Paul Gleason, PhD

“Sleep problems are understudied,” Ellen Lee, MD, told attendees at the 2021 American Psychiatric Association (APA) Annual Meeting. “They’re underdiagnosed and undertreated in people with mental illness.” Thus, Lee encouraged clinicians to screen for sleep problems, because sleep “is a modifiable and important target for intervention.” Lee, along with other colleagues, shared insights and preliminary research results on how sleep may impact mental health and psychiatric disorders.

Sleep problems affect between 30 and 80% of individuals with schizophrenia and are associated with lower quality of life and poorer cognitive and frontal lobe functioning, explained Lee, assistant professor in residence in the Department of Psychiatry at the University of California at 

 In as-yet unpublished research, Lee found that sleep apnea is associated with increased inflammation, while higher subjective reports of sleep quality are associated with lower levels of inflammation. Since inflammation is also associated with 

 treating sleep problems could also improve the symptoms of mental illnesses.

Beyond schizophrenia, sleep issues also appear in mood disorders like depression. Stephen Smagula, PhD, presented research on possible links between morning activation deficits and depression among family members caring for patients with dementia.

Older individuals with depression often report difficulty getting up and active in the 

 Morning activation deficits are sometimes thought to be immutable (some individuals are just not morning people), but in functional magnetic resonance imaging readings, dementia caregivers with depression showed higher resting-state amygdala-PCC connectivity, which is associated with stress, fear, and 

 “Although this is speculative,” Smagula cautioned, “it seems plausible that the non-morning type caregivers are doing behaviorally disengaged, emotion-focused coping. So put another way, some caregivers might wake up, feel overwhelmed, say ‘Expletive! I’m going back to bed.’”

This raises the possibility, according to Smagula, who is assistant professor of psychiatry and epidemiology at the University of Pittsburg, that “instead of treating the depression and hoping the morning activation deficit goes away, we could be targeting the morning activation deficit to treat the depression.” Clinicians could consider treatments such as activity scheduling, which would get the caregivers up and moving, increase their light exposure, decrease fragmented sleep, and limit the time they spend ruminating—all of which could improve their depressive symptoms.

Sleep also affects cognition, especially in older adults. Ruth O’Hara, PhD, presented initial data on the impacts of delta activity at sleep onset (DASO). Study participants with DASO demonstrated better affective function overall and over time, which led O’Hara to conclude that testing DASO or other variables may help clinicians predict patients’ cognitive futures. “We think that characterizing sleep dysregulation in older adults may in fact identify valuable biomarkers,” explained O’Hara, who is the Josephine Q. Berry Professor of Psychiatry and Behavioral Sciences at Stanford University. They could “help us predict cognitive decline and onset of dementia, as well as predicting affective dysfunction.”

1. Cohrs S. Sleep disturbances in patients with schizophrenia: impact and effect of antipsychotics. 

2. Keshavan MS, Montrose DM, Miewald JM, Jindal RD. Sleep correlates of cognition in early course psychotic disorders. 

3. Bromundt V, Köster M, Georgiev-Kill A, et al. Sleep-wake cycles and cognitive functioning in schizophrenia. 

4. Lee EE, Ancoli-Israel S, Eyler LT, et al. Sleep disturbances and inflammatory biomarkers in schizophrenia: focus on sex differences. 

5. Smagula SF, Capps CS, Krafty RT. Evaluating the timing of differences in activity related to depression symptoms across adulthood in the United States. 

6. Smagula SF, Karim HT, Ibrahim TS, et al. Resting-state function connectivity associated with being a "morning-type" dementia caregiver and having lower depression symptom severity. 

Articles

Sleep problems are understudied, underdiagnosed, and undertreated. 

Dreaming of New Treatments

 has partially clarified the role of microglia cells in the progression of Alzheimer disease (AD), which in turn may lead to new targets for 

Normally, microglia cells are responsible for clearing out amyloid plaques and other kinds of cellular debris, but in cases of AD progression 

 Investigators at Duke-National University of Singapore (NUS) Medical School and Monash University set out to discover why. “We sought to understand the molecular mechanisms and differences between microglia that were actively engulfing amyloid plaques in Alzheimer’s disease and those that weren’t,” Enrico Petretto, PhD, associate professor at Duke-NUS Medical School, said in a statement to the press.

When comparing microglia that were and were not eliminating amyloid plaque, Petretto and his co-investigators found that they had different gene expression patterns induced by the 

 gene. The researchers found that microglia cells with reduced 

 expression also had a decreased ability to take up and eliminate an abnormal protein like amyloid. Conversely, high expressions of 

 were associated with more active and effective microglia cells.

