This has been a great series! Thank you so much for sharing your experience, Alex, and also pointing out these methodological flaws which have been propagated down the line (and continue to be). Not to sound obtuse, but if I was understanding correctly, and Owen please chime in here as an expert, if a patient is on a SDD regimen, the “trough”, aka point where lithium levels are theoretically at the lowest serum concentration, should be measured roughly 24 hours after the most recent dose?
Also, based on the studies provided, is it then recommended that providers initiate patients on MDD dosing until the optimal therapeutic dose is discovered, and then switch to the equivalent dose on an SDD regimen?
In any case, thank you again for your contribution and look forward to reading more!
Very glad you enjoyed it! I don't think you sound obtuse at all - you seem to have a fairly good grasp of the basic pharmacokinetics. I enjoy thinking about questions asked to me - definitely encourage it. As usual the regular, I'm not a doctor, take everything I say with a pinch of salt disclaimer applies to the following. Owen has the expertise and experience - I just look at papers!
Yes, the serum lithium trough is at 24 hours for SDD - however current guidance still recommends measuring the lithium serum level at 12 hours.
From my ignorant scientific position, a couple of the reasons for this might be 1. Practicality. The dose is normally taken just before bed - Not many clinics are open at 9-11pm. 2. There isn't really any research on what the optimal range would be for a 24 hour level. In fact, generally the research on optimal ranges for 12 hour levels is poor (not my opinion - see the Nolen paper I reference).
In reference to what the recommend guidance should be. My honest answer is: I don't know, not enough research. Generally starting TDD (Twice Daily Dosing) first then switching to SDD theoretically would make the most sense in my opinion - but I'm not sure there is enough experimental evidence to make any conclusion.
My completely speculative answer would be: start people on TDD until patient is on an effective dose as low as it is reasonably possible to achieve (hard to do - in part 3 I am basically saying it is possible patients on MDD averaged over the population are on a lithium dose that is higher than necessary), record that 12 hour level, and then switch to SDD.
However, instead of staying at the same dose, change the dose so that the 12 hour level is the same as it was on TDD. Which would probably mean a slight decrease in the dose. Because, basically, the retrospective research I've referenced in this series (that is interpreting optimal 12 hour ranges as the same for SDD and TDD) seems to suggest there is less risk of renal problems without any drop in adherence.
With the proviso that every patient is different and a discussion with them of what regimen they are comfortable with is the most important factor.
Ultimately, I think discussion of which regimen is best takes away attention from a better research question. If the Gong paper from 2016 I mentioned in part 4 is shown to be correct, finding out the tipping point where serum lithium levels drop low enough so that instead of harming the kidneys they are regenerating them is crucial. Find this level, and how it changes from person to person, then you can design dosing regimens to take advantage of it.
Hi Adele, thanks for the question! To my understanding, there isn't a significant reason prohibiting the use of SDD right away. The BNF guidelines are just that, guidelines. And a discussion between the psychiatrist and patient about the benefits and risks of each dosing regimen would allow an informed decision either way.
My speculative answer is just following the currently known research. To my knowledge there is no research on optimal ranges for SDD dosing. Historically, most patients were given MDD regimens, which the optimal ranges were based on. I think starting patients on SDD started to happen more frequently around 10-20 years ago? Not sure on this.
While technically you could adjust the 12 hour level of SDD to represent TDD optimal ranges, the Moscoso paper in part 3 suggests this percentage adjustment lies between 10-30%. This is quite a wide range given the small therapeutic window of lithium!
I believe that finding the optimal dose for each individual patient is very tricky given the small therapeutic window of lithium. For instance a small number of patients experience toxicity symptoms within the currently outlined therapeutic range. The optimal ranges have been debated ever since they were first proposed in the 70s. Balancing treatment response with side effects is tricky regardless of whether you start on SDD or TDD. Psychiatrists with clinical experience would be better placed to confirm whether this is true. At the very least with TDD you have a trough level which I think is better information for helping to determine treatment response than a midpoint.
