Major Depressive Disorder

Mothers who have a family history of any psychiatric disorder have almost two times the risk of postpartum depression as do mothers without such history, according to a new study.

Mette-Marie Zacher Kjeldsen, MSc, with the National Centre for Register-based Research at Aarhus (Denmark) University, led the study, a meta-analysis that included 26 studies with information on 100,877 women.

Findings were published online in JAMA Psychiatry.

When mothers had a family history of psychiatric disorders, the odds ratio for PPD was 2.08 (95% confidence interval, 1.67-2.59). That corresponds to a risk ratio of 1.79 (95% CI, 1.52-2.09), assuming a 15% postpartum depression prevalence in the general population.
 

Not doomed to develop PPD

Polina Teslyar, MD, a perinatal psychiatrist at Brigham and Women’s Hospital in Boston told this news organization it’s important to point out that though the risk is higher, women with a family psychiatric history should not feel as though they are destined to develop PPD.

“You are still more likely to not have postpartum depression, but it is important to be aware of personal risk factors so that if a person is experiencing that, they ask for help quickly rather than suffering and not knowing something is amiss,” she emphasized. Dr. Teslyar says she does see the higher risk for PPD, which is preventable and treatable, in her own practice when women have had a family history of psychiatric disorders.

The association makes sense, but literature on why that is has been varied, she said, and likely involves both genetics and socioeconomic factors. It’s difficult to tease apart how big a part each plays.

In her perinatal practice she sees women even before they are pregnant to discuss risk factors for PPD so she does ask about family history of psychiatric disorders, specifically about history of PPD and anxiety.

The researchers suggest routine perinatal care should include an easy low-cost, two-part question about both personal and family history of psychiatric disorders.

“As the assessment is possible even prior to conception, this would leave time for planning preventive efforts, such as psychosocial and psychological interventions targeting these at-risk women,” the authors write.
 

Asking about family history a challenge

Dr. Teslyar noted though that one of the challenges in asking about family history is that families may not have openly shared psychiatric history details with offspring. Family members may also report conditions they suspect a family member had rather than having a documented diagnosis.

In places where there is universal health care, she noted, finding documented diagnoses is easier, but otherwise “you’re really taking a subjective interpretation.”

The researchers found that subgroup, sensitivity, and meta–regression analyses aligned with the primary findings. The overall certainty of evidence was graded as moderate.

This study was not able to make clear how the specific diagnoses of family members affect the risk of developing PPD because much of the data from the studies came from self-report and questions were not consistent across the studies.

For instance, only 7 studies asked specifically about first-degree family members and 10 asked about specific diagnoses. Diagnoses ranged from mild affective disorders to more intrusive disorders, such as schizophrenia.

And while this study doesn’t seek to determine why the family history and risk of PPD appear to be connected, the authors offer some possible explanations.

“Growing up in an environment with parents struggling with mental health problems potentially influences the social support received from these parents when going into motherhood,” the authors write. “This particular explanation is supported by umbrella reviews concluding that lack of social support is a significant PPD risk factor.”

Screening, extraction, and assessment of studies included was done independently by two reviewers, increasing validity, the authors note.

The authors state that approximately 10%-15% of new mothers experience PPD, but Dr. Teslyar points out the numbers in the United States are typically quoted at up to 20%-30%. PPD ranges from mild to severe episodes and includes symptoms like those for major depression outside the postpartum period.

Study authors received funding from The Lundbeck Foundation and the European Union’s Horizon 2020 Research and Innovation Programme. A coauthor, Vibe G. Frokjaer, MD, PhD, has served as consultant and lecturer for H. Lundbeck and Sage Therapeutics. No other disclosures were reported. Dr. Teslyar reports no relevant financial relationships.

Mothers who have a family history of any psychiatric disorder have almost two times the risk of postpartum depression as do mothers without such history, according to a new study.

Mette-Marie Zacher Kjeldsen, MSc, with the National Centre for Register-based Research at Aarhus (Denmark) University, led the study, a meta-analysis that included 26 studies with information on 100,877 women.

Findings were published online in JAMA Psychiatry.

When mothers had a family history of psychiatric disorders, the odds ratio for PPD was 2.08 (95% confidence interval, 1.67-2.59). That corresponds to a risk ratio of 1.79 (95% CI, 1.52-2.09), assuming a 15% postpartum depression prevalence in the general population.
 

Not doomed to develop PPD

Polina Teslyar, MD, a perinatal psychiatrist at Brigham and Women’s Hospital in Boston told this news organization it’s important to point out that though the risk is higher, women with a family psychiatric history should not feel as though they are destined to develop PPD.

“You are still more likely to not have postpartum depression, but it is important to be aware of personal risk factors so that if a person is experiencing that, they ask for help quickly rather than suffering and not knowing something is amiss,” she emphasized. Dr. Teslyar says she does see the higher risk for PPD, which is preventable and treatable, in her own practice when women have had a family history of psychiatric disorders.

The association makes sense, but literature on why that is has been varied, she said, and likely involves both genetics and socioeconomic factors. It’s difficult to tease apart how big a part each plays.

In her perinatal practice she sees women even before they are pregnant to discuss risk factors for PPD so she does ask about family history of psychiatric disorders, specifically about history of PPD and anxiety.

The researchers suggest routine perinatal care should include an easy low-cost, two-part question about both personal and family history of psychiatric disorders.

“As the assessment is possible even prior to conception, this would leave time for planning preventive efforts, such as psychosocial and psychological interventions targeting these at-risk women,” the authors write.
 

Asking about family history a challenge

Dr. Teslyar noted though that one of the challenges in asking about family history is that families may not have openly shared psychiatric history details with offspring. Family members may also report conditions they suspect a family member had rather than having a documented diagnosis.

In places where there is universal health care, she noted, finding documented diagnoses is easier, but otherwise “you’re really taking a subjective interpretation.”

The researchers found that subgroup, sensitivity, and meta–regression analyses aligned with the primary findings. The overall certainty of evidence was graded as moderate.

This study was not able to make clear how the specific diagnoses of family members affect the risk of developing PPD because much of the data from the studies came from self-report and questions were not consistent across the studies.

For instance, only 7 studies asked specifically about first-degree family members and 10 asked about specific diagnoses. Diagnoses ranged from mild affective disorders to more intrusive disorders, such as schizophrenia.

And while this study doesn’t seek to determine why the family history and risk of PPD appear to be connected, the authors offer some possible explanations.

“Growing up in an environment with parents struggling with mental health problems potentially influences the social support received from these parents when going into motherhood,” the authors write. “This particular explanation is supported by umbrella reviews concluding that lack of social support is a significant PPD risk factor.”

Screening, extraction, and assessment of studies included was done independently by two reviewers, increasing validity, the authors note.

The authors state that approximately 10%-15% of new mothers experience PPD, but Dr. Teslyar points out the numbers in the United States are typically quoted at up to 20%-30%. PPD ranges from mild to severe episodes and includes symptoms like those for major depression outside the postpartum period.

Study authors received funding from The Lundbeck Foundation and the European Union’s Horizon 2020 Research and Innovation Programme. A coauthor, Vibe G. Frokjaer, MD, PhD, has served as consultant and lecturer for H. Lundbeck and Sage Therapeutics. No other disclosures were reported. Dr. Teslyar reports no relevant financial relationships.

Mothers who have a family history of any psychiatric disorder have almost two times the risk of postpartum depression as do mothers without such history, according to a new study.

Mette-Marie Zacher Kjeldsen, MSc, with the National Centre for Register-based Research at Aarhus (Denmark) University, led the study, a meta-analysis that included 26 studies with information on 100,877 women.

Findings were published online in JAMA Psychiatry.

When mothers had a family history of psychiatric disorders, the odds ratio for PPD was 2.08 (95% confidence interval, 1.67-2.59). That corresponds to a risk ratio of 1.79 (95% CI, 1.52-2.09), assuming a 15% postpartum depression prevalence in the general population.
 

Not doomed to develop PPD

Polina Teslyar, MD, a perinatal psychiatrist at Brigham and Women’s Hospital in Boston told this news organization it’s important to point out that though the risk is higher, women with a family psychiatric history should not feel as though they are destined to develop PPD.

“You are still more likely to not have postpartum depression, but it is important to be aware of personal risk factors so that if a person is experiencing that, they ask for help quickly rather than suffering and not knowing something is amiss,” she emphasized. Dr. Teslyar says she does see the higher risk for PPD, which is preventable and treatable, in her own practice when women have had a family history of psychiatric disorders.

The association makes sense, but literature on why that is has been varied, she said, and likely involves both genetics and socioeconomic factors. It’s difficult to tease apart how big a part each plays.

In her perinatal practice she sees women even before they are pregnant to discuss risk factors for PPD so she does ask about family history of psychiatric disorders, specifically about history of PPD and anxiety.

The researchers suggest routine perinatal care should include an easy low-cost, two-part question about both personal and family history of psychiatric disorders.

“As the assessment is possible even prior to conception, this would leave time for planning preventive efforts, such as psychosocial and psychological interventions targeting these at-risk women,” the authors write.
 

Asking about family history a challenge

Dr. Teslyar noted though that one of the challenges in asking about family history is that families may not have openly shared psychiatric history details with offspring. Family members may also report conditions they suspect a family member had rather than having a documented diagnosis.

In places where there is universal health care, she noted, finding documented diagnoses is easier, but otherwise “you’re really taking a subjective interpretation.”

The researchers found that subgroup, sensitivity, and meta–regression analyses aligned with the primary findings. The overall certainty of evidence was graded as moderate.

This study was not able to make clear how the specific diagnoses of family members affect the risk of developing PPD because much of the data from the studies came from self-report and questions were not consistent across the studies.

For instance, only 7 studies asked specifically about first-degree family members and 10 asked about specific diagnoses. Diagnoses ranged from mild affective disorders to more intrusive disorders, such as schizophrenia.

And while this study doesn’t seek to determine why the family history and risk of PPD appear to be connected, the authors offer some possible explanations.

“Growing up in an environment with parents struggling with mental health problems potentially influences the social support received from these parents when going into motherhood,” the authors write. “This particular explanation is supported by umbrella reviews concluding that lack of social support is a significant PPD risk factor.”

Screening, extraction, and assessment of studies included was done independently by two reviewers, increasing validity, the authors note.

The authors state that approximately 10%-15% of new mothers experience PPD, but Dr. Teslyar points out the numbers in the United States are typically quoted at up to 20%-30%. PPD ranges from mild to severe episodes and includes symptoms like those for major depression outside the postpartum period.

Study authors received funding from The Lundbeck Foundation and the European Union’s Horizon 2020 Research and Innovation Programme. A coauthor, Vibe G. Frokjaer, MD, PhD, has served as consultant and lecturer for H. Lundbeck and Sage Therapeutics. No other disclosures were reported. Dr. Teslyar reports no relevant financial relationships.

Recent studies with hallucinogens have raised hopes for an effective drug-based therapy to treat chronic depression. At the German Congress of Psychosomatic Medicine and Psychotherapy, Torsten Passie, MD, PhD, professor of psychiatry and psychotherapy at the Hannover (Germay) Medical School, gave a presentation on the current state of psilocybin and ketamine/esketamine research.

Dr. Passie, who also is head physician of the specialist unit for addiction and addiction prevention at the Diakonisches Werk in Hannover, has been investigating hallucinogenic substances and their application in psychotherapy for decades.

New therapies sought

In depression, gloom extends beyond the patient’s mood. For some time there has been little cause for joy with regard to chronic depression therapy. Established drug therapies hardly perform any better than placebo in meta-analyses, as a study recently confirmed. The pharmaceutical industry pulled out of psycho-pharmaceutical development more than 10 years ago. What’s more, the number of cases is rising, especially among young people, and there are long waiting times for psychotherapy appointments.

It is no wonder that some are welcoming new drug-based approaches with lysergic acid diethylamide (LSD)–like hallucinogens. In 2016, a study on psilocybin was published in The Lancet Psychiatry, although the study was unblinded and included only 24 patients.
 

Evoking emotions

A range of substances can be classed as hallucinogens, including psilocybin, mescaline, LSD, 3,4-methylenedioxy-methamphetamine (MDMA, also known as ecstasy), and ketamine.

Taking hallucinogens can cause a release of serotonin and dopamine, an increase in activity levels in the brain, a shift in stimulus filtering, an increase in the production of internal stimuli (inner experiences), and a change in sensory integration (for example, synesthesia).

Besides falling into a dreamlike state, patients can achieve an expansion or narrowing of consciousness if they focus on an inner experience. Internal perception increases. Perceptual routines are broken apart. Thought processes become more image-based and are more associative than normal.

Patients therefore are more capable of making new and unusual connections between different biographical or current situations. Previously unconscious ideas can become conscious. At higher doses, ego loss can occur, which can be associated with a mystical feeling of connectedness.

Hallucinogens mainly evoke and heighten emotions. Those effects may be experienced strongly as internal visions or in physical manifestations (for example, crying or laughing). In contrast, conventional antidepressants work by suppressing emotions (that is, emotional blunting).

These different mechanisms result in two contrasting management strategies. For example, SSRI antidepressants cause a patient to perceive workplace bullying as less severe and to do nothing to change the situation; the patient remains passive.

In contrast, a therapeutically guided, emotionally activating experience on hallucinogens can help the patient to try more actively to change the stressful situation.

Ketamine has a special place among hallucinogens. Unlike other hallucinogens, ketamine causes a strong clouding of consciousness, a reduction in physical sensory perception, and significant disruption in thinking and memory. It is therefore only suitable as a short-term intervention and is therapeutically impractical over the long term.
 

Ketamine’s effects

Ketamine, a racemic mixture of the enantiomers S-ketamine and R-ketamine, was originally used only as an analgesic and anesthetic. Owing to its rapid antidepressant effect, it has since also been used as an emergency medication for severe depression, sometimes in combination with SSRIs or serotonin noradrenaline reuptake inhibitors.

Approximately 60% of patients respond to the treatment. Whereas with conventional antidepressants, onset of action requires 10-14 days, ketamine is effective within a few hours. However, relapse always occurs, usually very quickly. After 2-3 days, the effect is usually approximately that of a placebo. An administration interval of about 2 days is optimal. However, “resistance” to the effect often develops after some time: the drug’s antidepressant effect diminishes.

Ketamine also has some unpleasant side effects, such as depersonalization, dissociation, impaired thinking, nystagmus, and psychotomimetic effects. Nausea and vomiting also occur. Interestingly, the latter does not bother the patient much, owing to the drug’s psychological effects, and it does not lead to treatment discontinuation, said Dr. Passie, who described his clinical experiences with ketamine.

Since ketamine causes a considerable clouding of consciousness, sensory disorders, and significant memory problems, it is not suitable for psychedelic-assisted psychotherapy, unlike LSD or psilocybin, he emphasized.
 

Ketamine 2.0?

Esketamine, the pure S-enantiomer of ketamine, has been on the market since 2019 in the form of a nasal spray (Spravato). Esketamine has been approved in combination with oral antidepressant therapy for adults with a moderate to severe episode of major depression for acute treatment of a psychiatric emergency.

A meta-analysis from 2022 concluded that the original racemic ketamine is better than the new esketamine in reducing symptoms of depression.

In his own comprehensive study, Dr. Passie concluded that the mental impairments that occur during therapy did not differ significantly between substances. The patients even felt that the side effects from esketamine therapy were much more mentally unpleasant, said Dr. Passie. He concluded that the R-enantiomer may have a kind of protective effect against some of the psychopathological effects of the S-enantiomer (esketamine).

In addition, preclinical studies have indicated that the antidepressant effects of R-enantiomer, which is not contained in esketamine, are longer lasting and stronger.

Another problem is absorption, which can be inconsistent with a nasal spray. It may differ, for example, depending on the ambient humidity or whether the patient has recently had a cold. In addition, the spray is far more expensive than the ketamine injection, said Dr. Passie. Patients must also use the nasal spray under supervision at a medical practice (as with the intravenous application) and must receive follow-up care there. It therefore offers no advantage over the ketamine injection.

According to the Institute for Quality and Efficiency in Healthcare, no additional benefit has been proven for esketamine over standard therapies for adults who have experienced a moderate to severe depressive episode when used as short-term treatment for the rapid reduction of depressive symptoms in a psychiatric emergency. The German Medical Association agreed with this evaluation in October 2021.

In the United Kingdom, the medication was never approved, owing to the fact that it was too expensive and that no studies comparing it with psychotherapy were available.
 

Add-on psilocybin?

While ketamine is only suitable for acute intervention, owing to the short duration of effect, the effects of psilocybin can last for weeks or even months following administration, and this has been seen in more than just a few patients. What was experienced under the influence of psilocybin can also be subsequently processed and used in psychotherapy.

The acute effect of psilocybin begins after approximately 40 minutes and lasts for 4-6 hours. The antidepressant effect, if it occurs at all, is of immediate onset. Unlike ketamine/esketamine, psilocybin hardly has any physical side effects.

The neurologic mechanism of action has been investigated recently using fMRI and PET techniques. According to the investigations, the substance causes individual networks of activity in the patient’s brain to interconnect more strongly, said Dr. Passie. The thalamus, the filter station for sensory information, as well as the limbic and paralimbic structures, which generate emotions, and the cortex are all activated more strongly.
 

Two therapeutic settings

Psilocybin, at least in the context of studies, is used in two settings: psycholytic therapy and psychedelic therapy. Both settings originated in the 1950s and were also used with LSD as the active substance.

Psycholytic therapy with psilocybin entails multiple administrations at low doses (for example, 10-18 mg), incorporated into a longer, mostly psychodynamic therapy of around 50-100 hours (often on an inpatient basis at the beginning). It results in what is described as an extended encounter with oneself. The focus is on psychodynamic experiences, such as memories and internal conflicts. In addition, novel experiences with oneself and self-recognition are important.

Psychedelic therapy generally entails one or two sessions with a high dose (for example, 25-35 mg psilocybin). The preparation and follow-up are limited to a few sessions. These methods refer to so-called transpersonal psychology, which addresses extraordinary states of consciousness in line with religious experiences. It often leads to an intense self-confrontation as well as to new evaluations of self and world. The central element to this therapy is the experience of a mystical ego loss and the concomitant feeling of connectedness, which should help to expand one’s perspective.
 

Euphoria and disillusionment

The first promising studies with a few patients suffering from depression were followed by others in which the euphoria was allowed to fade away somewhat. In the first direct comparison in a methodically high-grade double-blind study, psilocybin was inferior to the SSRI antidepressant escitalopram.

“There is a great variation in response from person to person,” said Dr. Passie. “The better the study is methodically controlled, the worse the results,” he hypothesized.

“Since the method is up to 50 times more expensive in practice, compared to SSRI therapy over 6-12 weeks, the question clearly must be asked as to whether it really has any great future.”
 

Outlook for psilocybin

Nevertheless, Dr. Passie still sees potential in psilocybin. He considers an approach in which psilocybin therapy is more firmly incorporated into psychotherapy, with between four and 10 therapy sessions before and after administration of a lower therapeutic dose of the substance, to be more promising.

“With this kind of intensive preparation and follow-up, as well as the repeated psilocybin sessions, the patient can benefit much more than is possible with one or two high-dose sessions,” said Dr. Passie, who also is chair of the International Society for Substance-Assisted Psychotherapy. “The constant ‘in-depth work on the ego’ required for drastic therapeutic changes can be more effective and lead to permanent improvements. I have no doubt about this.”

In Dr. Passie’s opinion, the best approach would involve a dignified inpatient setting with a longer period of follow-up care and consistent posttreatment care, including group therapy. The shape of future psilocybin therapy depends on whether the rather abrupt change seen with high-dose psychedelic therapy is permanent. The answer to this question will be decisive for the method and manner of its future clinical use.

Because of the somewhat negative study results, however, the initial investors are pulling out. Dr. Passie is therefore skeptical about whether the necessary larger studies will take place and whether psilocybin will make it onto the market.

In Switzerland, which is not subject to EU restrictions, more than 30 physicians have been authorized to use psilocybin, LSD, and MDMA in psychotherapy sessions. Still, in some respects this is a special case that cannot be transferred easily to other countries, said Dr. Passie.
 

Possible psilocybin improvement?

Various chemical derivatives of psychoactive substances have been researched, including a psilocybin variant with the label CYB003. With CYB003, the length of the acute psychedelic experience is reduced from around 6 hours (such as with psilocybin) to 1 hour. The plasma concentration of the substance is less variable between different patients. It is assumed that its effects will also differ less from person to person.

In July, researchers began a study of the use of CYB003 in the treatment of major depression. In the randomized, double-blind, placebo-controlled study with 40 patients, multiple doses of the substance will be administered.

