Celebrating Psychiatry: Conference Highlights Advances

Kuntz,Leah;Heidi Anne Duerr, MPH;

Highlighting clinical pearls mixed with new research, the 2021 Annual Psychiatric Times^TMWorld CME Conference featured more than 30 sessions from leaders in the field.

“We have received fabulous feedback from the participants, who found our style of brief presentations followed by intensive Q&A sessions on a large range of topics engaging and enjoyable,” noted John J. Miller, MD, Co-Chair of the conference and Editor in Chief of Psychiatric Times^TM. “Our outstanding faculty facilitated fascinating discussions, complete with take-home messages and tips to keep attendees up-to-date on a wide range of psychiatric treatment approaches and protocols that continue to evolve rapidly.”

The conference, which was held virtually September 30 through October 2, also offered attendees 18.5 continuing education credits.

We are excited to begin developing our 2022 curriculum,” added Miller. Next year’s conference is scheduled for August 11 through 13 in San Diego, California.

Hello, From the Other Side: Psychiatric Complications in a Future Postpandemic World

Leah Kuntz

We all know that psychiatry, and the health care field at large, have been greatly impacted by the COVID-19 pandemic, but John J. Miller, MD, Editor in Chief of Psychiatric Times^TM, shared a little bit more about how psychiatry will be impacted in a postpandemic world during his presentation at the 2021 Annual Psychiatric Times^TMWorld CME Conference.

“This virus has impacted virtually everybody,” said Miller wistfully. “The health effects of the individual who’s infected. The effects on family and friends of the infected individual. Individuals who modify their life in many ways because of a fear of getting infected. The stress, the unknown, the guilt, the anxiety of first responders. Health care providers often with overwhelming situations and not enough staff and too many patients.”

Miller shared a range of psychiatric symptoms that can occur as a result of COVID-19, as published in the American Journal of Psychiatry, including anxiety, depression, insomnia, fear, grief, phobias, posttraumatic stress disorder, social avoidance, increased substance abuse, suicidality, psychosis, and obsessive-compulsive disorder.¹

Miller also shared a list specific to children and adolescents, based on a study published in JAMA Pediatrics.²Of about 81,000 participants included in 29 studies, 25% had clinically elevated depression and 20% had clinically elevated anxiety, and it was estimated that the degree of depression and anxiety in older children was double that of what would be expected prior to the pandemic.

Disturbingly, Miller shared that COVID-19 could have a more direct effect: “This is clearly in the early stages of understanding, but based on what is out there now, we do know that it appears the virus can directly attack the brain.”

The SARS-CoV-2 virus can access the brain through 3 tracks: the olfactory tract, the vagus nerve, or the trigeminal nerve, Miller explained. If SARS-CoV-2 traverses the olfactory mucosa, it can cause the loss of smell while gaining access to the brain.

Miller shared a number of ways the virus can damage the brain. Damage to endothelial cells that abut the brain can lead to inflammation in thrombi and thus cause direct brain damage. Astrocytes, the primary type of brain cell affected, play an important role in brain fog and fatigue. Also well known is the neuroinflammation caused by COVID-19, which can cause an aggressive, systemic cytokine storm in serious COVID-19 infections. This storm can damage the blood-brain barrier and make it more permeable, allowing in more cells and potential active viruses. Furthermore, Miller shared, cytokines in the brain can activate microglia and enact astrocytes, which puts a further stress on the brain and can result in damage.

“In an ideal situation, there would be a recovery. But sometimes there’s a partial recovery, and other times, there’s no recovery, such as if there was a subsequent stroke,” Miller added.

Substance abuse is another of Miller’s COVID-19–related concerns. The stress, trauma, and grief, compounded by a reduced access to treatments for substance use disorders, caused a rise in drug overdose deaths with more than 92,000 deaths according to the National Center for Health Statistics.³

Furthermore, the antivaccine movement poses a significant threat to the safety of the general populace, Miller fears, as described in the Journal of Clinical Psychiatry editorial written by Joseph Goldberg, MD.⁴ Miller calls it “mass hysteria.”

