I would love to hear more about how thoughtful psychiatrists approach prescribing for patients who have done well on lithium for years after initial manic psychosis and severe depressions, are stable and get regular lithium level tests, and are experiencing signs of renal failure.
Because renal impairment tends to progress with continued lithium use, the general approach in patients who are heading towards renal failure is to try to substitute with a different mood stabilizing medication. Some patients do unfortunately decompensate in the process. Many are able to figure out a workable substitute regimen. Those who can’t do well without lithium, they and their doctors face a difficult choice between a rock and a hard place
In my admittedly limited experience I’ve only come across one case so far where long term lithium monotherapy had to be stopped due to renal problems, and the family said there was simply no comparison. On lithium, the consumer lived a completely normal life, so much so that only the older family members still recalled the signs and symptoms of the illness. On valproate and a series of SGAs, the disease behaved like a caged animal. I have little doubt that this difference would barely register on a rating scale, and I’m not even sure it would be obvious to the doctor, but it was obvious to the family.
I’ve actually seen more cases of serious renal problems in people on long term antipsychotic treatment who, late in life, are found to be good lithium responders but have to come off it almost immediately. In these cases I’m not confident what caused the renal failure. All of them lived pretty hard lives, but that doesn’t change the outcome.
From my own observations, I suspect the typical Western dosing protocol is a hair too high. The Japanese targeted 0.4 at a time when the West still targeted 0.8. All kinds of reasons have been offered for this, but to me the most parsimonious is that the true mean response is below 0.8 and we’ve been overcooking it. I’ve seen people respond well to doses anywhere between 0.2 and 0.8, so in reality it doesn’t seem that high doses are always needed. It seems far more dependent on the case than the literature would have us believe. Lower the dose a touch and the renal impacts lessen exponentially. I also think a great many cases of renal failure might be avoided by instructing people to maintain normal electrolyte intake and avoid dehydration.
Here’s my take, based on talking with families of people on these drugs: the difference is visible to the naked eye. Lithium gets people well in ways the other drugs often do not, and if a little care is taken to lower the dose during maintenance, the side effect profile is in a completely different league. The only thing I have heard comparable results from is ECT.
Antipsychotics clearly work, and if they are used in extremely low doses, many side effects can be avoided. But the quality of life still does not seem the same. When you meet families with loved ones who have lived with bipolar disorder and have been on lithium for decades, versus antipsychotics for decades, the difference is obvious. In fact, at a decade in, the difference is so marked in every case I have encountered that I consider it extraordinary that anyone could miss it.
To me, it passes the “interocular trauma” test. Blind Freddie could see the difference.
So why can’t everyone spot it? For patients, I think they are often given too much lithium when they are manic, and that bad experience sets the tone. Once they are on an antipsychotic, they do not know any different. They often never get a solid experience of long-term maintenance lithium to compare with. Doctors miss it for the same reason they miss everything else: consumers do not tell them half of what they are actually experiencing, and they can feel a strange pressure to tell the doctor what they think the doctor wants to hear.
That said, I don't think lithium is specific to bipolar. I also think that a great many drugs can as Kraepelin said "ward off mania".
What is special about lithium to me is the relative completeness of its effects and the lack of mischievous side effects. Too many people focus on nuisance side effects. Mischievous side effects are a much bigger problem a decade in. The anticonvulsants and antipsychotics have far worse mischievous side effects that can take many years to become a problem.
My experience has been that there is a subset of mood disorder patients that show a clear and robust response to lithium, often after having failed other meds. Because lithium is often 2nd line, 3rd line, this pattern is hard to spot for some of the other mood stabilizing meds, but less clearly, I’ve also encountered a subset of Lamotrigine responders. I’ve also had many patients who tried lithium and hated it, and refuse to try it again. I do continue to suspect there is something distinctive about lithium but as far as clinical use is concerned, hard to know who is the right person for lithium.
Yes, I relate to a lot of what you are saying, and for many years I thought the same way, but my thinking changed, even before I had the opportunity to work at a hospital.
Many people hate lithium when they try it. The first time I saw lithium in action I was horrified. I thought it was by far the worst psychiatric drug that I had ever seen. Lithium can make a terrible first impression. But here is the rub, the anticonvulsants, especially lamotrigine, can make a lovely first impression. Lamotrigine will speak softly and gently, it will compliment your parents, it will whisper sweet words in your ear. It won’t betray you until a decade into the marriage, when it will reveal that it has slept with half the town and given you 12 STDs.
