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A year of research on lithium, including updates on its efficacy, renal risks, tremor, and a controlled trial of instant vs. extended release.
Publication Date: 01/01/2023
Duration: 22 minutes, 06 seconds
KELLIE NEWSOME: There were 361 papers on lithium published in 2023. Today we bring you the ones that inform our practice.
CHRIS AIKEN: Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the editor in chief of the Carlat Report.
KELLIE NEWSOME: And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.
Lithium is the oldest psych med still in use. And I mean old – there are reports of its use in psychiatry going back to the 1870’s, long before John Cade rediscovered it in 1949 from his hospital post in Melbourne, Australia (my hometown). But each year we learn more about this drug, and today we’ll update you on the 2023 addition to the lithium library.
CHRIS AIKEN: Our first papers deal with lithium’s efficacy, and here we have a significant update from the International Society for Bipolar Disorders. In 2023 they released guidelines on the early course of treatment in bipolar I and II disorder – in other words, which medication should you start first when you encounter a young person with a new diagnosis of bipolar disorder? We see guidelines like this all the time, and they usually do little more than recite the list of FDA approved – good bedtime reading if you have trouble falling asleep.
But this one woke me up. They actually took a stand. Here’s what they said “Available evidence suggested that in early illness course, lithium use was associated with lower recurrence risk compared with other mood stabilizers.” Inside the paper, they go on to describe studies where lithium not only provided better prevention but also improved long-term functioning better than antipsychotics.
A lot of this data gets overlooked because it is not randomized, but when we’re asking questions like “Which medication will put you in a better place over the next 10 years” we’re unlikely to see any randomized trials – and we need to look at the evidence we have. Science may be served by looking only at randomized controlled trials, but patients are not.
KELLIE NEWSOME: Here’s an eye-opening finding from one of those long-term observational studies. The COBY trial from 2020 followed 413 children and adolescents with bipolar disorder for an average of 10 years. After adjusting for confounding variables, those on lithium had half as many suicide attempts, fewer depressions, less aggression, fewer hospitalizations, and better psychosocial functioning.
Our next study is a meta-analysis of treatment resistant depression – not bipolar – but unipolar depression. We’ve seen a lot of papers like these, and while they all agree on the basic approach – augmentation is better than switching, and the best augmentation strategies are lithium, antipsychotics, thyroid, and the ketamines – they differ on how they rank those options. It all depends on which studies they include and how they slice the numbers, so we’ll take this next result with a grain of salt.
Itsuki Terao and colleagues from Japan compared four of the top augmentation options for treatment resistant depression in a network meta-analysis of 22 trials, namely: aripiprazole, lithium, IV ketamine, and intranasal esketamine. All of them worked, but lithium and IV ketamine rose to the top for both efficacy and tolerability.
CHRIS AIKEN: Some of our listeners are going to find holes in this next study, but it builds on a lot of other trials that came to the same conclusion: Lithium lowers hospitalization rates. Maurizio Pompili along with colleagues from Harvard in the US and Sapienza University in Italy, measured hospitalization rates for 260 patients with either bipolar or unipolar major depression 1 year before and 1 year after starting lithium. The hospitalization rates fell from 40% to 11% on lithium. Other trials have confirmed this effect with much larger samples and better controls, including one that focused only on unipolar patients and found that lithium alone – not antidepressants and not antipsychotics – reduced rehospitalization rates. If this observational data is true, it’s concerning, because lithium is not very popular in hospitals, perhaps because it’s a little slower than the antipsychotics.
KELLIE NEWSOME: Now for bipolar depression. Several antipsychotics are approved for bipolar depression – cariprazine, lumateperone, lurasidone, olanzapine-fluoxetine combo, and quetiapine – and with their large, rigorous trials it can seem like they have an evidence-based edge over lithium. This next study takes a different view. Jeff Rakofsky and colleagues from Emory University compared trials of lithium and antipsychotics in bipolar depression and found that it was apples and oranges. The antipsychotic trials enrolled a select group of treatment responsive patients, while the lithium trials enrolled the opposite. All of the lithium trials involved inpatients, while nearly all of the antipsychotic trials involved outpatients. Most antipsychotic trials excluded people who hadn’t responded to other treatments or had difficult-to treat features like chronic episodes, rapid cycling, psychosis, and suicidality, while lithium let them in. The bottom line: Next time you hear that antipsychotics have better evidence in bipolar depression than lithium, ask what type of bipolar depression they are talking about.
