Learning Objectives
After taking this webinar, clinicians should be able to:

1. Providers will understand the recent developments in psychedelic-assisted therapy, specifically the FDA's priority review of MDMA for the treatment of PTSD, and the supporting evidence from randomized phase III trials.
2. Providers will understand the findings from the study on benzodiazepine discontinuation, which showed an increased mortality risk compared to those who remained on the medication, even after adjusting for confounding factors.

[Transcript edited for clarity]

Chris Aiken, MD: I'm Dr. Chris Aiken.

Greg Malzberg, MD: I'm Dr. Greg Malzberg.

Kellie Newsome, PMNHP: And I'm Kelly Newsome, a PMHNP, and this is Carlat Psychiatry News for April 2024.

Greg Malzberg, MD: Our big topics this month are MDMA-assisted therapy for PTSD, benzodiazepine withdrawal, and lithium's medical benefits. The first story brings psychedelic-assisted therapy one step further.

On February 9th, the FDA granted priority review to Lycos Therapeutics for MDMA for psychedelic-assisted therapy for PTSD. So far studies on MDMA-assisted therapy have found the treatment to be highly effective in severe PTSD. MDMA is thought to work here because of its effect on memory reconsolidation, which is the brain's way of updating and reorganizing memories.

During therapy sessions, individuals may be better able to visit traumatic memories without being overwhelmed by fear and anxiety. This allows them to reframe the memories in a way that reduces their emotional impact. A big part of this may be related to the fact that NDMA bolsters social behavior in animals, which mirrors individual reports of feeling increased empathy and connectedness with others.

This is beneficial in building trust in therapy, which is especially relevant in PTSD, as individuals can have difficulty connecting with their emotions or with others. In 2017, the FDA granted MDMA-assisted therapy breakthrough therapy status. So this status is based on preliminary clinical data and allows the development of promising experimental drugs to be fast-tracked.

Whereas the priority review designation is for treatments with significant improvement in safety or effectiveness, and the benefit here is a review of application in six months. The FDA granted this priority review status. Based on 2 randomized phase 3 trials that compared MDMA-assisted therapy to placebo-assisted therapy.

Most notably from these trials is that they had a large effect size about 0. 7 to 0. 9 this is almost double the effect of SSRIs and PTSD, but the studies were small and involved only a total of 194 patients. So these studies use a manualized therapy with MDMA or placebo, consisting of 3 preparatory drug sessions and 9 nondrug sessions.

The drug dosing sessions are quite long. They last about 6 to 8 hours. And here, the patient lies on a sofa with eye shades and headphones on and interacts with a therapist as needed. The nondrug sessions begin the day after the dosing sessions and typically last 60 to 90 minutes. These sessions are where the patient processes the new experiences that were brought on by the MDMA.

So, this therapy draws on exposure-based, psychodynamic, Buddhist, and somatic experiencing approaches. And it's done with a team of two therapists, one male and one female. It's probably worth noting here that this isn't cheap, and estimates range from 13, 000 to 15, 000 per round of treatment. In the therapy, the therapists take an empathic, nondirective, listening stance.

The MDMA is thought to give people greater access to their inner experience as this drug creates feelings of connection and empathy, and therapists help the patients to integrate these into their present life.

Kellie Newsome, PMNHP: This MDMA is a sea change in many ways. I understand the drug companies behind these psychedelics are non profit.

Chris Aiken, MD: They were originally non profits, companies like MAPS for MDMA and Compass for psilocybin. But things have changed hands, and if this drug does launch, we expect it to be in the hands of a for-profit company. Specifically, one called Lycos, which branched off from MAPS in 2014 and then rebranded itself as Lycos in January of this year.

Kellie Newsome, PMNHP: So, when will we hear from the FDA next?

Chris Aiken, MD: We expect a final decision, up or down, on MDMA by August of 2024. Our next study from JAMA Open Network warns us not to be too aggressive when tapering benzodiazepines. The risks with benzodiazepines are well known. We're talking about falls, cognitive impairments, car accidents, and even respiratory problems like pneumonia.

And most of these risks get worse as the patient ages. One risk we're particularly worried about is combining benzodiazepines with opioids because both meds suppress respiration in different ways, raising the risk of accidental overdose deaths, which has already become a national epidemic. So when this team from the University of Michigan analyzed data on outcomes in 353, 000 patients who either came off or stayed on their benzodiazepines, they expected to see a change in mortality rates.