“Understanding this mechanism is important because now we have several new targets to go after, and in the future, these targets may open a new front against this devastating disease,” added Jose M. Polo, PhD, an ARC Future Fellow at Monash University.

 This research is built on a larger Duke-NUS initiative to create a comprehensive map of gene expression changes that are associated with AD 

 and AD remains incompletely understood, “future work could focus on using gene editing tool CRISPR to test the impact of manipulating Hif1a on symptom severity and disease progression,” Gabriel Chow, MD-PhD candidate at Duke-NUS Medical School, further explained.

1. Grubman A, Choo XY, Chew G, et al. Transcriptional signature in microglia associated with Aβ plaque phagocytosis. 

Scientists discover gene signature for plaque-eating microglia in Alzheimer’s disease

Duke-NUS study reveals how individual cell types in the brain contribute to Alzheimer’s disease

. Duke-NUS Medical School. November 28, 2019. Accessed May 27, 2021. 

Gene expressions in microglia cells may explain why some of them are ineffective and allow dementia to progress. 

A New Target for Intervention in Alzheimer Disease? 

“There’s more to trauma than physicality,” Rachel Yehuda, PhD told attendees at the 2021 American Psychiatric Association (APA) Annual Meeting. “For decades we have been talking about how to integrate pharmacotherapy with psychotherapy. But we haven’t understood how to do it.” 

For patients with posttraumatic stress disorder (PTSD), one possibility is combining therapy and mind-altering drugs, like 3,4-methyl​enedioxy​methamphetamine (MDMA), panelists explained.

Mark Bates, PhD, former branch chief for Psychological Health Promotion in the Department of Defense’ Psychological Health Center of Excellence, presented findings from 6 phase 2 trials of combined MDMA and psychotherapy in the 

 The studies included 103 participants who had experienced treatment-resistant PTSD symptoms on average for more than 15 years.

Participants progressed through several types of sessions in all of the studies. First, participants and clinicians conducted an initial, 90-minute interview, preparing the participants for the MDMA-assisted sessions and discussing their PTSD. Then participants underwent 8-hour MDMA-assisted or placebo sessions. During this time, participants wore eyeshades and listened to music, and had the option of discussing their troubling experiences.

The participants who received MDMA experienced an altered mental state, which was believed to make the discussion easier on them as compared with those in the placebo group. “One of the most important features,” Bates said, “is this reduced fear response in combination with increased empathy, trust, and closeness. In the words of one participant, ‘it’s like being in a box full of puppies.’ You can actually feel safe to bring up things that were otherwise very uncomfortable.”

Participants and therapists debriefed for 90 minutes the day after the MDMA session. Integration, Bates explained, helps “the patients retrieve and consolidate much of what happened during the dosing session and integrate it into their daily lives.”

The results of the studies were encouraging, he reported. Among participants who received MDMA, 56% no longer met PTSD criteria by the end of the study and, at a 12-month follow-up, that number rose to 67%.

 Mean change on participants’ Clinician Administered PTSD Scale (CAPS-IV) fell around 45 points. Meanwhile, 23% of participants who received the placebo did not meet criteria for PTSD by the end of the study.

Robert Koffman, MD, dug deeper into the science behind MDMA’s potential effects. “We really don’t know how it is that MDMA actually works,” admitted Koffman, first senior consultant for integrative medicine and behavioral health at the National Intrepid Center of Excellence. He noted research indicates that MDMA seems to create the exact opposite effects of PTSD: Whereas PTSD is associated with increases in amygdalar activity, heightened fear responses, decreased hippocampal activity, emotional numbness and distrustful hypervigilance, MDMA is associated with reduced amygdalar activity, increased hippocampal activity, reductions in fear and defensiveness, and higher feelings of 

 In short, Koffman said, “MDMA increases access to these traumatic memories without the kind of flooding and emotional numbing characterized by the speechless terrors” that usually accompany PTSD.

However, Koffman noted the altered mental state induced by MDMA is not enough to achieve positive results. “What we are really discussing in this talk,” he said, “is the relationship between the drug and the therapy.” In addition, the therapy involves additional training to be successful, he cautioned. A therapist should not try to understand the patients’ problems rationally and then use specific techniques to change their situation; instead, he explained, therapist’ goal should be to mediate their patient’s access to deep states of their psyches and facilitate “a powerful transformational experience of a 

During the Q and A session Yehuda, who is director of the Center for Psychedelic Psychotherapy and Trauma Research at Mount Sinai School of Medicine, said that psychedelic-assisted psychotherapy raised important questions about the nature of psychiatric healing. “This is almost treasonous for a psychiatry meeting,” she admitted, “but the actual molecule and neurochemical effects are probably a lot less important to the healing than the fact that you have provided an opportunity to look at something that [the patient] couldn’t see, because it was either too painful or it was blocked.”