When asked, Dr. Passie was rather skeptical about the study. He considers the approaches with psilocybin derivatives to be the consequences of a “gold-rush atmosphere” and expects there will be no real additional benefit, especially not a reduction in the period of action.

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

Recent studies with hallucinogens have raised hopes for an effective drug-based therapy to treat chronic depression. At the German Congress of Psychosomatic Medicine and Psychotherapy, Torsten Passie, MD, PhD, professor of psychiatry and psychotherapy at the Hannover (Germay) Medical School, gave a presentation on the current state of psilocybin and ketamine/esketamine research.

Dr. Passie, who also is head physician of the specialist unit for addiction and addiction prevention at the Diakonisches Werk in Hannover, has been investigating hallucinogenic substances and their application in psychotherapy for decades.

New therapies sought

In depression, gloom extends beyond the patient’s mood. For some time there has been little cause for joy with regard to chronic depression therapy. Established drug therapies hardly perform any better than placebo in meta-analyses, as a study recently confirmed. The pharmaceutical industry pulled out of psycho-pharmaceutical development more than 10 years ago. What’s more, the number of cases is rising, especially among young people, and there are long waiting times for psychotherapy appointments.

It is no wonder that some are welcoming new drug-based approaches with lysergic acid diethylamide (LSD)–like hallucinogens. In 2016, a study on psilocybin was published in The Lancet Psychiatry, although the study was unblinded and included only 24 patients.
 

Evoking emotions

A range of substances can be classed as hallucinogens, including psilocybin, mescaline, LSD, 3,4-methylenedioxy-methamphetamine (MDMA, also known as ecstasy), and ketamine.

Taking hallucinogens can cause a release of serotonin and dopamine, an increase in activity levels in the brain, a shift in stimulus filtering, an increase in the production of internal stimuli (inner experiences), and a change in sensory integration (for example, synesthesia).

Besides falling into a dreamlike state, patients can achieve an expansion or narrowing of consciousness if they focus on an inner experience. Internal perception increases. Perceptual routines are broken apart. Thought processes become more image-based and are more associative than normal.

Patients therefore are more capable of making new and unusual connections between different biographical or current situations. Previously unconscious ideas can become conscious. At higher doses, ego loss can occur, which can be associated with a mystical feeling of connectedness.

Hallucinogens mainly evoke and heighten emotions. Those effects may be experienced strongly as internal visions or in physical manifestations (for example, crying or laughing). In contrast, conventional antidepressants work by suppressing emotions (that is, emotional blunting).

These different mechanisms result in two contrasting management strategies. For example, SSRI antidepressants cause a patient to perceive workplace bullying as less severe and to do nothing to change the situation; the patient remains passive.

In contrast, a therapeutically guided, emotionally activating experience on hallucinogens can help the patient to try more actively to change the stressful situation.

Ketamine has a special place among hallucinogens. Unlike other hallucinogens, ketamine causes a strong clouding of consciousness, a reduction in physical sensory perception, and significant disruption in thinking and memory. It is therefore only suitable as a short-term intervention and is therapeutically impractical over the long term.
 

Ketamine’s effects

Ketamine, a racemic mixture of the enantiomers S-ketamine and R-ketamine, was originally used only as an analgesic and anesthetic. Owing to its rapid antidepressant effect, it has since also been used as an emergency medication for severe depression, sometimes in combination with SSRIs or serotonin noradrenaline reuptake inhibitors.

Approximately 60% of patients respond to the treatment. Whereas with conventional antidepressants, onset of action requires 10-14 days, ketamine is effective within a few hours. However, relapse always occurs, usually very quickly. After 2-3 days, the effect is usually approximately that of a placebo. An administration interval of about 2 days is optimal. However, “resistance” to the effect often develops after some time: the drug’s antidepressant effect diminishes.

Ketamine also has some unpleasant side effects, such as depersonalization, dissociation, impaired thinking, nystagmus, and psychotomimetic effects. Nausea and vomiting also occur. Interestingly, the latter does not bother the patient much, owing to the drug’s psychological effects, and it does not lead to treatment discontinuation, said Dr. Passie, who described his clinical experiences with ketamine.

Since ketamine causes a considerable clouding of consciousness, sensory disorders, and significant memory problems, it is not suitable for psychedelic-assisted psychotherapy, unlike LSD or psilocybin, he emphasized.
 

Ketamine 2.0?

Esketamine, the pure S-enantiomer of ketamine, has been on the market since 2019 in the form of a nasal spray (Spravato). Esketamine has been approved in combination with oral antidepressant therapy for adults with a moderate to severe episode of major depression for acute treatment of a psychiatric emergency.

A meta-analysis from 2022 concluded that the original racemic ketamine is better than the new esketamine in reducing symptoms of depression.

In his own comprehensive study, Dr. Passie concluded that the mental impairments that occur during therapy did not differ significantly between substances. The patients even felt that the side effects from esketamine therapy were much more mentally unpleasant, said Dr. Passie. He concluded that the R-enantiomer may have a kind of protective effect against some of the psychopathological effects of the S-enantiomer (esketamine).

In addition, preclinical studies have indicated that the antidepressant effects of R-enantiomer, which is not contained in esketamine, are longer lasting and stronger.

Another problem is absorption, which can be inconsistent with a nasal spray. It may differ, for example, depending on the ambient humidity or whether the patient has recently had a cold. In addition, the spray is far more expensive than the ketamine injection, said Dr. Passie. Patients must also use the nasal spray under supervision at a medical practice (as with the intravenous application) and must receive follow-up care there. It therefore offers no advantage over the ketamine injection.

According to the Institute for Quality and Efficiency in Healthcare, no additional benefit has been proven for esketamine over standard therapies for adults who have experienced a moderate to severe depressive episode when used as short-term treatment for the rapid reduction of depressive symptoms in a psychiatric emergency. The German Medical Association agreed with this evaluation in October 2021.

In the United Kingdom, the medication was never approved, owing to the fact that it was too expensive and that no studies comparing it with psychotherapy were available.
 

Add-on psilocybin?

While ketamine is only suitable for acute intervention, owing to the short duration of effect, the effects of psilocybin can last for weeks or even months following administration, and this has been seen in more than just a few patients. What was experienced under the influence of psilocybin can also be subsequently processed and used in psychotherapy.

The acute effect of psilocybin begins after approximately 40 minutes and lasts for 4-6 hours. The antidepressant effect, if it occurs at all, is of immediate onset. Unlike ketamine/esketamine, psilocybin hardly has any physical side effects.

The neurologic mechanism of action has been investigated recently using fMRI and PET techniques. According to the investigations, the substance causes individual networks of activity in the patient’s brain to interconnect more strongly, said Dr. Passie. The thalamus, the filter station for sensory information, as well as the limbic and paralimbic structures, which generate emotions, and the cortex are all activated more strongly.
 

Two therapeutic settings

Psilocybin, at least in the context of studies, is used in two settings: psycholytic therapy and psychedelic therapy. Both settings originated in the 1950s and were also used with LSD as the active substance.

Psycholytic therapy with psilocybin entails multiple administrations at low doses (for example, 10-18 mg), incorporated into a longer, mostly psychodynamic therapy of around 50-100 hours (often on an inpatient basis at the beginning). It results in what is described as an extended encounter with oneself. The focus is on psychodynamic experiences, such as memories and internal conflicts. In addition, novel experiences with oneself and self-recognition are important.

Psychedelic therapy generally entails one or two sessions with a high dose (for example, 25-35 mg psilocybin). The preparation and follow-up are limited to a few sessions. These methods refer to so-called transpersonal psychology, which addresses extraordinary states of consciousness in line with religious experiences. It often leads to an intense self-confrontation as well as to new evaluations of self and world. The central element to this therapy is the experience of a mystical ego loss and the concomitant feeling of connectedness, which should help to expand one’s perspective.
 

Euphoria and disillusionment

The first promising studies with a few patients suffering from depression were followed by others in which the euphoria was allowed to fade away somewhat. In the first direct comparison in a methodically high-grade double-blind study, psilocybin was inferior to the SSRI antidepressant escitalopram.

“There is a great variation in response from person to person,” said Dr. Passie. “The better the study is methodically controlled, the worse the results,” he hypothesized.

“Since the method is up to 50 times more expensive in practice, compared to SSRI therapy over 6-12 weeks, the question clearly must be asked as to whether it really has any great future.”
 

Outlook for psilocybin

Nevertheless, Dr. Passie still sees potential in psilocybin. He considers an approach in which psilocybin therapy is more firmly incorporated into psychotherapy, with between four and 10 therapy sessions before and after administration of a lower therapeutic dose of the substance, to be more promising.

“With this kind of intensive preparation and follow-up, as well as the repeated psilocybin sessions, the patient can benefit much more than is possible with one or two high-dose sessions,” said Dr. Passie, who also is chair of the International Society for Substance-Assisted Psychotherapy. “The constant ‘in-depth work on the ego’ required for drastic therapeutic changes can be more effective and lead to permanent improvements. I have no doubt about this.”

In Dr. Passie’s opinion, the best approach would involve a dignified inpatient setting with a longer period of follow-up care and consistent posttreatment care, including group therapy. The shape of future psilocybin therapy depends on whether the rather abrupt change seen with high-dose psychedelic therapy is permanent. The answer to this question will be decisive for the method and manner of its future clinical use.

Because of the somewhat negative study results, however, the initial investors are pulling out. Dr. Passie is therefore skeptical about whether the necessary larger studies will take place and whether psilocybin will make it onto the market.

In Switzerland, which is not subject to EU restrictions, more than 30 physicians have been authorized to use psilocybin, LSD, and MDMA in psychotherapy sessions. Still, in some respects this is a special case that cannot be transferred easily to other countries, said Dr. Passie.
 

Possible psilocybin improvement?

Various chemical derivatives of psychoactive substances have been researched, including a psilocybin variant with the label CYB003. With CYB003, the length of the acute psychedelic experience is reduced from around 6 hours (such as with psilocybin) to 1 hour. The plasma concentration of the substance is less variable between different patients. It is assumed that its effects will also differ less from person to person.

In July, researchers began a study of the use of CYB003 in the treatment of major depression. In the randomized, double-blind, placebo-controlled study with 40 patients, multiple doses of the substance will be administered.

When asked, Dr. Passie was rather skeptical about the study. He considers the approaches with psilocybin derivatives to be the consequences of a “gold-rush atmosphere” and expects there will be no real additional benefit, especially not a reduction in the period of action.

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

Recent studies with hallucinogens have raised hopes for an effective drug-based therapy to treat chronic depression. At the German Congress of Psychosomatic Medicine and Psychotherapy, Torsten Passie, MD, PhD, professor of psychiatry and psychotherapy at the Hannover (Germay) Medical School, gave a presentation on the current state of psilocybin and ketamine/esketamine research.

Dr. Passie, who also is head physician of the specialist unit for addiction and addiction prevention at the Diakonisches Werk in Hannover, has been investigating hallucinogenic substances and their application in psychotherapy for decades.

New therapies sought

In depression, gloom extends beyond the patient’s mood. For some time there has been little cause for joy with regard to chronic depression therapy. Established drug therapies hardly perform any better than placebo in meta-analyses, as a study recently confirmed. The pharmaceutical industry pulled out of psycho-pharmaceutical development more than 10 years ago. What’s more, the number of cases is rising, especially among young people, and there are long waiting times for psychotherapy appointments.

It is no wonder that some are welcoming new drug-based approaches with lysergic acid diethylamide (LSD)–like hallucinogens. In 2016, a study on psilocybin was published in The Lancet Psychiatry, although the study was unblinded and included only 24 patients.
 

Evoking emotions

A range of substances can be classed as hallucinogens, including psilocybin, mescaline, LSD, 3,4-methylenedioxy-methamphetamine (MDMA, also known as ecstasy), and ketamine.

Taking hallucinogens can cause a release of serotonin and dopamine, an increase in activity levels in the brain, a shift in stimulus filtering, an increase in the production of internal stimuli (inner experiences), and a change in sensory integration (for example, synesthesia).

Besides falling into a dreamlike state, patients can achieve an expansion or narrowing of consciousness if they focus on an inner experience. Internal perception increases. Perceptual routines are broken apart. Thought processes become more image-based and are more associative than normal.

Patients therefore are more capable of making new and unusual connections between different biographical or current situations. Previously unconscious ideas can become conscious. At higher doses, ego loss can occur, which can be associated with a mystical feeling of connectedness.

Hallucinogens mainly evoke and heighten emotions. Those effects may be experienced strongly as internal visions or in physical manifestations (for example, crying or laughing). In contrast, conventional antidepressants work by suppressing emotions (that is, emotional blunting).

These different mechanisms result in two contrasting management strategies. For example, SSRI antidepressants cause a patient to perceive workplace bullying as less severe and to do nothing to change the situation; the patient remains passive.

In contrast, a therapeutically guided, emotionally activating experience on hallucinogens can help the patient to try more actively to change the stressful situation.

Ketamine has a special place among hallucinogens. Unlike other hallucinogens, ketamine causes a strong clouding of consciousness, a reduction in physical sensory perception, and significant disruption in thinking and memory. It is therefore only suitable as a short-term intervention and is therapeutically impractical over the long term.
 

Ketamine’s effects

Ketamine, a racemic mixture of the enantiomers S-ketamine and R-ketamine, was originally used only as an analgesic and anesthetic. Owing to its rapid antidepressant effect, it has since also been used as an emergency medication for severe depression, sometimes in combination with SSRIs or serotonin noradrenaline reuptake inhibitors.

Approximately 60% of patients respond to the treatment. Whereas with conventional antidepressants, onset of action requires 10-14 days, ketamine is effective within a few hours. However, relapse always occurs, usually very quickly. After 2-3 days, the effect is usually approximately that of a placebo. An administration interval of about 2 days is optimal. However, “resistance” to the effect often develops after some time: the drug’s antidepressant effect diminishes.

Ketamine also has some unpleasant side effects, such as depersonalization, dissociation, impaired thinking, nystagmus, and psychotomimetic effects. Nausea and vomiting also occur. Interestingly, the latter does not bother the patient much, owing to the drug’s psychological effects, and it does not lead to treatment discontinuation, said Dr. Passie, who described his clinical experiences with ketamine.

Since ketamine causes a considerable clouding of consciousness, sensory disorders, and significant memory problems, it is not suitable for psychedelic-assisted psychotherapy, unlike LSD or psilocybin, he emphasized.
 

Ketamine 2.0?

Esketamine, the pure S-enantiomer of ketamine, has been on the market since 2019 in the form of a nasal spray (Spravato). Esketamine has been approved in combination with oral antidepressant therapy for adults with a moderate to severe episode of major depression for acute treatment of a psychiatric emergency.

A meta-analysis from 2022 concluded that the original racemic ketamine is better than the new esketamine in reducing symptoms of depression.

In his own comprehensive study, Dr. Passie concluded that the mental impairments that occur during therapy did not differ significantly between substances. The patients even felt that the side effects from esketamine therapy were much more mentally unpleasant, said Dr. Passie. He concluded that the R-enantiomer may have a kind of protective effect against some of the psychopathological effects of the S-enantiomer (esketamine).

In addition, preclinical studies have indicated that the antidepressant effects of R-enantiomer, which is not contained in esketamine, are longer lasting and stronger.

Another problem is absorption, which can be inconsistent with a nasal spray. It may differ, for example, depending on the ambient humidity or whether the patient has recently had a cold. In addition, the spray is far more expensive than the ketamine injection, said Dr. Passie. Patients must also use the nasal spray under supervision at a medical practice (as with the intravenous application) and must receive follow-up care there. It therefore offers no advantage over the ketamine injection.

According to the Institute for Quality and Efficiency in Healthcare, no additional benefit has been proven for esketamine over standard therapies for adults who have experienced a moderate to severe depressive episode when used as short-term treatment for the rapid reduction of depressive symptoms in a psychiatric emergency. The German Medical Association agreed with this evaluation in October 2021.

In the United Kingdom, the medication was never approved, owing to the fact that it was too expensive and that no studies comparing it with psychotherapy were available.
 

Add-on psilocybin?

While ketamine is only suitable for acute intervention, owing to the short duration of effect, the effects of psilocybin can last for weeks or even months following administration, and this has been seen in more than just a few patients. What was experienced under the influence of psilocybin can also be subsequently processed and used in psychotherapy.

The acute effect of psilocybin begins after approximately 40 minutes and lasts for 4-6 hours. The antidepressant effect, if it occurs at all, is of immediate onset. Unlike ketamine/esketamine, psilocybin hardly has any physical side effects.

The neurologic mechanism of action has been investigated recently using fMRI and PET techniques. According to the investigations, the substance causes individual networks of activity in the patient’s brain to interconnect more strongly, said Dr. Passie. The thalamus, the filter station for sensory information, as well as the limbic and paralimbic structures, which generate emotions, and the cortex are all activated more strongly.
 

Two therapeutic settings

Psilocybin, at least in the context of studies, is used in two settings: psycholytic therapy and psychedelic therapy. Both settings originated in the 1950s and were also used with LSD as the active substance.

Psycholytic therapy with psilocybin entails multiple administrations at low doses (for example, 10-18 mg), incorporated into a longer, mostly psychodynamic therapy of around 50-100 hours (often on an inpatient basis at the beginning). It results in what is described as an extended encounter with oneself. The focus is on psychodynamic experiences, such as memories and internal conflicts. In addition, novel experiences with oneself and self-recognition are important.

Psychedelic therapy generally entails one or two sessions with a high dose (for example, 25-35 mg psilocybin). The preparation and follow-up are limited to a few sessions. These methods refer to so-called transpersonal psychology, which addresses extraordinary states of consciousness in line with religious experiences. It often leads to an intense self-confrontation as well as to new evaluations of self and world. The central element to this therapy is the experience of a mystical ego loss and the concomitant feeling of connectedness, which should help to expand one’s perspective.
 

Euphoria and disillusionment

The first promising studies with a few patients suffering from depression were followed by others in which the euphoria was allowed to fade away somewhat. In the first direct comparison in a methodically high-grade double-blind study, psilocybin was inferior to the SSRI antidepressant escitalopram.

“There is a great variation in response from person to person,” said Dr. Passie. “The better the study is methodically controlled, the worse the results,” he hypothesized.

“Since the method is up to 50 times more expensive in practice, compared to SSRI therapy over 6-12 weeks, the question clearly must be asked as to whether it really has any great future.”
 

Outlook for psilocybin

Nevertheless, Dr. Passie still sees potential in psilocybin. He considers an approach in which psilocybin therapy is more firmly incorporated into psychotherapy, with between four and 10 therapy sessions before and after administration of a lower therapeutic dose of the substance, to be more promising.

“With this kind of intensive preparation and follow-up, as well as the repeated psilocybin sessions, the patient can benefit much more than is possible with one or two high-dose sessions,” said Dr. Passie, who also is chair of the International Society for Substance-Assisted Psychotherapy. “The constant ‘in-depth work on the ego’ required for drastic therapeutic changes can be more effective and lead to permanent improvements. I have no doubt about this.”

In Dr. Passie’s opinion, the best approach would involve a dignified inpatient setting with a longer period of follow-up care and consistent posttreatment care, including group therapy. The shape of future psilocybin therapy depends on whether the rather abrupt change seen with high-dose psychedelic therapy is permanent. The answer to this question will be decisive for the method and manner of its future clinical use.

Because of the somewhat negative study results, however, the initial investors are pulling out. Dr. Passie is therefore skeptical about whether the necessary larger studies will take place and whether psilocybin will make it onto the market.

In Switzerland, which is not subject to EU restrictions, more than 30 physicians have been authorized to use psilocybin, LSD, and MDMA in psychotherapy sessions. Still, in some respects this is a special case that cannot be transferred easily to other countries, said Dr. Passie.
 

Possible psilocybin improvement?

Various chemical derivatives of psychoactive substances have been researched, including a psilocybin variant with the label CYB003. With CYB003, the length of the acute psychedelic experience is reduced from around 6 hours (such as with psilocybin) to 1 hour. The plasma concentration of the substance is less variable between different patients. It is assumed that its effects will also differ less from person to person.

In July, researchers began a study of the use of CYB003 in the treatment of major depression. In the randomized, double-blind, placebo-controlled study with 40 patients, multiple doses of the substance will be administered.

When asked, Dr. Passie was rather skeptical about the study. He considers the approaches with psilocybin derivatives to be the consequences of a “gold-rush atmosphere” and expects there will be no real additional benefit, especially not a reduction in the period of action.

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

The last 15 years have brought increased effort to screen for postpartum psychiatric illness. That’s exceedingly welcome given the morbidity and potential mortality associated with postpartum psychiatric disorders across the country.

