A new form of Lithium is being developed. Plus, updates on lithium in younger, older, and peripartum patients.
Note: This podcast episode presents information about new formulations of Lithium being developed to inform clinicians about their existence. Once a new formulation is tested and data can be evaluated, there will be additional information available about its clinical potential.Transcript:
KELLIE NEWSOME: Lithium has been generic since the day it was released, but a branded formulation is under development that hopes to make the medication safer and easier to take.
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.
361 papers on lithium. That’s what we combed through in 2023, and that’s after removing the articles on batteries. In the end, we whittled it down to 25 papers that informed our practice. It was hard. It means we don’t get to share how lithium is being repurposed as an anticancer drug, how lithium changes circadian rhythms in bees, and a study of what happens when you ask CHATGPT about lithium.
CHRIS AIKEN: We also cut two large analyses that – surprisingly – showed no significant weight gain on lithium – only non-significant trends. We covered those last month in our November 13th Podcast, Ketamine: Six New Findings Part 2.
KELLIE NEWSOME: And this is part II – the final part of our lithium updates. Let’s recap what we learned last week:
- Lithium has moved up to first line in guidelines for the early course of bipolar disorder because it can nip the disease in the bud. The average patient is more likely to stay well, function well, and live longer on it.
- Lithium may not have the brand-name shine of the atypical antipsychotics in bipolar depression, but we can’t compare the two because the trials that tested lithium enrolled a more severely ill and treatment resistant group of patients.
- Patients are more afraid of lithium than the antipsychotics, but in the end they tend to stick with it longer and report fewer side effects on it.
- Extended release lithium is better tolerated than instant release, particularly when it comes to tremor
- Long-term lithium use doubles the risk of developing stage III renal failure, which means their eGFR has fallen to 60 or below. When it gets to that level, don’t reflexively stop the medication, but bring it down to the lowest effective level and get a renal consult. You can protect the kidneys further by keeping the level below 0.8 and giving the dose all at night.
KELLIE NEWSOME: Today we’ll bring you papers that tell us what lithium levels to aim for and how to use lithium in special populations – the young, the old, and the postpartum period. We’ll end with an exciting update from the FDA – which has paved the way for new formulation of lithium to enter clinical trials. But let’s start at the beginning – the very beginning – a look at lithium levels in breastfeeding infants.
CHRIS AIKEN: For women with bipolar disorder, the riskiest time for a new episode is postpartum. During pregnancy, lithium has risks but can still be used – rewind to our December 2022 episode on pregnancy and breastfeeding for full details. This new study from Essi Heinonen and colleagues in Sweden brings reassurance for lithium during breastfeeding. They measured lithium levels in 30 infants who breastfed while their mothers took lithium, and they were close to zero: 0.06-0.10 mmol/L, with a tendency to decrease over time. However, 2 of the 30 infants had higher levels approaching the therapeutic range, so the conclusion here is that breastfeeding on lithium is possible, but only with close monitoring of the infant.
KELLIE NEWSOME: Close monitoring of the infant….That sounds like a lot of trouble. Why bother with a medication that requires you to check blood levels in the infant when there are so many other psych meds to choose from? This next paper gives an answer. An international team led by Chaitra Jairaj developed the first treatment guidelines for postpartum psychosis. This devastating syndrome – which occurs in about 1 in 1000 births – is a psychiatric emergency – and the recent batch of postpartum depression medications like zuranolone are not known to help because they excluded psychotic patients from their trials. Postpartum psychosis has a closer relationship to bipolar disorder than schizophrenia, and the new guidelines recommend three treatments: ECT, antipsychotics, and lithium. Lithium, they conclude, has “the best evidence for relapse prevention and prophylaxis in PPP.”
CHRIS AIKEN: Pregnancy is iffy territory for lithium, but age not so much. This year, two reviews looked at lithium in the young and old and concluded it’s a go. A few years ago, the FDA lowered the age limit for lithium use in bipolar disorder down to age 7, and an umbrella review concluded the evidence behind that is sound. Separately, another paper from Julia Christl and colleagues in Germany surveyed geropsychiatry experts for their opinion on lithium in the elderly and found solid consensus. 100% of experts considered lithium appropriate for older patients with bipolar disorder, or as augmentation in recurrent depression and treatment-resistant depression, as well as for suicide prevention.
Their paper is full of tips on how to use lithium in the elderly, and it’s free online if you search in pubmed for “Lithium Therapy in Old Age: Recommendations from a Delphi Survey.” All of the papers are also linked in the script for this podcast on the Carlat Report website. Here’s one pearl: while most patients need lithium levels of 0.6-0.8 for maintenance therapy in bipolar or treatment of depression, the targets are lower for the elderly. For ages 60-79, aim for 0.4 – 0.8; above age 80 aim for 0.4 – 0.7.
KELLIE NEWSOME: Here’s a fun paper. Some parts of the world have lithium in the drinking water, and people who grow up with that super low dose on tap have lower rates of dementia, suicide, and criminal behavior. But how low is the dose? This next paper from an international team of public health researchers points the way. Let’s assume someone drinks the maximum recommended daily allowance of water, 3.7 Liter/day.
Nearly every locale has some lithium in the water, and the body requires trace amounts of lithium to survive, but the daily dose from a full allowance of water is very low in most locales, around 0.02 mg/day. The highest levels are in Mexico, 8 mg/day. That’s close to some of the ultra-low doses used to prevent dementia, but far lower than the lowest pharmacy dose of 150 mg.