Lithium behaves different. It has nuisance side effects, not mischievous side effects. People who have a horrible time on 0.8 often feel perfectly well on 0.4. Lowering the dose seems to be where the magic is in lithium treatment. This is almost the opposite of the original research. So much has been said about the “narrow therapeutic window” that most people never explore doses far below the one that bought them out of their mania while in hospital. Even my copy of Michael Alan Taylor’s textbook says the dose they respond to in hospital is the dose they should be on in the community. I think that is wrong, and I think realising that it's wrong is when you realise the real advantages of lithium.
One of my current interests is withdrawal syndromes. I’m a member of a Facebook group for lamotrigine withdrawal. I think it is utterly fascinating and I cannot understand why interest in such phenomenon isn’t the hottest ticket in town, but each to their own. Regardless, I noticed a curious thing. There was a group on Facebook for withdrawal syndromes on just about every psychiatric drug, with thousands of members. The lithium group only had a couple of hundred, and it was a ghost town. The reports were different too, no long term sequelae, just a bad reaction upfront and some instability after coming off. Nothing remotely similar to the bizarre organic neurasthenia, neuropathy, autonomic and autoimmune problems I saw in the lamotrigine group. Now people will rush to say the reason the withdrawal groups are smaller for lithium is down to prescribing rates. I agree that is part of it, but I think it falls a long way short of explaining the difference. Many in the lamotrigine group had also been on lithium and hated it, but again, when asked, they didn’t have bizarre horror stories, just straightforward bad experiences. Almost universally, they had been put on the drug, taken up to 0.8 or so, and found they felt like their brain was in molasses. An unsettling experience, but never any of the weird scary stuff or the protracted withdrawals of the other drugs.
I also notice that people on lithium monotherapy for decades are healthy and normal, have careers, and raise families. Whereas the people on antipsychotic and anticonvulsant treatment for decades often have visibly poor physical health, they’re often quite “sickly” for lack of a better word. Now most people would conclude that is due to diagnostic differences. "Hasn’t schizophrenia always been associated with deterioration?", "Isn't this just the course of the illness?", "The lithium reponders are healthier because they had a less treatment resitant disease". I don’t think that is it at all. I think these drugs make people sickly with long term use. I do think this can be greatly ameliorated with minimal dosing regimes. Indeed I think that people can often be maintained on astonishingly low doses in the case of all of these drugs. That can go a long way towards solving the problem. The difference is this. When you low dose lithium, the side effects are often completely non-existent.
I still don't think lithium is specific to MDI. I just think that in real life, if the doctor knows how to use it, people get "well" in a way they don't with anything else except ECT. ECT is where I've hear similar reports. Again, think of how many people hate ECT. Most people if asked will tell you they would much prefer an antipsychotic over ECT and I don't think that should be the least bit surprising.
Maybe you could say its a bit like cod-live oil. People hate the stuff but it does seem to be... I don't know, healthier?
Yeah, cod-liver oil. That's it, awful taste, people hate it but mothers know the truth.
This was very informative and thought provoking. Thanks as always, Awais. I’m curious to hear what others will share. As a clinician who is trying to use lithium more in my practice, mostly in lower doses ranging from 300mg-600mg, this piece is a good reminder that there are many other effective options to treat recurrent affective illness. I think many of us can get “stuck” in our prescribing patterns and it is always good to take a step back, remember that we do have many options, including non-pharmacological interventions, provide a multitude of treatment options to our patients, and make a collective decision together.
Good to know I’m in line with other providers I respect 😉
Also, I recently heard someone refer to you as an “influencer”. I found it interesting. I have such a negative internal reaction to that word, I immediately rejected the concept of you as an “influencer”, but it caused me to wonder, “I wonder if he considers himself as such…?”
Hah! I have similar negative associations with the word, so I don’t like to think of myself as an influencer, but there is a general sense in which I can characterized that way.
Though my career is slightly shorter and clinical experience with patients diagnosed as bipolar significantly less, I could not agree more with Professor Belmaker. Thanks both to him and Awais.
Such an interesting read. I would love to hear group thoughts on using subclinical blood level dosing for patients with mood lability or dysthymia or over the counter supplement with lithium oratate or lithium combined with ascorbic acid? So many questions to still explore.
I’ve had good success with using lithium 300-600 mg as adjunct in depression and bipolar II. It’s tolerated quite well, although I’ve had patients where it caused a flare up of psoriasis or showed some mild decline in GFR over time.
Interesting and thought provoking and I applauded people who are able to criticize what they spent their life building, that said:
1. I think we should be skeptical of individual doctors and patients assessment of treatments, we consciously or unconsciously select/self select for treatment, ergo we have to depend mostly on RCTs.