From small community hospitals to major academic centers, screening for postpartum depression is part of the clinical fabric of routine obstetrical care. There is a growing appreciation for the complexity of perinatal psychiatric illness, particularly with respect to the commingling of both mood and anxiety disorders during the postpartum period. However, willingness to treat and appreciation of the urgency to treat with both pharmacologic and nonpharmacologic interventions can vary. For women who suffer from postpartum depression and their families, there are real-world implications of both treating and failing to treat this illness, and there is an urgent need to really help these women “climb out of the darkness” that is and defines postpartum depression.

Less common but of great clinical importance is postpartum psychosis, which occurs in approximately 1 in 1,000-2,000 women based on estimates from several studies. As noted in previous columns, the presentation is a dramatic one, with the typical onset of psychotic symptoms in the first days to weeks post partum. The disorder typically has a mood component and is not an exacerbation of underlying chronic psychotic illness. While there have been few systematic treatment studies, the clinical consensus is treatment usually includes hospitalization to ensure the safety of both the patient and infant. Use of medications, including mood stabilizers, antipsychotics, and benzodiazepines may be appropriate when expeditious treatment is needed.

Appropriate treatment by informed clinical staff is essential, as untreated or incompletely treated postpartum psychosis with its attendant morbidity and potential mortality is a very real concern. As I speak with women across the country with histories of postpartum psychosis, I’m often told of the difficult exchanges that women and their partners have at EDs in various clinical settings where diagnosis was delayed, or treatment was incomplete because of staff without expertise in postpartum psychosis management.

Another dilemma that patients and clinicians face after acute treatment is treatment duration, which is derived from how we conceptualize the illness. Even for experts in the area, there is not a consensus on whether postpartum psychosis should be considered as bipolar disorder or whether it is a circumscribed diagnostic entity. This issue has been hotly debated for many years and is one of the reasons why the illness is not included in the DSM classification system.

At Massachusetts General Hospital, we are systematically studying a large cohort of women with histories of postpartum psychosis as part of the MGH Postpartum Psychosis Project to better understand the phenomenology of postpartum psychosis, and also to understand the possible genomic underpinning of the illness. Most recently, we are conducting a neuroimaging study of women with histories of postpartum psychosis, compared with women in a healthy control group. We hope the results of this novel investigation will help to answer whether there is a neural signature identifiable with neuroimaging techniques such as functional MRI, if those findings are similar to other findings of neural circuitry we see in other forms of psychotic illness, or if the illness has a more distinct neural signature.

A question patients and colleagues often ask is what is the long-term nature of postpartum psychosis. If one considers it clearly to be bipolar disorder, the most intuitive approach would be long-term treatment with mood stabilizers. We now have a growing amount of data on the longitudinal course of postpartum psychosis. In one meta-analysis, 64% of women who had an episode of postpartum psychosis developed episodes of recurrent psychiatric disorder mostly consistent with bipolar illness. However, 36% of women appear to have more circumscribed illness without recurrence. In those women with recurrent disease, the presumption was those patients who had bipolar disorder and their presentation postpartum was simply their index episode of bipolar illness. However, there were other women who looked as if they had developed subsequent illness over the 11-26 years of follow-up, and those women did not receive long-term treatment.

A more recent prospective study of 106 women with postpartum psychosis who had their medication tapered and discontinued showed that 32% of women went on to have recurrent disease with a median time to illness of 20.3 months, and those patients presented primarily with illness that looked like bipolar disorder.

These accumulating data support the impression we’ve had for years that there’s a very strong relationship between bipolar disorder and postpartum psychiatric illness. Regardless of what side of the debate you fall on, the acute treatment is really the same. The real question for the clinician is what to do over the long term. Frequently, patients feel very strongly about a taper and discontinuation of medicine, and even the data show between 30% and 45% of women seem to have relatively circumscribed disease. There may be an issue in terms of prophylaxis if a patient gets pregnant and delivers another child, but that’s a separate issue. The issue is really whether there is a way to “thread the clinical needle” and meet patients where they are who do not want to continue long-term treatment.

I think we are at a point where we could argue the clinical treatment algorithm for patients who present with a new-onset manic-like psychosis postpartum is clear: initial treatment to stabilize, and then treatment with mood stabilizers for at least 12 months to follow is indicated. However, it may also be reasonable to taper treatment at 12-18 months, particularly for patients who have discussed this option with their clinician and who have been totally well for a year. (Women with previously documented bipolar disorder who have episodes of postpartum psychosis should obviously be treated with longer-term treatment aimed at maintenance of euthymia, as discontinuation of mood stabilizer is well known to be associated with risk for relapse.)

It should be noted that the longitudinal course and the treatment implications for women with postpartum psychosis are not etched in stone absent a clear evidence base driving care guidelines. Treatment must still be individualized. Women with underlying mood diatheses will typically declare themselves over time, and others may do well if they discontinue treatment, particularly if they are followed closely and instructed to present to a clinician at the earliest symptoms of mood dysregulation. The good news is we’ve seen an evolution of both interest and expertise in acute management of postpartum psychosis and a richer appreciation of the potential heterogeneity of this sample of women. There may be some variability in terms of long-term course requiring personalized treatment and obviously close follow-up of these women.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].

The last 15 years have brought increased effort to screen for postpartum psychiatric illness. That’s exceedingly welcome given the morbidity and potential mortality associated with postpartum psychiatric disorders across the country.

From small community hospitals to major academic centers, screening for postpartum depression is part of the clinical fabric of routine obstetrical care. There is a growing appreciation for the complexity of perinatal psychiatric illness, particularly with respect to the commingling of both mood and anxiety disorders during the postpartum period. However, willingness to treat and appreciation of the urgency to treat with both pharmacologic and nonpharmacologic interventions can vary. For women who suffer from postpartum depression and their families, there are real-world implications of both treating and failing to treat this illness, and there is an urgent need to really help these women “climb out of the darkness” that is and defines postpartum depression.

Less common but of great clinical importance is postpartum psychosis, which occurs in approximately 1 in 1,000-2,000 women based on estimates from several studies. As noted in previous columns, the presentation is a dramatic one, with the typical onset of psychotic symptoms in the first days to weeks post partum. The disorder typically has a mood component and is not an exacerbation of underlying chronic psychotic illness. While there have been few systematic treatment studies, the clinical consensus is treatment usually includes hospitalization to ensure the safety of both the patient and infant. Use of medications, including mood stabilizers, antipsychotics, and benzodiazepines may be appropriate when expeditious treatment is needed.

Appropriate treatment by informed clinical staff is essential, as untreated or incompletely treated postpartum psychosis with its attendant morbidity and potential mortality is a very real concern. As I speak with women across the country with histories of postpartum psychosis, I’m often told of the difficult exchanges that women and their partners have at EDs in various clinical settings where diagnosis was delayed, or treatment was incomplete because of staff without expertise in postpartum psychosis management.

Another dilemma that patients and clinicians face after acute treatment is treatment duration, which is derived from how we conceptualize the illness. Even for experts in the area, there is not a consensus on whether postpartum psychosis should be considered as bipolar disorder or whether it is a circumscribed diagnostic entity. This issue has been hotly debated for many years and is one of the reasons why the illness is not included in the DSM classification system.

At Massachusetts General Hospital, we are systematically studying a large cohort of women with histories of postpartum psychosis as part of the MGH Postpartum Psychosis Project to better understand the phenomenology of postpartum psychosis, and also to understand the possible genomic underpinning of the illness. Most recently, we are conducting a neuroimaging study of women with histories of postpartum psychosis, compared with women in a healthy control group. We hope the results of this novel investigation will help to answer whether there is a neural signature identifiable with neuroimaging techniques such as functional MRI, if those findings are similar to other findings of neural circuitry we see in other forms of psychotic illness, or if the illness has a more distinct neural signature.

A question patients and colleagues often ask is what is the long-term nature of postpartum psychosis. If one considers it clearly to be bipolar disorder, the most intuitive approach would be long-term treatment with mood stabilizers. We now have a growing amount of data on the longitudinal course of postpartum psychosis. In one meta-analysis, 64% of women who had an episode of postpartum psychosis developed episodes of recurrent psychiatric disorder mostly consistent with bipolar illness. However, 36% of women appear to have more circumscribed illness without recurrence. In those women with recurrent disease, the presumption was those patients who had bipolar disorder and their presentation postpartum was simply their index episode of bipolar illness. However, there were other women who looked as if they had developed subsequent illness over the 11-26 years of follow-up, and those women did not receive long-term treatment.

A more recent prospective study of 106 women with postpartum psychosis who had their medication tapered and discontinued showed that 32% of women went on to have recurrent disease with a median time to illness of 20.3 months, and those patients presented primarily with illness that looked like bipolar disorder.

These accumulating data support the impression we’ve had for years that there’s a very strong relationship between bipolar disorder and postpartum psychiatric illness. Regardless of what side of the debate you fall on, the acute treatment is really the same. The real question for the clinician is what to do over the long term. Frequently, patients feel very strongly about a taper and discontinuation of medicine, and even the data show between 30% and 45% of women seem to have relatively circumscribed disease. There may be an issue in terms of prophylaxis if a patient gets pregnant and delivers another child, but that’s a separate issue. The issue is really whether there is a way to “thread the clinical needle” and meet patients where they are who do not want to continue long-term treatment.

I think we are at a point where we could argue the clinical treatment algorithm for patients who present with a new-onset manic-like psychosis postpartum is clear: initial treatment to stabilize, and then treatment with mood stabilizers for at least 12 months to follow is indicated. However, it may also be reasonable to taper treatment at 12-18 months, particularly for patients who have discussed this option with their clinician and who have been totally well for a year. (Women with previously documented bipolar disorder who have episodes of postpartum psychosis should obviously be treated with longer-term treatment aimed at maintenance of euthymia, as discontinuation of mood stabilizer is well known to be associated with risk for relapse.)

It should be noted that the longitudinal course and the treatment implications for women with postpartum psychosis are not etched in stone absent a clear evidence base driving care guidelines. Treatment must still be individualized. Women with underlying mood diatheses will typically declare themselves over time, and others may do well if they discontinue treatment, particularly if they are followed closely and instructed to present to a clinician at the earliest symptoms of mood dysregulation. The good news is we’ve seen an evolution of both interest and expertise in acute management of postpartum psychosis and a richer appreciation of the potential heterogeneity of this sample of women. There may be some variability in terms of long-term course requiring personalized treatment and obviously close follow-up of these women.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].

The last 15 years have brought increased effort to screen for postpartum psychiatric illness. That’s exceedingly welcome given the morbidity and potential mortality associated with postpartum psychiatric disorders across the country.

From small community hospitals to major academic centers, screening for postpartum depression is part of the clinical fabric of routine obstetrical care. There is a growing appreciation for the complexity of perinatal psychiatric illness, particularly with respect to the commingling of both mood and anxiety disorders during the postpartum period. However, willingness to treat and appreciation of the urgency to treat with both pharmacologic and nonpharmacologic interventions can vary. For women who suffer from postpartum depression and their families, there are real-world implications of both treating and failing to treat this illness, and there is an urgent need to really help these women “climb out of the darkness” that is and defines postpartum depression.

Less common but of great clinical importance is postpartum psychosis, which occurs in approximately 1 in 1,000-2,000 women based on estimates from several studies. As noted in previous columns, the presentation is a dramatic one, with the typical onset of psychotic symptoms in the first days to weeks post partum. The disorder typically has a mood component and is not an exacerbation of underlying chronic psychotic illness. While there have been few systematic treatment studies, the clinical consensus is treatment usually includes hospitalization to ensure the safety of both the patient and infant. Use of medications, including mood stabilizers, antipsychotics, and benzodiazepines may be appropriate when expeditious treatment is needed.

Appropriate treatment by informed clinical staff is essential, as untreated or incompletely treated postpartum psychosis with its attendant morbidity and potential mortality is a very real concern. As I speak with women across the country with histories of postpartum psychosis, I’m often told of the difficult exchanges that women and their partners have at EDs in various clinical settings where diagnosis was delayed, or treatment was incomplete because of staff without expertise in postpartum psychosis management.

Another dilemma that patients and clinicians face after acute treatment is treatment duration, which is derived from how we conceptualize the illness. Even for experts in the area, there is not a consensus on whether postpartum psychosis should be considered as bipolar disorder or whether it is a circumscribed diagnostic entity. This issue has been hotly debated for many years and is one of the reasons why the illness is not included in the DSM classification system.

At Massachusetts General Hospital, we are systematically studying a large cohort of women with histories of postpartum psychosis as part of the MGH Postpartum Psychosis Project to better understand the phenomenology of postpartum psychosis, and also to understand the possible genomic underpinning of the illness. Most recently, we are conducting a neuroimaging study of women with histories of postpartum psychosis, compared with women in a healthy control group. We hope the results of this novel investigation will help to answer whether there is a neural signature identifiable with neuroimaging techniques such as functional MRI, if those findings are similar to other findings of neural circuitry we see in other forms of psychotic illness, or if the illness has a more distinct neural signature.

A question patients and colleagues often ask is what is the long-term nature of postpartum psychosis. If one considers it clearly to be bipolar disorder, the most intuitive approach would be long-term treatment with mood stabilizers. We now have a growing amount of data on the longitudinal course of postpartum psychosis. In one meta-analysis, 64% of women who had an episode of postpartum psychosis developed episodes of recurrent psychiatric disorder mostly consistent with bipolar illness. However, 36% of women appear to have more circumscribed illness without recurrence. In those women with recurrent disease, the presumption was those patients who had bipolar disorder and their presentation postpartum was simply their index episode of bipolar illness. However, there were other women who looked as if they had developed subsequent illness over the 11-26 years of follow-up, and those women did not receive long-term treatment.

A more recent prospective study of 106 women with postpartum psychosis who had their medication tapered and discontinued showed that 32% of women went on to have recurrent disease with a median time to illness of 20.3 months, and those patients presented primarily with illness that looked like bipolar disorder.

These accumulating data support the impression we’ve had for years that there’s a very strong relationship between bipolar disorder and postpartum psychiatric illness. Regardless of what side of the debate you fall on, the acute treatment is really the same. The real question for the clinician is what to do over the long term. Frequently, patients feel very strongly about a taper and discontinuation of medicine, and even the data show between 30% and 45% of women seem to have relatively circumscribed disease. There may be an issue in terms of prophylaxis if a patient gets pregnant and delivers another child, but that’s a separate issue. The issue is really whether there is a way to “thread the clinical needle” and meet patients where they are who do not want to continue long-term treatment.

I think we are at a point where we could argue the clinical treatment algorithm for patients who present with a new-onset manic-like psychosis postpartum is clear: initial treatment to stabilize, and then treatment with mood stabilizers for at least 12 months to follow is indicated. However, it may also be reasonable to taper treatment at 12-18 months, particularly for patients who have discussed this option with their clinician and who have been totally well for a year. (Women with previously documented bipolar disorder who have episodes of postpartum psychosis should obviously be treated with longer-term treatment aimed at maintenance of euthymia, as discontinuation of mood stabilizer is well known to be associated with risk for relapse.)

It should be noted that the longitudinal course and the treatment implications for women with postpartum psychosis are not etched in stone absent a clear evidence base driving care guidelines. Treatment must still be individualized. Women with underlying mood diatheses will typically declare themselves over time, and others may do well if they discontinue treatment, particularly if they are followed closely and instructed to present to a clinician at the earliest symptoms of mood dysregulation. The good news is we’ve seen an evolution of both interest and expertise in acute management of postpartum psychosis and a richer appreciation of the potential heterogeneity of this sample of women. There may be some variability in terms of long-term course requiring personalized treatment and obviously close follow-up of these women.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].

Adults with major depressive disorder (MDD) had significantly reduced expression of chemokine receptor 4 on blood T lymphocytes, which predicted disease severity in combination with polygenic risk scores in a study of 54 individuals.

Chemokines and their receptors “influence neuroendocrine signaling, neurotransmission, and interaction between neurons and microglia and have therefore been suggested to be involved in the pathophysiology of MDD and depression-like behavior,” but their potential as a predictor of disease severity has not been explored, Jana Freff, a PhD candidate at the University of Münster (Germany), and colleagues wrote.

Recent research has identified disease-associated single-nucleotide polymorphisms that can be used to calculate a cumulative polygenic risk score (PRS) for an individual, they said. “While PRS only explain a small proportion of the phenotypic variance, they provide a valuable tool to study the influence of common genetic factors in complex disorders, such as MDD.”

In a study published in the Journal of Affective Disorders , the researchers identified 33 adult inpatients with MDD and 21 healthy controls. Blood samples were collected at the time of inpatient admission and after 6 weeks of treatment. MDD severity was measured using the Hamilton Rating Scale for Depression and Inventory of Depressive Symptomatology. Chemokine receptor 4 (CCR4) was measured using mean fluorescence intensity (MFI).

The MDD patients showed significant decreases in CCR4 expression on CD4+ T cells; these patients also had elevated serum levels of the ligands CLL17 and CLL22, compared with healthy controls.

The researchers examined the relationship between CCR4 expression on T cells and MDD severity. Individuals with severe depression had lower levels of CCR4 on CD4+ T cells, compared with nondepressed or mildly depressed individuals.

CCR4 expression also was significantly associated with several somatic and cognitive-affective items on the Beck Depression Inventory II including loss of pleasure (P < .05), agitation (P < .01), and difficulty concentrating (P < .05). “In addition, the total score of BDI-II correlated negatively with the CCR4 MFI (P < .05) emphasizing that greater MDD severity is associated with lower CCR4 expression on CD4+ T cells,” the researchers said.

The researchers also assessed the predictive value of immune parameters and PRS for MDD severity. They did not find significant correlations between PRS and these parameters; however, “including PRS for a cross-disorder phenotype and chronotype could improve the predictive performance of immune parameters on MDD severity,” and genetic data should be considered in future studies.

The study findings were limited mainly by the small size, the researchers noted. Additional studies with larger patient populations are needed, not only to investigate the functional role of CCR4 in MDD, and the association between CCR4 and remission or treatment resistance, but also the impact of genetic factors on MDD status, they said.

However, the results of the current study show an altered expression of CCR4 in MDD, and “Future augmented strategies to treat depression may therefore target CCR4 specifically on CD4+ T cells,” they concluded.

The study was funded in part by grants to several coauthors from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy. Ms. Freff had no financial conflicts to disclose.
 

Adults with major depressive disorder (MDD) had significantly reduced expression of chemokine receptor 4 on blood T lymphocytes, which predicted disease severity in combination with polygenic risk scores in a study of 54 individuals.

Chemokines and their receptors “influence neuroendocrine signaling, neurotransmission, and interaction between neurons and microglia and have therefore been suggested to be involved in the pathophysiology of MDD and depression-like behavior,” but their potential as a predictor of disease severity has not been explored, Jana Freff, a PhD candidate at the University of Münster (Germany), and colleagues wrote.

Recent research has identified disease-associated single-nucleotide polymorphisms that can be used to calculate a cumulative polygenic risk score (PRS) for an individual, they said. “While PRS only explain a small proportion of the phenotypic variance, they provide a valuable tool to study the influence of common genetic factors in complex disorders, such as MDD.”

In a study published in the Journal of Affective Disorders , the researchers identified 33 adult inpatients with MDD and 21 healthy controls. Blood samples were collected at the time of inpatient admission and after 6 weeks of treatment. MDD severity was measured using the Hamilton Rating Scale for Depression and Inventory of Depressive Symptomatology. Chemokine receptor 4 (CCR4) was measured using mean fluorescence intensity (MFI).

The MDD patients showed significant decreases in CCR4 expression on CD4+ T cells; these patients also had elevated serum levels of the ligands CLL17 and CLL22, compared with healthy controls.

The researchers examined the relationship between CCR4 expression on T cells and MDD severity. Individuals with severe depression had lower levels of CCR4 on CD4+ T cells, compared with nondepressed or mildly depressed individuals.

CCR4 expression also was significantly associated with several somatic and cognitive-affective items on the Beck Depression Inventory II including loss of pleasure (P < .05), agitation (P < .01), and difficulty concentrating (P < .05). “In addition, the total score of BDI-II correlated negatively with the CCR4 MFI (P < .05) emphasizing that greater MDD severity is associated with lower CCR4 expression on CD4+ T cells,” the researchers said.

The researchers also assessed the predictive value of immune parameters and PRS for MDD severity. They did not find significant correlations between PRS and these parameters; however, “including PRS for a cross-disorder phenotype and chronotype could improve the predictive performance of immune parameters on MDD severity,” and genetic data should be considered in future studies.

The study findings were limited mainly by the small size, the researchers noted. Additional studies with larger patient populations are needed, not only to investigate the functional role of CCR4 in MDD, and the association between CCR4 and remission or treatment resistance, but also the impact of genetic factors on MDD status, they said.