CHRIS AIKEN: Where we live in NC, the ground water dose goes up to 3 mg/day in some areas. Lithium trickles from the Appalachian Mountains, particularly Kings Mountain 30 miles south of Charlotte NC which is the largest lithium deposit in the US.
But lithium is not an elixir of health, and few things in life do all good and no harm. So far we don’t know of any clear harms from trace lithium in the drinking water, except an unproven link to autism that needs more study.
KELLIE NEWSOME: And now for a preview of the CME quiz. Earn CME for each podcast through the link in the show notes.
1. Which lifestyle change can lower lithium levels?
A. Switching to instant release formulation
B. Switching to a low salt diet
C. Intensive exercise
D. Sleep disruption
Our next studies look at lithium levels. First, a quick update. A few years ago the International Society for Bipolar Disorder (ISBD) put out new recommendations for lithium levels: 0.6 to 0.8 for long-term treatment in bipolar. That’s lower than some older guidelines, and part of the thinking is that lithium is much better tolerated and patients are more likely to stick with it in those levels. Indeed, a few papers from the past year found lower rates of renal problems when the level is kept below 0.8. The same 0.6-0.8 range is recommended for acute bipolar and unipolar depression, but you can go slightly higher for bipolar mania.
Children also need 0.6-0.8, but older adults need lower levels, and here the ISBD has new guidance: for ages 60-79, aim for 0.4 – 0.8; above age 80 aim for 0.4 – 0.7.
CHRIS AIKEN: But what if you could check your level more often than the usual 6-12 months? How steady would it be? This next study from Iñaki Zorrilla and colleagues in Spain looked at that scenario. Every two weeks, they checked lithium levels and correlated it with various lifestyle factors – mainly diet, weight, and activity and sleep patterns measured by actigraph. Here’s what they found: Sleep, diet, alcohol, and drug use had no impact on lithium levels – although we should point out that they didn’t look at switching to a low salt diet which is known to raise lithium. The two things that lowered lithium levels were physical activity and increase in weight. Specifically, an increase of 10,000 daily steps lowered lithium levels by 0.05 mEq/L, about equal to lowering the daily dose by 200 mg. Why? We don’t know, but it may be that people excrete more lithium as they sweat. Obesity was associated with lower lithium levels – a finding backed by other studies, and here we know the reason. It’s not that you need more lithium to fill a bigger body size. It’s because people who are overweight get rid of lithium faster through their kidneys.
KELLIE NEWSOME: This year, the FDA gave the greenlight to a new branded formulation of lithium that aims to make the medication safer and easier to take. LiProSal pairs lithium with the amino acid proline and salicylate, otherwise known as aspirin, to allow more of it to cross the blood brain barrier and enter the CNS. That way patients can get therapeutic brain levels with a lower serum level, potentially lowering the risk of physical side effects. Specifically, this formulation allows 20% lower serum levels. The new lithium was created 10 years ago at the University of South Florida, and it is being developed by the Atlanta based Alzamend pharmaceuticals for four potential indications: Alzheimer’s disease, PTSD, Major Depression, and Bipolar. We spoke with their CEO, Stephan Jackman.
CHRIS AIKEN: How did the discovery of crystallized lithium come about?
STEPHAN JACKMAN: Yes, so the inventors at the University of South Florida had family members suffering from bipolar disorder and major depressive disorder, and were on a lithium regimen. They saw that the benefits were that lithium was extremely efficacious, where they said you have to have your blood monitored for the side effects in general. They said how can we do something or create a lithium product to minimize the side effects, and they took about ten years to invent the product. Alzamend was formed in 2016 because [of] the founder of the organization. Alzheimer's had not skipped a generation on both his side and his wife's side. They were watching television and one of the inventors of the product was being interviewed by Dr. Sanjay Gupta, and they said hey, we need to look into this. They reached out to the university and said well, you can license a product and take it out. They had no idea what to do. They said we would license it, and we would form a company and look and see how we can get this product to market.
CHRIS AIKEN: What is the new lithium formulation made of?
STEPHAN JACKMAN: Our lithium is an ionic -- crystal of lithium delivering lithium combined with lithium salicylate. Salicylic acid is an anti-inflammatory and proline is an amino acid, and it will crystalize, you can picture sugar or salt crystals, thats the product. The beauty of that is that it gives the product greater biodistribution and greater bioavailability, so it allows your body to absorb and process it that much better. It would be the same chemical formulation for Alzheimer's, Bipolar disorder, Major Depressive Disorder, and PTSD. The dosage may be different.
CHRIS AIKEN: Is the brand name going to be LiProSal?
STEPHAN JACKMAN: LiProSal is basically the name that was given by the inventors L-I-P-R-O-S-A-L. So, they that is lithium, salicylate, and proline. It is kind of a working brand name, something that will be revealed as we enter Phase II B and Phase III. So, as we enter clinical trials, we are looking to measure lithium in the brain. We are looking to compare our lithium to the current market of lithium. The patients, of course, being the control, would take the correct market lithium for two weeks, wash out, and [then] take our lithium. What we are looking to show is that our lithium in terms of in the brain compared to the current market lithium.
KELLIE NEWSOME: Alzamend hopes this new formulation will be safe enough that laboratory monitoring will not be required. Those are bold ambitions, and we look forward to what the data shows.