2. It's important to separate what aspect of BP that a specific treatment addresses - valproate and carbamazepine effect on preventing and treating manic episodes relative to depressive episodes.
3. TD is not the only major side effect of antipsychotics, metabolic side effects (and TD) is a much more serious problem than hypothyroidism or hyperthyroidism.
4. Valproate and Carbamazepine are both side effect-heavy - decreased cognitive performance, high teratogenicity - excluding it as an option for most women. There is even some indication that at least valproate increase dementia risk substantially.
5. Nitpicking, but the I'd much rather use Quetiapine than Olanzapine - unless you are treating a full on manic episode.
Though I'm not a psychiatrist (a clinical psychologist), but I'm not aware of any Psychiatric facility in Nigeria that treats Bipolar with Lithium. It has mostly been a combination of those other alternatives mentioned by the author.
Sometimes it's necessary for psychiatrists ( like me) to stop and take stock of how little usable knowledge we've gained in the last 50 years or so. It's fascinating to realize that people at the apparent top tier of our field can be so far apart on things like when and for whom to use lithium. I think our field has been under intense pressure for a long time to come up with reliable diagnoses and dependable and safe treatments (even if we can't explain well how they work or what they're exactly addressing). I think the public has been demanding we come up with something they can trust, and we've not found enough. So we dig in and act as if we're really pretty close, making just enough incremental progress to make us feel better while the rest of the world is not impressed. Perhaps we need to do more to tell the outside world that we're really more at a loss than we'd wish we were; not for lack of trying, but more due to the elusiveness of what we're after. If you remember the "Decade of the Brain" and ask we got from that that has made a difference, I guess I'd like to be reminded first. It's not that patients are not better off than decades ago, but that we have so painfully far to go. Sometimes it seems like we're asking the wrong questions; I'm not sure what the right ones are, but perhaps we're somewhat like the proverbial husband who (back in the day) thought he was close and was not going to stop and ask for directions.
Fascinating piece. Would love to see a dialogue between Drs. Belmaker and Ghaemi on their contrasting positions on lithium and psychiatric nosology.
I had this very same thought as I was reading this.
I would love to hear more about how thoughtful psychiatrists approach prescribing for patients who have done well on lithium for years after initial manic psychosis and severe depressions, are stable and get regular lithium level tests, and are experiencing signs of renal failure.
Because renal impairment tends to progress with continued lithium use, the general approach in patients who are heading towards renal failure is to try to substitute with a different mood stabilizing medication. Some patients do unfortunately decompensate in the process. Many are able to figure out a workable substitute regimen. Those who can’t do well without lithium, they and their doctors face a difficult choice between a rock and a hard place
In my admittedly limited experience I’ve only come across one case so far where long term lithium monotherapy had to be stopped due to renal problems, and the family said there was simply no comparison. On lithium, the consumer lived a completely normal life, so much so that only the older family members still recalled the signs and symptoms of the illness. On valproate and a series of SGAs, the disease behaved like a caged animal. I have little doubt that this difference would barely register on a rating scale, and I’m not even sure it would be obvious to the doctor, but it was obvious to the family.
I’ve actually seen more cases of serious renal problems in people on long term antipsychotic treatment who, late in life, are found to be good lithium responders but have to come off it almost immediately. In these cases I’m not confident what caused the renal failure. All of them lived pretty hard lives, but that doesn’t change the outcome.
From my own observations, I suspect the typical Western dosing protocol is a hair too high. The Japanese targeted 0.4 at a time when the West still targeted 0.8. All kinds of reasons have been offered for this, but to me the most parsimonious is that the true mean response is below 0.8 and we’ve been overcooking it. I’ve seen people respond well to doses anywhere between 0.2 and 0.8, so in reality it doesn’t seem that high doses are always needed. It seems far more dependent on the case than the literature would have us believe. Lower the dose a touch and the renal impacts lessen exponentially. I also think a great many cases of renal failure might be avoided by instructing people to maintain normal electrolyte intake and avoid dehydration.
This is an interesting article.
Here’s my take, based on talking with families of people on these drugs: the difference is visible to the naked eye. Lithium gets people well in ways the other drugs often do not, and if a little care is taken to lower the dose during maintenance, the side effect profile is in a completely different league. The only thing I have heard comparable results from is ECT.
Antipsychotics clearly work, and if they are used in extremely low doses, many side effects can be avoided. But the quality of life still does not seem the same. When you meet families with loved ones who have lived with bipolar disorder and have been on lithium for decades, versus antipsychotics for decades, the difference is obvious. In fact, at a decade in, the difference is so marked in every case I have encountered that I consider it extraordinary that anyone could miss it.