Based on the pharmacokinetics, It would make sense that starting SDD would have just a slightly higher risk over the patient population of experiencing acute side effects or mild acute toxicity symptoms than on TDD. This is because the peak serum concentration is higher than TDD over the course of a dosing cycle (24 hours).
"I have observed the line between confidence and arrogance being crossed far more prevalently than in other walks of my life." This is so incredibly common in our field. I tell my residents, "Believe nothing, fact check everything."
I am curious to hear your thoughts on adherence of SDD vs MDD dosing. I know for me and my family, it's hard enough to remember to take every dose of an antibiotic prescription, and that's only 7-10 days worth. I try to put myself in the shoes of my patients and I wonder how realistic it is for me to expect consistent adherence to MDD, especially in folks that I see with minimal psychosocial support, homeless, etc. Maybe I underestimate them, but I worry that sending them home with MDD regimens may set them up for failure.
Either way, I loved the series. Great read as always.
Hi Joe, thanks very much for the kind words! You bring up an interesting issue. I can only really talk about my perspective as a patient & scientist. I do not have the qualifications/experience to give a clinical perspective. Owen is much better placed to help you there.
I can very much attest and empathise with you about the problems of making sure I remember to take every dose! I have a watch set with alarms, Alexa’s blurting out reminders in my house, along with the occasional reminders from relatives. I have been on a MDD regimen (not lithium, other medication) for a few years now and have yet to miss a dose. I found that after a while I fell into a habit – a medicine circadian rhythm if you will!
But that is me. The nature of complexity suggests that other patients will exhibit a wide range of behaviours related to taking MDD regimens.
You know the much-used Hollywood scene of both pilots in a plane being incapacitated meaning a passenger has to take over the controls? I like to see a doctor-patient relationship as like the air traffic controller (doctor) trying to help that passenger (patient) land the plane (recovery from illness). The doctor can give recommendations, but it is up to the patient to carry them out (whether taking medication, mental/physical therapy etc.).
The problem is that in medicine, the doctor often has very little information about what plane the patient is flying. Each plane is different - sometimes by a lot, sometimes by a little. And, the doctors have an incomplete (and sometimes wrong) understanding of how the planes generally work, while the patient usually has little to no understanding of how the plane works at all.
When framed this way, I believe it is easier to see why reciprocal communication and trust between patient & doctor is, in my opinion, vital for the plane to land safely.
When I say I would have loved to have had a conversation with my psychiatrist about the benefits and risks of different dosing regimens, this is because it would have allowed me to build a communication & trust relationship.
For instance, if my psychiatrist said “A twice daily dose regimens would help reduce the small risk of acute toxicity symptoms to start off with, but this regimen is more difficult to keep to than SDD – which is important with lithium [insert explanation here why keeping to regimen with lithium is very important]”. I could have responded with what I said in the second paragraph (of what I am realising is a very long reply - my apologies). Someone else might say “oh no doc, I have a terrible memory, I would find it difficult to take lithium more than once per day”.
So, long story short, I guess my patient-centric answer about adherence is "it depends".
I do understand that this is also all dependent on how much time you can afford each patient in a stretched medical system, and some patients are better able to communicate than others etc.
As a final curiosity, I am wondering whether reaching out to a clinician who has no choice but to prescribe MDD regimens to a lot of people (an endocrinologist prescribing insulin for diabetes for instance?) might help. They might have ideas, strategies or ways of communicating to patients with minimal psychosocial support that would help adherence to MDD? Just a thought.
Anyway, I hope there is something useful in what I have written Joe! And Owen please do add to this if necessary and/or correct me if I have written anything that I’ve misunderstood, or you disagree with, clinically.