There are three main reasons to use lithium:
1. Bipolar Disorder, where it works in all 3 phases of the illness – depression, mania and maintenance
2. Major Depression, where it works to augment antidepressants and prevent future episodes, and is particularly useful for prevent depression after ECT
3. Prevention of suicide. Lithium is one of only two medications that prevents suicide – the other is clozapine. Its anti suicide effects are partly independent of its mood benefits, and they apply to both unipolar and bipolar disorder. But a study from 2022 called all that to question.
CHRIS AIKEN: It was the largest randomized controlled trial of lithium for suicidality, and it failed to work. Before this, lithium’s anti-suicide effects were backed up by huge observational studies and a few randomized trials where suicide. So when Ira Katz and colleagues designed this new trial they thought they were just confirming what was already known, but things did not go as planned. After enrolling 519 veterans with mood disorders who had made a recent suicide attempt, they took a peak at the data and were surprised to find lithium made absolutely no difference. They halted the study as it looked pointless to enroll anymore.
Since the study came out, people have scurried to explain it. Maybe the dose was too low – half were subtherapeutic and average serum levels were only 0.54. Maybe they didn’t test it long enough, but the study went a full year. Maybe the veteran population had too many comorbidities. Or maybe they weren’t even taking the lithium.
This year Alejandro Szmulewicz joined with some of the original investigators to look at that last possibilities, filtering the data so it included only visits where patients were taking the lithium or placebo. The dose was still low – 600mg per day with an average blood level of 0.5 – but with this highly adherent sample they did see a mild reduction in suicide attempts in the lithium group.
This doesn’t prove that lithium prevents suicide, but it does tell us that the flaws in the original study compromised its results.
KELLIE NEWSOME: Let us pause for a preview of the CME quiz for this episode. Earn CME through the link in the show notes.
1. Which dosing strategy improved tremor on lithium?
A. Extended release formulation
B. Instant release formulation
C. Dividing the dose twice a day
D. Giving the dose all at night
Next we have a few studies that looked at the patient experience of lithium. Sometimes these finer points are lost in the quantitative world of rating scales.Two studies from 2023 surveyed patients about their experience with lithium and found positive experiences in 60-70% of patients. One of them by Lucas McKeown and colleagues from London dug deeper, interviewing patients about their experiences with quetiapine (Seroquel) and lithium – they found this paradox which rings true for my own practice, quote, “Greater apprehension about side effects was reported for lithium prior to treatment initiation, but greater experience of negative side effects was reported for quetiapine.”
CHRIS AIKEN: Another study compared lithium and quetiapine through the more traditional lens of randomized controlled trials. This was interesting to me because in Terrence Ketter’s textbook on bipolar disorder he calculated the efficacy – the number needed to treat – for all mood stabilizers up to 2015 – and lithium and quetiapine had the best overall effect in all three phases of the illness – depression, mania, and prevention. This new study paints a more accurate picture because it included only head-to-head trials of quetiapine and lithium – three in all. All of them involved bipolar depression, and in line with the earlier analysis lithium and quetiapine came out equal in terms of efficacy and side effects.
KELLIE NEWSOME: But wait, the patients reported more problems with side effects on quetiapine than lithium.
CHRIS AIKEN: I think randomized trials do a poor job of capturing side effects because they don’t have a good way of measuring how much the side effect bothers the patient. It’s not how many side effects you have, but how much they bother you that matters. In analyses like this one they take a coarse measure – which is they count up only the side effects that made people stop the med or drop out of the trial. But that leaves out all the moderate side effects – the ones with a slow build that wear down people’s quality of life, like fatigue or dry mouth, but that are not so dramatic that they cause them to stop the med.
KELLIE NEWSOME: The next study looked at just that – which mood stabilizers patients with bipolar disorder are most likely to stop. Jonne Lintunen and colleagues in Finland looked at pharmacy data for 33,131 patients with bipolar disorder. 60% had some non-adherence, and 30% had pretty significant non-adherence, but when it comes to voting with your feet lithium was the medication they were most likely to stick with.
CHRIS AIKEN: I’m struck by something from those patient interviews – that they were more afraid of side effects on lithium, but actually experienced more side effects on quetiapine. Fear of a medication is likely to accentuate any side effects, and dampen down the benefits as well. So you need to address those fears before starting lithium. If I’m working with a patient who is particularly fearful of lithium, I’ll give them the lowest dose – 150 mg – and won’t raise it until they feel more confident in their ability to handle it. I’ll tell patients that I’m committed to making lithium tolerable for them and to contact me about any side effects they encounter because nearly all of them are treatable. This next study brings us a new tool to manage tremor.
