for age, gender, and mood stabilizer use after ECT, relapse was approximately four times more likely among individuals with BPD, compared with those without (hazard ratio, 4.14). No significant association appeared between increased relapse and other comorbid personality disorders, anxiety disorders, alcohol or substance use disorders, or hospitalization during the ECT treatment period.

Potential reasons for the increased relapse risk among individuals with MDD and BPD include the younger age of the individuals with BPD, which has been shown to increase MDD relapse risk; the direct negative impact of BPD on mental functioning; and the documented tendency to poor treatment adherence, the researchers wrote in their discussion.

“Given these different elements, it seems important to screen more systematically for BPD in major depressed individuals treated with ECT in order to allow the implementation of more effective prevention strategies for relapse within 6 months in this particular subpopulation,” they emphasized.

“The demonstration of this higher risk of relapse within 6 months associated with BPD in major depressed individuals treated with ECT could open new therapeutic perspectives to allow better maintenance of euthymia in this particular subpopulation,” they added.

The study findings were limited by several factors including the retrospective design and the focus on only BPD, which may not generalize to other personality disorders, the researchers noted.

However, the results support data from previous studies and highlight the need for more systematic BPD screening in MDD patients to prevent relapse after ECT, they said.

The study received no outside funding. The researchers had no financial conflicts to disclose.
 

Borderline personality disorder was significantly associated with relapse after 6 months in adults with major depressive disorder who underwent electroconvulsive therapy (ECT), based on data from 109 individuals.

ECT has demonstrated effectiveness for treatment of unipolar and bipolar major depression, but relapses within 6 months are frequent, and potential factors affecting relapse have not been well studied, wrote Matthieu Hein, MD, PhD, of Erasme Hospital, Université Libre de Bruxelles, and colleagues.

Borderline personality disorder (BPD) is a common comorbidity among individuals with major depressive disorder, and previous research suggests a possible negative effect of BPD on ECT response in MDD patients, they wrote.

In a study published in Psychiatry Research, the researchers recruited 68 females and 41 males aged 18 years and older with diagnosed MDD who had partial or complete response to ECT after receiving treatment at a single center. Approximately two-thirds of the patients were aged 50 years and older, and 22 met criteria for BPD. The ECT consisted of three sessions per week; the total number of sessions ranged from 6 to 18.

The primary outcome was relapse at 6 months after ECT treatment. Relapse was defined as a score of 16 or higher on the Hamilton Depression Rating Scale in combination with a mean absolute increase of at least 10 points from the psychiatric interview at the end of the ECT.

Relapse rates at 6 months were 37.6% for the study population overall, but significantly higher for those with BPD, compared with those without BPD (72.7% vs. 28.7%; P < .001).

In a multivariate analysis, adjusting for age, gender, and mood stabilizer use after ECT, relapse was approximately four times more likely among individuals with BPD, compared with those without (hazard ratio, 4.14). No significant association appeared between increased relapse and other comorbid personality disorders, anxiety disorders, alcohol or substance use disorders, or hospitalization during the ECT treatment period.

Potential reasons for the increased relapse risk among individuals with MDD and BPD include the younger age of the individuals with BPD, which has been shown to increase MDD relapse risk; the direct negative impact of BPD on mental functioning; and the documented tendency to poor treatment adherence, the researchers wrote in their discussion.

“Given these different elements, it seems important to screen more systematically for BPD in major depressed individuals treated with ECT in order to allow the implementation of more effective prevention strategies for relapse within 6 months in this particular subpopulation,” they emphasized.

“The demonstration of this higher risk of relapse within 6 months associated with BPD in major depressed individuals treated with ECT could open new therapeutic perspectives to allow better maintenance of euthymia in this particular subpopulation,” they added.

The study findings were limited by several factors including the retrospective design and the focus on only BPD, which may not generalize to other personality disorders, the researchers noted.

However, the results support data from previous studies and highlight the need for more systematic BPD screening in MDD patients to prevent relapse after ECT, they said.

The study received no outside funding. The researchers had no financial conflicts to disclose.
 

The Brief Psychiatric Rating Scale (BPRS) was an effective tool for measuring general and specific psychiatric symptoms across the diagnostic spectrum, based on data from 600 psychiatric inpatients.

“Current DSM and ICD diagnoses do not depict psychopathology accurately, therefore their validity in research and utility in clinical practice is questioned,” wrote Andreas B. Hofmann, PhD, of the University of Zürich and colleagues.