I agree with Alex's perspective here, and I've done a non-trivial amount of work in this area. Starting all the way back in 1997, and yes I was in high school, I participated in the national engineering design challenge on the topic of medication, Even winning a prize for that project... We built a medication adherence machine. I've been thinking about this problem of Medication adherence for years. I don't think it's a problem with the patient. I think it's a problem with the brains we all have. More recently, I began Working with Anthony Sterns and our team, and we're building technology That helps remind people, in keeping with the way their brains work, To take their medicine. The data is that almost nobody successfully takes medication twice a day, If they're just trying to remember. The rates of non adherence to medication even once a day are around 50%. The challenge in taking medication multiple times a day only increases. Some very diligent people, like Alex, are able to make a choice, and have intact brains enough to be able to pull off the series of remembering and reminding strategies, along with habits, to make twice daily medication a Reality most of the time.
For many individuals this is just tremendously more difficult. And we're stuck with the bind, there are some medications that it would be best to take twice daily. There are some medication which people have to take multiple times a day. Some of these medication you'll die without, transplant rejection prevention suppressive medication, cancer medicines, and even some psychiatric medications are that life-saving.
The challenge, for all of us, is to recognize that humans aren't going to change. We need to augment and equip them with tools. We're not gonna dig the foundation for a building with our bare hands, not easily anyway. We need prosthetics. And the prosthetics we've tried to build historically for medication adherence have not been successful. So, that's some of what I've been working on. Prosthetics to help people with brains, even Brains that are not working perfectly, get help that reinforces Medication adherence compared to Not.
I think Alex's point is important: there are some medications, lithium might be among them, where multiple times a day dosing would be preferable.
Others were it is absolutely mandatory.
And, I'll refer you to one of my podcasts about this, Featuring Anthony Sterns, the strategy of just hoping people do this on their own isn't based on evidence, it's based on faith. Faith has not been born out by the evidence.
I do think that giving patients the information they need to make the decision for themselves is crucial, and that means weighing risks and benefits, even when it comes to the number of times per day we expect them to take a medicine.
Lithium has a challenging monitoring profile, which makes it unpopular among clinicians for prescribing. There are several factors involved in obtaining an accurate lithium monitoring sample, and often patients are unable to maintain the consistency required for safe medication use, monitoring, and dosing. Many patients discontinue their medication and struggle to adhere to the required scheduling and treatment regimen. Because lithium is an ion, any fluctuations in nutritional ions and electrolytes can cause changes in serum levels. Variability in values can also occur due to changes in hydration status, NSAIDs, ACE inhibitors, diuretics, certain antibiotics, recent infection, the time of the last dosing, the time of the last dosing prior to the lab draw, and thyroid function. Our current guidelines aim to reach and treat the population, but a more integrative, functional, and educational approach should be utilized to support clients taking this medication, which has beneficial properties for brain-derived neurotrophic factor (BDNF) and neuronal health. I became interested in the benefits of low-dose lithium because many of my clients with mild depressive, anxiety, or cognitive-related concerns are recommended low-dose lithium, much like low-dose naltrexone, as a preventive measure with potential prophylactic effects. Since the doses are microdoses, monitoring is not necessary, unlike larger doses. However, I understand that this approach may not be applicable to chronically ill patients with depression or manic bipolar disorder who require larger doses. My client base mainly consists of high-functioning CEOs, VPs, medical providers, and founders. My post- a minimization of some of the work others have written on lithium but maybe a different perspective. Feel free to provide a feedback https://limbicintegrative.substack.com/p/title-lithium-neurogenesis-and-anti?r=3ytur0&utm_campaign=post&utm_medium=web
This has been a great series! Thank you so much for sharing your experience, Alex, and also pointing out these methodological flaws which have been propagated down the line (and continue to be). Not to sound obtuse, but if I was understanding correctly, and Owen please chime in here as an expert, if a patient is on a SDD regimen, the “trough”, aka point where lithium levels are theoretically at the lowest serum concentration, should be measured roughly 24 hours after the most recent dose?
Also, based on the studies provided, is it then recommended that providers initiate patients on MDD dosing until the optimal therapeutic dose is discovered, and then switch to the equivalent dose on an SDD regimen?