“When these mass groups with mass hysteria mistrust, or frankly develop pure paranoia, and the secondary behaviors intrude into the realm of public safety, society needs to engage in a serious ethical debate as to what actions should be taken to protect [against] harm or risk to the many from the distortions or actions, or lack thereof, from the few,” said Miller.

Miller called COVID-19 a “modern medical challenge of the first order,” as it was described by authors in a Lancet editorial,⁵ and one that will continue to affect psychiatry and the health care field as a whole for many years to come.

Miller offered some common-sense suggestions: Individuals should get vaccinated and educate others compassionately and accurately, and the number of vaccines available to the global community should be increased—that way, everyone can be safe.

Chronic Adolescent THC Exposure: Mental Health Crisis?

Leah Kuntz

“Adolescence is a critical period, with increased risk for use of cannabis and, in particular, high tetrahydrocannabinol (THC)-potency cannabis. This may represent a public health crisis,” Christopher J. Hammond, MD, PhD, shared with attendees of the 2021 Annual Psychiatric Times^TM World CME Conference.

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In his presentation, “Impact of THC on Adolescents: Neurodevelopment,” Hammond shared that chronic adolescent THC exposure across animal and human studies is associated with disruptions or alterations in brain development. Furthermore, it is associated with adverse mental health outcomes, including depression and anxiety.

“Contrary to a lot of what the popular media messaging has communicated to us, data across studies of young people show that adolescents who use cannabis regularly and [then] cut down or stop using cannabis show reductions in depression and anxiety and improvements in cognition,” said Hammond.

Abstinence from cannabis for 3 to 4 weeks could reduce anxiety and depression, improve sleep, and boost cognition in adolescent regular cannabis users.

Abstinence from cannabis for 3 to 4 weeks could reduce anxiety and depression, improve sleep, and boost cognition in adolescent regular cannabis users.^1-3

Cannabis is the most commonly used federally illicit drug by US youth, and it accounts for more than 75% of teen admissions to substance use treatment programs. About 1.4 million adolescents try cannabis for the first time each year.⁴

Early-onset cannabis use, according to Hammond, can lead to numerous health issues, including major depressive disorder, alcohol use disorders, substance use disorders, suicidality, anxiety disorders, bipolar disorders, psychosis, and delinquent behaviors.^5-8

“There appears to be a relatively consistent pattern of findings showing that adolescent cannabis use is associated in a dose-dependent manner with poor outcomes in academic and occupational functioning, in cognition, and in psychiatric and substance use outcomes, and that these may be worse for young people with mental health problems,” said Hammond.

Adolescent cannabis use could also lead to potential long-term brain effects, like dysfunction in white matter tracts, altered brain waves, and decreased blood flow in the brain. These effects are larger and more consistent with earlier age of onset and heavy use.

“As more data come in, we can further update and inform this field, but using the data as they exist now is important,” concluded Hammond.

Pioneering Psychopharmacology: Educator of the Year Award

Leah Kuntz

Psychiatric Times^TM was honored and delighted to present Sheldon H. Preskorn, MD, as Educator of the Year at this year’s Annual Psychiatric Times^TM World CME Conference. An academic psychiatrist, researcher, educator, and mentor, Preskorn is, as John J. Miller, MD, described, “a pioneer in the field of psychopharmacology.” He is currently a professor in the Department of Psychiatry and Behavioral Sciences at the University of Kansas School of Medicine.

Preskorn shared with attendees the unexpected beginning of his career in psychiatry, tallied at 40 years and running. He recalled watching videotape of Jose Delgado on television, the player being able to stop a ball while “charging in his tracks.” To Preskorn, that meant that the brain was related to behavior—and he wanted to learn more.

Among his many honors and awards and specialty areas, Preskorn is known for spending the 1980s establishing the value of therapeutic drug monitoring for tricyclic antidepressants and for clarifying the drugs’ toxicity. Additionally, in the 1990s, he helped explain the liver cytochrome P450 enzyme system.

“My personal goal has been, and remains, bringing science to the practice of psychiatry,” Preskorn shared.

“My personal goal has been, and remains, bringing science to the practice of psychiatry,” Preskorn shared.

