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Learning Objectives
After taking this webinar, clinicians should be able to:
- Providers will review new guidelines for benzodiazepine tapering, implementing evidence-based strategies for safely tapering benzodiazepines as recommended by the ASAM, while managing patient safety and potential resistance to discontinuation.
- Providers will recognize the role of antidepressants in bipolar disorder treatment by critically evaluating findings from the Danish study on the use of antidepressants in bipolar patients, including risks such as mania and rapid cycling.
In this episode:
- DOJ Charges Telehealth Executives
- Oral Extended Release Ketamine
- MDMA Trials Suspended
- Liquid Clonidine and Liquid Lithium
- Benzodiazepine Tapering Guidelines
- Antidepressants in Bipolar Disorder
- Vaping Trials and Smoking Cessation
- Brexpiprazole & Sertraline For PTSD
- CBD Oil for Anxiety
[Transcript edited for clarity]
Chris Aiken, MD: I'm Dr. Chris Akin.
Gregory Malzberg, MD: I'm Dr. Greg Malzberg.
Kellie Newsome, PMHNP: And I'm Kelly Newsome, a psychiatric NP.
Gregory Malzberg, MD: Welcome to Carlat News for September 2024. This month we talk about the first oral ketamine trial, some new liquid formulations, new benzo tapering guidelines, CBD for anxiety, and more.
Kellie Newsome, PMHNP: The US Justice Department has charged two executives from Dunn, a California-based telehealth company, with healthcare fraud for allegedly providing easy access to Adderall and other stimulants to patients who didn't need them.
This marks the first time the DOJ has prosecuted a digital health company for distributing controlled substances through telemedicine. The charges are based on allegations that Dunn prescribed over 40 million pills and generated more than 100 million in revenues since the start of the COVID-19 pandemic.
Prosecutors claim the company implemented policies prioritizing prescribing over patient care, including an auto refill policy that discouraged providers from following up with patients and compensation based solely on prescription numbers. The CDC estimates 30, 000 to 50, 000 patients across all 50 states could be impacted by this disruption in care.
And this comes at a time when there's already a nationwide shortage of stimulant medications commonly used to treat ADHD. This case raises important questions about the balance between increasing access to mental health care and maintaining responsible prescribing practices. As clinicians, we should be prepared for a potential influx of patients seeking alternative care and use this as an opportunity to reinforce ADHD evaluations in our practices.
Gregory Malzberg, MD: Esketamine is a highly controlled drug that needs to be given in the clinic. But a new version is under development that hopes to change all that. It's not esketamine, but ketamine. And it's being tested as an oral, at-home, extended-release drug. The first phase 2 trial is out, and here's what it showed.
The multi-center trial, published in Nature Medicine, involved 231 patients. So here is at the bottom. ketamine, 120 mg daily for 5 days. Next, those who responded, 168 in total, were randomized to have the drug either replaced with a placebo or extended-release ketamine at doses of 30, 60, 120, or 180 mg twice weekly for 12 weeks.
With a drug as powerful as ketamine, you're probably expecting to hear about positive results at this point. But they were mixed. Only the high dose, 100mg twice weekly, separated from the placebo. But that might be because ketamine is difficult to absorb, which is why it's traditionally given IV or intranasal.
We expect to see more trials of this high-dose oral medication in the future. But the FDA will ultimately have to grapple with broader implications of at-home ketamine before approving it. Broadening access is a worthy cause, but at-home ketamine clinics have already tested this idea, and it's been met with media reports of patients developing tolerance, abuse, and bladder problems with this looser delivery.
Chris Aiken, MD: The treatment seemed well tolerated. The effect size was large, but after 20 years of promising trials, the FDA pulled the plug on MDMA-assisted psychotherapy for PTSD. The reason was the agency did not trust the data. There were too many reports of covering up problems and coaxing research subjects to exaggerate their improvement.
That's something that was unfortunately easy to do in a trial like this, where the drug's effects are vibrant enough to unblind, both participant and scientist. Many of the MDMA trials were also retracted last month from the journals that published them due again to underreporting of adverse effects, including prolonged psychotic symptoms, suicidality, and sexual boundary violations in the therapy setting.
We covered many of those problems in our June CARLAT podcast, but the FDA left the door open for future trials to correct this. And that's something that might happen. Right now, 20 such trials are recruiting or underway. It's going to be several years before this psychedelic can try again. It just might.
We'll keep you posted.
Kellie Newsome, PMHNP: Liquid formulations are making a splash at the FDA. Recently, the agency approved Oneida, a liquid formulation of Clonidine XR. The approval was based on pharmacokinetic data, which showed the Liquid XR to have similar serum levels as the tablets, although the Liquid peaks a little faster. Lacking any new clinical data, Anyaida piggybacked on the ADHD trials that brought the tablet approval.