KELLIE NEWSOME: The trial compared two forms of lithium head to head – instant and extended release – to see which had lower rates of tremor. The type of tremor lithium causes is called a postural tremor, which means it gets worse when the patient tries to hold a posture against gravity, like holding a glass, a fork, or a golf club. Federica Pelacchi and colleagues from Italy randomized 73 patient with stable bipolar disorder and a lithium-tremor to either stay on the instant release or switch to extended release. Within a week, they could see a difference: tremor improved in 63% who switched to extended release vs 20% who stayed with instant release. The main limitation was that only the raters – not the patients – were blind to the treatment.
Before this we mainly had before-and-after comparisons of instant and extended release, and those generally favored the smoother plasma levels of the XR lithium for most side effects, especially nausea and tremor, but this is the first randomized comparison. Other ways to treat lithium tremor include propranolol 40-120 mg/day, and vitamin B6 500 mg/day.
CHRIS AIKEN: Recent papers highlighted many newly discovered medical benefits with lithium, which lowers the risk of COVID infection, cancer, osteoporosis, and dementia. Lithium has anti-aging effects and lowers rates of all-cause mortality more than other mood stabilizers, a finding confirmed by two large studies from 2023. On the other hand, it’s most serious risk is renal impairment.
No one thought much about renal risks on lithium – or even checked creatinine levels –until 1977. That was when the first human evidence came out. Before 1977, animal studies had raised concerns about renal risks, but read through the PDR on any drug and you’ll see all kinds of potential risks from animal studies. It’s human studies where we pay more attention.
In 1977 Danish pathologists examined the kidneys of 14 patients who presented with acute lithium toxicity. What they saw surprised them. They expected to see acute injury in the kidneys, in line with the acute toxicity, but there was hardly any. Instead, they saw chronic injury, suggesting that the renal injury had built up over years of lithium exposure.
KELLIE NEWSOME: Fast forward to 2023 and here’s what we’ve learned. First, it’s very difficult to estimate the risk of renal problems on lithium because bipolar itself raises the risk of renal disease. Next, are we talking about the risk of renal decline – the slowing of the kidneys that happens to most of us as we age – or the risk of full on renal disease, as in stage 3 and beyond. Let’s take those one at a time. Current estimates are that lithium slows the kidneys about 30% more than what you’d expect with normal aging. And when it comes to overt renal disease, lithium doubles the risk: About 1 in 4 patients on long term lithium will develop stage III renal disease, which means their eGFR falls to 60 or below.
CHRIS AIKEN: Those figures are from a recent reviews by Ewa Ferensztajn-Rochowiak and Janusz Rybakowski, but they don’t include a new paper with surprising results. Alessandro Bosi and colleagues in Sweden compared rates of renal problems over 10 years in 10,000 patients on either lithium or valproate (Depakote). Surprisingly, rates of both acute and chronic renal injury were the same in both groups, although they did see an increase on lithium when the serum level went at or above 1.0.
Other studies suggest you can avoid renal problems on lithium by keeping the serum level below 0.8. Most experts agree that dosing lithium entirely at night lowers the risk, based on observational data from the 1980’s, but they argue over whether instant release or extended release is better for the kidneys. Those who think you need to minimize the duration of exposure favor instant release, while those who think you need to minimize the peak levels argue for the extended release. My own view is that we don’t have the data to answer that question, but for now I’ll stick with extended release for its superior tolerability.
KELLIE NEWSOME: A recent review from Michael Gitlin reminds us of who is at greater risk for renal problems on lithium: Older patients, and those with diabetes or hypertension. But the greatest risk is the dose and duration. The longer you take lithium, and the higher the dose, the greater the renal risk.
Dr. Gitlin recommends following the estimated glomerular filtration rate, or eGFR, which gives a more accurate measure of renal function than creatinine. And here’s the cut off: Get nephrology consult if the eGFR falls rapidly or goes below 60 ml/minute, which is also the cut off for stage III renal disease. For creatinine, a nephrology consult is in order if creatinine goes above 1.5.
CHRIS AIKEN: Journal articles were not the only place where lithium was making news in 2023. This year, the FDA gave the go ahead for a new, branded formulation of lithium to launch its first clinical trials. Learn all about this crystalized lithium next week.
KELLIE NEWSOME: Stay up with the latest research through Dr. Aiken’s social media feed, The Daily Psych. Search for ChrisAikenMD on Facebook, and as always on LinkedIn, Twitter, and Threads.
Earn CME for this episode from the link in the show notes, or subscribe online for all our content and get $30 off with the promo code PODCAST. Thank you for helping us stay free of commercial support.
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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.