However, the results of the current study show an altered expression of CCR4 in MDD, and “Future augmented strategies to treat depression may therefore target CCR4 specifically on CD4+ T cells,” they concluded.

The study was funded in part by grants to several coauthors from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy. Ms. Freff had no financial conflicts to disclose.
 

Adults with major depressive disorder (MDD) had significantly reduced expression of chemokine receptor 4 on blood T lymphocytes, which predicted disease severity in combination with polygenic risk scores in a study of 54 individuals.

Chemokines and their receptors “influence neuroendocrine signaling, neurotransmission, and interaction between neurons and microglia and have therefore been suggested to be involved in the pathophysiology of MDD and depression-like behavior,” but their potential as a predictor of disease severity has not been explored, Jana Freff, a PhD candidate at the University of Münster (Germany), and colleagues wrote.

Recent research has identified disease-associated single-nucleotide polymorphisms that can be used to calculate a cumulative polygenic risk score (PRS) for an individual, they said. “While PRS only explain a small proportion of the phenotypic variance, they provide a valuable tool to study the influence of common genetic factors in complex disorders, such as MDD.”

In a study published in the Journal of Affective Disorders , the researchers identified 33 adult inpatients with MDD and 21 healthy controls. Blood samples were collected at the time of inpatient admission and after 6 weeks of treatment. MDD severity was measured using the Hamilton Rating Scale for Depression and Inventory of Depressive Symptomatology. Chemokine receptor 4 (CCR4) was measured using mean fluorescence intensity (MFI).

The MDD patients showed significant decreases in CCR4 expression on CD4+ T cells; these patients also had elevated serum levels of the ligands CLL17 and CLL22, compared with healthy controls.

The researchers examined the relationship between CCR4 expression on T cells and MDD severity. Individuals with severe depression had lower levels of CCR4 on CD4+ T cells, compared with nondepressed or mildly depressed individuals.

CCR4 expression also was significantly associated with several somatic and cognitive-affective items on the Beck Depression Inventory II including loss of pleasure (P < .05), agitation (P < .01), and difficulty concentrating (P < .05). “In addition, the total score of BDI-II correlated negatively with the CCR4 MFI (P < .05) emphasizing that greater MDD severity is associated with lower CCR4 expression on CD4+ T cells,” the researchers said.

The researchers also assessed the predictive value of immune parameters and PRS for MDD severity. They did not find significant correlations between PRS and these parameters; however, “including PRS for a cross-disorder phenotype and chronotype could improve the predictive performance of immune parameters on MDD severity,” and genetic data should be considered in future studies.

The study findings were limited mainly by the small size, the researchers noted. Additional studies with larger patient populations are needed, not only to investigate the functional role of CCR4 in MDD, and the association between CCR4 and remission or treatment resistance, but also the impact of genetic factors on MDD status, they said.

However, the results of the current study show an altered expression of CCR4 in MDD, and “Future augmented strategies to treat depression may therefore target CCR4 specifically on CD4+ T cells,” they concluded.

The study was funded in part by grants to several coauthors from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy. Ms. Freff had no financial conflicts to disclose.
 

A new study sheds light on the neurologic underpinnings of late-life depression (LLD) with apathy and its frequently poor response to treatment.

Investigators headed by Faith Gunning, PhD, of the Institute of Geriatric Psychiatry, Weill Cornell Medicine, New York, analyzed baseline and posttreatment brain MRIs and functional MRIs (fMRIs) of older adults with depression who participated in a 12-week open-label nonrandomized clinical trial of escitalopram. Participants had undergone clinical and cognitive assessments.

Disturbances were found in resting state functional connectivity (rsFC) between the salience network (SN) and other large-scale networks that support goal-directed behavior, especially in patients with depression who also had features of apathy.

Even after participants had completed escitalopram treatment, apathy-related variability in functional connectivity was associated with poor antidepressant response and persistent cognitive dysfunction.

“This study suggests that, among older adults with depression, distinct network abnormalities may be associated with apathy and poor response to first-line pharmacotherapy and may serve as promising targets for novel interventions,” the investigators write.

The study was published online in JAMA Network Open.
 

A leading cause of disability

LLD is a “leading cause of disability and medical morbidity in older adulthood,” with one-third to one-half of patients with LLD also suffering from apathy, the authors write.

Older adults with depression and comorbid apathy have poorer outcomes, including lower remission rates and poorer response to first-line antidepressants, compared with those with LLD but who do not have apathy.

Despite the high prevalence of apathy in people with depression, “little is known about its optimal treatment and, more broadly, about the brain-based mechanisms of apathy,” the authors note.

An “emerging hypothesis” points to the role of a compromised SN and its large-scale connections between apathy and poor treatment response in LLD.

The SN (which includes the insula and the dorsal anterior cingulate cortex) “attributes motivational value to a stimulus” and “dynamically coordinates the activity of other large-scale networks, including the executive control network and default mode network (DMN).”

Preliminary studies of apathy in patients with depression report reduced volume in structures of the SN and suggest disruption in functional connectivity among the SN, DMN, and the executive control network; but the mechanisms linking apathy to poor antidepressant response in LLD “are not well understood.”

“Connectometry” is a “novel approach to diffusion MRI analysis that quantifies the local connectome of white matter pathways.” It has been used along with resting-state imagery, but it had not been used in studying apathy.

The researchers investigated the functional connectivity of the SN, hypothesizing that alterations in connectivity among key nodes of the SN and other core circuits that modulate goal-directed behavior (DMN and the executive control network) were implicated in individuals with depression and apathy.

They applied connectometry to “identify pathway-level disruptions in structural connectivity,” hypothesizing that compromise of frontoparietal and frontolimbic pathways would be associated with apathy in patients with LLD.

They also wanted to know whether apathy-related network abnormalities were associated with antidepressant response after 12 weeks of pharmacotherapy with the selective serotonin reuptake inhibitor escitalopram.
 

Emerging model

The study included 40 older adults (65% women; mean [SD] age, 70.0 [6.6] years) with DSM-IV–diagnosis major depressive disorder (without psychotic features) who were from a single-group, open-label escitalopram treatment trial.

The Hamilton-Depression (HAM-D) scale was used to assess depression, while the Apathy Evaluation Scale was used to assess apathy. On the Apathy Evaluation Scale, a score of greater than 40.5 represents “clinically significant apathy.” Participants completed these tests at baseline and after 12 weeks of escitalopram treatment.

They also completed a battery of neuropsychological tests to assess cognition and underwent MRI imaging. fMRI was used to map group differences in rsFC of the SN, and diffusion connectometry was used to “evaluate pathway-level disruptions in structural connectivity.”

Of the participants, 20 had clinically significant apathy. There were no differences in age, sex, educational level, or the severity of depression at baseline between those who did and those who did not have apathy.

Compared with participants with depression but not apathy, those with depression and comorbid apathy had lower rsFC of salience network seeds (specifically, the dorsolateral prefrontal cortex [DLPFC], premotor cortex, midcingulate cortex, and paracentral lobule).

They also had greater rsFC in the lateral temporal cortex and temporal pole (z > 2.7; Bonferroni-corrected threshold of P < .0125).

Additionally, participants with apathy had lower structural connectivity in the splenium, cingulum, and fronto-occipital fasciculus, compared with those without apathy (t > 2.5; false discovery rate–corrected P = .02).

Of the 27 participants who completed escitalopram treatment; 16 (59%) achieved remission (defined as an HAM-D score <10). Participants with apathy had poorer response to escitalopram treatment.

Lower insula-DLPFC/midcingulate cortex rsFC was associated with less improvement in depressive symptoms (HAM-D percentage change, beta [df] = .588 [26]; P = .001) as well as a greater likelihood that the participant would not achieve remission after treatment (odds ratio, 1.041; 95% confidence interval, 1.003-1.081; P = .04).

In regression models, lower insula-DLPFC/midcingulate cortex rsFC was found to be a mediator of the association between baseline apathy and persistence of depression.

The SN findings were also relevant to cognition. Lower dorsal anterior cingulate-DLPFC/paracentral rsFC was found to be associated with residual cognitive difficulties on measures of attention and executive function (beta [df] = .445 [26] and beta [df] = .384 [26], respectively; for each, P = .04).

“These findings support an emerging model of apathy, which proposes that apathy may arise from dysfunctional interactions among core networks (that is, SN, DMN, and executive control) that support motivated behavior,” the investigators write.

“This may cause a failure of network integration, leading to difficulties with salience processing, action planning, and behavioral initiation that manifests clinically as apathy,” they conclude.

One limitation they note was the lack of longitudinal follow-up after acute treatment and a “relatively limited neuropsychological battery.” Therefore, they could not “establish the persistence of treatment differences nor the specificity of cognitive associations.”

The investigators add that “novel interventions that modulate interactions among affected circuits may help to improve clinical outcomes in this distinct subgroup of older adults with depression, for whom few effective treatments exist.”

Commenting on the study, Helen Lavretsy, MD, professor of psychiatry in residence and director of the Late-Life Mood, Stress, and Wellness Research Program and the Integrative Psychiatry Clinic, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, said, the findings “can be used in future studies targeting apathy and the underlying neural mechanisms of brain connectivity.” Dr. Lavretsy was not involved with the study.
The study was supported by grants from the National Institute of Mental Health. Dr. Gunning reported receiving grants from the National Institute of Mental Health during the conduct of the study and grants from Akili Interactive. The other authors’ disclosures are listed on the original article. Dr. Lavretsky reports no relevant financial relationships.

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

A new study sheds light on the neurologic underpinnings of late-life depression (LLD) with apathy and its frequently poor response to treatment.

Investigators headed by Faith Gunning, PhD, of the Institute of Geriatric Psychiatry, Weill Cornell Medicine, New York, analyzed baseline and posttreatment brain MRIs and functional MRIs (fMRIs) of older adults with depression who participated in a 12-week open-label nonrandomized clinical trial of escitalopram. Participants had undergone clinical and cognitive assessments.

Disturbances were found in resting state functional connectivity (rsFC) between the salience network (SN) and other large-scale networks that support goal-directed behavior, especially in patients with depression who also had features of apathy.

Even after participants had completed escitalopram treatment, apathy-related variability in functional connectivity was associated with poor antidepressant response and persistent cognitive dysfunction.

“This study suggests that, among older adults with depression, distinct network abnormalities may be associated with apathy and poor response to first-line pharmacotherapy and may serve as promising targets for novel interventions,” the investigators write.

The study was published online in JAMA Network Open.
 

A leading cause of disability

LLD is a “leading cause of disability and medical morbidity in older adulthood,” with one-third to one-half of patients with LLD also suffering from apathy, the authors write.

Older adults with depression and comorbid apathy have poorer outcomes, including lower remission rates and poorer response to first-line antidepressants, compared with those with LLD but who do not have apathy.

Despite the high prevalence of apathy in people with depression, “little is known about its optimal treatment and, more broadly, about the brain-based mechanisms of apathy,” the authors note.

An “emerging hypothesis” points to the role of a compromised SN and its large-scale connections between apathy and poor treatment response in LLD.

The SN (which includes the insula and the dorsal anterior cingulate cortex) “attributes motivational value to a stimulus” and “dynamically coordinates the activity of other large-scale networks, including the executive control network and default mode network (DMN).”

Preliminary studies of apathy in patients with depression report reduced volume in structures of the SN and suggest disruption in functional connectivity among the SN, DMN, and the executive control network; but the mechanisms linking apathy to poor antidepressant response in LLD “are not well understood.”

“Connectometry” is a “novel approach to diffusion MRI analysis that quantifies the local connectome of white matter pathways.” It has been used along with resting-state imagery, but it had not been used in studying apathy.

The researchers investigated the functional connectivity of the SN, hypothesizing that alterations in connectivity among key nodes of the SN and other core circuits that modulate goal-directed behavior (DMN and the executive control network) were implicated in individuals with depression and apathy.

They applied connectometry to “identify pathway-level disruptions in structural connectivity,” hypothesizing that compromise of frontoparietal and frontolimbic pathways would be associated with apathy in patients with LLD.

They also wanted to know whether apathy-related network abnormalities were associated with antidepressant response after 12 weeks of pharmacotherapy with the selective serotonin reuptake inhibitor escitalopram.
 

Emerging model

The study included 40 older adults (65% women; mean [SD] age, 70.0 [6.6] years) with DSM-IV–diagnosis major depressive disorder (without psychotic features) who were from a single-group, open-label escitalopram treatment trial.

The Hamilton-Depression (HAM-D) scale was used to assess depression, while the Apathy Evaluation Scale was used to assess apathy. On the Apathy Evaluation Scale, a score of greater than 40.5 represents “clinically significant apathy.” Participants completed these tests at baseline and after 12 weeks of escitalopram treatment.

They also completed a battery of neuropsychological tests to assess cognition and underwent MRI imaging. fMRI was used to map group differences in rsFC of the SN, and diffusion connectometry was used to “evaluate pathway-level disruptions in structural connectivity.”

Of the participants, 20 had clinically significant apathy. There were no differences in age, sex, educational level, or the severity of depression at baseline between those who did and those who did not have apathy.

Compared with participants with depression but not apathy, those with depression and comorbid apathy had lower rsFC of salience network seeds (specifically, the dorsolateral prefrontal cortex [DLPFC], premotor cortex, midcingulate cortex, and paracentral lobule).

They also had greater rsFC in the lateral temporal cortex and temporal pole (z > 2.7; Bonferroni-corrected threshold of P < .0125).

Additionally, participants with apathy had lower structural connectivity in the splenium, cingulum, and fronto-occipital fasciculus, compared with those without apathy (t > 2.5; false discovery rate–corrected P = .02).

Of the 27 participants who completed escitalopram treatment; 16 (59%) achieved remission (defined as an HAM-D score <10). Participants with apathy had poorer response to escitalopram treatment.

Lower insula-DLPFC/midcingulate cortex rsFC was associated with less improvement in depressive symptoms (HAM-D percentage change, beta [df] = .588 [26]; P = .001) as well as a greater likelihood that the participant would not achieve remission after treatment (odds ratio, 1.041; 95% confidence interval, 1.003-1.081; P = .04).

In regression models, lower insula-DLPFC/midcingulate cortex rsFC was found to be a mediator of the association between baseline apathy and persistence of depression.

The SN findings were also relevant to cognition. Lower dorsal anterior cingulate-DLPFC/paracentral rsFC was found to be associated with residual cognitive difficulties on measures of attention and executive function (beta [df] = .445 [26] and beta [df] = .384 [26], respectively; for each, P = .04).

“These findings support an emerging model of apathy, which proposes that apathy may arise from dysfunctional interactions among core networks (that is, SN, DMN, and executive control) that support motivated behavior,” the investigators write.

“This may cause a failure of network integration, leading to difficulties with salience processing, action planning, and behavioral initiation that manifests clinically as apathy,” they conclude.

One limitation they note was the lack of longitudinal follow-up after acute treatment and a “relatively limited neuropsychological battery.” Therefore, they could not “establish the persistence of treatment differences nor the specificity of cognitive associations.”

The investigators add that “novel interventions that modulate interactions among affected circuits may help to improve clinical outcomes in this distinct subgroup of older adults with depression, for whom few effective treatments exist.”

Commenting on the study, Helen Lavretsy, MD, professor of psychiatry in residence and director of the Late-Life Mood, Stress, and Wellness Research Program and the Integrative Psychiatry Clinic, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, said, the findings “can be used in future studies targeting apathy and the underlying neural mechanisms of brain connectivity.” Dr. Lavretsy was not involved with the study.
The study was supported by grants from the National Institute of Mental Health. Dr. Gunning reported receiving grants from the National Institute of Mental Health during the conduct of the study and grants from Akili Interactive. The other authors’ disclosures are listed on the original article. Dr. Lavretsky reports no relevant financial relationships.

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

A new study sheds light on the neurologic underpinnings of late-life depression (LLD) with apathy and its frequently poor response to treatment.

Investigators headed by Faith Gunning, PhD, of the Institute of Geriatric Psychiatry, Weill Cornell Medicine, New York, analyzed baseline and posttreatment brain MRIs and functional MRIs (fMRIs) of older adults with depression who participated in a 12-week open-label nonrandomized clinical trial of escitalopram. Participants had undergone clinical and cognitive assessments.

Disturbances were found in resting state functional connectivity (rsFC) between the salience network (SN) and other large-scale networks that support goal-directed behavior, especially in patients with depression who also had features of apathy.

Even after participants had completed escitalopram treatment, apathy-related variability in functional connectivity was associated with poor antidepressant response and persistent cognitive dysfunction.

“This study suggests that, among older adults with depression, distinct network abnormalities may be associated with apathy and poor response to first-line pharmacotherapy and may serve as promising targets for novel interventions,” the investigators write.

The study was published online in JAMA Network Open.
 

A leading cause of disability

LLD is a “leading cause of disability and medical morbidity in older adulthood,” with one-third to one-half of patients with LLD also suffering from apathy, the authors write.

Older adults with depression and comorbid apathy have poorer outcomes, including lower remission rates and poorer response to first-line antidepressants, compared with those with LLD but who do not have apathy.

Despite the high prevalence of apathy in people with depression, “little is known about its optimal treatment and, more broadly, about the brain-based mechanisms of apathy,” the authors note.

An “emerging hypothesis” points to the role of a compromised SN and its large-scale connections between apathy and poor treatment response in LLD.

The SN (which includes the insula and the dorsal anterior cingulate cortex) “attributes motivational value to a stimulus” and “dynamically coordinates the activity of other large-scale networks, including the executive control network and default mode network (DMN).”

Preliminary studies of apathy in patients with depression report reduced volume in structures of the SN and suggest disruption in functional connectivity among the SN, DMN, and the executive control network; but the mechanisms linking apathy to poor antidepressant response in LLD “are not well understood.”

“Connectometry” is a “novel approach to diffusion MRI analysis that quantifies the local connectome of white matter pathways.” It has been used along with resting-state imagery, but it had not been used in studying apathy.

The researchers investigated the functional connectivity of the SN, hypothesizing that alterations in connectivity among key nodes of the SN and other core circuits that modulate goal-directed behavior (DMN and the executive control network) were implicated in individuals with depression and apathy.

They applied connectometry to “identify pathway-level disruptions in structural connectivity,” hypothesizing that compromise of frontoparietal and frontolimbic pathways would be associated with apathy in patients with LLD.

They also wanted to know whether apathy-related network abnormalities were associated with antidepressant response after 12 weeks of pharmacotherapy with the selective serotonin reuptake inhibitor escitalopram.
 

Emerging model

The study included 40 older adults (65% women; mean [SD] age, 70.0 [6.6] years) with DSM-IV–diagnosis major depressive disorder (without psychotic features) who were from a single-group, open-label escitalopram treatment trial.

The Hamilton-Depression (HAM-D) scale was used to assess depression, while the Apathy Evaluation Scale was used to assess apathy. On the Apathy Evaluation Scale, a score of greater than 40.5 represents “clinically significant apathy.” Participants completed these tests at baseline and after 12 weeks of escitalopram treatment.

They also completed a battery of neuropsychological tests to assess cognition and underwent MRI imaging. fMRI was used to map group differences in rsFC of the SN, and diffusion connectometry was used to “evaluate pathway-level disruptions in structural connectivity.”

Of the participants, 20 had clinically significant apathy. There were no differences in age, sex, educational level, or the severity of depression at baseline between those who did and those who did not have apathy.

Compared with participants with depression but not apathy, those with depression and comorbid apathy had lower rsFC of salience network seeds (specifically, the dorsolateral prefrontal cortex [DLPFC], premotor cortex, midcingulate cortex, and paracentral lobule).

They also had greater rsFC in the lateral temporal cortex and temporal pole (z > 2.7; Bonferroni-corrected threshold of P < .0125).

Additionally, participants with apathy had lower structural connectivity in the splenium, cingulum, and fronto-occipital fasciculus, compared with those without apathy (t > 2.5; false discovery rate–corrected P = .02).

Of the 27 participants who completed escitalopram treatment; 16 (59%) achieved remission (defined as an HAM-D score <10). Participants with apathy had poorer response to escitalopram treatment.

Lower insula-DLPFC/midcingulate cortex rsFC was associated with less improvement in depressive symptoms (HAM-D percentage change, beta [df] = .588 [26]; P = .001) as well as a greater likelihood that the participant would not achieve remission after treatment (odds ratio, 1.041; 95% confidence interval, 1.003-1.081; P = .04).

In regression models, lower insula-DLPFC/midcingulate cortex rsFC was found to be a mediator of the association between baseline apathy and persistence of depression.

The SN findings were also relevant to cognition. Lower dorsal anterior cingulate-DLPFC/paracentral rsFC was found to be associated with residual cognitive difficulties on measures of attention and executive function (beta [df] = .445 [26] and beta [df] = .384 [26], respectively; for each, P = .04).