Both are approved for childhood ADHD ages 6 and up. Next is a re-release of lithium citrate. The sole liquid formulation of the Mood Stabilizer disappeared from the market in 2022 due to declining sales but was recently resurrected by Rosamont Pharma. Liquid lithium is a great option for those who have trouble swallowing or need tiny dose increments, such as in the elderly or when tapering lithium off, which needs to be done slowly over at least a month and preferably three to six months to prevent severe mood worsening and suicidality.
Gregory Malzberg, MD: The American Society of Addiction Medicine has released new draft guidelines for tapering benzodiazepines to provide evidence-based strategies for safely discontinuing these drugs. Here's a peek at their recommendations. For patients who would benefit from discontinuation, taper gradually, lowering the dose by 5 to 25 percent every 2 to 4 weeks, and don't go faster than 25 percent every 2 weeks.
And when should you start thinking about discontinuing them? The guidelines highlight these risks. Falls, motor vehicle accidents, cognitive impairments, and overdose, particularly when combined with opioids. Benzo risks are highest for older adults and pregnant patients, we know benzos can harm the fetus and patients with substance use disorders.
And here's a new recommendation. They advise that clinicians assess patients on benzodiazepines at least every three months, whether they're tapering or not, and they should review the risks and benefits of ongoing use at each visit. The guidelines also address the delicate issue of tapering these medications when a shared decision can't be reached with the patient, recognizing that there are instances when clinicians may need to do a taper against the patient's wishes, such as when the patient poses a safety threat, if they're diverting the medications, or if they're engaging in criminal behaviors within the treatment setting.
In such cases, the guidelines recommend clear communication, thorough documentation, and consideration of a more rapid taper if necessary. Thank you for your time, everybody. They even present a few strategies for managing potentially explosive situations. Maintain a calm demeanor, position yourself near the door, have another staff member present, conduct visits via telemedicine when appropriate, and install silent alarm systems when possible.
We agree with these guidelines but need to add a warning, something you might recall from the April episode of Carlat News. While benzos do carry risks, tapering them may be just as risky, even when the patient is elderly or taking opioids. This was the conclusion of a large observational study from JAMA Open Network, which found a greater mortality risk in all groups after benzodiazepine tapering.
This result underscores the complexity of benzo discontinuation and serves as a stark reminder that there are no easy answers in our field.
Chris Aiken, MD: Just how dangerous are antidepressants in bipolar disorder? A new study from Denmark gives some reassurance here, but it leaves a lot of open questions. The authors followed 979 patients who were recently hospitalized for bipolar depression for about a year. This study was not randomized. That's a major flaw.
However it was controlled, comparing roughly a third of the patients who received antidepressants with another two-thirds who did not. To measure manic switches, they tallied all re-hospitalizations for mania over the next year. That's another flaw because just looking at hospitalizations for mania is gonna miss milder cases that were managed on an outpatient level.
Here's what they found. There was no difference in hospitalization for mania with or without antidepressants. Ah, that's surprising. When they looked into the patients who were taking antidepressants without a protective mood stabilizer, There was no difference for them either. That last finding contrasts with earlier studies, which show a higher risk of mania when antidepressants are used as monotherapy in bipolar disorder.
So, the lack of randomization here does make conclusions difficult to draw. You know, it's possible that doctors avoided antidepressants in patients who were at high risk of mania. And we know who those patients are, it's obvious. It's patients with bipolar 1 disorder, it's patients with recent manias and patients who, of course, have a history of antidepressant-induced mania.
The authors did not adjust for those variables, although they did adjust for the number of past manic episodes, the severity of the disorder, and other demographic variables. Well here's our take. Antidepressant-induced mania is controversial, and this study suggests that if it is real, it's a rare phenomenon.
On the other hand, antidepressants do have other risks in bipolar disorder besides mania, and those risks were not examined in this study, but they have been confirmed in randomized controlled trials. Namely, Antidepressants can cause rapid cycling and can add mixed symptoms to the depression, worsening mood, without causing overt mania.
More importantly, control trials have found little to no benefit with antidepressants in bipolar disorder, as did this one. There was also no difference in the rates of readmission for depression in those who took, or did not take,
Kellie Newsome, PMHNP: We have three updates on smoking cessation and e-cigarettes, also known as vapes. The first is a large randomized trial, published in JAMA Internal Medicine. It found that nicotine-containing e-cigarettes are as effective as a prescription medication, Varenicline. Chantix, in helping adults quit smoking traditional cigarettes.
The study, conducted in Finland, looked at 458 adults with moderate to heavy nicotine dependence. They showed then at 26 weeks, 40. 4 percent of participants using e-cigarettes and 43. 8 percent using varenicline had quit smoking, compared to only 19. 7 percent in the placebo group. While e-cigarettes might help people stop smoking, they also carry risks for the heart and lungs.
Many smokers who switch to e-cigarettes find themselves unable to quit vaping, trading one form of nicotine addiction for another. However, our next trial offers hope for those who can't get off the vapes. The study, published in the American Journal of Preventative Medicine, found that varenicline was effective in helping adults quit e-cigarettes.