In any case, thank you again for your contribution and look forward to reading more!
Hi Ben,
Very glad you enjoyed it! I don't think you sound obtuse at all - you seem to have a fairly good grasp of the basic pharmacokinetics. I enjoy thinking about questions asked to me - definitely encourage it. As usual the regular, I'm not a doctor, take everything I say with a pinch of salt disclaimer applies to the following. Owen has the expertise and experience - I just look at papers!
Yes, the serum lithium trough is at 24 hours for SDD - however current guidance still recommends measuring the lithium serum level at 12 hours.
From my ignorant scientific position, a couple of the reasons for this might be 1. Practicality. The dose is normally taken just before bed - Not many clinics are open at 9-11pm. 2. There isn't really any research on what the optimal range would be for a 24 hour level. In fact, generally the research on optimal ranges for 12 hour levels is poor (not my opinion - see the Nolen paper I reference).
In my opinion, perhaps the most worrying thing is the current dependence on research conducted in the 70s. A lot has changed since then! I argue about the overreliance on the 12 hour level in the article I wrote with Dr Aftab: https://www.psychiatrictimes.com/view/securing-the-future-of-lithium-research
In reference to what the recommend guidance should be. My honest answer is: I don't know, not enough research. Generally starting TDD (Twice Daily Dosing) first then switching to SDD theoretically would make the most sense in my opinion - but I'm not sure there is enough experimental evidence to make any conclusion.
My completely speculative answer would be: start people on TDD until patient is on an effective dose as low as it is reasonably possible to achieve (hard to do - in part 3 I am basically saying it is possible patients on MDD averaged over the population are on a lithium dose that is higher than necessary), record that 12 hour level, and then switch to SDD.
However, instead of staying at the same dose, change the dose so that the 12 hour level is the same as it was on TDD. Which would probably mean a slight decrease in the dose. Because, basically, the retrospective research I've referenced in this series (that is interpreting optimal 12 hour ranges as the same for SDD and TDD) seems to suggest there is less risk of renal problems without any drop in adherence.
With the proviso that every patient is different and a discussion with them of what regimen they are comfortable with is the most important factor.
Ultimately, I think discussion of which regimen is best takes away attention from a better research question. If the Gong paper from 2016 I mentioned in part 4 is shown to be correct, finding out the tipping point where serum lithium levels drop low enough so that instead of harming the kidneys they are regenerating them is crucial. Find this level, and how it changes from person to person, then you can design dosing regimens to take advantage of it.
why not to start SDD right away?
Hi Adele, thanks for the question! To my understanding, there isn't a significant reason prohibiting the use of SDD right away. The BNF guidelines are just that, guidelines. And a discussion between the psychiatrist and patient about the benefits and risks of each dosing regimen would allow an informed decision either way.
My speculative answer is just following the currently known research. To my knowledge there is no research on optimal ranges for SDD dosing. Historically, most patients were given MDD regimens, which the optimal ranges were based on. I think starting patients on SDD started to happen more frequently around 10-20 years ago? Not sure on this.
While technically you could adjust the 12 hour level of SDD to represent TDD optimal ranges, the Moscoso paper in part 3 suggests this percentage adjustment lies between 10-30%. This is quite a wide range given the small therapeutic window of lithium!
I believe that finding the optimal dose for each individual patient is very tricky given the small therapeutic window of lithium. For instance a small number of patients experience toxicity symptoms within the currently outlined therapeutic range. The optimal ranges have been debated ever since they were first proposed in the 70s. Balancing treatment response with side effects is tricky regardless of whether you start on SDD or TDD. Psychiatrists with clinical experience would be better placed to confirm whether this is true. At the very least with TDD you have a trough level which I think is better information for helping to determine treatment response than a midpoint.