“The future is here,” Koffman concluded. Although MDMA is currently a Schedule 1 drug, the Multidisciplinary Association for Psychedelic Studies “fully expects MDMA to be rescheduled by 2023, possibly even by next year.”

In fact, MDMA treatments are about to pass another important milestone. Next month 

will publish results of a phase 3 trial in which 67% of participants no longer met criteria for PTSD after 2 months of treatment with 

“We are so comfortable with our molecules and our neurochemistry,” said Yehuda. “But I know enough to know that the answers are not just in the molecule. It has to do with the entire healing process. The good news is that makes clinicians really important.”

1. Jerome L, Feduccia AA, Wang JB, et al. Long-term follow-up outcomes of MDMA-assisted psychotherapy for treatment of PTSD: a longitudinal pooled analysis of six phase 2 trials. 

2. Mithoefer MC, Wagner MT, Mithoefer AT, et al. The safety and efficacy of {+/-}3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. 

3. Feduccia AA, Mithoefer MC. MDMA-assisted psychotherapy for PTSD: Are memory reconsolidation and fear extinction underlying mechanisms? 

Prog Neuropsychopharmacol Biol Psychiatry

4. Mithoefer, MD. A manual for MDMA-assisted psychotherapy in the treatment of posttraumatic stress disorder. Multidisciplinary Association for Psychedelic Studies. August 19, 2015. Accessed May 5, 2021. 

5. Nuwer R. A psychedelic drug passes a big test for PTSD treatment. 

New research find altered states of consciousness may allow veterans and other patients with PTSD to face unspeakable experiences and find peace. 

Looking to the Future of MDMA-Assisted Psychotherapy

Psychiatry may be lagging behind other branches of medicine in an important way.

“In the rest of medicine, as you increase the acuity you increase the number of treatments,” Nolan Williams, MD, told the attendees of the 2021 American Psychiatric Association (APA) Annual Meeting, but in psychiatry, “as we increase acuity we actually lose treatment options.”

Williams and his fellow presenters at a panel on rapidly acting medications

 all had the same question: How can psychiatrists design treatments to respond to sudden-onset conditions?

Williams, assistant professor of psychiatry and behavioral sciences at Stanford University Medical Center, described the situation as “emergency room purgatory.” Because of slow-acting treatments and limited hospital capacity, “the whole process of going through the inpatient unit can take several months,” he said. “The only treatment that we have available for these folks is ECT [electroconvulsive therapy.” But ECT is available in only 10% of US hospitals.

However, psychiatrists might have other options for fast-acting treatments. He shared 

showing that accelerated theta burst repetitive transcranial magnetic stimulation (r-TMS) had positive results for mood disorders, including MDD.

 R-TMS treatment works by stimulating the left dorsolateral prefrontal cortex (DLPFC). In MDD, the DLPFC may be failing to inhibit the subgenual cingulate, and the result of this network failure is cognitive impairment and inwardly directed negative thoughts,” Nolan explained. “By stimulating DLPFC, r-TMS corrects the mood imbalance and restores mood regulation.”

In initial numbers from his study of patients with a treatment-resistant mood disorder (TRD), Nolan found that after 5 days of sessions (10 hourly sessions at 1800 theta-burst pulses per hour), participants improved. On the Montgomery Asberg Depression Rating Scale (MADRS), he found an 80% average reduction of participants MADRS scores.

Another options for fast-acting treatment is ketamine. Charles DeBattista, MD, professor of psychiatry and behavioral sciences at Stanford University, presented evidence for its efficacy for TRD. He noted that ketamine is an anesthetic agent, a μ-opioid agonist, and while its effects on TRD are rapid, making it potentially helpful in psychiatric emergencies. “Often within a couple of hours to a day, patients experience a significant improvement, and the effects were sustained for a week or so,” he said. These effects did decrease after a week, but there is also evidence that repeated injections may lead to 

DeBattista also presented the option of esketamine, which has been fast tracked by the US Food and Drug Administration for treating TRD and acute suicidality in MDD. Multiple studies have found that it rapidly 

New mothers represent another population that might benefit from fast-acting medications. “Maternal mental health is something that’s been an enormous problem forever,” said Samantha Meltzer-Brody, MD, MPH. “Those of us that have the privilege of working with perinatal women are always struck by how debilitating PPD [postpartum depression] can be.” Rapidly acting medications could reduce mortality and morbidity, she said, and allow for more positive interactions between mothers and their newborns.