The BPRS was developed to assess changes in psychopathology across a range of severe psychiatric disorders, but its potential to assess symptoms in nonpsychotic disorders has not been explored, the researchers said.

In a study published in Psychiatry Research, the investigators analyzed data from 600 adult psychiatric inpatients divided equally into six diagnostic categories: alcohol use disorder, major depressive disorder, anxiety disorders, bipolar disorder, schizophrenia, and personality disorders. The mean age of the patients was 41.5 years and 45.5% were women. The demographic characteristics were similar across most groups, although patients with a personality disorder were significantly more likely than other patients to be younger and female.

Patients were assessed using the BPRS based on their main diagnosis. The mini-ICF-APP, another validated measure for assessing psychiatric disorders, served as a comparator, and both were compared to the Clinical Global Impression Scale (CGI).

Overall, the BPRS and mini-ICF-APP showed moderate correlation and good agreement, the researchers said. The Pearson correlation coefficient for the BPRS and mini-ICF-APP scales was 0.53 and the concordance correlation coefficient was 0.52. The mean sum scores for the BPRS, the mini-ICF-APP, and the CGI were 45.4 (standard deviation, 14.4), 19.93 (SD, 8.21), and 5.55 (SD, 0.84), respectively, which indicated “markedly ill” to “severely ill” patients, the researchers said.

The researchers were able to detect three clusters of symptoms corresponding to externalizing, internalizing, and thought disturbance domains using the BPRS, and four clusters using the mini-ICF-APP.

The symptoms using BPRS and the functionality domains using the mini-ICF-APP “showed a close interplay,” the researchers noted.

“The symptoms and functional domains we found to be central within the network structure are among the first targets of any psychiatric or psychotherapeutic intervention, namely the building of a common language and understanding as well as the establishment of confidence in relationships and a trustworthy therapeutic alliance,” they wrote in their discussion.

The study findings were limited by several factors including the collection of data from routine practice rather than clinical trials, the focus on only the main diagnosis without comorbidities, and the inclusion only of patients requiring hospitalization, the researchers noted.

However, the results were strengthened by the large sample size, and demonstrate the validity of the BPRS as a measurement tool across a range of psychiatric diagnoses, they said.

“Since the BPRS is a widely known and readily available psychometric scale, our results support its use as a transdiagnostic measurement instrument of psychopathology,” they concluded.

The study received no outside funding. The researchers had no financial conflicts to disclose.

The Brief Psychiatric Rating Scale (BPRS) was an effective tool for measuring general and specific psychiatric symptoms across the diagnostic spectrum, based on data from 600 psychiatric inpatients.

“Current DSM and ICD diagnoses do not depict psychopathology accurately, therefore their validity in research and utility in clinical practice is questioned,” wrote Andreas B. Hofmann, PhD, of the University of Zürich and colleagues.

The BPRS was developed to assess changes in psychopathology across a range of severe psychiatric disorders, but its potential to assess symptoms in nonpsychotic disorders has not been explored, the researchers said.

In a study published in Psychiatry Research, the investigators analyzed data from 600 adult psychiatric inpatients divided equally into six diagnostic categories: alcohol use disorder, major depressive disorder, anxiety disorders, bipolar disorder, schizophrenia, and personality disorders. The mean age of the patients was 41.5 years and 45.5% were women. The demographic characteristics were similar across most groups, although patients with a personality disorder were significantly more likely than other patients to be younger and female.

Patients were assessed using the BPRS based on their main diagnosis. The mini-ICF-APP, another validated measure for assessing psychiatric disorders, served as a comparator, and both were compared to the Clinical Global Impression Scale (CGI).

Overall, the BPRS and mini-ICF-APP showed moderate correlation and good agreement, the researchers said. The Pearson correlation coefficient for the BPRS and mini-ICF-APP scales was 0.53 and the concordance correlation coefficient was 0.52. The mean sum scores for the BPRS, the mini-ICF-APP, and the CGI were 45.4 (standard deviation, 14.4), 19.93 (SD, 8.21), and 5.55 (SD, 0.84), respectively, which indicated “markedly ill” to “severely ill” patients, the researchers said.

The researchers were able to detect three clusters of symptoms corresponding to externalizing, internalizing, and thought disturbance domains using the BPRS, and four clusters using the mini-ICF-APP.