“These findings support an emerging model of apathy, which proposes that apathy may arise from dysfunctional interactions among core networks (that is, SN, DMN, and executive control) that support motivated behavior,” the investigators write.

“This may cause a failure of network integration, leading to difficulties with salience processing, action planning, and behavioral initiation that manifests clinically as apathy,” they conclude.

One limitation they note was the lack of longitudinal follow-up after acute treatment and a “relatively limited neuropsychological battery.” Therefore, they could not “establish the persistence of treatment differences nor the specificity of cognitive associations.”

The investigators add that “novel interventions that modulate interactions among affected circuits may help to improve clinical outcomes in this distinct subgroup of older adults with depression, for whom few effective treatments exist.”

Commenting on the study, Helen Lavretsy, MD, professor of psychiatry in residence and director of the Late-Life Mood, Stress, and Wellness Research Program and the Integrative Psychiatry Clinic, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, said, the findings “can be used in future studies targeting apathy and the underlying neural mechanisms of brain connectivity.” Dr. Lavretsy was not involved with the study.
The study was supported by grants from the National Institute of Mental Health. Dr. Gunning reported receiving grants from the National Institute of Mental Health during the conduct of the study and grants from Akili Interactive. The other authors’ disclosures are listed on the original article. Dr. Lavretsky reports no relevant financial relationships.

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

Intensive home treatment may offer an alternative to inpatient care for patients in acute psychiatric crisis – but the intervention is no outright substitute, new research suggests.

In a randomized controlled trial of more than 200 participants, intensive home treatment was associated with a 34% decrease in the number of inpatient hospital days in the year following therapy, compared with usual care.

However, there was no difference between treatment groups in improvement in quality of life or patient satisfaction; and a reduction in symptom severity noted after 6 weeks of home treatment faded within 6 months.

“We found no differences in admission rates either, which suggests that intensive home treatment is not a substitute for inpatient care but a different treatment opportunity for psychiatric patients in crisis,” Jurgen Cornelis, MD, Arkin Institute for Mental Health, Amsterdam, and colleagues write.

The findings were published online in The Lancet Psychiatry.
 

Increasingly popular

“Intensive home treatment is increasingly popular as an alternative to hospitalization. It was developed to prevent or reduce levels of inpatient care and facilitate the transition between inpatient care and low-intensity outpatient care,” the investigators write.

However, there have previously been only two randomized controlled trials published that assessed this type of care, resulting in “somewhat conflicting findings,” they add.

For the current study, participants presented to psychiatric emergency wards at two medical centers in the Netherlands. They were included only if they were able to offer informed consent within 14 days.

The intensive home treatment group (n = 183) worked with a multidisciplinary team that designed a care plan tailored to their specific crisis. Treatment components included pharmacotherapy, up to three home visits each day, psychoeducation, brief supportive and cognitive behavioral therapy, social care, and support and empowerment of the patient’s informal care system.

The usual care group (n = 63) commonly received a combination of highly intensive inpatient treatment in the first phase and outpatient treatment up to two times a week in the second phase. Treatment included similar components as those in intensive home treatment.

The most common primary clinical diagnosis in both groups was mood disorder, followed by psychotic disorders, personality disorders, or anxiety disorders.

The home treatment group had a significantly higher total mean item score on the Brief Psychiatric Rating Scale (BPRS) at baseline (2.23 vs. 2.04, P = .04).
 

Mixed results

Results at 6 weeks showed the number of hospital days was 25.3% lower in the home treatment group, compared with those who received usual care.

That trend continued at 1 year, with the intensive home treatment group recording 36.6% fewer hospital days than the usual care group (mean, 42.5 days vs. 67 days, respectively; P = .03).

However, the number of patients who were admitted in the first 6 weeks and at 1 year stayed the same, as did the mean number of admissions per patient over 12 months.

The home treatment group reported significantly fewer symptoms on the BPRS depression and anxiety scale at 6 weeks, compared with the usual treatment group (P = .025), but that difference was not maintained after 6 months.

The number of adverse events, including suicide attempts, was similar between the groups. Three patients in the home treatment group and two in the usual care group died by suicide.

“Future research should focus on which components of intensive home treatment or hospitalization can be used when, for whom, and meet which goals, so that both hospital care and intensive home treatment can be used proportionally and efficiently for patients in psychiatric crisis,” the investigators write.
 

Not generalizable?

In an accompanying editorial, Claire Henderson, PhD, Institute of Psychiatry, Psychology, and Neuroscience at King’s College London, noted that generalizing the study’s results to other countries could be problematic, especially to regions such as North America, which have shorter lengths of stay for psychiatric hospitalization.

“Future trials looking at intensive home treatment would be most informative if done in countries with relatively short lengths of stay, and without separate crisis services for people receiving assertive community treatment,” Dr. Henderson writes.

The study was funded by De Stichting tot Steun Vereniging voor Christelijke Verzorging van Geestes-en Zenuwzieken. The investigators and Dr. Henderson have reported no relevant financial relationships.

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

Intensive home treatment may offer an alternative to inpatient care for patients in acute psychiatric crisis – but the intervention is no outright substitute, new research suggests.

In a randomized controlled trial of more than 200 participants, intensive home treatment was associated with a 34% decrease in the number of inpatient hospital days in the year following therapy, compared with usual care.

However, there was no difference between treatment groups in improvement in quality of life or patient satisfaction; and a reduction in symptom severity noted after 6 weeks of home treatment faded within 6 months.

“We found no differences in admission rates either, which suggests that intensive home treatment is not a substitute for inpatient care but a different treatment opportunity for psychiatric patients in crisis,” Jurgen Cornelis, MD, Arkin Institute for Mental Health, Amsterdam, and colleagues write.

The findings were published online in The Lancet Psychiatry.
 

Increasingly popular

“Intensive home treatment is increasingly popular as an alternative to hospitalization. It was developed to prevent or reduce levels of inpatient care and facilitate the transition between inpatient care and low-intensity outpatient care,” the investigators write.

However, there have previously been only two randomized controlled trials published that assessed this type of care, resulting in “somewhat conflicting findings,” they add.

For the current study, participants presented to psychiatric emergency wards at two medical centers in the Netherlands. They were included only if they were able to offer informed consent within 14 days.

The intensive home treatment group (n = 183) worked with a multidisciplinary team that designed a care plan tailored to their specific crisis. Treatment components included pharmacotherapy, up to three home visits each day, psychoeducation, brief supportive and cognitive behavioral therapy, social care, and support and empowerment of the patient’s informal care system.

The usual care group (n = 63) commonly received a combination of highly intensive inpatient treatment in the first phase and outpatient treatment up to two times a week in the second phase. Treatment included similar components as those in intensive home treatment.

The most common primary clinical diagnosis in both groups was mood disorder, followed by psychotic disorders, personality disorders, or anxiety disorders.

The home treatment group had a significantly higher total mean item score on the Brief Psychiatric Rating Scale (BPRS) at baseline (2.23 vs. 2.04, P = .04).
 

Mixed results

Results at 6 weeks showed the number of hospital days was 25.3% lower in the home treatment group, compared with those who received usual care.

That trend continued at 1 year, with the intensive home treatment group recording 36.6% fewer hospital days than the usual care group (mean, 42.5 days vs. 67 days, respectively; P = .03).

However, the number of patients who were admitted in the first 6 weeks and at 1 year stayed the same, as did the mean number of admissions per patient over 12 months.

The home treatment group reported significantly fewer symptoms on the BPRS depression and anxiety scale at 6 weeks, compared with the usual treatment group (P = .025), but that difference was not maintained after 6 months.

The number of adverse events, including suicide attempts, was similar between the groups. Three patients in the home treatment group and two in the usual care group died by suicide.

“Future research should focus on which components of intensive home treatment or hospitalization can be used when, for whom, and meet which goals, so that both hospital care and intensive home treatment can be used proportionally and efficiently for patients in psychiatric crisis,” the investigators write.
 

Not generalizable?

In an accompanying editorial, Claire Henderson, PhD, Institute of Psychiatry, Psychology, and Neuroscience at King’s College London, noted that generalizing the study’s results to other countries could be problematic, especially to regions such as North America, which have shorter lengths of stay for psychiatric hospitalization.

“Future trials looking at intensive home treatment would be most informative if done in countries with relatively short lengths of stay, and without separate crisis services for people receiving assertive community treatment,” Dr. Henderson writes.

The study was funded by De Stichting tot Steun Vereniging voor Christelijke Verzorging van Geestes-en Zenuwzieken. The investigators and Dr. Henderson have reported no relevant financial relationships.

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

Intensive home treatment may offer an alternative to inpatient care for patients in acute psychiatric crisis – but the intervention is no outright substitute, new research suggests.

In a randomized controlled trial of more than 200 participants, intensive home treatment was associated with a 34% decrease in the number of inpatient hospital days in the year following therapy, compared with usual care.

However, there was no difference between treatment groups in improvement in quality of life or patient satisfaction; and a reduction in symptom severity noted after 6 weeks of home treatment faded within 6 months.

“We found no differences in admission rates either, which suggests that intensive home treatment is not a substitute for inpatient care but a different treatment opportunity for psychiatric patients in crisis,” Jurgen Cornelis, MD, Arkin Institute for Mental Health, Amsterdam, and colleagues write.

The findings were published online in The Lancet Psychiatry.
 

Increasingly popular

“Intensive home treatment is increasingly popular as an alternative to hospitalization. It was developed to prevent or reduce levels of inpatient care and facilitate the transition between inpatient care and low-intensity outpatient care,” the investigators write.

However, there have previously been only two randomized controlled trials published that assessed this type of care, resulting in “somewhat conflicting findings,” they add.

For the current study, participants presented to psychiatric emergency wards at two medical centers in the Netherlands. They were included only if they were able to offer informed consent within 14 days.

The intensive home treatment group (n = 183) worked with a multidisciplinary team that designed a care plan tailored to their specific crisis. Treatment components included pharmacotherapy, up to three home visits each day, psychoeducation, brief supportive and cognitive behavioral therapy, social care, and support and empowerment of the patient’s informal care system.

The usual care group (n = 63) commonly received a combination of highly intensive inpatient treatment in the first phase and outpatient treatment up to two times a week in the second phase. Treatment included similar components as those in intensive home treatment.

The most common primary clinical diagnosis in both groups was mood disorder, followed by psychotic disorders, personality disorders, or anxiety disorders.

The home treatment group had a significantly higher total mean item score on the Brief Psychiatric Rating Scale (BPRS) at baseline (2.23 vs. 2.04, P = .04).
 

Mixed results

Results at 6 weeks showed the number of hospital days was 25.3% lower in the home treatment group, compared with those who received usual care.

That trend continued at 1 year, with the intensive home treatment group recording 36.6% fewer hospital days than the usual care group (mean, 42.5 days vs. 67 days, respectively; P = .03).

However, the number of patients who were admitted in the first 6 weeks and at 1 year stayed the same, as did the mean number of admissions per patient over 12 months.

The home treatment group reported significantly fewer symptoms on the BPRS depression and anxiety scale at 6 weeks, compared with the usual treatment group (P = .025), but that difference was not maintained after 6 months.

The number of adverse events, including suicide attempts, was similar between the groups. Three patients in the home treatment group and two in the usual care group died by suicide.

“Future research should focus on which components of intensive home treatment or hospitalization can be used when, for whom, and meet which goals, so that both hospital care and intensive home treatment can be used proportionally and efficiently for patients in psychiatric crisis,” the investigators write.
 

Not generalizable?

In an accompanying editorial, Claire Henderson, PhD, Institute of Psychiatry, Psychology, and Neuroscience at King’s College London, noted that generalizing the study’s results to other countries could be problematic, especially to regions such as North America, which have shorter lengths of stay for psychiatric hospitalization.

“Future trials looking at intensive home treatment would be most informative if done in countries with relatively short lengths of stay, and without separate crisis services for people receiving assertive community treatment,” Dr. Henderson writes.

The study was funded by De Stichting tot Steun Vereniging voor Christelijke Verzorging van Geestes-en Zenuwzieken. The investigators and Dr. Henderson have reported no relevant financial relationships.

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

In September 2022, the University of California, Berkeley, will start training its first class of “trip facilitators,” who will learn how to guide individuals through therapeutic psychedelic experiences aimed at addressing a variety of mental health problems.

The UC Berkeley Center for the Science of Psychedelics (BCSP) training program aims to create a cadre of facilitators who will be ready to help if, and when, substances such as psilocybin, MDMA, and LSD are approved in the United States, Tina Trujillo, PhD, an associate professor at UC Berkeley’s School of Education, told reporters at a press briefing.

Hallucinogenic drugs are on the Drug Enforcement Administration’s (DEA) Schedule I list because they are considered to have no currently accepted medical use and high abuse potential. But there has been an explosion of research into psychedelics – combined with therapy – as treatment for severe depression, posttraumatic stress disorder, substance-use disorder, and other mental health conditions. Some 100 clinical trials are underway.

“The estimates are that we’re going to need 100,000 trained psychedelic facilitators once psilocybin and MDMA are approved by the [U.S. Food and Drug Administration] FDA, which is expected to happen within the next 5 years or so,” said Michael Pollan, co-founder of the BCSP. He is author of “How to Change Your Mind,” a 2018 book about psychedelics, which has been adapted into a four-part docuseries currently streaming on Netflix.

Courtesy Alia Malley

Nine-month program

The first 24 trainees – a mix of physicians, nurses, psychotherapists, and social workers – will undergo 9 months of education and preparation in “the technical, the cultural, the mystical, and the ethical dimensions of psychedelic facilitation,” said Dr. Trujillo.

The BCSP’s Certificate Program in Psychedelic Facilitation will have “an emphasis on both western science and spiritual care traditions,” she said.

Trainees will receive 150 instructional hours and a 25-hour practicum and will take part in a final 5-day retreat. The program will initially focus only on psilocybin, in part because the BCSP is involved in several FDA-approved trials testing the drug.

In one study – which aims to enroll participants in the fall – researchers will use functional MRI to examine the neural correlates of the psychedelic experience in individuals receiving low-dose psilocybin.

Eligible trainees will have an opportunity to participate in the Berkeley psilocybin trials and “increase their first-hand knowledge,” Dr. Trujillo said.

At the conclusion of the training, students will receive a certificate, “not a license or sanction to go off and practice,” she said. She noted that eventually, when facilitation is legal, certificate holders will be able to practice in clinical research settings or in health care settings.
 

Growing acceptance in psychiatry

Mr. Pollan said there has been a radical change in acceptance of psychedelics as potential therapies.

“The shift from destroyer of young minds in the ‘60s to effective medicine in the 2020s is as sudden as it is confusing for many people,” he said. He noted that the Berkeley center hopes to provide evidence-based information for journalists, the public, and clinicians.

He said that after his book was released, he expected pushback from “mainstream psychiatry.” Instead, he was invited to give grand rounds talks. Psychiatrists are “very open to the potential of psychedelics,” Mr. Pollan said.

“The reason for that, quite frankly, is because they are desperate,” he said. “The tools of conventional psychiatry to deal with things like depression and anxiety and addiction are not very good, and some of them are failing,” he said.

Mr. Pollan cited some other indicators of acceptance. In Oregon, beginning in 2023, psilocybin will be available to anyone older than 21 years but only for use in licensed facilities with licensed facilitators, and the substance must be produced by a licensed manufacturer.

In November, Colorado will ask voters whether they want to follow the Oregon model and legalize psilocybin. If approved, another Colorado ballot initiative would decriminalize possession.

Mr. Pollan noted that Cory Booker, the Democratic Senator from New Jersey, and Rand Paul, a conservative Republican Senator from Kentucky, have found a common cause, introducing legislation to let select terminally ill patients have access to psychedelics and other Schedule I drugs.

Some 400 companies are conducting research on psychedelics. Researchers must have a license from the DEA to obtain and study the substances, Andrea Gomez, assistant professor of neurobiology at UC Berkeley, told reporters.

She said growing interest in the potential of these drugs might lead more researchers to “jump through the hoops” to get the licenses. The floodgates would truly open if the National Institutes of Health started funding studies, she said.

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

In September 2022, the University of California, Berkeley, will start training its first class of “trip facilitators,” who will learn how to guide individuals through therapeutic psychedelic experiences aimed at addressing a variety of mental health problems.

The UC Berkeley Center for the Science of Psychedelics (BCSP) training program aims to create a cadre of facilitators who will be ready to help if, and when, substances such as psilocybin, MDMA, and LSD are approved in the United States, Tina Trujillo, PhD, an associate professor at UC Berkeley’s School of Education, told reporters at a press briefing.

Hallucinogenic drugs are on the Drug Enforcement Administration’s (DEA) Schedule I list because they are considered to have no currently accepted medical use and high abuse potential. But there has been an explosion of research into psychedelics – combined with therapy – as treatment for severe depression, posttraumatic stress disorder, substance-use disorder, and other mental health conditions. Some 100 clinical trials are underway.

“The estimates are that we’re going to need 100,000 trained psychedelic facilitators once psilocybin and MDMA are approved by the [U.S. Food and Drug Administration] FDA, which is expected to happen within the next 5 years or so,” said Michael Pollan, co-founder of the BCSP. He is author of “How to Change Your Mind,” a 2018 book about psychedelics, which has been adapted into a four-part docuseries currently streaming on Netflix.

Courtesy Alia Malley

Nine-month program

The first 24 trainees – a mix of physicians, nurses, psychotherapists, and social workers – will undergo 9 months of education and preparation in “the technical, the cultural, the mystical, and the ethical dimensions of psychedelic facilitation,” said Dr. Trujillo.

The BCSP’s Certificate Program in Psychedelic Facilitation will have “an emphasis on both western science and spiritual care traditions,” she said.

Trainees will receive 150 instructional hours and a 25-hour practicum and will take part in a final 5-day retreat. The program will initially focus only on psilocybin, in part because the BCSP is involved in several FDA-approved trials testing the drug.

In one study – which aims to enroll participants in the fall – researchers will use functional MRI to examine the neural correlates of the psychedelic experience in individuals receiving low-dose psilocybin.

Eligible trainees will have an opportunity to participate in the Berkeley psilocybin trials and “increase their first-hand knowledge,” Dr. Trujillo said.

At the conclusion of the training, students will receive a certificate, “not a license or sanction to go off and practice,” she said. She noted that eventually, when facilitation is legal, certificate holders will be able to practice in clinical research settings or in health care settings.
 

Growing acceptance in psychiatry

Mr. Pollan said there has been a radical change in acceptance of psychedelics as potential therapies.

“The shift from destroyer of young minds in the ‘60s to effective medicine in the 2020s is as sudden as it is confusing for many people,” he said. He noted that the Berkeley center hopes to provide evidence-based information for journalists, the public, and clinicians.

He said that after his book was released, he expected pushback from “mainstream psychiatry.” Instead, he was invited to give grand rounds talks. Psychiatrists are “very open to the potential of psychedelics,” Mr. Pollan said.

“The reason for that, quite frankly, is because they are desperate,” he said. “The tools of conventional psychiatry to deal with things like depression and anxiety and addiction are not very good, and some of them are failing,” he said.

Mr. Pollan cited some other indicators of acceptance. In Oregon, beginning in 2023, psilocybin will be available to anyone older than 21 years but only for use in licensed facilities with licensed facilitators, and the substance must be produced by a licensed manufacturer.

In November, Colorado will ask voters whether they want to follow the Oregon model and legalize psilocybin. If approved, another Colorado ballot initiative would decriminalize possession.

Mr. Pollan noted that Cory Booker, the Democratic Senator from New Jersey, and Rand Paul, a conservative Republican Senator from Kentucky, have found a common cause, introducing legislation to let select terminally ill patients have access to psychedelics and other Schedule I drugs.

Some 400 companies are conducting research on psychedelics. Researchers must have a license from the DEA to obtain and study the substances, Andrea Gomez, assistant professor of neurobiology at UC Berkeley, told reporters.

She said growing interest in the potential of these drugs might lead more researchers to “jump through the hoops” to get the licenses. The floodgates would truly open if the National Institutes of Health started funding studies, she said.

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

In September 2022, the University of California, Berkeley, will start training its first class of “trip facilitators,” who will learn how to guide individuals through therapeutic psychedelic experiences aimed at addressing a variety of mental health problems.

The UC Berkeley Center for the Science of Psychedelics (BCSP) training program aims to create a cadre of facilitators who will be ready to help if, and when, substances such as psilocybin, MDMA, and LSD are approved in the United States, Tina Trujillo, PhD, an associate professor at UC Berkeley’s School of Education, told reporters at a press briefing.