During the session, he pointed out the overlap between diagnoses and science in the signs and symptoms of borderline personality, bipolar disorder, and major depression. Preskorn claimed it is not the symptoms themselves that distinguish these disorders, but rather the stability of the symptoms.¹

“Psychiatry has been mainly stuck at the level of syndromic diagnoses, but we are making inroads, and [we’ve been making these inroads] over the last 50 years into pathophysiology and etiology,” he stated.

Additionally, Preskorn said, he thinks of his therapeutic drug monitoring focus as toxicity-centric rather than efficacy-centric. The reason? “We’ve had a better signal-to-noise ratio in trying to understand toxicity of the drugs and the avoidance of that than we did with antidepressant efficacy,” he explained. “As a matter of fact, in another article that I published, I showed that it’s really almost impossible, given the signal-to-noise problem in clinical trials of antidepressants, to show any relationship between our blood levels and clinical benefit.”

Preskorn also shared an equation that he created. According to him, 3 variables determine clinical response: sites of action (ie, affinity, intrinsic activity); drug concentration and its site(s) of action (ie, absorption, distribution, metabolism, elimination); and underlying biology of the patient (ie, genetics, age, disease, environment).²

“We are born different,” said Preskorn. “Age, how we vary over our lifespan, disease—which is acquired through pathophysiological processes—and then…[our] internal environment. That is what underlies drug-drug interactions, where a drug enters the environment of the body and interacts with another drug, either pharmacodynamically, which is the first variable, or pharmacokinetically, which is the second variable in this equation.”

Preskorn closed his speech with a smile and a promise for the future: “It’s been a great pleasure for me to have shared these few minutes with you and to talk about the developments over the last 40 years, but I would say: ‘You ain’t seen nothing yet.’”

2. Preskorn SH. Clinical Pharmacology of Selective Serotonin Reuptake Inhibitors. Professional Communications, Inc; 1996.

Finding Antidotes to Burnout Through Contradictory Truths

Heidi Anne Duerr, MPH

“For us to say that this has been a time of change, stress, and loss is an understatement,” Alana Iglewicz, MD, told attendees, “because the COVID-19 pandemic has fundamentally taken the rug from underneath our feet. [It has] changed the fabric of how we live our lives [and] how we work, and understandably, the amount of change and stress is very palpable and the amount of loss is even more.”

Iglewicz, assistant clinical professor of psychiatry at the University of California San Diego, shared insights on COVID-19's impact on health care workers. In addition to the regular stressors, health care professionals faced many challenges during the height of the pandemic. Work-life balance was disrupted, shifts were longer, and fears about personal risk and risk to family members abounded, she said. There also were increased home-life demands associated with children’s virtual schooling, caregiver burdens, and a general sense of lack of control.

A recent study of COVID-19 and stressors of almost 21,000 health care professionals between May and October 2020 and discovered alarming rates of burnout and stress, Iglewicz reported.¹ Investigators found that 61% feared virus exposure or transmission, 38% reported anxiety or depression, 43% reported work overload, and 49% reported burnout. Not surprisingly, there were some gender and racial differences, she said. Higher rates of burnout were found among females and minorities.

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Iglewicz reminded attendees that burnout has been an issue for years and has even garnered media attention due to its very real consequences. In health care, burnout can affect patients, the health care system, and the individual, she explained. In patient care, burnout leads to worse patient outcomes and increased medical errors. On a systems level, there is a drop in productivity as well as a great cost in replacing clinicians. On an individual level, burnout can lead to substance use and abuse, depression and suicidal ideation, and even an increase in motor vehicle accidents, Iglewicz said.

Fortunately, improvement in burnout started before the pandemic, Iglewicz said, noting a study by Tait D. Shanafelt, MD, and colleagues that looked at rates of burnout in 2011, 2014, and 2017.² A number of interventions took place between 2014 and 2017; accordingly, Shanafelt et al found a slight decrease in burnout reports in the 2017 data. Interestingly, psychiatrists had some of the lowest reported rates of burnout. “But it’s still unacceptable,” Igelwicz added, “as about 50% of psychiatrists are experiencing burnout.”

“Maybe we have got some of this wrong,” Iglewicz said of the attempts to address burnout. She compared the situation to the straw that broke the camel’s back. “We put our focus on trying to make that camel stronger. Tell the camel to meditate, teach that camel to be more mindful, tell that camel, ‘You better sleep more, better eat healthier.’ Encourage that camel to exercise, and coach that camel to be more resilient.”

