A new risk with benzo discontinuation. A new approval in bipolar disorder. ECT in schizophrenia, circadian therapy for depression, and hope for multi-trauma PTSD. It’s all in this batch of six research updates.

Publication Date: 08/05/2024

Duration: 16 minutes, 10 seconds

KELLIE NEWSOME: Welcome to The Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. 

CHRIS AIKEN: I’m Chris Aiken, the editor-in-chief of The Carlat Psychiatry Report. 

KELLIE NEWSOME: And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.

Today we bring you 6 research updates, starting with a new risk with stopping benzos.

CHRIS AIKEN: On this podcast, we’ve raised attention to the risks of long-term benzo use – particularly in the elderly and people taking opioids. Well, this study challenges that message. It was a large, retrospective analysis that looked at what happened when patients either came off – or stayed on – a benzodiazepine. They used a from a commercial insurance database, and the study was done by Donovan Maust and colleagues in JAMA Open Network. The risks with benzos are well known, and they get worse with age: falls, car accidents, memory problems, pneumonia, and other respiratory disorders. And we’re especially worried about combining benzos with opioids - because both drugs suppress breathing in different ways, and their combination has fueled an epidemic of drug overdose deaths that has shown no signs of slowing down over the past two decades. So, when this team from the University of Michigan analyzed outcomes on 353,000 patients who either stayed on or came off a benzodiazepine, they expected to see change in mortality rates with benzodiazepine discontinuation, and they did, but not in the direction they expected. The risk of death over a year of follow-up was slightly greater for those who came off their benzodiazepines vs those who stayed on. This was a broad sample from a commercial insurance database, and it leaned toward the older side with an average age of 61. Now, the sample was large enough to subdivide it into those who were taking opioids with the benzo and those who were taking the benzo alone. But even then, with that subdivision there was no difference in mortality rates. We still saw the same degree of elevated mortality in coming off a benzo. That mortality rate was 1.6 times higher for those who came off. Just as surprising, older adults who discontinued a benzodiazepine had the same elevated mortality risk as younger adults. This study was not randomized, so we have to be cautious in drawing conclusions. Perhaps doctors were more likely to stop benzos in riskier patients. But, the study did adjust for potential confounders like age, social-economic status, and medical or psychiatric co-morbidities. Now, as we look closer at the types of deaths that happened off the benzo, one that stands out is drug overdose deaths. That particular risk remained high after coming off the benzodiazepine, and it suggest that the well-intentioned tapers might have led some patients to replace the prescription with more dangerous street drugs. We saw a similar pattern in a VA study of opioids from 2020, where a well-meaning program to reduce opioids in VA clinics- that is opioid prescriptions- lead to an unexpected rise in overdose deaths and overall mortality in these patients who came off their opioids. Taken together, what these studies tell us is that withdrawing from benzos and opioids can be just as dangerous as the drugs themselves. Benzo withdrawal causes terrible suffering, and when I posted this study on social media feeds, many patients chimed in and reminded me of the suffering that they went through as they came off of benzodiazepines. What this study doesn’t tell us is which patients are at greater risk for the dangers of benzo withdrawal, and which ones might benefit from such a taper. I have seen many older patients gain greater mental clarity, energy, and better balance after tapering off a benzo, but benzo tapers must be done therapeutically in every sense of the word, slowly, over months if not year. Next: Is Lithium good for the bones?

KELLIE NEWSOME: 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 risks 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. And 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 larger 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% 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. It’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. Next, a new antipsychotic gains approval in bipolar mania.

CHRIS AIKEN: Antipsychotics are used so often for bipolar mania that it’s tempting to think they all work, but that’s not true. Some – like brexpiprazole (Rexulti) and paliperidone (Invega) – have actually failed in large trials – which is why they are not approved. And others like lurasidone (Latuda) and lumateperone (Caplyta) are just completely untested in mania. So, it’s news when iloperidone (Fanapt) released its first positive trial in mania, marking new territory for this antipsychotic which has no approvals in bipolar or unipolar depression. The 4-week trial was large and industry-sponsored, and reduced mania at a dose of 24 mg/day with a very small p-value, while causing side effects known to iloperidone like fatigue, weight gain, dizziness, and dry mouth. This adds iloperidone to the long list of reasonable options for mania, but we’d suggest starting with one that has benefits for the depressed phase as well – of which there are only two – that's quetiapine and cariprazine – two that can claim to work on both sides of bipolar. Next, a door closes for clozapine-resistant schizophrenia.