The symptoms using BPRS and the functionality domains using the mini-ICF-APP “showed a close interplay,” the researchers noted.

“The symptoms and functional domains we found to be central within the network structure are among the first targets of any psychiatric or psychotherapeutic intervention, namely the building of a common language and understanding as well as the establishment of confidence in relationships and a trustworthy therapeutic alliance,” they wrote in their discussion.

The study findings were limited by several factors including the collection of data from routine practice rather than clinical trials, the focus on only the main diagnosis without comorbidities, and the inclusion only of patients requiring hospitalization, the researchers noted.

However, the results were strengthened by the large sample size, and demonstrate the validity of the BPRS as a measurement tool across a range of psychiatric diagnoses, they said.

“Since the BPRS is a widely known and readily available psychometric scale, our results support its use as a transdiagnostic measurement instrument of psychopathology,” they concluded.

The study received no outside funding. The researchers had no financial conflicts to disclose.

The Brief Psychiatric Rating Scale (BPRS) was an effective tool for measuring general and specific psychiatric symptoms across the diagnostic spectrum, based on data from 600 psychiatric inpatients.

“Current DSM and ICD diagnoses do not depict psychopathology accurately, therefore their validity in research and utility in clinical practice is questioned,” wrote Andreas B. Hofmann, PhD, of the University of Zürich and colleagues.

The BPRS was developed to assess changes in psychopathology across a range of severe psychiatric disorders, but its potential to assess symptoms in nonpsychotic disorders has not been explored, the researchers said.

In a study published in Psychiatry Research, the investigators analyzed data from 600 adult psychiatric inpatients divided equally into six diagnostic categories: alcohol use disorder, major depressive disorder, anxiety disorders, bipolar disorder, schizophrenia, and personality disorders. The mean age of the patients was 41.5 years and 45.5% were women. The demographic characteristics were similar across most groups, although patients with a personality disorder were significantly more likely than other patients to be younger and female.

Patients were assessed using the BPRS based on their main diagnosis. The mini-ICF-APP, another validated measure for assessing psychiatric disorders, served as a comparator, and both were compared to the Clinical Global Impression Scale (CGI).

Overall, the BPRS and mini-ICF-APP showed moderate correlation and good agreement, the researchers said. The Pearson correlation coefficient for the BPRS and mini-ICF-APP scales was 0.53 and the concordance correlation coefficient was 0.52. The mean sum scores for the BPRS, the mini-ICF-APP, and the CGI were 45.4 (standard deviation, 14.4), 19.93 (SD, 8.21), and 5.55 (SD, 0.84), respectively, which indicated “markedly ill” to “severely ill” patients, the researchers said.

The researchers were able to detect three clusters of symptoms corresponding to externalizing, internalizing, and thought disturbance domains using the BPRS, and four clusters using the mini-ICF-APP.

The symptoms using BPRS and the functionality domains using the mini-ICF-APP “showed a close interplay,” the researchers noted.

“The symptoms and functional domains we found to be central within the network structure are among the first targets of any psychiatric or psychotherapeutic intervention, namely the building of a common language and understanding as well as the establishment of confidence in relationships and a trustworthy therapeutic alliance,” they wrote in their discussion.

The study findings were limited by several factors including the collection of data from routine practice rather than clinical trials, the focus on only the main diagnosis without comorbidities, and the inclusion only of patients requiring hospitalization, the researchers noted.

However, the results were strengthened by the large sample size, and demonstrate the validity of the BPRS as a measurement tool across a range of psychiatric diagnoses, they said.

“Since the BPRS is a widely known and readily available psychometric scale, our results support its use as a transdiagnostic measurement instrument of psychopathology,” they concluded.

The study received no outside funding. The researchers had no financial conflicts to disclose.

The U.S. Food and Drug Administration has approved the first oral N-methyl D-aspartate (NMDA) receptor antagonist for the treatment of major depressive disorder (MDD) in adults, its manufacturer has announced.

Auvelity (Axsome Therapeutics) is a proprietary extended-release oral tablet containing dextromethorphan (45 mg) and bupropion (105 mg).

It is the “first and only rapid-acting oral medicine approved for the treatment of MDD with labeling of statistically significant antidepressant efficacy compared to placebo starting at one week,” the company said in a news release.