Based on the pharmacokinetics, It would make sense that starting SDD would have just a slightly higher risk over the patient population of experiencing acute side effects or mild acute toxicity symptoms than on TDD. This is because the peak serum concentration is higher than TDD over the course of a dosing cycle (24 hours).
"I have observed the line between confidence and arrogance being crossed far more prevalently than in other walks of my life." This is so incredibly common in our field. I tell my residents, "Believe nothing, fact check everything."
I am curious to hear your thoughts on adherence of SDD vs MDD dosing. I know for me and my family, it's hard enough to remember to take every dose of an antibiotic prescription, and that's only 7-10 days worth. I try to put myself in the shoes of my patients and I wonder how realistic it is for me to expect consistent adherence to MDD, especially in folks that I see with minimal psychosocial support, homeless, etc. Maybe I underestimate them, but I worry that sending them home with MDD regimens may set them up for failure.
Either way, I loved the series. Great read as always.
Hi Joe, thanks very much for the kind words! You bring up an interesting issue. I can only really talk about my perspective as a patient & scientist. I do not have the qualifications/experience to give a clinical perspective. Owen is much better placed to help you there.
I can very much attest and empathise with you about the problems of making sure I remember to take every dose! I have a watch set with alarms, Alexa’s blurting out reminders in my house, along with the occasional reminders from relatives. I have been on a MDD regimen (not lithium, other medication) for a few years now and have yet to miss a dose. I found that after a while I fell into a habit – a medicine circadian rhythm if you will!
But that is me. The nature of complexity suggests that other patients will exhibit a wide range of behaviours related to taking MDD regimens.
You know the much-used Hollywood scene of both pilots in a plane being incapacitated meaning a passenger has to take over the controls? I like to see a doctor-patient relationship as like the air traffic controller (doctor) trying to help that passenger (patient) land the plane (recovery from illness). The doctor can give recommendations, but it is up to the patient to carry them out (whether taking medication, mental/physical therapy etc.).
The problem is that in medicine, the doctor often has very little information about what plane the patient is flying. Each plane is different - sometimes by a lot, sometimes by a little. And, the doctors have an incomplete (and sometimes wrong) understanding of how the planes generally work, while the patient usually has little to no understanding of how the plane works at all.
When framed this way, I believe it is easier to see why reciprocal communication and trust between patient & doctor is, in my opinion, vital for the plane to land safely.
When I say I would have loved to have had a conversation with my psychiatrist about the benefits and risks of different dosing regimens, this is because it would have allowed me to build a communication & trust relationship.
For instance, if my psychiatrist said “A twice daily dose regimens would help reduce the small risk of acute toxicity symptoms to start off with, but this regimen is more difficult to keep to than SDD – which is important with lithium [insert explanation here why keeping to regimen with lithium is very important]”. I could have responded with what I said in the second paragraph (of what I am realising is a very long reply - my apologies). Someone else might say “oh no doc, I have a terrible memory, I would find it difficult to take lithium more than once per day”.
So, long story short, I guess my patient-centric answer about adherence is "it depends".
I do understand that this is also all dependent on how much time you can afford each patient in a stretched medical system, and some patients are better able to communicate than others etc.
As a final curiosity, I am wondering whether reaching out to a clinician who has no choice but to prescribe MDD regimens to a lot of people (an endocrinologist prescribing insulin for diabetes for instance?) might help. They might have ideas, strategies or ways of communicating to patients with minimal psychosocial support that would help adherence to MDD? Just a thought.
Anyway, I hope there is something useful in what I have written Joe! And Owen please do add to this if necessary and/or correct me if I have written anything that I’ve misunderstood, or you disagree with, clinically.