Hallucinogenic drugs are on the Drug Enforcement Administration’s (DEA) Schedule I list because they are considered to have no currently accepted medical use and high abuse potential. But there has been an explosion of research into psychedelics – combined with therapy – as treatment for severe depression, posttraumatic stress disorder, substance-use disorder, and other mental health conditions. Some 100 clinical trials are underway.

“The estimates are that we’re going to need 100,000 trained psychedelic facilitators once psilocybin and MDMA are approved by the [U.S. Food and Drug Administration] FDA, which is expected to happen within the next 5 years or so,” said Michael Pollan, co-founder of the BCSP. He is author of “How to Change Your Mind,” a 2018 book about psychedelics, which has been adapted into a four-part docuseries currently streaming on Netflix.

Courtesy Alia Malley

Nine-month program

The first 24 trainees – a mix of physicians, nurses, psychotherapists, and social workers – will undergo 9 months of education and preparation in “the technical, the cultural, the mystical, and the ethical dimensions of psychedelic facilitation,” said Dr. Trujillo.

The BCSP’s Certificate Program in Psychedelic Facilitation will have “an emphasis on both western science and spiritual care traditions,” she said.

Trainees will receive 150 instructional hours and a 25-hour practicum and will take part in a final 5-day retreat. The program will initially focus only on psilocybin, in part because the BCSP is involved in several FDA-approved trials testing the drug.

In one study – which aims to enroll participants in the fall – researchers will use functional MRI to examine the neural correlates of the psychedelic experience in individuals receiving low-dose psilocybin.

Eligible trainees will have an opportunity to participate in the Berkeley psilocybin trials and “increase their first-hand knowledge,” Dr. Trujillo said.

At the conclusion of the training, students will receive a certificate, “not a license or sanction to go off and practice,” she said. She noted that eventually, when facilitation is legal, certificate holders will be able to practice in clinical research settings or in health care settings.
 

Growing acceptance in psychiatry

Mr. Pollan said there has been a radical change in acceptance of psychedelics as potential therapies.

“The shift from destroyer of young minds in the ‘60s to effective medicine in the 2020s is as sudden as it is confusing for many people,” he said. He noted that the Berkeley center hopes to provide evidence-based information for journalists, the public, and clinicians.

He said that after his book was released, he expected pushback from “mainstream psychiatry.” Instead, he was invited to give grand rounds talks. Psychiatrists are “very open to the potential of psychedelics,” Mr. Pollan said.

“The reason for that, quite frankly, is because they are desperate,” he said. “The tools of conventional psychiatry to deal with things like depression and anxiety and addiction are not very good, and some of them are failing,” he said.

Mr. Pollan cited some other indicators of acceptance. In Oregon, beginning in 2023, psilocybin will be available to anyone older than 21 years but only for use in licensed facilities with licensed facilitators, and the substance must be produced by a licensed manufacturer.

In November, Colorado will ask voters whether they want to follow the Oregon model and legalize psilocybin. If approved, another Colorado ballot initiative would decriminalize possession.

Mr. Pollan noted that Cory Booker, the Democratic Senator from New Jersey, and Rand Paul, a conservative Republican Senator from Kentucky, have found a common cause, introducing legislation to let select terminally ill patients have access to psychedelics and other Schedule I drugs.

Some 400 companies are conducting research on psychedelics. Researchers must have a license from the DEA to obtain and study the substances, Andrea Gomez, assistant professor of neurobiology at UC Berkeley, told reporters.

She said growing interest in the potential of these drugs might lead more researchers to “jump through the hoops” to get the licenses. The floodgates would truly open if the National Institutes of Health started funding studies, she said.

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

Pharmacogenetic testing, which is used to classify how patients with major depressive disorder (MDD) metabolize medications, reduces adverse drug-gene interactions, new research shows.

In a randomized clinical trial that included almost 2,000 adults with MDD, patients in the pharmacogenomics-guided group were more likely to receive an antidepressant that had no potential drug-gene interaction than the patients who received usual care.

In addition, among the intervention group, the rate of remission over 24 weeks was significantly greater.

“These tests can be helpful in rethinking choices of antidepressants, but clinicians should not expect them to be helpful for every patient,” study investigator David W. Oslin, MD, Corporal Michael J. Crescenz VA Medical Center and professor of psychiatry at Perelman School of Medicine, University of Pennsylvania, Philadelphia, said in an interview.

The findings were published online  in JAMA.

Less trial and error

Pharmacogenomic testing can provide information to inform drug selection or dosing for patients with a genetic variation that alters pharmacokinetics or pharmacodynamics. Such testing may be particularly useful for patients with MDD, as fewer than 40% of these patients achieve clinical remission after an initial treatment with an antidepressant, the investigators note.

“To get to a treatment that works for an individual, it’s not unusual to have to try two or three or four antidepressants,” said Dr. Oslin. “If we could reduce that variance a little bit with a test like this, that would be huge from a public health perspective.”

The study included 676 physicians and 1,944 adults with MDD (mean age, 48 years; 24% women) who were receiving care at 22 Department of Veterans Affairs medical centers. Eligible patients were set to start a new antidepressant monotherapy, and all underwent a pharmacogenomic test using a cheek swab.

Investigators randomly assigned patients to receive test results when available (pharmacogenomic-guided group) or 24 weeks later (usual-care group). For the former group, clinicians were asked to initiate treatment when test results were available, typically within 2-3 days. For the latter group, they were asked to initiate treatment on a day of randomization.

Assessments included the 9-item Patient Health questionnaire (PHQ-9), scores for which range from 0-27 points, with higher scores indicating worse symptoms.

Of the total patient population, 79% completed the 24-week assessment.

Researchers characterized antidepressant medications on the basis of drug-gene interaction categories: no known interactions, moderate interactions, and substantial interactions.

The co-primary outcomes were treatment initiation within 30 days, determined on the basis of drug-gene interaction categories, and remission from depression symptoms, defined as a PHQ-9 score of less than or equal to 5.

Raters who were blinded to clinical care and study randomization assessed outcomes at 4, 8, 12, 18, and 24 weeks.
 

Significant impact?

Results showed that the pharmacogenomic-guided group was more likely to receive an antidepressant that had no potential drug-gene interaction, as opposed to one with a moderate/substantial interaction (odds ratio, 4.32; 95% confidence interval, 3.47-5.39; P < .001).

The usual-care group was more likely to receive a drug with mild potential drug-gene interaction (no/moderate interaction vs. substantial interaction: OR, 2.08; 95% CI, 1.52-2.84; P = .005).

For the intervention group, the estimated rates of receiving an antidepressant with no, moderate, and substantial drug-gene interactions were 59.3%, 30.0%, and 10.7%, respectively. For the usual-care group, the estimates were 25.7%, 54.6%, and 19.7%.

The finding that 1 in 5 patients who received usual care were initially given a medication for which there were significant drug-gene interactions means it is “not a rare event,” said Dr. Oslin. “If we can make an impact on 20% of the people we prescribe to, that’s actually pretty big.”

Rates of remission were greater in the pharmacogenomic-guided group over 24 weeks (OR, 1.28; 95% CI, 1.05-1.57; P = .02; absolute risk difference, 2.8%; 95% CI, 0.6%-5.1%).

The secondary outcomes of response to treatment, defined as at least a 50% decrease in PHQ-9 score, also favored the pharmacogenomic-guided group. This was also the case for the secondary outcome of reduction in symptom severity on the PHQ-9 score.

Some physicians have expressed skepticism about pharmacogenomic testing, but the study provides additional evidence of its usefulness, Dr. Oslin noted.

“While I don’t think testing should be standard of practice, I also don’t think we should put barriers into the testing until we can better understand how to target the testing” to those who will benefit the most, he added.

The tests are available at a commercial cost of about $1,000 – which may not be that expensive if testing has a significant impact on a patient’s life, said Dr. Oslin.
 

Important research, but with several limitations

In an accompanying editorial, Dan V. Iosifescu, MD, associate professor of psychiatry at New York University School of Medicine and director of clinical research at the Nathan Kline Institute for Psychiatric Research, called the study an important addition to the literature on pharmacogenomic testing for patients with MDD.

The study was significantly larger and had broader inclusion criteria and longer follow-up than previous clinical trials and is one of the few investigations not funded by a manufacturer of pharmacogenomic tests, writes Dr. Iosifescu, who was not involved with the research.

However, he notes that an antidepressant was not initiated for 30 days after randomization in 25% of the intervention group and in 31% of the usual-care group, which was “puzzling.” “Because these rates were comparable in the 2 groups, it cannot be explained primarily by the delay of the pharmacogenomic test results in the intervention group,” he writes.

In addition, in the co-primary outcome of symptom remission rate, the difference in clinical improvement in favor of the pharmacogenomic-guided treatment was only “modest” – the gain was of less than 2% in the proportion of patients achieving remission, Dr. Iosifescu adds.

He adds this is “likely not very meaningful clinically despite this difference achieving statistical significance in this large study sample.”

Other potential study limitations he cites include the lack of patient blinding to treatment assignment and the absence of clarity about why rates of MDD response and remission over time were relatively low in both treatment groups.

A possible approach to optimize antidepressant choices could involve integration of pharmacogenomic data into larger predictive models that include clinical and demographic variables, Dr. Iosifescu notes.

“The development of such complex models is challenging, but it is now possible given the recent substantial advances in the proficiency of computational tools,” he writes.

The study was funded by the U.S. Department of Veterans Affairs (VA), Health Services Research and Development Service, and the Mental Illness Research, Education, and Clinical Center at the Corporal Michael J. Crescenz VA Medical Center. Dr. Oslin reports having received grants from the VA Office of Research and Development and Janssen Pharmaceuticals and nonfinancial support from Myriad Genetics during the conduct of the study. Dr. Iosifescu report having received personal fees from Alkermes, Allergan, Axsome, Biogen, the Centers for Psychiatric Excellence, Jazz, Lundbeck, Precision Neuroscience, Sage, and Sunovion and grants from Alkermes, AstraZeneca, Brainsway, Litecure, Neosync, Otsuka, Roche, and Shire.

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

Pharmacogenetic testing, which is used to classify how patients with major depressive disorder (MDD) metabolize medications, reduces adverse drug-gene interactions, new research shows.

In a randomized clinical trial that included almost 2,000 adults with MDD, patients in the pharmacogenomics-guided group were more likely to receive an antidepressant that had no potential drug-gene interaction than the patients who received usual care.

In addition, among the intervention group, the rate of remission over 24 weeks was significantly greater.

“These tests can be helpful in rethinking choices of antidepressants, but clinicians should not expect them to be helpful for every patient,” study investigator David W. Oslin, MD, Corporal Michael J. Crescenz VA Medical Center and professor of psychiatry at Perelman School of Medicine, University of Pennsylvania, Philadelphia, said in an interview.

The findings were published online  in JAMA.

Less trial and error

Pharmacogenomic testing can provide information to inform drug selection or dosing for patients with a genetic variation that alters pharmacokinetics or pharmacodynamics. Such testing may be particularly useful for patients with MDD, as fewer than 40% of these patients achieve clinical remission after an initial treatment with an antidepressant, the investigators note.

“To get to a treatment that works for an individual, it’s not unusual to have to try two or three or four antidepressants,” said Dr. Oslin. “If we could reduce that variance a little bit with a test like this, that would be huge from a public health perspective.”

The study included 676 physicians and 1,944 adults with MDD (mean age, 48 years; 24% women) who were receiving care at 22 Department of Veterans Affairs medical centers. Eligible patients were set to start a new antidepressant monotherapy, and all underwent a pharmacogenomic test using a cheek swab.

Investigators randomly assigned patients to receive test results when available (pharmacogenomic-guided group) or 24 weeks later (usual-care group). For the former group, clinicians were asked to initiate treatment when test results were available, typically within 2-3 days. For the latter group, they were asked to initiate treatment on a day of randomization.

Assessments included the 9-item Patient Health questionnaire (PHQ-9), scores for which range from 0-27 points, with higher scores indicating worse symptoms.

Of the total patient population, 79% completed the 24-week assessment.

Researchers characterized antidepressant medications on the basis of drug-gene interaction categories: no known interactions, moderate interactions, and substantial interactions.

The co-primary outcomes were treatment initiation within 30 days, determined on the basis of drug-gene interaction categories, and remission from depression symptoms, defined as a PHQ-9 score of less than or equal to 5.

Raters who were blinded to clinical care and study randomization assessed outcomes at 4, 8, 12, 18, and 24 weeks.
 

Significant impact?

Results showed that the pharmacogenomic-guided group was more likely to receive an antidepressant that had no potential drug-gene interaction, as opposed to one with a moderate/substantial interaction (odds ratio, 4.32; 95% confidence interval, 3.47-5.39; P < .001).

The usual-care group was more likely to receive a drug with mild potential drug-gene interaction (no/moderate interaction vs. substantial interaction: OR, 2.08; 95% CI, 1.52-2.84; P = .005).

For the intervention group, the estimated rates of receiving an antidepressant with no, moderate, and substantial drug-gene interactions were 59.3%, 30.0%, and 10.7%, respectively. For the usual-care group, the estimates were 25.7%, 54.6%, and 19.7%.

The finding that 1 in 5 patients who received usual care were initially given a medication for which there were significant drug-gene interactions means it is “not a rare event,” said Dr. Oslin. “If we can make an impact on 20% of the people we prescribe to, that’s actually pretty big.”

Rates of remission were greater in the pharmacogenomic-guided group over 24 weeks (OR, 1.28; 95% CI, 1.05-1.57; P = .02; absolute risk difference, 2.8%; 95% CI, 0.6%-5.1%).

The secondary outcomes of response to treatment, defined as at least a 50% decrease in PHQ-9 score, also favored the pharmacogenomic-guided group. This was also the case for the secondary outcome of reduction in symptom severity on the PHQ-9 score.

Some physicians have expressed skepticism about pharmacogenomic testing, but the study provides additional evidence of its usefulness, Dr. Oslin noted.

“While I don’t think testing should be standard of practice, I also don’t think we should put barriers into the testing until we can better understand how to target the testing” to those who will benefit the most, he added.

The tests are available at a commercial cost of about $1,000 – which may not be that expensive if testing has a significant impact on a patient’s life, said Dr. Oslin.
 

Important research, but with several limitations

In an accompanying editorial, Dan V. Iosifescu, MD, associate professor of psychiatry at New York University School of Medicine and director of clinical research at the Nathan Kline Institute for Psychiatric Research, called the study an important addition to the literature on pharmacogenomic testing for patients with MDD.

The study was significantly larger and had broader inclusion criteria and longer follow-up than previous clinical trials and is one of the few investigations not funded by a manufacturer of pharmacogenomic tests, writes Dr. Iosifescu, who was not involved with the research.

However, he notes that an antidepressant was not initiated for 30 days after randomization in 25% of the intervention group and in 31% of the usual-care group, which was “puzzling.” “Because these rates were comparable in the 2 groups, it cannot be explained primarily by the delay of the pharmacogenomic test results in the intervention group,” he writes.

In addition, in the co-primary outcome of symptom remission rate, the difference in clinical improvement in favor of the pharmacogenomic-guided treatment was only “modest” – the gain was of less than 2% in the proportion of patients achieving remission, Dr. Iosifescu adds.

He adds this is “likely not very meaningful clinically despite this difference achieving statistical significance in this large study sample.”

Other potential study limitations he cites include the lack of patient blinding to treatment assignment and the absence of clarity about why rates of MDD response and remission over time were relatively low in both treatment groups.

A possible approach to optimize antidepressant choices could involve integration of pharmacogenomic data into larger predictive models that include clinical and demographic variables, Dr. Iosifescu notes.

“The development of such complex models is challenging, but it is now possible given the recent substantial advances in the proficiency of computational tools,” he writes.

The study was funded by the U.S. Department of Veterans Affairs (VA), Health Services Research and Development Service, and the Mental Illness Research, Education, and Clinical Center at the Corporal Michael J. Crescenz VA Medical Center. Dr. Oslin reports having received grants from the VA Office of Research and Development and Janssen Pharmaceuticals and nonfinancial support from Myriad Genetics during the conduct of the study. Dr. Iosifescu report having received personal fees from Alkermes, Allergan, Axsome, Biogen, the Centers for Psychiatric Excellence, Jazz, Lundbeck, Precision Neuroscience, Sage, and Sunovion and grants from Alkermes, AstraZeneca, Brainsway, Litecure, Neosync, Otsuka, Roche, and Shire.

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

Pharmacogenetic testing, which is used to classify how patients with major depressive disorder (MDD) metabolize medications, reduces adverse drug-gene interactions, new research shows.

In a randomized clinical trial that included almost 2,000 adults with MDD, patients in the pharmacogenomics-guided group were more likely to receive an antidepressant that had no potential drug-gene interaction than the patients who received usual care.

In addition, among the intervention group, the rate of remission over 24 weeks was significantly greater.

“These tests can be helpful in rethinking choices of antidepressants, but clinicians should not expect them to be helpful for every patient,” study investigator David W. Oslin, MD, Corporal Michael J. Crescenz VA Medical Center and professor of psychiatry at Perelman School of Medicine, University of Pennsylvania, Philadelphia, said in an interview.

The findings were published online  in JAMA.

Less trial and error

Pharmacogenomic testing can provide information to inform drug selection or dosing for patients with a genetic variation that alters pharmacokinetics or pharmacodynamics. Such testing may be particularly useful for patients with MDD, as fewer than 40% of these patients achieve clinical remission after an initial treatment with an antidepressant, the investigators note.

“To get to a treatment that works for an individual, it’s not unusual to have to try two or three or four antidepressants,” said Dr. Oslin. “If we could reduce that variance a little bit with a test like this, that would be huge from a public health perspective.”

The study included 676 physicians and 1,944 adults with MDD (mean age, 48 years; 24% women) who were receiving care at 22 Department of Veterans Affairs medical centers. Eligible patients were set to start a new antidepressant monotherapy, and all underwent a pharmacogenomic test using a cheek swab.

Investigators randomly assigned patients to receive test results when available (pharmacogenomic-guided group) or 24 weeks later (usual-care group). For the former group, clinicians were asked to initiate treatment when test results were available, typically within 2-3 days. For the latter group, they were asked to initiate treatment on a day of randomization.

Assessments included the 9-item Patient Health questionnaire (PHQ-9), scores for which range from 0-27 points, with higher scores indicating worse symptoms.

Of the total patient population, 79% completed the 24-week assessment.

Researchers characterized antidepressant medications on the basis of drug-gene interaction categories: no known interactions, moderate interactions, and substantial interactions.

The co-primary outcomes were treatment initiation within 30 days, determined on the basis of drug-gene interaction categories, and remission from depression symptoms, defined as a PHQ-9 score of less than or equal to 5.

Raters who were blinded to clinical care and study randomization assessed outcomes at 4, 8, 12, 18, and 24 weeks.
 

Significant impact?

Results showed that the pharmacogenomic-guided group was more likely to receive an antidepressant that had no potential drug-gene interaction, as opposed to one with a moderate/substantial interaction (odds ratio, 4.32; 95% confidence interval, 3.47-5.39; P < .001).

The usual-care group was more likely to receive a drug with mild potential drug-gene interaction (no/moderate interaction vs. substantial interaction: OR, 2.08; 95% CI, 1.52-2.84; P = .005).

For the intervention group, the estimated rates of receiving an antidepressant with no, moderate, and substantial drug-gene interactions were 59.3%, 30.0%, and 10.7%, respectively. For the usual-care group, the estimates were 25.7%, 54.6%, and 19.7%.

The finding that 1 in 5 patients who received usual care were initially given a medication for which there were significant drug-gene interactions means it is “not a rare event,” said Dr. Oslin. “If we can make an impact on 20% of the people we prescribe to, that’s actually pretty big.”

Rates of remission were greater in the pharmacogenomic-guided group over 24 weeks (OR, 1.28; 95% CI, 1.05-1.57; P = .02; absolute risk difference, 2.8%; 95% CI, 0.6%-5.1%).

The secondary outcomes of response to treatment, defined as at least a 50% decrease in PHQ-9 score, also favored the pharmacogenomic-guided group. This was also the case for the secondary outcome of reduction in symptom severity on the PHQ-9 score.

Some physicians have expressed skepticism about pharmacogenomic testing, but the study provides additional evidence of its usefulness, Dr. Oslin noted.

“While I don’t think testing should be standard of practice, I also don’t think we should put barriers into the testing until we can better understand how to target the testing” to those who will benefit the most, he added.

The tests are available at a commercial cost of about $1,000 – which may not be that expensive if testing has a significant impact on a patient’s life, said Dr. Oslin.
 

Important research, but with several limitations

In an accompanying editorial, Dan V. Iosifescu, MD, associate professor of psychiatry at New York University School of Medicine and director of clinical research at the Nathan Kline Institute for Psychiatric Research, called the study an important addition to the literature on pharmacogenomic testing for patients with MDD.