“We realized that there was a flaw, because we were essentially blaming the victim.”

“We realized that there was a flaw,” she said, “because we were essentially blaming the victim.”

Then the focus in addressing burnout shifted to one’s environment, Iglewicz said. Electronic health records, excessive workloads, and clerical burdens were addressed. Although these are important aspects, they still involved finger-pointing. She suggested it would be more productive to move to an understanding and self-introspective perspective.

Iglewicz entertained the idea of changing the term burnout to “loss of meaning.” People enter medicine with idealistic notions and then their work no longer matches those notions and loses meaning. Similarly, she suggested considering burnout as unresolved grief. In other words, she said, there is so much to mourn in terms of why people entered the medical field. This definition allows you to face the limitations and begin to accept the issues.

Additionally, burnout in the health care field may be code for depression, she suggested. There is no stigma associated with the term burnout; it is tossed around casually in conversations, the media, and the like. However, there is still stigma associated with depression. Iglewicz added there is a very fine line between depression and burnout.

So what can be done? The first step, she said, is that clinicians must become reformed perfectionists. “The same traits that helped us get into medical school come with a price,” she said. Perfectionism, detail-oriented focus, desire for control, empathy, and competitiveness are among those traits. Whenever possible, clinicians should try to turn down the level of perfectionism. Let the struggles, hurdles, and adversities refine you, not define you, she urged.

It is also important to engage in system level change, she added. And although it should not be a singular focus, self-care is vital.

She then shared 5 antidotes to burnout: find a healthy relationship with anger, pick your battles, practice ordinary kindness and compassion, support one another and seek out support when needed, and live with contradictory truths.

Iglewicz took the opportunity to conclude her talk with a contradictory truth that rings very true on the subject of burnout: “We’re all stronger than we know. Simultaneously, we are all more vulnerable than we’d like to acknowledge.”

Psychedelics: Psychiatry of the Future

Leah Kuntz

Rick Doblin, PhD, gave an overview of the recent research on psychedelics in psychiatry. Doblin is the founder and executive director of Multidisciplinary Association for Psychedelic Studies (MAPS), which has raised more than $115 million in grants and donations for psychedelic therapy and medical marijuana research and education.

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According to Doblin, phase 3 trial results¹ examining 3,4-methylenedioxy-methamphetamine (MDMA)-assisted therapy for posttraumatic stress disorder (PTSD) look promising, as echoed by a number of publications, including The New York Times² and Scientific American.³ By the study’s end, after 3 MDMA sessions, two-thirds of the MDMA group no longer qualified for a PTSD diagnosis. There was a small P value (.0001), a large effect size (0.91 and 2.1), no site-to-site variability, and a good safety profile; additionally, results were replicated from phase 2 trials. The 12-month follow-up results will be available next year.

Doblin also believes psychedelics show promise in treating depression,⁴ alcohol dependence,⁵ obsessive-compulsive disorder,⁶ and even demoralization in AIDS survivors.⁷

“I really think psychedelics will play a major role in psychiatry in the future,” concluded Doblin.

Borderline Personality Disorder: 3 Things You Need to Do for Patients

Heidi Anne Duerr, MPH

There are 13 million adults with borderline personality disorder (BPD) in the United States and, of that number, 1.5 million are adolescents, according to Carl Fleisher, MD. To best support patients with BPD, there are 3 important tasks to consider, explained Fleisher, assistant clinical professor of psychiatry at University of California Los Angeles Health.

To kick off the discussion, Fleisher shared the case example of “Hannah,” a girl aged 16 years, who presents wondering if she has BPD after Googling her experience. Specifically, she has rapid mood swings, feels numb more often than sad, and cuts herself superficially several times a week. She has 1 friend and spends all of her time with that friend out of fear that the friend will desert her. She is interested in boys, but avoids them. Hannah does not voice her needs to parents, teachers, or friend; instead, she goes along with whatever they want or like.