Participants receiving Varenicline had a 45 percent quit rate compared to a 30 percent quit rate in the placebo group, and that's a significant 15 percent difference. This success rate is similar to what we've seen in Varenicline smoking cessation trials. Finally, we have an update from the FDA on vaping regulation.
The agency recently authorized the first flavored vape products, a move it had previously avoided due to concerns that flavored products might entice children to start vaping. Why did they then change their mind? Well, quitting is not a one-size-fits-all all kind of thing, and some adults prefer flavored vapes for smoking cessation.
We'll keep a close eye on this move, as will the FDA, who warned they'll withdraw the approval if marketers start to target youth.
Gregory Malzberg, MD: Otsuka Pharmaceutical and Lumbac have submitted a supplemental new drug application to the FDA for Brexpiprazole, brand name Rixulti, as an augmentation with the SSRI Sertraline in adult PTSD. The submission is based on the results from three clinical trials, including two phase three studies and one phase two study, involving over 1, 200 patients.
While the full data has yet to be published, preliminary results from the ASCP annual meeting in Miami last May showed promising outcomes. In two out of the three studies, the combination of brexpiprazole and sertraline demonstrated significantly better outcomes compared to sertraline with a placebo.
When analyzing the data from all three studies collectively, There remains a strong indication that this combination therapy outperformed sertraline alone. The antipsychotic was flexibly dosed in the range of 1 to 3 mg per day. Antipsychotics carry significant risks, and the FDA has a history of turning them down when they don't think the disorder is serious enough to warrant those risks like they did with quetiapine for generalized anxiety.
Will brexpiprazole meet the same fate? We don't know, but we can say that with 2 out of 3 positive trials, it will. It passes the FDA's minimum bar for efficacy.
Chris Aiken, MD: Many patients think that CBD oil treats anxiety. Providers aren't always so sure, but this next study does give it some support. A new liquid version of CBD, that's cannabidiol, reduced anxiety in this patient. phase 3 controlled trial of 178 patients who had various anxiety disorders. The five-week study was sponsored by the manufacturer of this CBD product, which is not yet commercially available.
The dose they used, 300 milligrams per day, is supported by smaller studies of CBD oil. Many patients take CBD either through a vape or as an orally ingested oil, but the 300-milligram dose is expensive, so it's unlikely that your patient is taking that therapeutic dose. CBD is the safer ingredient in marijuana.
It counters the paranoia and anxiety that's produced by the less safe ingredient. THC. CBD also has neuroprotective properties. CBD is available as a prescription med for seizures, called Epidiolex, where it's schedule 5, which means it has a low potential for abuse, according to the DEA. There was no reward, liking, withdrawal, abuse, or even cross-generalization to the effects of THC.
in animal or human studies of CBD. THC is the addictive, rewarding, and psychosis-causing strain in the marijuana plant, and most marijuana that's sold in the U. S. is high in THC, including in states where marijuana is legal. Also in the news, high potency THC marijuana doubled the risk of psychosis in a new large study of British teens.
While in that study, low-potency THC marijuana didn't seem to increase the risk.
References:
Hines, Lindsey A et al. “Incident psychotic experiences following self-reported use of high-potency cannabis: Results from a longitudinal cohort study.” Addiction (Abingdon, England) vol. 119,9 (2024): 1629-1634. doi:10.1111/add.16517
Fucito, Lisa M et al. “Varenicline for E-Cigarette Cessation in Adults: A Preliminary Placebo-Controlled Randomized Trial.” American journal of preventive medicine vol. 67,2 (2024): 296-298. doi:10.1016/j.amepre.2024.04.007
Glue, Paul et al. “Extended-release ketamine tablets for treatment-resistant depression: a randomized placebo-controlled phase 2 trial.” Nature medicine vol. 30,7 (2024): 2004-2009. doi:10.1038/s41591-024-03063-x
Gundugurti, Prasad Rao et al. “Evaluation of the efficacy, safety, and pharmacokinetics of nanodispersible cannabidiol oral solution (150 mg/mL) versus placebo in mild to moderate anxiety subjects: A double blind multicenter randomized clinical trial.” Asian journal of psychiatry vol. 97 (2024): 104073. doi:10.1016/j.ajp.2024.104073
Rohde, Christopher et al. “A Nationwide Target Trial Emulation Assessing the Risk of Antidepressant-Induced Mania Among Patients With Bipolar Depression.” The American journal of psychiatry vol. 181,7 (2024): 630-638. doi:10.1176/appi.ajp.20230477
Tuisku, Anna et al. “Electronic Cigarettes vs Varenicline for Smoking Cessation in Adults: A Randomized Clinical Trial.” JAMA internal medicine vol. 184,8 (2024): 915-921. doi:10.1001/jamainternmed.2024.1822
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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 quarter (.25) AMA PRA Category 1 CreditsTM. Physicians or psychologists should claim credit commensurate only with the extent of their participation in the activity.