The study was significantly larger and had broader inclusion criteria and longer follow-up than previous clinical trials and is one of the few investigations not funded by a manufacturer of pharmacogenomic tests, writes Dr. Iosifescu, who was not involved with the research.

However, he notes that an antidepressant was not initiated for 30 days after randomization in 25% of the intervention group and in 31% of the usual-care group, which was “puzzling.” “Because these rates were comparable in the 2 groups, it cannot be explained primarily by the delay of the pharmacogenomic test results in the intervention group,” he writes.

In addition, in the co-primary outcome of symptom remission rate, the difference in clinical improvement in favor of the pharmacogenomic-guided treatment was only “modest” – the gain was of less than 2% in the proportion of patients achieving remission, Dr. Iosifescu adds.

He adds this is “likely not very meaningful clinically despite this difference achieving statistical significance in this large study sample.”

Other potential study limitations he cites include the lack of patient blinding to treatment assignment and the absence of clarity about why rates of MDD response and remission over time were relatively low in both treatment groups.

A possible approach to optimize antidepressant choices could involve integration of pharmacogenomic data into larger predictive models that include clinical and demographic variables, Dr. Iosifescu notes.

“The development of such complex models is challenging, but it is now possible given the recent substantial advances in the proficiency of computational tools,” he writes.

The study was funded by the U.S. Department of Veterans Affairs (VA), Health Services Research and Development Service, and the Mental Illness Research, Education, and Clinical Center at the Corporal Michael J. Crescenz VA Medical Center. Dr. Oslin reports having received grants from the VA Office of Research and Development and Janssen Pharmaceuticals and nonfinancial support from Myriad Genetics during the conduct of the study. Dr. Iosifescu report having received personal fees from Alkermes, Allergan, Axsome, Biogen, the Centers for Psychiatric Excellence, Jazz, Lundbeck, Precision Neuroscience, Sage, and Sunovion and grants from Alkermes, AstraZeneca, Brainsway, Litecure, Neosync, Otsuka, Roche, and Shire.

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

Medically reviewed by Jennifer Casarella, MD

Dan Miller has parked his Nissan Altima on the side of the road near a field outside Chicago and is holding a gun to his head. 

Haunted for years by the compounded trauma of tours of duty in the Middle East and his work as a police officer in Chicago, at that moment, Dr. Miller saw no reason to live. And there were troubles at home with his wife and children, who had grown fearful of his behavior.

“My whole world was falling apart,” he says of that dark night in 2014. “It left a hole I didn’t know how to fill.”

He chose not to pull the trigger after a brochure on the passenger seat of his car gave him an unexpected perspective – and launched him on a path to help others in his situation.

Had Mr. Miller taken his life that night, he would have joined thousands of other veterans who died by suicide. About 17 U.S. veterans lose their lives this way each day, on average, according to the Department of Veterans Affairs. In 2019, the last year for which records are available, 6,261 veterans took their own lives – and the suicide rate for veterans was 52% higher than for nonveterans, the agency’s records show. 

The problem has become so severe that the Veterans Health Administration now uses artificial intelligence (AI) to help identify veterans at the highest risk of suicide – and reach out to them before a crisis strikes.

But that wasn’t available when Dan Miller’s life was unraveling.

In the years leading up to his near-suicide, his wife had pushed him to get help. “She said, ‘You’re not the same person you were when you left. The kids are scared of you. The pets are scared of you,” he recalls.

He resisted, even when his wife threatened divorce. Rising through the ranks of the Marines, Mr. Miller had become more emotionally isolated. He feared losing his job and the respect of others if he let anyone know what he was going through.

Finally, he gave the VHA a chance. He went in for an initial consultation in 2010 and didn’t find it helpful. He didn’t like being told what to do. So he stopped. He turned to obsessive exercise and excessive drinking.

That day in 2014, Mr. Miller’s wife told him she was taking the kids out for a playdate. After she left, he was served with divorce papers. Less than an hour later, he was parked in his car with his gun, ready to end his life.

But if it all had happened just a few years later, things might never have gotten to that point.
 

Scanning for suicide risk

In 2017, the VHA piloted its AI program, called REACH VET, that aims to help prevent veterans from dying by suicide.

Every month, a computer scans the electronic health records of all VHA patients who’ve had a health care visit for any reason in the last 2 years. It checks more than 140 variables and weights them to estimate someone’s overall suicide risk at that moment in time.

To build the risk algorithm, a computer combed through the medical records of 6,360 veterans confirmed to have died by suicide between 2009 and 2011. (The VHA continually updates the list of variables from the health records of VHA patients, including those who have died by suicide since then and others.)

Some variables are things you’d expect:

• A past suicide attempt.
• A diagnosis of depression or other mental illness.
• A diagnosis of a terminal illness.

Others are more surprising. For example, a diagnosis of arthritis or diabetes adds weight.

REACH VET flags the riskiest cases – the top 0.1% – for a mental health or primary care provider to review. They reach out to the patient to tell them how and why their record was flagged, discuss any recommended treatment changes, and ask them to come in for a visit.

“It’s an opportunity to talk about their risk factors, which is designed to lead to a conversation about safety planning,” says clinical psychologist Matthew Miller, PhD, national director of the U.S. Department of Veterans Affairs’ Suicide Prevention Program. He’s not related to Dan Miller.

Making a suicide safety plan

A safety plan is a document that outlines how a person can help prevent their own suicide in a crisis. 

The plan may include:

• A list of personal triggers or warning signs.
• What’s helped them in the past.
• Names of people or organizations who can support them.
• Plans to remove means of suicide, such as guns, from their environment.
• Their reasons for living.

In people at risk for suicide, research shows that having a safety plan reduces suicidal thoughts and attempts, lowers rates of depression and hopelessness, and boosts veterans’ engagement with the health care system. It may also help people manage things that trigger their suicidal thoughts.
 

Getting the call

What if REACH VET had been around when Dan Miller was in crisis – and he’d gotten a call from the VHA?

“It absolutely, positively would have helped because one of the biggest things on that day when I got served was feeling completely alone and that I had no one to turn to,” Mr. Miller says. He’s now a speaker for the Wounded Warrior Project, a nonprofit that serves veterans and active-duty service people.

Vets’ reactions to the unexpected VHA phone call, psychologist Dr. Miller says, “run the gamut from ‘Thank you for contacting me. Let’s talk,’ to ‘What are you talking about? Leave me alone!’ ”

Nothing stops all suicides. But REACH VET is having an impact. In a clinical trial, vets contacted through REACH VET had more doctor visits, were more likely to have a written suicide prevention safety plan, and had fewer hospital admissions for mental health, ER visits, and suicide attempts.
 

An assist from AI

Even simple outreach can make a big difference. And there’s research to prove it.

One study included 4,730 veterans recently discharged from psychiatric care at the VHA, a group considered at high risk for suicide. 

Half of them got 13 caring emails from hospital staff in the weeks after leaving the hospital. The emails mentioned personal things the patient had shared, like a love of hiking, and wished them well. The other veterans got routine follow-up but no emails.

Two years later, those who got the caring emails were less likely to have died by suicide than the other vets. The study was published in 2014 in Contemporary Clinical Trials.

Researchers have done studies like this many times: with handwritten notes from the primary care doctor, postcards from the ER, and so forth. The results never vary: The notes reduce suicide risk.

“If we could use AI to identify people to receive notes or phone calls, it would be a very effective and inexpensive way to guide follow-up care,” says Rebecca Bernert, PhD, director and founder of the Suicide Prevention Research Laboratory at Stanford (Calif.) University.
 

AI doesn’t replace clinical judgment.

“AI can capture data that we miss due to the limits of our humanity,” psychologist Dr. Miller says. “There’s suicide prevention processes founded on big data and AI, and there are processes founded in clinical intuition and acumen.”

AI is only as good as the data it’s based on. If that data lacks diversity, it may miss things. And variables that apply to veterans may differ in civilians.
 

Stopping suicidal thoughts

Google is putting AI to work against suicide, too. Its MUM (Multitask Unified Model) technology seeks to understand the intent behind what we google.

MUM powers Google Search. It can often tell the difference between a search for information about suicide for someone writing a research paper on the topic and a search for information on how or where to carry out a suicide.

When Google Search detects that someone in the United States might be in crisis and at risk of suicide, the first search results that person gets are the number for the National Suicide Prevention Lifeline and other resources for people in crisis.

Google Home Assistant works in the same way. When a user makes a query that signals a suicide-related crisis, the gadget serves up resources that offer help.

MUM is working to understand the nuances of crisis language in 75 languages so that Google Search can provide people in crisis with hotlines or other resources in many countries.

“We want to find partners that are accessible to users in terms of hours of operation. We have a strong preference for finding partners that promise confidentiality and privacy to the extent that those are permitted [in that country],” says Anne Merritt, MD, a product manager at Google Search.

Other companies are working on apps that use AI to spot suicide risk in other ways, including voice technology that may notice subtle changes in the voice of someone who’s depressed and may be thinking of suicide. Those are still in development but show promise. Keep in mind that apps do not require government approval, so if you try one, be sure to let your health care provider know.
 

Changing the channel

Seeing a hotline number on your phone or computer screen can help, Dan Miller says. “If I happened to be online, searching maybe for a bridge to jump off of ... and suddenly that pops up on the screen, it’s like it changes the channel.”

It may not work for everyone, he says, but that search result could interrupt someone’s suicidal train of thought.

That’s crucial, psychologist Dr. Miller says, because most suicide attempts escalate from first thought to potentially fatal action in just 1 hour. That’s how fast it happened for Dan Miller in 2014.

“When you’re able to put time and space between the suicidal thought and the access to the method to act on that thought, you save lives,” Dr. Bernert says.
 

Making a different choice

An interruption in Mr. Miller’s thinking is what had saved his life.

Holding the gun to his head, Mr. Miller looked over at the passenger seat at a brochure from Wounded Warrior Project, which he had just learned about. Mr. Miller noticed a photo of a man in a wheelchair, a veteran like him, who had no legs. He thought that the man looked worse off than him but hadn’t given up.

Mr. Miller put down his gun and decided to get help.

Recovering from a near suicide attempt, he says, is a journey. It doesn’t happen overnight. Now, 8 years later, Mr. Miller is planning a brief break from the speaker circuit. He plans to spend 2 weeks in an outpatient counseling program for posttraumatic stress disorder and traumatic brain injury.

“Telling my story to strangers – part of it is healing me in a way, but I’m learning that repeating the story over and over again is also keeping me from letting it go. And I’m still healing.”

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

Medically reviewed by Jennifer Casarella, MD

Dan Miller has parked his Nissan Altima on the side of the road near a field outside Chicago and is holding a gun to his head. 

Haunted for years by the compounded trauma of tours of duty in the Middle East and his work as a police officer in Chicago, at that moment, Dr. Miller saw no reason to live. And there were troubles at home with his wife and children, who had grown fearful of his behavior.

“My whole world was falling apart,” he says of that dark night in 2014. “It left a hole I didn’t know how to fill.”

He chose not to pull the trigger after a brochure on the passenger seat of his car gave him an unexpected perspective – and launched him on a path to help others in his situation.

Had Mr. Miller taken his life that night, he would have joined thousands of other veterans who died by suicide. About 17 U.S. veterans lose their lives this way each day, on average, according to the Department of Veterans Affairs. In 2019, the last year for which records are available, 6,261 veterans took their own lives – and the suicide rate for veterans was 52% higher than for nonveterans, the agency’s records show. 

The problem has become so severe that the Veterans Health Administration now uses artificial intelligence (AI) to help identify veterans at the highest risk of suicide – and reach out to them before a crisis strikes.

But that wasn’t available when Dan Miller’s life was unraveling.

In the years leading up to his near-suicide, his wife had pushed him to get help. “She said, ‘You’re not the same person you were when you left. The kids are scared of you. The pets are scared of you,” he recalls.

He resisted, even when his wife threatened divorce. Rising through the ranks of the Marines, Mr. Miller had become more emotionally isolated. He feared losing his job and the respect of others if he let anyone know what he was going through.

Finally, he gave the VHA a chance. He went in for an initial consultation in 2010 and didn’t find it helpful. He didn’t like being told what to do. So he stopped. He turned to obsessive exercise and excessive drinking.

That day in 2014, Mr. Miller’s wife told him she was taking the kids out for a playdate. After she left, he was served with divorce papers. Less than an hour later, he was parked in his car with his gun, ready to end his life.

But if it all had happened just a few years later, things might never have gotten to that point.
 

Scanning for suicide risk

In 2017, the VHA piloted its AI program, called REACH VET, that aims to help prevent veterans from dying by suicide.

Every month, a computer scans the electronic health records of all VHA patients who’ve had a health care visit for any reason in the last 2 years. It checks more than 140 variables and weights them to estimate someone’s overall suicide risk at that moment in time.

To build the risk algorithm, a computer combed through the medical records of 6,360 veterans confirmed to have died by suicide between 2009 and 2011. (The VHA continually updates the list of variables from the health records of VHA patients, including those who have died by suicide since then and others.)

Some variables are things you’d expect:

• A past suicide attempt.
• A diagnosis of depression or other mental illness.
• A diagnosis of a terminal illness.

Others are more surprising. For example, a diagnosis of arthritis or diabetes adds weight.

REACH VET flags the riskiest cases – the top 0.1% – for a mental health or primary care provider to review. They reach out to the patient to tell them how and why their record was flagged, discuss any recommended treatment changes, and ask them to come in for a visit.

“It’s an opportunity to talk about their risk factors, which is designed to lead to a conversation about safety planning,” says clinical psychologist Matthew Miller, PhD, national director of the U.S. Department of Veterans Affairs’ Suicide Prevention Program. He’s not related to Dan Miller.

Making a suicide safety plan

A safety plan is a document that outlines how a person can help prevent their own suicide in a crisis. 

The plan may include:

• A list of personal triggers or warning signs.
• What’s helped them in the past.
• Names of people or organizations who can support them.
• Plans to remove means of suicide, such as guns, from their environment.
• Their reasons for living.

In people at risk for suicide, research shows that having a safety plan reduces suicidal thoughts and attempts, lowers rates of depression and hopelessness, and boosts veterans’ engagement with the health care system. It may also help people manage things that trigger their suicidal thoughts.
 

Getting the call

What if REACH VET had been around when Dan Miller was in crisis – and he’d gotten a call from the VHA?

“It absolutely, positively would have helped because one of the biggest things on that day when I got served was feeling completely alone and that I had no one to turn to,” Mr. Miller says. He’s now a speaker for the Wounded Warrior Project, a nonprofit that serves veterans and active-duty service people.

Vets’ reactions to the unexpected VHA phone call, psychologist Dr. Miller says, “run the gamut from ‘Thank you for contacting me. Let’s talk,’ to ‘What are you talking about? Leave me alone!’ ”

Nothing stops all suicides. But REACH VET is having an impact. In a clinical trial, vets contacted through REACH VET had more doctor visits, were more likely to have a written suicide prevention safety plan, and had fewer hospital admissions for mental health, ER visits, and suicide attempts.
 

An assist from AI

Even simple outreach can make a big difference. And there’s research to prove it.

One study included 4,730 veterans recently discharged from psychiatric care at the VHA, a group considered at high risk for suicide. 

Half of them got 13 caring emails from hospital staff in the weeks after leaving the hospital. The emails mentioned personal things the patient had shared, like a love of hiking, and wished them well. The other veterans got routine follow-up but no emails.

Two years later, those who got the caring emails were less likely to have died by suicide than the other vets. The study was published in 2014 in Contemporary Clinical Trials.

Researchers have done studies like this many times: with handwritten notes from the primary care doctor, postcards from the ER, and so forth. The results never vary: The notes reduce suicide risk.

“If we could use AI to identify people to receive notes or phone calls, it would be a very effective and inexpensive way to guide follow-up care,” says Rebecca Bernert, PhD, director and founder of the Suicide Prevention Research Laboratory at Stanford (Calif.) University.
 

AI doesn’t replace clinical judgment.

“AI can capture data that we miss due to the limits of our humanity,” psychologist Dr. Miller says. “There’s suicide prevention processes founded on big data and AI, and there are processes founded in clinical intuition and acumen.”

AI is only as good as the data it’s based on. If that data lacks diversity, it may miss things. And variables that apply to veterans may differ in civilians.
 

Stopping suicidal thoughts

Google is putting AI to work against suicide, too. Its MUM (Multitask Unified Model) technology seeks to understand the intent behind what we google.

MUM powers Google Search. It can often tell the difference between a search for information about suicide for someone writing a research paper on the topic and a search for information on how or where to carry out a suicide.

When Google Search detects that someone in the United States might be in crisis and at risk of suicide, the first search results that person gets are the number for the National Suicide Prevention Lifeline and other resources for people in crisis.

Google Home Assistant works in the same way. When a user makes a query that signals a suicide-related crisis, the gadget serves up resources that offer help.

MUM is working to understand the nuances of crisis language in 75 languages so that Google Search can provide people in crisis with hotlines or other resources in many countries.

“We want to find partners that are accessible to users in terms of hours of operation. We have a strong preference for finding partners that promise confidentiality and privacy to the extent that those are permitted [in that country],” says Anne Merritt, MD, a product manager at Google Search.

Other companies are working on apps that use AI to spot suicide risk in other ways, including voice technology that may notice subtle changes in the voice of someone who’s depressed and may be thinking of suicide. Those are still in development but show promise. Keep in mind that apps do not require government approval, so if you try one, be sure to let your health care provider know.
 

Changing the channel

Seeing a hotline number on your phone or computer screen can help, Dan Miller says. “If I happened to be online, searching maybe for a bridge to jump off of ... and suddenly that pops up on the screen, it’s like it changes the channel.”

It may not work for everyone, he says, but that search result could interrupt someone’s suicidal train of thought.

That’s crucial, psychologist Dr. Miller says, because most suicide attempts escalate from first thought to potentially fatal action in just 1 hour. That’s how fast it happened for Dan Miller in 2014.

“When you’re able to put time and space between the suicidal thought and the access to the method to act on that thought, you save lives,” Dr. Bernert says.
 

Making a different choice

An interruption in Mr. Miller’s thinking is what had saved his life.

Holding the gun to his head, Mr. Miller looked over at the passenger seat at a brochure from Wounded Warrior Project, which he had just learned about. Mr. Miller noticed a photo of a man in a wheelchair, a veteran like him, who had no legs. He thought that the man looked worse off than him but hadn’t given up.

Mr. Miller put down his gun and decided to get help.

Recovering from a near suicide attempt, he says, is a journey. It doesn’t happen overnight. Now, 8 years later, Mr. Miller is planning a brief break from the speaker circuit. He plans to spend 2 weeks in an outpatient counseling program for posttraumatic stress disorder and traumatic brain injury.

“Telling my story to strangers – part of it is healing me in a way, but I’m learning that repeating the story over and over again is also keeping me from letting it go. And I’m still healing.”

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

Medically reviewed by Jennifer Casarella, MD

Dan Miller has parked his Nissan Altima on the side of the road near a field outside Chicago and is holding a gun to his head. 

Haunted for years by the compounded trauma of tours of duty in the Middle East and his work as a police officer in Chicago, at that moment, Dr. Miller saw no reason to live. And there were troubles at home with his wife and children, who had grown fearful of his behavior.

“My whole world was falling apart,” he says of that dark night in 2014. “It left a hole I didn’t know how to fill.”

He chose not to pull the trigger after a brochure on the passenger seat of his car gave him an unexpected perspective – and launched him on a path to help others in his situation.

Had Mr. Miller taken his life that night, he would have joined thousands of other veterans who died by suicide. About 17 U.S. veterans lose their lives this way each day, on average, according to the Department of Veterans Affairs. In 2019, the last year for which records are available, 6,261 veterans took their own lives – and the suicide rate for veterans was 52% higher than for nonveterans, the agency’s records show. 

The problem has become so severe that the Veterans Health Administration now uses artificial intelligence (AI) to help identify veterans at the highest risk of suicide – and reach out to them before a crisis strikes.

But that wasn’t available when Dan Miller’s life was unraveling.

In the years leading up to his near-suicide, his wife had pushed him to get help. “She said, ‘You’re not the same person you were when you left. The kids are scared of you. The pets are scared of you,” he recalls.

He resisted, even when his wife threatened divorce. Rising through the ranks of the Marines, Mr. Miller had become more emotionally isolated. He feared losing his job and the respect of others if he let anyone know what he was going through.

Finally, he gave the VHA a chance. He went in for an initial consultation in 2010 and didn’t find it helpful. He didn’t like being told what to do. So he stopped. He turned to obsessive exercise and excessive drinking.