The first task, therefore, is to make the diagnosis, Fleischer said. There are 9 criteria to consider, and sometimes it feels like they are all over the map. As such, the patient might not see the connections, so it is important to help draw them for patients. One way to do that, he explained, is to use a model of interpersonal hypersensitivity. Since we all want and need to be in relationships, and we all are hypersensitive, we may have a fear of abandonment. From there, you can talk about the other symptoms.

Fleischer also likes the McLean Screening Instrument for rapid assessment of patients. It helps patients think things through, he explained. It also provides an opportunity for further discussion, as the clinician may have a different perspective than the patient does on a particular item.

Most patients are relieved when they finally receive a diagnosis, Fleischer said. He shared the following patient perspective: “It explained a lot of things and I felt an enormous sense of relief that there was an explanation for the way I was.”¹

The second task is to refer patients to helpful resources, including psychoeducation, support, and treatment strategies, Fleisher said. He recommended a number of resources both for patients and their clinicians: the National Education Alliance for Borderline Personality Disorder, Mentalizing Initiative, the Anna Freud National Centre for Children and Families, and McLean Hospital’s Borderline Personality Disorder Training Institute.

“It is also possible also that plain old talk therapy is an adequate treatment for borderline personality disorder, especially if you have nothing else."

In terms of treatments, Fleisher said, there are 4 evidence-based psychotherapy modalities: dialectical behavioral therapy, transference-focused psychotherapy, mentalizing-based therapy, and good psychiatric management, which is not an orientation but more of framework for clinicians. “It is also possible also that plain old talk therapy is an adequate treatment for borderline personality disorder, especially if you have nothing else,” he told attendees.

It is also important to consider psychoeducation and family support, Fleischer added. He shared the results of a study looking at the impact of 6 weeks of psychoeducation on patients with BPD. The investigators found that symptom presentation was reduced by about half and stayed low for 2 months after the intervention protocol.² Similarly, since caregivers and family members of those with BPD are often under a lot of stress and strain, it is important to broaden the treatment lens and provide support to them, too.

Unfortunately, Fleischer noted that no medications are approved by the US Food and Drug Administration to treat BPD specifically, and no medication is uniformly helpful. Too often, patients find themselves on multiple medications, he said, and polypharmacy poses a significant danger because of adverse effects, like weight gain associated with antipsychotics.

“We can do a whole hour-long talk on just medication for BPD, but the short of it would be this: If you’re going to use medication to treat one of the comorbid illnesses that BPD presents with, as opposed to the BPD itself, then you can try that,” Fleisher told attendees. “But if we’re going to try to treat the symptoms of BPD itself like lability, paranoia, that sort of thing, then it may be that we want to consider a brief trial of medication to get people through a crisis.” After using a medication in a way that is helpful, it is important to consider reducing then eliminating it, because they are not expected to be helpful in the long term and want to avoid polypharmacy problems, he added.

The third task is to monitor the effectiveness of the treatment, Fleischer said. Start with baseline measurements on the areas you and the patient want to address, such as self-harm, work performance, risky behaviors, and quality of life and relationships.

Clinicians can best support their patients with BPD by keeping these 3 tasks in mind, Fleisher concluded. “Borderline personality disorder is worth treating,” he noted, “and people with BPD are very rewarding to work with.”

How Did Virtual Schooling Affect Youth?

Heidi Anne Duerr, MPH

Virtual schooling during the pandemic presented challenges that might have long-term effects on children and adolescents, according to Karen Dineen Wagner, MD, PhD.

Wagner, who is professor and chair in the Department of Psychiatry and Behavioral Sciences at University of Texas Medical Branch, reported results from studies indicating increases in anxiety, obsessive compulsive disorder, conduct problems, prosocial behavioral problems, sleep issues, and worsening of preexisting mental health disorders. This, in turn, resulted in increased mental health-related visits to the emergency department. Children at highest risk for increased psychiatric and behavioral problems included youth who were disadvantaged or refugees as well as those who had a chronic disorder, adverse childhood experiences, and a preexisting mental health disorder, noted Wagner.

Virtual schooling affected other areas of well-being, Wagner said. For example, in a nationwide survey of parents (N = 1290) with children aged 5 to 12 years, youth who attended virtual school were more likely to have decreased physical activity compared with students attending school in person and those attending combined in-person and virtual school (62.9%, 30.3%, and 52.1%, respectively).¹ Virtual students also reported spending less time outdoors, less time with friends virtually, and less time with friends in person. Similarly, 24.9% of students attending virtual school reported worsened depression and anxiety compared with 24.7% of those in combined schooling and 15.9% of those attending school in person.