To me, it passes the “interocular trauma” test. Blind Freddie could see the difference.
So why can’t everyone spot it? For patients, I think they are often given too much lithium when they are manic, and that bad experience sets the tone. Once they are on an antipsychotic, they do not know any different. They often never get a solid experience of long-term maintenance lithium to compare with. Doctors miss it for the same reason they miss everything else: consumers do not tell them half of what they are actually experiencing, and they can feel a strange pressure to tell the doctor what they think the doctor wants to hear.
That said, I don't think lithium is specific to bipolar. I also think that a great many drugs can as Kraepelin said "ward off mania".
What is special about lithium to me is the relative completeness of its effects and the lack of mischievous side effects. Too many people focus on nuisance side effects. Mischievous side effects are a much bigger problem a decade in. The anticonvulsants and antipsychotics have far worse mischievous side effects that can take many years to become a problem.
I share some of this sentiment but have also met a handful of patients who developed renal failure after decades of lithium use
My experience has been that there is a subset of mood disorder patients that show a clear and robust response to lithium, often after having failed other meds. Because lithium is often 2nd line, 3rd line, this pattern is hard to spot for some of the other mood stabilizing meds, but less clearly, I’ve also encountered a subset of Lamotrigine responders. I’ve also had many patients who tried lithium and hated it, and refuse to try it again. I do continue to suspect there is something distinctive about lithium but as far as clinical use is concerned, hard to know who is the right person for lithium.
Yes, I relate to a lot of what you are saying, and for many years I thought the same way, but my thinking changed, even before I had the opportunity to work at a hospital.
Many people hate lithium when they try it. The first time I saw lithium in action I was horrified. I thought it was by far the worst psychiatric drug that I had ever seen. Lithium can make a terrible first impression. But here is the rub, the anticonvulsants, especially lamotrigine, can make a lovely first impression. Lamotrigine will speak softly and gently, it will compliment your parents, it will whisper sweet words in your ear. It won’t betray you until a decade into the marriage, when it will reveal that it has slept with half the town and given you 12 STDs.
Lithium behaves different. It has nuisance side effects, not mischievous side effects. People who have a horrible time on 0.8 often feel perfectly well on 0.4. Lowering the dose seems to be where the magic is in lithium treatment. This is almost the opposite of the original research. So much has been said about the “narrow therapeutic window” that most people never explore doses far below the one that bought them out of their mania while in hospital. Even my copy of Michael Alan Taylor’s textbook says the dose they respond to in hospital is the dose they should be on in the community. I think that is wrong, and I think realising that it's wrong is when you realise the real advantages of lithium.
One of my current interests is withdrawal syndromes. I’m a member of a Facebook group for lamotrigine withdrawal. I think it is utterly fascinating and I cannot understand why interest in such phenomenon isn’t the hottest ticket in town, but each to their own. Regardless, I noticed a curious thing. There was a group on Facebook for withdrawal syndromes on just about every psychiatric drug, with thousands of members. The lithium group only had a couple of hundred, and it was a ghost town. The reports were different too, no long term sequelae, just a bad reaction upfront and some instability after coming off. Nothing remotely similar to the bizarre organic neurasthenia, neuropathy, autonomic and autoimmune problems I saw in the lamotrigine group. Now people will rush to say the reason the withdrawal groups are smaller for lithium is down to prescribing rates. I agree that is part of it, but I think it falls a long way short of explaining the difference. Many in the lamotrigine group had also been on lithium and hated it, but again, when asked, they didn’t have bizarre horror stories, just straightforward bad experiences. Almost universally, they had been put on the drug, taken up to 0.8 or so, and found they felt like their brain was in molasses. An unsettling experience, but never any of the weird scary stuff or the protracted withdrawals of the other drugs.
I also notice that people on lithium monotherapy for decades are healthy and normal, have careers, and raise families. Whereas the people on antipsychotic and anticonvulsant treatment for decades often have visibly poor physical health, they’re often quite “sickly” for lack of a better word. Now most people would conclude that is due to diagnostic differences. "Hasn’t schizophrenia always been associated with deterioration?", "Isn't this just the course of the illness?", "The lithium reponders are healthier because they had a less treatment resitant disease". I don’t think that is it at all. I think these drugs make people sickly with long term use. I do think this can be greatly ameliorated with minimal dosing regimes. Indeed I think that people can often be maintained on astonishingly low doses in the case of all of these drugs. That can go a long way towards solving the problem. The difference is this. When you low dose lithium, the side effects are often completely non-existent.