And they did. but not in the direction they expected. Over the year of follow-up in this study, the risk of death rose in patients who came off the benzodiazepine 1. 6 fold. This was a broad sample of patients from a national insurance database, and the patients tended toward the older side around age 61, but even when they subdivided the data by those who were younger or older, There was no difference in this elevated mortality rate in coming off of benzodiazepine.

Even more surprising, the elevated mortality rate remained high, even when they stratified the data to look just at those who were on opioids with the benzodiazepine. As large as this study was, it was not randomized, so we have to be cautious in interpreting the data. Like, it's possible that doctors were just more likely to take riskier patients off benzodiazepines, hence the higher mortality rate in that group.

To its credit, the authors did try to control for confounding factors like psychiatric diagnosis, medical comorbidities, age, and socioeconomic status, but it's always possible that other variables could have skewed the data. And as we look closer at the kinds of deaths here, one that stands out is overdose deaths.

That risk remained high when coming off of benzodiazepine, suggesting that some of these patients might have been replacing their prescribed drug with other sources of the drug, such as on the street. We saw a similar pattern in a large study from the VA system in 2020 where they looked at patients who came off Opioids by their doctor and also saw higher death rates in those who came off Benzodiazepine withdrawal causes terrible suffering Something that many patients reminded us of when we posted this study online One thing this study does not tell us is which particular patients are going to do better if we keep them on the benzo versus take them off.

In my own practice, I've seen many older patients gain greater mental clarity, greater energy, and better balance after coming off of benzodiazepine. But benzodiazepine tapers must be done therapeutically in every sense of the word. And that means slow, very slow, over months if not years.

Kellie Newsome, PMNHP: Lithium has a host of medical risks. Toxicity, renal impairment, thyroid and parathyroid hormones. So it's surprising that patients who take lithium for bipolar disorder tend to live longer than those who take other mood stabilizers. That increase in life expectancy is not just due to lithium's anti suicide effects.

Lithium has medical benefits as well that we're just beginning to understand. Lowering the risk of cancer, stroke, Alzheimer's, and neurologic disorders, improving immunity, and killing off viruses. This next study from Acta Psychiatrica, Scandinavia, adds bone health to that list. Researchers from Australia measured bone mineral density in 117 women with bipolar disorder.

Those on lithium were twice as likely to have normal bone density. This is not a randomized trial, so it may be a false association. But it held up after controlling for confounders and is supported by a largest study from 2022 that compared rates of osteoporosis in 147, 000 people with or without bipolar disorder.

In that study, lithium, but not other mood stabilizers, was associated with a 40 percent lower risk of osteoporosis. These two studies mark a new understanding of lithium's health benefits, and they follow on earlier work in animals. In animal models, lithium stimulates bone formation, socket repair, and reduces estrogen-deficient bone loss.

That's encouraging news you can share with your patients, and it contrasts with the known effects of serotonergic antidepressants, which raise the risk of osteoporosis.

Greg Malzberg, MD: Antipsychotics are used often in bipolar mania, so it's tempting to think that they all work, but it's not true. Some, like brexpiprazole and paliperidone, have failed in large trials, and others, like lorazodone and lumatoperone, are completely untested.

So it's news that iloperidone released its first positive trial in mania. Marking new territory for this antipsychotic, which has no approvals in bipolar or depression. This four-week trial was large and industry-sponsored, and reduced mania at a dose of 24 mg per day with a very small p-value. And it caused side effects known to illeperidone, like fatigue, weight gain, dizziness, and dry mouth.

This adds illeperidone to the long list of reasonable options for mania, but we'd suggest starting with one that benefits the depression pull as well. And there are only two antipsychotics that can claim to work on both sides of bipolar, and that's quetiapine and criprazine. All right, now back to you, Kelly.

Kellie Newsome, PMNHP: This next study validates a simple behavioral approach for depression, one that you can apply at your next brief therapy with medication visit. It's called a transdiagnostic sleep and circadian treatment for major depressive disorder. What that means in plain English is regular sleep and activity, and patients with depression were taught to wake up at the same time each day, stay active during the day, and keep a sense of ritual by doing key activities at regular times, and at night to follow the guidelines of cognitive behavioral therapy for insomnia.

The researchers from Hong Kong compared this approach, taught in a group format, to treatment 151 patients with major depression. After three months, all symptoms were better with the circadian treatment. including depression, sleep, and overall functioning. This type of therapy has strong support in bipolar disorder, where it's called social rhythm therapy, and it involves doing key activities at the same time each day, like getting out of bed, starting work or your chores, and eating your meals.