24.9% of students attending virtual school reported worsened depression and anxiety compared with 24.7% of those in combined schooling and 15.9% of those attending school in person.

The effects were also felt by the parents. Compared to parents whose children attended in-person or combined schooling, parents whose children attended virtual school were more likely to report loss of work, childcare challenges, conflict between working and providing childcare, emotional distress, and difficulty sleeping.¹

Negative effects on youth were seen in countries around the world. Wagner discussed the results of a cross-sectional survey of 367 students in Saudi Arabia.² The investigators found 55% of respondents had moderate stress, and 30.2% had high stress levels.

Youth with attention-deficit/hyperactivity disorder (ADHD) and their parents especially struggled, Wagner added. In one study of 239 adolescents, 118 of whom had ADHD, those with ADHD had fewer routines and more difficulties with remote learning.³ Parents of adolescents with ADHD reported more difficulty in supporting home learning and home school communication. Even parents whose children with ADHD had an individual education program reported increased challenges. Asa result, 22% of families incurred financial costs.³

Wagner noted the American Academy of Child & Adolescent Psychiatry and the American Psychiatric Association developed a list of recommendations for virtual schooling.⁴ The organizations noted that education, including school attendance, is an essential component of health development. When classroom-based education is not possible, they said it is a priority to optimize social interaction. They noted additional resources should be made available for children with special needs, and the mental health of students must be continually addressed. They also advocated for systems that effectively and efficiently identify issues early and have means for interventions.

Ultimately, certain things are needed to better support a virtual schooling system. “There needs to be access to mental health services, as well as individual educational programs. There also needs to be resources for disadvantaged youth,” Wagner concluded. “Attention has to be directed toward the importance of physical activity and also participation in extracurricular activities as well as other peer group activities.”

4. American Academy of Child and Adolescent Psychiatry (AACAP) and American Psychiatric Association (APA) detail steps necessary for safely reopening schools this fall. News release. American Academy of Child and Adolescent Psychiatry and American Psychiatric Association. July 15, 2020. Accessed September 30, 2021. https://www.aacap.org/AACAP/Press/Press_Releases/2020/Needs_Students_During_COVID-19_Era.aspx

The Challenges and Rewards of Working With Culturally Different Patients

Leah Kuntz

Working with culturally different patients can be challenging and rewarding, and it is rarely avoided in current-day psychiatry, Larry Merkel, MD, PhD, told 2021 Annual Psychiatric Times^TM World CME Conference attendees.

“Everyone’s backgrounds are very complicated, multilayered, and dynamic,” said Merkel, who is a professor of psychiatry and neurobehavioral sciences and the director of outreach at the University of Virginia. “No person has influences these days from just 1 culture—we live in multiple cultures.”

Cultural distance is, essentially, qualitatively thinking about the difference between doctor and patient: How many facets of your background are and are not similar to facets of theirs?

“Research [results have shown] that the greater the cultural difference between the psychiatrist and the patient, the more likely there are to be mistakes of all sorts,” Merkel said.

Merkel also covered models for managing cultural differences, including the Cultural Formulation Interview (CFI) from DSM-5, which patients seem to value over traditional interactions.¹ Field trials in a variety of locations (ie, United States, Canada, Netherlands, India, Kenya, and Peru) showed CFI is feasible, acceptable, and useful, and it sensitizes clinicians to cultural issues.² An implementation study in an outpatient psychiatric clinic demonstrated that CFI is an integral part of cultural competence training; there was a 50% reduction in discontinuation rate vs treatment as usual after 1 training session.³

CFI does have some potential problems, Merkel noted. CFI can help with direction of therapy, but not diagnosis. Additionally, it is not able to be used with a patient who has a cognitive disability or such severe symptoms as acute psychosis, suicidal behavior, or aggression.