“The approval of Auvelity represents a milestone in depression treatment based on its novel oral NMDA antagonist mechanism, its rapid antidepressant efficacy demonstrated in controlled trials, and a relatively favorable safety profile,” Maurizio Fava, MD, psychiatrist-in-chief, Massachusetts General Hospital, Boston, added in the release. 
 

‘Milestone’ in depression treatment?

Dr. Fava noted that nearly two-thirds of patients treated with currently available antidepressants fail to respond adequately, and those who do may not achieve clinically meaningful responses for up to 6-8 weeks.

“Given the debilitating nature of depression, the efficacy of Auvelity observed at 1 week and sustained thereafter may have a significant impact on the current treatment paradigm for this condition,” he said.

The company noted the drug was studied in a comprehensive clinical program that included more than 1,100 patients with MDD.

The efficacy of the drug was demonstrated in the GEMINI placebo-controlled study – with confirmatory evidence provided by the ASCEND study, which  compared it with bupropion sustained-release tablets.

Axsome said it expects to launch the new oral medication in the fourth quarter of this year. It is not approved for use in children.

The full prescribing information and medication guide are available online.

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

The U.S. Food and Drug Administration has approved the first oral N-methyl D-aspartate (NMDA) receptor antagonist for the treatment of major depressive disorder (MDD) in adults, its manufacturer has announced.

Auvelity (Axsome Therapeutics) is a proprietary extended-release oral tablet containing dextromethorphan (45 mg) and bupropion (105 mg).

It is the “first and only rapid-acting oral medicine approved for the treatment of MDD with labeling of statistically significant antidepressant efficacy compared to placebo starting at one week,” the company said in a news release.

“The approval of Auvelity represents a milestone in depression treatment based on its novel oral NMDA antagonist mechanism, its rapid antidepressant efficacy demonstrated in controlled trials, and a relatively favorable safety profile,” Maurizio Fava, MD, psychiatrist-in-chief, Massachusetts General Hospital, Boston, added in the release. 
 

‘Milestone’ in depression treatment?

Dr. Fava noted that nearly two-thirds of patients treated with currently available antidepressants fail to respond adequately, and those who do may not achieve clinically meaningful responses for up to 6-8 weeks.

“Given the debilitating nature of depression, the efficacy of Auvelity observed at 1 week and sustained thereafter may have a significant impact on the current treatment paradigm for this condition,” he said.

The company noted the drug was studied in a comprehensive clinical program that included more than 1,100 patients with MDD.

The efficacy of the drug was demonstrated in the GEMINI placebo-controlled study – with confirmatory evidence provided by the ASCEND study, which  compared it with bupropion sustained-release tablets.

Axsome said it expects to launch the new oral medication in the fourth quarter of this year. It is not approved for use in children.

The full prescribing information and medication guide are available online.

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

The U.S. Food and Drug Administration has approved the first oral N-methyl D-aspartate (NMDA) receptor antagonist for the treatment of major depressive disorder (MDD) in adults, its manufacturer has announced.

Auvelity (Axsome Therapeutics) is a proprietary extended-release oral tablet containing dextromethorphan (45 mg) and bupropion (105 mg).

It is the “first and only rapid-acting oral medicine approved for the treatment of MDD with labeling of statistically significant antidepressant efficacy compared to placebo starting at one week,” the company said in a news release.

“The approval of Auvelity represents a milestone in depression treatment based on its novel oral NMDA antagonist mechanism, its rapid antidepressant efficacy demonstrated in controlled trials, and a relatively favorable safety profile,” Maurizio Fava, MD, psychiatrist-in-chief, Massachusetts General Hospital, Boston, added in the release. 
 

‘Milestone’ in depression treatment?

Dr. Fava noted that nearly two-thirds of patients treated with currently available antidepressants fail to respond adequately, and those who do may not achieve clinically meaningful responses for up to 6-8 weeks.

“Given the debilitating nature of depression, the efficacy of Auvelity observed at 1 week and sustained thereafter may have a significant impact on the current treatment paradigm for this condition,” he said.

The company noted the drug was studied in a comprehensive clinical program that included more than 1,100 patients with MDD.

The efficacy of the drug was demonstrated in the GEMINI placebo-controlled study – with confirmatory evidence provided by the ASCEND study, which  compared it with bupropion sustained-release tablets.

Axsome said it expects to launch the new oral medication in the fourth quarter of this year. It is not approved for use in children.

The full prescribing information and medication guide are available online.

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