Although many selective serotonin reuptake inhibitors are approved to treat PPD, she pointed out that their initial effects may not be felt for weeks or even months, and many women’s symptoms do not respond to them. Meltzer-Brody, the Assad Meymandi Distinguished Professor and Chair in the University of North Carolina Department of Psychiatry, also considers an alternative to these medications: neurosteroids like brexanolone.

In a 2018 paper, Meltzer-Brody and her coauthors found brexanolone to be effective for

 Using the HDRS for measurement, the researchers found an average 8- to 10-point reduction in 12 hours, and around an 18-point reduction at 60 hours, the study’s primary endpoint. At day 30, participants average reduction remained, on average, 16 points down from baseline. The paper hypothesized that brexanolone works by increasing γ-aminobutyric acid (GABA) function, which appears to be inhibited during PPD.

With these new options, it seems psychiatry may not lag behind other branches of medicine for long. 

1. Williams N. Developing rapidly acting antidepressants: neurosteroids, dissociative agents (Ketamine Analogues and Psilocybin), and Accelerated Theta Burst r-TMS. Paper presented at: American Psychiatric Association Annual Meeting; May 1-3, 2021; virtual.

2. Nettekoven C, Volz LJ, Kutscha M, et al. Dose-dependent effects of theta burst rTMS on cortical excitability and resting-state connectivity of the human motor system. 

3. Li CT, Chen MH, Juan CH, et al. Efficacy of prefrontal theta-burst stimulation in refractory depression: a randomized sham-controlled study. 

4. Yip AG, George MS, Tendler A, et al. 61% of unmedicated treatment resistant depression patients who did not respond to acute TMS treatment responded after four weeks of twice weekly deep TMS in the Brainsway pivotal trial. 

5. Murrough JW, Perez AM, Pillemer S, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. 

6. Canuso CM, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: results of a double-blind, randomized, placebo-controlled study. 

7. Fu DJ, Ionescu DF, Li X, et al. Esketamine nasal spray for rapid reduction of major depressive disorder symptoms in patients who have active suicidal ideation with intent: double-blind, randomized study (ASPIRE I). 

8. Meltzer-Brody S, Colquhoun H, Riesenberg R, et al. Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials. 

What treatments could handle both psychiatric emergencies and long-standings mental health conditions—in a hurry?  

Fast-Acting Options for Mood Disorders and Psychiatric Emergencies

“Ethical dilemmas arise when there are multiple ethical responsibilities that stand in tension with each other,” Charles Dike, FRCPsych, MBChB, MPH, told the attendees of the American Psychiatric Association (APA) Annual Meeting.

At a panel on “Ethical Dilemmas in Psychiatric Practice,” one dilemma stood out: the possible conflict between psychiatrists’ duties to their individual patients and their duties to promote the good of the public as a whole.

This conflict has become particularly pressing this past year due to the global pandemic, and the panelists considered the problem from several angles as they answered previously submitted questions.

One question concerned confidentiality: What should be done when a patient reports her parents are sending another child to school despite the child’s positive SARS-COV-2 virus results?

Daniel J. Anzia, MD, a member of the expert panel, explained “the participation in public health endeavors is a long-standing, recognized potential exception to the obligations of psychiatrists, and all physicians, maintaining confidentiality.” Past department chair for psychiatry at Advocate Lutheran General Hospital in Park Ridge, Illinois, Anzia said ideally the patient (who was no longer a minor) would make the report to the school, and then inform the family that public health officials might be contacting them. But, he added, if the patient refused, “it is permissible for the psychiatrist to make such a report.”

Another question asked what psychiatrists should do if patients insisted on being seen in person, even at the height of the pandemic. Panel member, Tia Patricia Powell, MD, Director of the 

, told attendees they are not required to put themselves at physical risk. “Among our many obligations as psychiatrists is to provide a safe space in which we can offer therapy for our patients. That includes keeping the patient and psychiatrist safe from each other in terms of communicating the virus,” she explained.

Powell noted that many psychiatrists have extended their own knowledge of telehealth, discharging their obligation to offer care in person by working with patients to make telehealth possible. If the patient refuses telehealth, protective gear, and vaccination, “it could be legitimate for a psychiatrist to say, ‘I’m not at this time able to continue working with you.’”