Further, the concept of identity may be difficult to translate, according to Merkel. “We all have multiple identities. We’re fathers, mothers, children, physicians, barbers, Protestants, Catholics, Jews—all sorts of identities. We use those identities in different ways at different times. Sometimes, if you ask a person what their identity is, they may have no idea what you’re talking about.”

Major Depressive Disorder Understanding Treatment-Resistant Depression

Heidi Anne Duerr, MPH

“There appear to be at least 3 types of major depressive disorder [MDD] based on pharmacology,” Sheldon H. Preskorn, MD, told attendees. Preskorn, a professor in the Department of Psychiatry and Behavioral Sciences at University of Kansas School of Medicine in Wichita and psychopharmacology section editor of Psychiatric Times^TM, was named Educator of the Year at the conference.

The first type of MDD responds to biogenic amine antidepressants, Preskorn said, and represents approximately 60% to 65% of patients. The second group is nonresponsive to biogenic amine antidepressants but responsive to glutaminergic (NMDA) antidepressants. It represents approximately 25% of patients with MDD. The third group is nonresponsive to both biogenic amine and glutaminergic antidepressants and represents approximately 15% of patients with MDD.

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To get a clearer understanding of this philosophy, Preskorn turned to the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, which was funded by the National Institute of Mental Health to determine the effectiveness of treatments for MDD in patients who failed to respond to initial treatment with an antidepressant. In the study, the initial treatment was citalopram. If MDD was not responsive to treatment, patients were switched to bupropion SR, sertraline, or venlafaxine XR, or their treatment was augmented with bupropion SR or buspirone.¹ In cases that remained unresponsive, patients were switched to mirtazapine or nortriptyline, or they were given augmentation with lithium or triiodothyronine. Finally, if treatment still failed, participants were switched to tranylcypromine or mirtazapine combined with venlafaxine SR.

What was noteworthy, Preskorn explained, was that acute outcomes worsened with increasing number of prior treatment failures. In the group with no or limited prior medications, 27.5% achieved remission as measured by HAM-D 17. Patients in the group with 1 prior failure had remission rates of 21.1%. And those with 2 and 3 prior failures had remission rates drop of 16.2% and 6.9%, respectively.^1-4

“If you’re like me, you see these patients every day in the clinic, because we usually get patients after they have already been tried on an antidepressant in primary care,” Preskorn said. “So we always are getting someone who has probably not benefited from treatment. And not only did they not benefit [but] they also were much more likely to relapse.”

In looking at current treatment strategies, Preskorn said the vast majority of patients initially receive a selective serotonin reuptake inhibitor. The next step most likely is either a serotonin-norepinephrine reuptake inhibitor or a norepinephrine dopamine reuptake inhibitor, he said. If that does not work, he explained there is the likelihood of augmentation with atypical antipsychotics or other kinds of medications, or a new drug such as esketamine. If there still is not a proper response, the patient would move into monoamine oxidase inhibitors or various kinds of electrical treatments such as transcranial magnetic stimulation.

So, why is there so little benefit from switching among the various antidepressants, Preskorn asked the audience. “First and foremost, you have to realize that the FDA only requires superiority over placebo for approval. There is no requirement that a new drug is superior to antidepressants, be it superior either in efficacy or tolerability…new does not mean improved.

“The second thing is psychiatric drug development for antidepressants and antipsychotics has, for 60 years, mainly been reshuffling the relative receptor binding affinity of biogenic amine mechanisms of action. So they all work on the same neurotransmitter system.”

To better help understand the situation Preskorn gave the example of a patient with pneumonia. A certain percentage of patients treated with penicillin 1 will get better. Those who do not are then given penicillin 2, and a smaller percentage likely will improve because the infectious agent causing the pneumonia does not respond to penicillin. The same thing happens with antidepressants. If you keep using the same type of antidepressants, the chance of response will continue to diminish because the depression is not responding to that mechanism of action.

Although shuffling identical mechanisms has not necessarily improved efficacy, Preskorn noted it has improved safety and tolerability. “That’s the reason why SSRIs, SNRIs, and other newer antidepressants have replaced tricyclic antidepressants—not because they are more efficacious, but because they are safer and better tolerated,” he explained. Preskorn added it is also why there is a meaningful subset of patients with seemingly treatment-resistant depression, because they are not responding to biogenic amine antidepressants.