I agree with Alex's perspective here, and I've done a non-trivial amount of work in this area. Starting all the way back in 1997, and yes I was in high school, I participated in the national engineering design challenge on the topic of medication, Even winning a prize for that project... We built a medication adherence machine. I've been thinking about this problem of Medication adherence for years. I don't think it's a problem with the patient. I think it's a problem with the brains we all have. More recently, I began Working with Anthony Sterns and our team, and we're building technology That helps remind people, in keeping with the way their brains work, To take their medicine. The data is that almost nobody successfully takes medication twice a day, If they're just trying to remember. The rates of non adherence to medication even once a day are around 50%. The challenge in taking medication multiple times a day only increases. Some very diligent people, like Alex, are able to make a choice, and have intact brains enough to be able to pull off the series of remembering and reminding strategies, along with habits, to make twice daily medication a Reality most of the time.
For many individuals this is just tremendously more difficult. And we're stuck with the bind, there are some medications that it would be best to take twice daily. There are some medication which people have to take multiple times a day. Some of these medication you'll die without, transplant rejection prevention suppressive medication, cancer medicines, and even some psychiatric medications are that life-saving.
The challenge, for all of us, is to recognize that humans aren't going to change. We need to augment and equip them with tools. We're not gonna dig the foundation for a building with our bare hands, not easily anyway. We need prosthetics. And the prosthetics we've tried to build historically for medication adherence have not been successful. So, that's some of what I've been working on. Prosthetics to help people with brains, even Brains that are not working perfectly, get help that reinforces Medication adherence compared to Not.
I think Alex's point is important: there are some medications, lithium might be among them, where multiple times a day dosing would be preferable.
Others were it is absolutely mandatory.
And, I'll refer you to one of my podcasts about this, Featuring Anthony Sterns, the strategy of just hoping people do this on their own isn't based on evidence, it's based on faith. Faith has not been born out by the evidence.
I do think that giving patients the information they need to make the decision for themselves is crucial, and that means weighing risks and benefits, even when it comes to the number of times per day we expect them to take a medicine.
This series of columns on lithium is not written by a psychiatrist--it's a guest series written by a scientist who
Happens to be a patient prescribed lithium.
Thank you for the clarification. I decided to delete my pervious comment as this may not be appropriate forum — although I stand by what I said.
Thanks for reading. He has his own substack too...worth a read.
Always great to read your perspective on lithium!
Thanks very much Awais :)
The link to the article by Alex and Dr. Aftab seems to be broken?
Ah, I've got the added advantage of the day starting earlier in the UK! I'll message Owen - thank you for pointing it out Mary. In the meantime, this link should work: https://www.psychiatrictimes.com/view/securing-the-future-of-lithium-research
Lithium has a challenging monitoring profile, which makes it unpopular among clinicians for prescribing. There are several factors involved in obtaining an accurate lithium monitoring sample, and often patients are unable to maintain the consistency required for safe medication use, monitoring, and dosing. Many patients discontinue their medication and struggle to adhere to the required scheduling and treatment regimen. Because lithium is an ion, any fluctuations in nutritional ions and electrolytes can cause changes in serum levels. Variability in values can also occur due to changes in hydration status, NSAIDs, ACE inhibitors, diuretics, certain antibiotics, recent infection, the time of the last dosing, the time of the last dosing prior to the lab draw, and thyroid function. Our current guidelines aim to reach and treat the population, but a more integrative, functional, and educational approach should be utilized to support clients taking this medication, which has beneficial properties for brain-derived neurotrophic factor (BDNF) and neuronal health. I became interested in the benefits of low-dose lithium because many of my clients with mild depressive, anxiety, or cognitive-related concerns are recommended low-dose lithium, much like low-dose naltrexone, as a preventive measure with potential prophylactic effects. Since the doses are microdoses, monitoring is not necessary, unlike larger doses. However, I understand that this approach may not be applicable to chronically ill patients with depression or manic bipolar disorder who require larger doses. My client base mainly consists of high-functioning CEOs, VPs, medical providers, and founders. My post- a minimization of some of the work others have written on lithium but maybe a different perspective. Feel free to provide a feedback https://limbicintegrative.substack.com/p/title-lithium-neurogenesis-and-anti?r=3ytur0&utm_campaign=post&utm_medium=web