Along the lines of vaccinations, are psychiatrists obligated to get an available vaccine for SARS-COV-2? Although “a psychiatrist has a right to refuse the vaccine, the psychiatrist should consider their wider obligations of such a decision, including an unspoken statement—to the psychiatrist’s colleagues and patients—that the psychiatrist does not trust the vaccine,” said Dike, associate professor of psychiatry at Yale School of Medicine and associate program director of its 

. “This could discourage vulnerable patients from taking what could be a life-saving intervention.”

What are the obligations of a psychiatrist to a new patient who has yet to be seen? The panel was presented with a situation in which a patient fills in a reports suicidal thoughts on a new pre-visit questionnaire, and then does not come to the appointment or answer calls. Should the psychiatrist send someone to check on the patient?

Panelist Rebecca Brendel, MD, JD, detected a potential conflict between the psychiatrist’s duty to the individual patient and the public at large. “We’d hate to say we’re not going to screen patients for suicidality because it’s too hard to figure out what to do with the information,” said Brendel, assistant professor of psychiatry at Harvard Medical School and director of its Master in Bioethics program. However, she noted the need for a follow-up mechanism that does not overstep the bounds of a nascent doctor-patient relationship by violating the prospective patient’s rights to privacy and confidentiality.

One of the more controversial topics over the past few years has been what psychiatrists—or the APA as a whole—should say about the national psyche and potentially dangerous political leaders or movements. Brendel quickly reaffirmed the 

 but also insisted that “psychiatrists can participate in public life by adding insight and knowledge about mental health more generally.” For instance, psychiatrists might use their knowledge of history and psychology to “make some comment about what might lead groups of persons to become susceptible to certain beliefs, be prone to questioning authority in violent ways, and also to be thinking about how unrest or extremism or discriminatory views might affect certain members of our society, and in particular their mental health.”

Striking a balance between obligations to patients and society during a plague year might seem like an exceptional circumstance, but Philip Candilis, MD, reminded attendees that medical ethicists have previously faced similar situations. In fact, Candilis, professor of psychiatry and behavioral sciences at George Washington University School of Medicine and Health, noted that the field of medical ethics arguably began during a deadly outbreak. “When Thomas Percival wrote his 

, it was in response to the typhus epidemic in Manchester [UK],” Candilis said. During the plague, doctors fled the city, leaving many patients without care. In response the government demanded new professional guidance and ethical standards for physicians, 

Several decades later, the American Medical Association adopted Percival’s standards. The ethical dilemmas with which he grappled remain relevant today, and they will likely come up again. “How do you protect yourself as a doctor,” asked Candilis, “How do you protect your family, and how do you work for the public good at the same time? This is a difficult, difficult balance to strike.”

The panel reminded attendees that ethics resources and official APA opinions could be find on the APA’s Ethics webpage 

https://www.psychiatry.org/psychiatrists/practice/ethics

. Queries can be submitted to the APA’s Ethics Committee staff liaison for further guidance at apaethics@psych.org. Similarly, 

 readers can submit ethical dilemmas to our Ethics Editor via 

What’s a psychiatrist to do? An APA ethics panel at the Annual Meeting considered various dilemmas, including possible conflicts between physicians’ obligations to individual patients and their obligation to promote the public good. 

Expert Panel Ponders What It Takes To Be an Ethical Psychiatrist  

has identified a potential new mechanism for treating depression. 

The study, conducted by researchers at the Icahn School of Medicine at Mount Sinai, used the drug ezogabine to open the KCNQ2/3 potassium channels in participants’ brains. The results showed significant improvements in 

 Because anhedonia is associated with poor response to antidepressant medication, worse overall outcomes, and increased suicide risk, this finding is especially important. 

“Our study is the first randomized, placebo-controlled trial to show that a drug affecting this type of ion channel in the brain can improve depression and anhedonia in patients,” said the paper’s lead author, James Murrough, MD, PhD, associate professor of Psychiatry and Neuroscience at the Icahn School of Medicine at Mount Sinai. “Targeting this channel represents a completely different mechanism of action than any currently available antidepressant treatment.”

The study included 45 participants with high levels of anhedonia and divided them into 

 The treatment lasted 5 weeks, with clinical measures of depression and anhedonia taken at weekly visits. Although the study did not meet its primary endpoint at the 5-week mark, it found that participants on ezogabine had increased reward anticipation and large improvements on the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Snaith-Hamilton Pleasure Scale (SHAPS), compared with the placebo.

The United States Food and Drug Administration approved ezogabine in 2011 as an anticonvulsant for epilepsy, but this is the first study to test it as a depression treatment. The drug acts on the KCQ2/3 channel, which affects brain cell function by regulating the movement of electrical charges across cell membranes.