I still don't think lithium is specific to MDI. I just think that in real life, if the doctor knows how to use it, people get "well" in a way they don't with anything else except ECT. ECT is where I've hear similar reports. Again, think of how many people hate ECT. Most people if asked will tell you they would much prefer an antipsychotic over ECT and I don't think that should be the least bit surprising.
Maybe you could say its a bit like cod-live oil. People hate the stuff but it does seem to be... I don't know, healthier?
Yeah, cod-liver oil. That's it, awful taste, people hate it but mothers know the truth.
This was very informative and thought provoking. Thanks as always, Awais. I’m curious to hear what others will share. As a clinician who is trying to use lithium more in my practice, mostly in lower doses ranging from 300mg-600mg, this piece is a good reminder that there are many other effective options to treat recurrent affective illness. I think many of us can get “stuck” in our prescribing patterns and it is always good to take a step back, remember that we do have many options, including non-pharmacological interventions, provide a multitude of treatment options to our patients, and make a collective decision together.
Low dose lithium as an adjunct in depression and bipolar II can be very beneficial! I also use it commonly
Good to know I’m in line with other providers I respect 😉
Also, I recently heard someone refer to you as an “influencer”. I found it interesting. I have such a negative internal reaction to that word, I immediately rejected the concept of you as an “influencer”, but it caused me to wonder, “I wonder if he considers himself as such…?”
Hah! I have similar negative associations with the word, so I don’t like to think of myself as an influencer, but there is a general sense in which I can characterized that way.
“Collaborating with Joeseph Biederman who went on to become a distinguished Harvard professor of child psychiatry in later years in Boston” 😬
Fascinating stuff. Thank you for sharing all these insights.
Though my career is slightly shorter and clinical experience with patients diagnosed as bipolar significantly less, I could not agree more with Professor Belmaker. Thanks both to him and Awais.
Such an interesting read. I would love to hear group thoughts on using subclinical blood level dosing for patients with mood lability or dysthymia or over the counter supplement with lithium oratate or lithium combined with ascorbic acid? So many questions to still explore.
I’ve had good success with using lithium 300-600 mg as adjunct in depression and bipolar II. It’s tolerated quite well, although I’ve had patients where it caused a flare up of psoriasis or showed some mild decline in GFR over time.
Thanks for writing about this medicine. I have never on Lithium, but have always been told of its efficacy.
As someone from Modi'in, Israel never thought I would come across modiin in this substack. Thanks for covering this topic
Thank you very much for this extensive summary.
Interesting and thought provoking and I applauded people who are able to criticize what they spent their life building, that said:
1. I think we should be skeptical of individual doctors and patients assessment of treatments, we consciously or unconsciously select/self select for treatment, ergo we have to depend mostly on RCTs.
2. It's important to separate what aspect of BP that a specific treatment addresses - valproate and carbamazepine effect on preventing and treating manic episodes relative to depressive episodes.
3. TD is not the only major side effect of antipsychotics, metabolic side effects (and TD) is a much more serious problem than hypothyroidism or hyperthyroidism.
4. Valproate and Carbamazepine are both side effect-heavy - decreased cognitive performance, high teratogenicity - excluding it as an option for most women. There is even some indication that at least valproate increase dementia risk substantially.
5. Nitpicking, but the I'd much rather use Quetiapine than Olanzapine - unless you are treating a full on manic episode.
Though I'm not a psychiatrist (a clinical psychologist), but I'm not aware of any Psychiatric facility in Nigeria that treats Bipolar with Lithium. It has mostly been a combination of those other alternatives mentioned by the author.
Sometimes it's necessary for psychiatrists ( like me) to stop and take stock of how little usable knowledge we've gained in the last 50 years or so. It's fascinating to realize that people at the apparent top tier of our field can be so far apart on things like when and for whom to use lithium. I think our field has been under intense pressure for a long time to come up with reliable diagnoses and dependable and safe treatments (even if we can't explain well how they work or what they're exactly addressing). I think the public has been demanding we come up with something they can trust, and we've not found enough. So we dig in and act as if we're really pretty close, making just enough incremental progress to make us feel better while the rest of the world is not impressed. Perhaps we need to do more to tell the outside world that we're really more at a loss than we'd wish we were; not for lack of trying, but more due to the elusiveness of what we're after. If you remember the "Decade of the Brain" and ask we got from that that has made a difference, I guess I'd like to be reminded first. It's not that patients are not better off than decades ago, but that we have so painfully far to go. Sometimes it seems like we're asking the wrong questions; I'm not sure what the right ones are, but perhaps we're somewhat like the proverbial husband who (back in the day) thought he was close and was not going to stop and ask for directions.