What's new here is that this is the second trial to test this circadian approach in nonbipolar depression, and with two confirmation points, we're confident to put it into practice. Circadian rhythm abnormalities loom large in major depression, though not as large as in bipolar disorder. And even night owls benefit from getting out of bed at a reasonable hour and staying out of bed during the day.

Greg Malzberg, MD: So when patients with schizophrenia don't respond to clozapine, it's not really clear what will help. Addition of topiramate, aripiprazole, and ECT have all been suggested. But none of them have been proven. Unfortunately, this next study from schizophrenia research takes ECT off that hopeful list. So ECT failed to reduce psychotic symptoms in the sham control trial.

This is the second negative trial in clozapine-resistant cases. So while this takes ECT off the clozapine-resistant schizophrenia list, we still know that it's very effective for psychotic depression in catatonia.

Kellie Newsome, PMNHP: I guess I'll think twice before sending someone with treatment-resistant schizophrenia for ECT.

But what about nontreatment-resistant schizophrenia?

Chris Aiken, MD: ECT probably works in general nontreatment-resistant schizophrenia. That's according to a meta-analysis from Cochran Group of 26 controlled trials. So it might be worth considering ECT after, say, one failed antipsychotic. But in what kind of scenarios are you really going to use it in schizophrenia?

Well, its main advantage is speed, so you might consider it for a patient who's hospitalized and has severe psychotic symptoms that you need to reduce rapidly. But the place where ECT does have a clear role, like Greg pointed out, is in psychotic depression. In one large trial, the remission rates for that group with ECT were over 90%, something we rarely see in psychiatry.

We end this program where we started. With a study that brings new hope for patients with PTSD. It's often said that people with PTSD do better with psychotherapy if they've had just one trauma. Like an assault or a car accident. And that multiple trauma causes a more complex syndrome that doesn't respond as well to psychotherapy.

That's what I was taught in residency, and that was the hypothesis of this European team of researchers as they sifted through 137 controlled trials of psychotherapy for PTSD. But the results published in this month's Lancet Psychiatry were not what they expected. Therapy outcomes were similar for both single trauma and

In practice, patients with multi-trauma PTSD tend to have much more severe cases, so this is encouraging news. When you're referring someone for psychotherapy for PTSD, you can do so with an extra dose of optimism. For both types of trauma, psychotherapy worked, and it worked very well, with a large effect size in the 1.

Kellie Newsome, PMNHP: Thank you for tuning in to the first episode of Carlat Psychiatry News.

Chris Aiken, MD: Our field changes every month, and we'll be back in May with more updates of all things psychiatric. Now, can we get back to the podcast?

References: 

Hoppen, Thole H et al. "The efficacy of psychological interventions for adult post-traumatic stress disorder following exposure to single versus multiple traumatic events: a meta-analysis of randomised controlled trials." The lancet. Psychiatry vol. 11,2 (2024): 112-122. doi:10.1016/S2215-0366(23)00373-5

Maust, Donovan T et al. "Benzodiazepine Discontinuation and Mortality Among Patients Receiving Long-Term Benzodiazepine Therapy." JAMA network open vol. 6,12 e2348557. 1 Dec. 2023, doi:10.1001/jamanetworkopen.2023.48557

Melzer-Ribeiro, D L et al. "Randomized, double-blind, sham-controlled trial to evaluate the efficacy and tolerability of electroconvulsive therapy in patients with clozapine-resistant schizophrenia." Schizophrenia research, S0920-9964(23)00421-8. 26 Dec. 2023, doi:10.1016/j.schres.2023.11.009

Torres, Rosarelis et al. "Efficacy and Safety of Iloperidone in Bipolar Mania: A Double-Blind, -Controlled Study." The Journal of clinical psychiatry vol. 85,1 23m14966. 15 Jan. 2024, doi:10.4088/JCP.23m14966

Williams, Lana J et al. "Lithium use and bone health in women with bipolar disorder: A cross-sectional study." Acta psychiatrica Scandinavica vol. 149,4 (2024): 332-339. doi:10.1111/acps.13660

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The Carlat CME Institute is accredited by the ACCME to provide continuing medical education for physicians. Carlat CME Institute maintains responsibility for this program and its content. Carlat CME Institute designates this enduring material educational activity for a maximum of one half (.25) AMA PRA Category 1 Credits^TM. Physicians or psychologists should claim credit commensurate only with the extent of their participation in the activity.