A previous study led by co-author Ming-Hu Han, PhD, found that changes in KCNQ2/3 potassium partially determined whether mice showed 

signs of depression and anhedonia following stress

 Mice with increased KCNQ2/3 channels in their brains appeared resistant to depression. When the mice were given drugs to increase KCNQ2/3 channel activity, previously depressed mice no longer showed depressive or anhedonic behaviors.

“The fundamental insight by Dr Han’s group that a drug that essentially mimicked a mechanism of stress resilience in the brain could represent a whole new approach to the treatment of depression was very exciting to us,” said Murrough.

 The previous study by Han’s group paved the way for the current study.

“I think it’s fair to say that most of us on the study team were quite surprised at the large size of the beneficial effect of ezogabine on clinical symptoms across multiple measures related to depression,” Han said of the current study.

 “We are greatly encouraged by these findings and the hope they offer for the prospect of developing novel, effective treatments for depression and related disorders.”

1. Mount Sinai Health System. Researchers identify brain ion channel as new approach to treating depression. 

. March 1, 2021. Accessed April 7, 2021. 

https://www.newswise.com/articles/researchers-identify-brain-ion-channel-as-new-approach-to-treating-depression?sc=dwhr&xy=5013482

2. Costi S, Morris LS, Kirkwood KA, et al. Impact of the KCNQ2/3 channel opener ezogabine on reward circuit activity and clinical symptoms in depression: results from a randomized controlled trial. 

3. Friedman AK, Juarez B, Ku SM, et al. KCNQ channel openers reverse depressive symptoms via an active resilience mechanism. 

Opening certain potassium channels in the brain reduces depressive symptoms and anhedonia. 

Is There a New Mechanism for Treating Depression?

“The problem of treatment-resistant depression in later life [TRD-LL] is increasingly recognized but remains poorly characterized,” Randall Espinoza, MD, MPH, told the audience at the American Association of Geriatric Psychiatry Annual Meeting. According to Espinoza, estimates of its prevalence run from 6% up to 40% in geriatric patients with depression, depending on how treatment-resistant depression (TRD) is defined.

At a session titled “Beyond ECT – Neuromodulation and Interventional Psychiatry for Treatment Resistant Depression in Later Life,” Espinoza and his colleagues Aaron Kaufman, MD, and Ali Ashghar-Ali, MD, discussed the challenges of identifying and treating TRD in older patients, including the latest results from clinical research.

TRD is associated with increases in morbidity and mortality, including greater levels of pain and suicide. It leads to higher health care costs, lower quality of life, and reduced workplace productivity. TRD can be chronic and recurrent: 20% to 35% of patients have continuous depression for more than 1 year, and 25% to 40% of patients experience a recurrence within 2 years, and 60% have a recurrence after 

Despite the prevalence of TRD, simply identifying it may be a challenge, Espinoza noted. He broke it down into 3 possible categories: 1) nonresponse to treatment and a high degree of functional impairment, 2) treatment resistant depression, which shows minimal to partial response to treatment, and 3) treatment refractory depression, which shows no response to treatment and 

 He noted that TRD may have a different epidemiology in older adult populations and may arise due to trauma, social adversity, and losses. Furthermore, treatment is complicated by brain aging and the fact that most clinical trials deliberately exclude older adults, which makes pharmacological options uncertain.

Espinoza also warned that TRD in older patients may be accompanied by significant comorbidities, including anxiety disorders, substance abuse, and cognitive and personality disorders.

In terms of treatment, Espinoza suggested that clinicians consider moving from the framing of “treatment-resistant” to a “difficult to treat” depression (DTD) model.

 The TRD model treats depression as a chronic rather than acute illness. To the biological emphasis of the TRD model, it would add a neurobiopsychosocial focus. Rather than judging progress according to cure or remission alone, it also emphasizes capability, recovery, and symptom management.

As Espinoza explained, “DTD captures not only acute phase treatment but also encourages a shift of focus to long-term treatment with the goals of improving overall function, quality of life, and optimization of treatment when full remission is no longer viable.”

Turning to more specific treatment options, Ashghar-Ali noted that “ECT remains [the] gold standard for neuromodulation intervention in older adults,” and noted clinicians have other options as well. He reviewed 2 studies of repetitive transcranial magnetic stimulation (RTMS)/DEEP TMS, which 

Ashghar-Ali also discussed ketamine. Although it is not approved by the US Federal Drug Administration (FDA) for treating TRD, ketamine has shown 

 Esketamine, however, is FDA approved for treating depression. Ashghar-Ali noted that esketamine plus an antidepressant demonstrated a statistically significant treatment effects in patients aged 65 to 74 years (although not for patients aged more than 75 years).