KELLIE NEWSOME: Wait, can we pause for the CME quiz for this episode? I mean, our listeners can earn CME for each episode with two quick questions – check the link in the show notes and here’s a sample:

1. What did a 2024 meta-analysis conclude about psychotherapy for PTSD?

A. Patients with single traumas responded better to therapy than multiple traumas

B. Patients with multiple traumas responded better to therapy than single traumas

C. Responses to psychotherapy were similar for those with single and multiple traumas

D. Patients with combat traumas responded better to therapy than sexual traumas*

KELLIE NEWSOME: When patients with schizophrenia don’t respond to clozapine, it’s not clear what will help. Addition of topiramate, or a course of ECT have all been suggested, but none of them proven. This next study from Schizophrenia Research takes ECT off that hopeful list - the treatment failed to reduce psychotic symptoms in this sham-controlled trial - the second negative trial in clozapine-resistant cases. I guess I’ll think twice before sending someone with treatment-resistant schizophrenia for ECT, but Dr. Aiken what about ECT in general schizophrenia?

CHRIS AIKEN: ECT does seem to work for general schizophrenia, not the clozapine-resistant type, and that's according to a Cochrane review of 26 studies. So, ECT might be worth a trial after, say one failed anti-psychotic instead of two, but, it's rare that you would use it then. Its main advantage is probably speed, so it might have a role for hospitalized patients who need rapid reduction of severe symptoms. Otherwise, when you get into failing two antipsychotics, you are usually going to go to clozapine, not to ECT. But, let's keep in mind that the place where ECT does have a clear role in psychiatry is in psychotic depression and in catatonia. In one large study, the remission rates were over 95% with ECT. That's unheard of in psychiatry. Next up is a study that’s close to my heart. But I want to get back to the iloperidone (Fanapt) study. We reported on the study there, but iloperidone is also newly approved in bipolar mania. It was approved in April of this year. So, next up is a study that reminds me of a book I published in 2020 called The Depression and Bipolar Workbook. That book outlines brief behavioral approaches you can add to a medication visit, and many of them focus on regulating circadian rhythm. We’ve known for decades that regulating circadian rhythms is beneficial in bipolar disorder, and we’re just starting to see studies that test this circadian rhythm approach in regular unipolar depression.

KELLIE NEWSOME: This next paper is a controlled trial that tested a behavioral therapy in depression. They called it “transdiagnostic sleep and circadian treatment for major depressive disorder.” What that means in plain English is regular sleep and activity. 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 following the guidelines of Cognitive Behavioral Therapy for Insomnia. The researchers from Hong Kong compared this approach – taught in a group format - to treatment as usual in 151 patients with Major Depression. After 3 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 involves doing key activities at the same time each day, like rising out of bed, starting work or chores, and eating meals. What’s new here is that this is the second trial to test this circadian approach in non-bipolar depression, and with 2 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. Next, some hopeful news for PTSD.

CHRIS AIKEN: We end this podcast with a study that challenges one of my own assumptions about PTSD. It’s often said that psychotherapy works best for people who’ve experienced a single trauma, like a car accident or an assault, but that multiple traumas create 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 team of European investigators as they sifted through 137 randomized controlled trials of psychotherapy on PTSD. But, the results, published in the Lancet Psychiatry, were not what they expected. Therapy outcomes were similar for both groups – multi- and single-trauma PTSD – across many types of psychotherapy. In practice, patients with multiple traumas tend to have more severe PTSD, so this is encouraging news. Clinicians who treat or refer patients with PTSD for psychotherapy can do so with a bigger dose of optimism – therapy worked here with a large effect size around 1.0 for both types of trauma. What is a 1.0 effect size, that means the difference would be noticeable to the casual observer. To put that in perspective we don't have effect sizes that big for any of our medications except stimulants in ADHD, and acute effects of ketamine in depression.

KELLIE NEWSOME: We featured many of these studies in the April edition of The Carlat Psychiatry News, a news video we put out each month with Dr. Greg Maltzberg. So, apologies if it gave you déjà vu, but if you want new updates check out our August episode on Youtube or under the Webinars tab on the Carlat website. And if you want these research updates even faster, follow Dr. Aiken’s DailyPsych feed on LinkedIn, Twitter, Facebook, and Threads, search for Chris Aiken MD. The Carlat Report is one of the few CME publications that depends entirely on subscribers. Thank you for helping us stay free of commercial support.

*The podcast audio includes another option for answer D, this option has been revised.

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 Credits^TM. Physicians or psychologists should claim credit commensurate only with the extent of their participation in the activity.