That day in 2014, Mr. Miller’s wife told him she was taking the kids out for a playdate. After she left, he was served with divorce papers. Less than an hour later, he was parked in his car with his gun, ready to end his life.

But if it all had happened just a few years later, things might never have gotten to that point.
 

Scanning for suicide risk

In 2017, the VHA piloted its AI program, called REACH VET, that aims to help prevent veterans from dying by suicide.

Every month, a computer scans the electronic health records of all VHA patients who’ve had a health care visit for any reason in the last 2 years. It checks more than 140 variables and weights them to estimate someone’s overall suicide risk at that moment in time.

To build the risk algorithm, a computer combed through the medical records of 6,360 veterans confirmed to have died by suicide between 2009 and 2011. (The VHA continually updates the list of variables from the health records of VHA patients, including those who have died by suicide since then and others.)

Some variables are things you’d expect:

• A past suicide attempt.
• A diagnosis of depression or other mental illness.
• A diagnosis of a terminal illness.

Others are more surprising. For example, a diagnosis of arthritis or diabetes adds weight.

REACH VET flags the riskiest cases – the top 0.1% – for a mental health or primary care provider to review. They reach out to the patient to tell them how and why their record was flagged, discuss any recommended treatment changes, and ask them to come in for a visit.

“It’s an opportunity to talk about their risk factors, which is designed to lead to a conversation about safety planning,” says clinical psychologist Matthew Miller, PhD, national director of the U.S. Department of Veterans Affairs’ Suicide Prevention Program. He’s not related to Dan Miller.

Making a suicide safety plan

A safety plan is a document that outlines how a person can help prevent their own suicide in a crisis. 

The plan may include:

• A list of personal triggers or warning signs.
• What’s helped them in the past.
• Names of people or organizations who can support them.
• Plans to remove means of suicide, such as guns, from their environment.
• Their reasons for living.

In people at risk for suicide, research shows that having a safety plan reduces suicidal thoughts and attempts, lowers rates of depression and hopelessness, and boosts veterans’ engagement with the health care system. It may also help people manage things that trigger their suicidal thoughts.
 

Getting the call

What if REACH VET had been around when Dan Miller was in crisis – and he’d gotten a call from the VHA?

“It absolutely, positively would have helped because one of the biggest things on that day when I got served was feeling completely alone and that I had no one to turn to,” Mr. Miller says. He’s now a speaker for the Wounded Warrior Project, a nonprofit that serves veterans and active-duty service people.

Vets’ reactions to the unexpected VHA phone call, psychologist Dr. Miller says, “run the gamut from ‘Thank you for contacting me. Let’s talk,’ to ‘What are you talking about? Leave me alone!’ ”

Nothing stops all suicides. But REACH VET is having an impact. In a clinical trial, vets contacted through REACH VET had more doctor visits, were more likely to have a written suicide prevention safety plan, and had fewer hospital admissions for mental health, ER visits, and suicide attempts.
 

An assist from AI

Even simple outreach can make a big difference. And there’s research to prove it.

One study included 4,730 veterans recently discharged from psychiatric care at the VHA, a group considered at high risk for suicide. 

Half of them got 13 caring emails from hospital staff in the weeks after leaving the hospital. The emails mentioned personal things the patient had shared, like a love of hiking, and wished them well. The other veterans got routine follow-up but no emails.

Two years later, those who got the caring emails were less likely to have died by suicide than the other vets. The study was published in 2014 in Contemporary Clinical Trials.

Researchers have done studies like this many times: with handwritten notes from the primary care doctor, postcards from the ER, and so forth. The results never vary: The notes reduce suicide risk.

“If we could use AI to identify people to receive notes or phone calls, it would be a very effective and inexpensive way to guide follow-up care,” says Rebecca Bernert, PhD, director and founder of the Suicide Prevention Research Laboratory at Stanford (Calif.) University.
 

AI doesn’t replace clinical judgment.

“AI can capture data that we miss due to the limits of our humanity,” psychologist Dr. Miller says. “There’s suicide prevention processes founded on big data and AI, and there are processes founded in clinical intuition and acumen.”

AI is only as good as the data it’s based on. If that data lacks diversity, it may miss things. And variables that apply to veterans may differ in civilians.
 

Stopping suicidal thoughts

Google is putting AI to work against suicide, too. Its MUM (Multitask Unified Model) technology seeks to understand the intent behind what we google.

MUM powers Google Search. It can often tell the difference between a search for information about suicide for someone writing a research paper on the topic and a search for information on how or where to carry out a suicide.

When Google Search detects that someone in the United States might be in crisis and at risk of suicide, the first search results that person gets are the number for the National Suicide Prevention Lifeline and other resources for people in crisis.

Google Home Assistant works in the same way. When a user makes a query that signals a suicide-related crisis, the gadget serves up resources that offer help.

MUM is working to understand the nuances of crisis language in 75 languages so that Google Search can provide people in crisis with hotlines or other resources in many countries.

“We want to find partners that are accessible to users in terms of hours of operation. We have a strong preference for finding partners that promise confidentiality and privacy to the extent that those are permitted [in that country],” says Anne Merritt, MD, a product manager at Google Search.

Other companies are working on apps that use AI to spot suicide risk in other ways, including voice technology that may notice subtle changes in the voice of someone who’s depressed and may be thinking of suicide. Those are still in development but show promise. Keep in mind that apps do not require government approval, so if you try one, be sure to let your health care provider know.
 

Changing the channel

Seeing a hotline number on your phone or computer screen can help, Dan Miller says. “If I happened to be online, searching maybe for a bridge to jump off of ... and suddenly that pops up on the screen, it’s like it changes the channel.”

It may not work for everyone, he says, but that search result could interrupt someone’s suicidal train of thought.

That’s crucial, psychologist Dr. Miller says, because most suicide attempts escalate from first thought to potentially fatal action in just 1 hour. That’s how fast it happened for Dan Miller in 2014.

“When you’re able to put time and space between the suicidal thought and the access to the method to act on that thought, you save lives,” Dr. Bernert says.
 

Making a different choice

An interruption in Mr. Miller’s thinking is what had saved his life.

Holding the gun to his head, Mr. Miller looked over at the passenger seat at a brochure from Wounded Warrior Project, which he had just learned about. Mr. Miller noticed a photo of a man in a wheelchair, a veteran like him, who had no legs. He thought that the man looked worse off than him but hadn’t given up.

Mr. Miller put down his gun and decided to get help.

Recovering from a near suicide attempt, he says, is a journey. It doesn’t happen overnight. Now, 8 years later, Mr. Miller is planning a brief break from the speaker circuit. He plans to spend 2 weeks in an outpatient counseling program for posttraumatic stress disorder and traumatic brain injury.

“Telling my story to strangers – part of it is healing me in a way, but I’m learning that repeating the story over and over again is also keeping me from letting it go. And I’m still healing.”

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

Patients with a history of depression who are also being treated with opioid analgesics have a lower risk for overdose and self-harm after taking antidepressants, new research suggests.

Investigators analyzed insurance claims for more than 200,000 adults with a history of depression. Of these, 8,200 experienced adverse events (AEs) during the year after initiation of opioid therapy.

However, the risk for an AE such as overdose and other forms of self-harm was reduced among patients who had been treated with antidepressants for at least 6 weeks.

The take-home message is that clinicians and health systems need to be more aware that individuals in pain are more likely to be depressed and at higher risk for AEs – so the depression should be treated “more liberally,” corresponding author Bradley Stein, MD, PhD, a practicing psychiatrist in Pittsburgh and director of the Rand Corporation Opioid Policy Center, told this news organization.

“If you are treating someone with pain, particularly chronic pain, it’s critically important to better assess their depression and not to attribute depressive symptoms only to pain,” Dr. Stein said.

The findings were published online  in Psychiatric Services.
 

Promising approach?

Opioid treatment for pain “complicates the interactions among pain, depression, and self-harm,” the investigators write. Individuals with depression receiving long-term opioid therapy are two to three times more likely to misuse opioids, compared with individuals who do not have depression.

Although comorbid depression “substantially increases overdose and suicide risk, it remains underdiagnosed and undertreated among individuals with chronic pain,” the researchers note. They add that increasing access to depression treatment may be a “potentially promising approach to preventing overdoses and suicide” in these patients.

“We know that individuals using opioids who have a history of depression are more likely to have negative outcomes, such as overdoses and self-harm events,” Dr. Stein said. “We wanted to see whether antidepressants, which would treat depression in these individuals, would help with that.”

The researchers assessed a database of commercial insurance claims of adults with a history of depression who received opioids between 2007 and 2017 (n = 283,374). The data included 336,599 opioid treatment episodes.

To be included in the study, patients had to have been diagnosed with depression before they filled their first opioid prescription.

The “outcome of interest” was time from the beginning of an opioid episode until an adverse event, such as opioid poisoning, overdose of nonopioid controlled or illicit substances, or self-harm unrelated to overdose.

Participants were followed from the onset of the opioid episode until an AE occurred, loss to follow-up, or week 52, whichever came first.

The “key independent variable” was filling an antidepressant prescription. The patient’s sex and age were considered to be independent variables as well.
 

Teasing out antidepressant effect

Of participants with a history of depression treatment, 8,203 experienced at least one AE during the 12 months after treatment initiation (n = 47,486 AEs). Approximately half (50.8%) filled an antidepressant prescription at least once during the 12 months after the opioid episode began.

AEs were more likely among men than among women. The highest risk was in patients aged 18-24 years.

After adjusting for age and sex, participants who had received antidepressants had a greater risk for all adverse outcomes during the first 6 weeks of antidepressant treatment. However, those who had received antidepressants for 6 weeks or longer were at reduced risk for all adverse outcomes.

Consider CBT?

Andrew Saxon, MD, professor, department of psychiatry and behavioral sciences, University of Washington School of Medicine, Seattle, said clinicians “tend to think categorically and give people diagnoses that are clear-cut.” But neurobiologically, “it may be hard to distinguish where chronic pain ends and depression begins, or whether there’s some commonality.”

For patients with chronic pain and those taking opioids, “we need to be very attuned to the possibility or likelihood that they have major depression and other psychiatric diagnoses, like PTSD and anxiety disorders, which are very common,” said Dr. Saxon, who is also the director of the Center of Excellence in Substance Abuse Treatment and Education at the VA Puget Sound Health Care System. He was not involved with the current research.

He noted that treating those disorders “is a very important component of managing chronic pain.” However, “patients just starting antidepressants need to be carefully monitored when they’re getting stabilized on their antidepressants because they can have side effects, particularly early on, that can destabilize them.”

Dr. Saxon added that beyond pharmacotherapy, cognitive-behavioral therapy (CBT) for pain might be an even better intervention for addressing both pain and depression.

Also commenting for this article, Brian Hurley, MD, an addiction medicine specialist and the medical director of the Division of Substance Abuse Prevention and Control for the Los Angeles County Department of Public Health, said: “In the context of the largest wave of overdose mortality in U.S. history, we know comparatively little about the impact of mental health interventions that mitigate overdose risks.”

This study “contributes important new information that treating depression with antidepressant medications reduces overdose and self-harm risks for people who are prescribed opioids,” said Dr. Hurley, who is also the president-elect of the American Society of Addiction Medicine.

It also “underscores the general importance of integrated mental health and substance use disorder treatment in both primary care and in mental health settings,” added Dr. Hurley, who was not involved with the study.

The study was funded by the National Institute on Drug Abuse. The investigators and commenters reported no relevant financial relationships.

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

Patients with a history of depression who are also being treated with opioid analgesics have a lower risk for overdose and self-harm after taking antidepressants, new research suggests.

Investigators analyzed insurance claims for more than 200,000 adults with a history of depression. Of these, 8,200 experienced adverse events (AEs) during the year after initiation of opioid therapy.

However, the risk for an AE such as overdose and other forms of self-harm was reduced among patients who had been treated with antidepressants for at least 6 weeks.

The take-home message is that clinicians and health systems need to be more aware that individuals in pain are more likely to be depressed and at higher risk for AEs – so the depression should be treated “more liberally,” corresponding author Bradley Stein, MD, PhD, a practicing psychiatrist in Pittsburgh and director of the Rand Corporation Opioid Policy Center, told this news organization.

“If you are treating someone with pain, particularly chronic pain, it’s critically important to better assess their depression and not to attribute depressive symptoms only to pain,” Dr. Stein said.

The findings were published online  in Psychiatric Services.
 

Promising approach?

Opioid treatment for pain “complicates the interactions among pain, depression, and self-harm,” the investigators write. Individuals with depression receiving long-term opioid therapy are two to three times more likely to misuse opioids, compared with individuals who do not have depression.

Although comorbid depression “substantially increases overdose and suicide risk, it remains underdiagnosed and undertreated among individuals with chronic pain,” the researchers note. They add that increasing access to depression treatment may be a “potentially promising approach to preventing overdoses and suicide” in these patients.

“We know that individuals using opioids who have a history of depression are more likely to have negative outcomes, such as overdoses and self-harm events,” Dr. Stein said. “We wanted to see whether antidepressants, which would treat depression in these individuals, would help with that.”

The researchers assessed a database of commercial insurance claims of adults with a history of depression who received opioids between 2007 and 2017 (n = 283,374). The data included 336,599 opioid treatment episodes.

To be included in the study, patients had to have been diagnosed with depression before they filled their first opioid prescription.

The “outcome of interest” was time from the beginning of an opioid episode until an adverse event, such as opioid poisoning, overdose of nonopioid controlled or illicit substances, or self-harm unrelated to overdose.

Participants were followed from the onset of the opioid episode until an AE occurred, loss to follow-up, or week 52, whichever came first.

The “key independent variable” was filling an antidepressant prescription. The patient’s sex and age were considered to be independent variables as well.
 

Teasing out antidepressant effect

Of participants with a history of depression treatment, 8,203 experienced at least one AE during the 12 months after treatment initiation (n = 47,486 AEs). Approximately half (50.8%) filled an antidepressant prescription at least once during the 12 months after the opioid episode began.

AEs were more likely among men than among women. The highest risk was in patients aged 18-24 years.

After adjusting for age and sex, participants who had received antidepressants had a greater risk for all adverse outcomes during the first 6 weeks of antidepressant treatment. However, those who had received antidepressants for 6 weeks or longer were at reduced risk for all adverse outcomes.

Consider CBT?

Andrew Saxon, MD, professor, department of psychiatry and behavioral sciences, University of Washington School of Medicine, Seattle, said clinicians “tend to think categorically and give people diagnoses that are clear-cut.” But neurobiologically, “it may be hard to distinguish where chronic pain ends and depression begins, or whether there’s some commonality.”

For patients with chronic pain and those taking opioids, “we need to be very attuned to the possibility or likelihood that they have major depression and other psychiatric diagnoses, like PTSD and anxiety disorders, which are very common,” said Dr. Saxon, who is also the director of the Center of Excellence in Substance Abuse Treatment and Education at the VA Puget Sound Health Care System. He was not involved with the current research.

He noted that treating those disorders “is a very important component of managing chronic pain.” However, “patients just starting antidepressants need to be carefully monitored when they’re getting stabilized on their antidepressants because they can have side effects, particularly early on, that can destabilize them.”

Dr. Saxon added that beyond pharmacotherapy, cognitive-behavioral therapy (CBT) for pain might be an even better intervention for addressing both pain and depression.

Also commenting for this article, Brian Hurley, MD, an addiction medicine specialist and the medical director of the Division of Substance Abuse Prevention and Control for the Los Angeles County Department of Public Health, said: “In the context of the largest wave of overdose mortality in U.S. history, we know comparatively little about the impact of mental health interventions that mitigate overdose risks.”

This study “contributes important new information that treating depression with antidepressant medications reduces overdose and self-harm risks for people who are prescribed opioids,” said Dr. Hurley, who is also the president-elect of the American Society of Addiction Medicine.

It also “underscores the general importance of integrated mental health and substance use disorder treatment in both primary care and in mental health settings,” added Dr. Hurley, who was not involved with the study.

The study was funded by the National Institute on Drug Abuse. The investigators and commenters reported no relevant financial relationships.

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

Patients with a history of depression who are also being treated with opioid analgesics have a lower risk for overdose and self-harm after taking antidepressants, new research suggests.

Investigators analyzed insurance claims for more than 200,000 adults with a history of depression. Of these, 8,200 experienced adverse events (AEs) during the year after initiation of opioid therapy.

However, the risk for an AE such as overdose and other forms of self-harm was reduced among patients who had been treated with antidepressants for at least 6 weeks.

The take-home message is that clinicians and health systems need to be more aware that individuals in pain are more likely to be depressed and at higher risk for AEs – so the depression should be treated “more liberally,” corresponding author Bradley Stein, MD, PhD, a practicing psychiatrist in Pittsburgh and director of the Rand Corporation Opioid Policy Center, told this news organization.

“If you are treating someone with pain, particularly chronic pain, it’s critically important to better assess their depression and not to attribute depressive symptoms only to pain,” Dr. Stein said.

The findings were published online  in Psychiatric Services.
 

Promising approach?

Opioid treatment for pain “complicates the interactions among pain, depression, and self-harm,” the investigators write. Individuals with depression receiving long-term opioid therapy are two to three times more likely to misuse opioids, compared with individuals who do not have depression.

Although comorbid depression “substantially increases overdose and suicide risk, it remains underdiagnosed and undertreated among individuals with chronic pain,” the researchers note. They add that increasing access to depression treatment may be a “potentially promising approach to preventing overdoses and suicide” in these patients.

“We know that individuals using opioids who have a history of depression are more likely to have negative outcomes, such as overdoses and self-harm events,” Dr. Stein said. “We wanted to see whether antidepressants, which would treat depression in these individuals, would help with that.”

The researchers assessed a database of commercial insurance claims of adults with a history of depression who received opioids between 2007 and 2017 (n = 283,374). The data included 336,599 opioid treatment episodes.

To be included in the study, patients had to have been diagnosed with depression before they filled their first opioid prescription.

The “outcome of interest” was time from the beginning of an opioid episode until an adverse event, such as opioid poisoning, overdose of nonopioid controlled or illicit substances, or self-harm unrelated to overdose.

Participants were followed from the onset of the opioid episode until an AE occurred, loss to follow-up, or week 52, whichever came first.

The “key independent variable” was filling an antidepressant prescription. The patient’s sex and age were considered to be independent variables as well.
 

Teasing out antidepressant effect

Of participants with a history of depression treatment, 8,203 experienced at least one AE during the 12 months after treatment initiation (n = 47,486 AEs). Approximately half (50.8%) filled an antidepressant prescription at least once during the 12 months after the opioid episode began.

AEs were more likely among men than among women. The highest risk was in patients aged 18-24 years.

After adjusting for age and sex, participants who had received antidepressants had a greater risk for all adverse outcomes during the first 6 weeks of antidepressant treatment. However, those who had received antidepressants for 6 weeks or longer were at reduced risk for all adverse outcomes.

Consider CBT?

Andrew Saxon, MD, professor, department of psychiatry and behavioral sciences, University of Washington School of Medicine, Seattle, said clinicians “tend to think categorically and give people diagnoses that are clear-cut.” But neurobiologically, “it may be hard to distinguish where chronic pain ends and depression begins, or whether there’s some commonality.”

For patients with chronic pain and those taking opioids, “we need to be very attuned to the possibility or likelihood that they have major depression and other psychiatric diagnoses, like PTSD and anxiety disorders, which are very common,” said Dr. Saxon, who is also the director of the Center of Excellence in Substance Abuse Treatment and Education at the VA Puget Sound Health Care System. He was not involved with the current research.

He noted that treating those disorders “is a very important component of managing chronic pain.” However, “patients just starting antidepressants need to be carefully monitored when they’re getting stabilized on their antidepressants because they can have side effects, particularly early on, that can destabilize them.”

Dr. Saxon added that beyond pharmacotherapy, cognitive-behavioral therapy (CBT) for pain might be an even better intervention for addressing both pain and depression.

Also commenting for this article, Brian Hurley, MD, an addiction medicine specialist and the medical director of the Division of Substance Abuse Prevention and Control for the Los Angeles County Department of Public Health, said: “In the context of the largest wave of overdose mortality in U.S. history, we know comparatively little about the impact of mental health interventions that mitigate overdose risks.”

This study “contributes important new information that treating depression with antidepressant medications reduces overdose and self-harm risks for people who are prescribed opioids,” said Dr. Hurley, who is also the president-elect of the American Society of Addiction Medicine.

It also “underscores the general importance of integrated mental health and substance use disorder treatment in both primary care and in mental health settings,” added Dr. Hurley, who was not involved with the study.

The study was funded by the National Institute on Drug Abuse. The investigators and commenters reported no relevant financial relationships.

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