 He concluded that esketamine might play a helpful role in treating TRD in patients during the 64 to 75 age band.

Kaufman considered the possible role of lithium augmentation. He discussed 1 study in which lithium augmentation had a high remission rate (63.6%) among elderly patients with treatment resistant depression, and another in which geriatric patients responded significantly better to lithium augmentation than 

 He noted that some evidence also existed for augmenting with atypical antipsychotics and stimulants.

Psychotherapy is also an option. Kaufman presented from a meta-analysis of psychotherapy in later-life depression that found large effects, when compared with 

 The evidence is strongest for problem-solving therapy, interpersonal psychotherapy, and cognitive behavioral therapy. Exercise, meditation, acupuncture, and Tai Chi had also been shown to help in a number of cases.

During the Question and Answer period, both Kaufman and Ashghar-Ali spoke to why treatments beyond ETC may be necessary.

“These are of course really challenging cases,” Kaufman said. Some patients may have trouble recalling the details of her medication and adherence history, and many do not trust ECT. “We’ve all had patients decline ETC and want to pursue alternatives,” Kaufman said further.

Alternately, said Ashghar-Ali, “a lot of people come to ECT with the assumption that it’s the only option left.”

But, Ashghar-Ali and Kaufman concluded, ECT is in fact only 1 option, and there are many others for clinicians and patients.

1. Benson C, Szukis H, Sheehan JJ, et al. An evaluation of the clinical and economic burden among older adult Medicare-covered beneficiaries with treatment-resistant depression. 

2. Pilon D, Joshi K, Sheehan JJ, et al. Burden of treatment-resistant depression in Medicare: a retrospective claims database analysis. 

3. Rush AJ, Aaronson ST, Demyttenaere K. Difficult-to-treat depression: a clinical and research roadmap for when remission is elusive. 

4. Lisanby SH, Husain MM, Rosenquist PB, et al. Daily left prefrontal repetitive transcranial magnetic stimulation in the acute treatment of major depression: clinical predictors of outcome in a multisite, randomized controlled clinical trial. 

5. Conelea CA, Philip NS, Yip AG, et al. Transcranial magnetic stimulation for treatment-resistant depression: naturalistic treatment outcomes for younger versus older patients. 

6. Murrough JW, Perez AM, Pillemer S, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. 

7. Ochs-Ross R, Daly EJ, Zhang Y, et al. Efficacy and safety of esketamine nasal spray plus an oral antidepressant in elderly patients with treatment-resistant depression-TRANSFORM-3. 

8. Kok RM, Nolen WA, Heeren TJ. Outcome of late-life depression after 3 years of sequential treatment. 

9. Buspavanich P, Behr J, Stamm T, et al. Treatment response of lithium augmentation in geriatric compared to non-geriatric patients with treatment-resistant depression. 

10. Huang AX, Delucchi K, Dunn LB, Nelson JC. A systematic review and meta-analysis of psychotherapy for late-life depression. 

If patients decline electroconvulsive therapy, psychiatrists still have many good options. 

How to Identify and Tackle Treatment-Resistant Depression in Geriatric Patients

The medical science and research company Clarivate has named aducanumab, a potential Alzheimer disease (AD) treatment, as one of its top 5 “Drugs to Watch 2021.”

 Clarivate, which has published the “Drugs to Watch” list 

, included aducanumab on the list because it has a new mechanism of action and would be the first novel therapeutic for AD in more than 15 years. The company selects drugs in phase 2 or 3 trials that have the potential to bring in $1 billion in sales 

. Aducanumab is in phase 3 trials, and the US Food and Drug Administration (FDA) has promised to render its verdict in June.

, expects it will be a game changer. Lavretsky, professor in-residence in the Department of Psychiatry at the University of California, Los Angeles, told 

, “It will revolutionize Alzheimer disease treatment and care, and will have a profound impact on the lives of millions of family caregivers, who will be relieved from caring for their relatives, or the time of caregiving will be shortened, improving lives of millions of people around the world, and reducing the cost of the disease to the society.”

Aducanumab would be the first approved drug in the last 15 years that could slow down the cognitive decline associated with AD. 

, for cases across the spectrum from mild to severe, are 

The drug might address a root cause of AD. It builds on the amyloid cascade hypothesis, in which “production and accumulation of excessive amyloid-β (Aβ) may be the main cause in the onset and progression of Alzheimer's disease.”

 If so, removing or lowering of Aβ in patients with presymptomatic and early AD could be an effective therapy, and even used as a preventive, subunit vaccine.

, noted, “this drug will be the first antiamyloid therapy and disease modifying therapy for Alzheimer disease.” Tampi is professor and chairman of the Department of Psychiatry & Behavioral Sciences at the Cleveland Clinic. Lavretsky described aducanumab as a “breakthrough treatment with a novel mechanism as recombinant chimeric human IgG1 mAb targeting beta-amyloid.”

Excitement is especially strong for the drug since innovation in therapies for AD has been frustratingly slow. The problem, Tampi explained, is that AD is caused by neurological degeneration, and “it is very difficult to develop different therapies to reverse these neurobiological changes in the brain.”

Finding effective treatments has also been difficult due to “uncertainty about the underlying mechanisms of the disease, the reliance on postmortem diagnosis, and the lack of reliable biomarkers for disease early diagnosis and progression, despite almost 120-year history of research,” Lavretsky added. “Many potential therapies failed to document efficacy and did not achieve the FDA approvals.”

Sure enough, despite its promise, aducanumab has had its own set of struggles. Last November brought disappointment, when the FDA published a negative review of aducanumab, citing insufficient evidence of clinical efficacy.

The news was especially disappointing, given aducanumab’s success in previous trials. In 2015, aducanumab underwent two phase 3 efficacy trials.

 The 221AD301 ENGAGE study enrolled 1350 participants with mild cognitive impairment due to AD. It compared monthly infusions of 1 or 3 doses of aducanumab with placebo over an 18-month period, and their effects on cognitive decline. In 2017 and 2018, data from the trials showed that the treatment was slowing cognitive decline. Consequently, aducanumab became the first such DMT for AD to demonstrate clinical efficacy in a phase 3 trial.

However, in March 2019 Biogen and Eisai announced termination of ongoing aducanumab trials, due to missing primary endpoints.

 Despite the termination, further analysis of the data suggested that a subgroup of participants experienced slower cognitive decline.

Trials resumed on January 27, 2020, when Biogen announced a phase 3b study of 2400 participants who had previously used aducanumab.

 Participants were scheduled to receive monthly injections over the next 2 years. Based on this trial, Biogen requested priority review from the FDA for licensing. The FDA turned down the application in November 2020, citing the weakness of efficacy data.

After aducanumab’s developers, Biogen Inc and Eisai Co Ltd, submitted additional data, the FDA extended its decision date to June 7, 2021.

If approved, aducanumab would meet an enormous need.

“It will offer a new hope to patients and their families and therapeutic optimism to geriatric clinicians and researchers,” said Lavretsky.

https://clarivate.com/drugs-to-watch/drugs-to-watch-listing/aducanumab/

2. Yu YZ, Xu Q. Prophylactic immunotherapy of Alzheimer's disease using recombinant amyloid-β B-cell epitope chimeric protein as subunit vaccine. 

3. Talan J. FDA Panel Votes ‘No’ to Approving Audcanumab for Alzheimer’s, Citing Inconsistent Data. 

. December 3, 2020. Accessed March 9, 2021. 

https://journals.lww.com/neurotodayonline/Fulltext/2020/12030/FDA_Panel_Votes__No__to_Approving_Aducanumab_for.1.aspx

4. Aducanumab. Therapeutics. Alzforum: networking for a cure. Accessed March 9, 2021. 

https://www.alzforum.org/therapeutics/aducanumab

5. Biogen/Eisai Halt Phase 3 Aducanumab Trials. Alzforum: networking for a cure. March 21, 2019. Accessed March 9, 2021. 

https://www.alzforum.org/news/research-news/biogeneisai-halt-phase-3-aducanumab-trials

6. Biogen and Eisai Announce FDA’s 3-Month Extension of Review Period for the Biologics License Application for Aducanumab. News release. GlobeNewswire. January 29, 2021. Accessed March 9, 2021. 

https://www.globenewswire.com/news-release/2021/01/29/2166560/0/en/Biogen-and-Eisai-Announce-FDA-s-3-Month-Extension-of-Review-Period-for-the-Biologics-License-Application-for-Aducanumab.html

Aducanumab is named 1 of the 5 “Drugs to Watch” for 2021.

Is the First Disease-Modifying Therapy for Alzheimer Disease on the Horizon?

found that a combinational pharmacogenetic test was a better predictor of medication blood level and patient outcomes than single-gene testing alone.

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