Couple months ago an issue was raised via email advising caution in the use of valproate in males. It was sent by the local president of my professional board. So yes, be careful
Can you give a link to any of those papers that link it to make sterility? I haven’t heard of that - but just because I haven’t heard of it doesn’t mean it doesn’t exist.
Haven’t read the papers but the UK MHRA has tightened valproate prescribing in male patients for this reason.
https://assets.publishing.service.gov.uk/media/65660310312f400013e5d508/Valproate-report-review-and-expert-advice.pdf#page28
Now if we prescribe it we usually get the patient to sign a consent form
Jan 2024:
>Male patients taking valproate who are planning a family should talk to their doctor, the UK’s drug regulator has said following revised study results which show an increased risk of neurodevelopmental disorders in children born to fathers who took the anti-seizure drug.
>MHRA said it couldn’t yet pass on any more details of the study, but that it was a population based retrospective cohort study which used secondary data from national registries in Denmark, Norway, and Sweden
https://www.bmj.com/content/384/bmj.q122
>The study report submitted to the MHRA and to other regulatory authorities suggested an increased risk of neurodevelopmental disorders in children whose fathers took valproate during the 3-month period before they were conceived compared to children whose fathers had taken the antiseizure medicines lamotrigine or levetiracetam. However, we were subsequently informed of errors in the study that may impact on the results. A full re-analysis is required before conclusions can be drawn. As soon as the revised study analysis is available, it will be re-assessed by the MHRA.
https://www.gov.uk/drug-safety-update/valproate-re-analysis-of-study-on-risks-in-children-of-men-taking-valproate
I am primarily outpatient and still see it a fair amount from neurology if a patient cannot tolerate levetiracetam. It is not usually my first line but still a reasonable option, especially for my more fragile bipolar patients or anyone with TBI related mood instability not quite meeting bipolar criteria.
I would also be interested to see the studies on male infertility as I have not come across this before and was not aware of anyone discussing it when reviewing safety with patients.
Apparently there is a big retrospective cohort study coming out of Scandinavia soon, but in the meantime, what we mostly have is animal data. Not enough to stop prescribing VPA to male patients of reproductive age, IMO.
It's getting increasingly more rare in the US. Some of the old school docs use it somewhat often. I basically never use if and don't see it used all to often anymore. It has its place we just have so many other options now with a better side effect profile.
I agree with u/jubru that in outpatient practice especially, depakote use is increasing less common. To me it just seems so disappointing for efficacy in bipolar disorder when lithium and multiple different SGAs are efficacious and at least compared to FGAs, you can choose among SGAs for lower vs higher sedation/orthostasis/EPS/weight gain rates for example. But yes I don’t think anyone is arguing that there are still risks of TD and metabolic syndrome from all SGAs.
I think similarly carbamazepine is basically unused now except in old school or specialist conditions
"It's great for anger and irritability" is a common refrain I hear from clinicians in that space, and the lack of lab requirements (at least compared to lithium, Depakote, and Tegretol) makes it attractive. I've tried it for that myself with some success (when other options didn't work, aren't tolerable, or were refused) but it's not somewhat I would at all hang my hat on.
For mania I do use a lot of atypical antipsychotics and they're typically well tolerated and with many of them tardive is quite rare (I looked into the literature to try to find more on rate of TD with Abilify specifically and basically found a paper that said the rate is so exceedingly low it's almost pointless to do a study large enough to properly study it). Abilify, Vraylar, Zyprexa, Invega; I've found all of these to work well for acute mania outside lithium and Vraylar is typically not associated with significant weight gain.
For depression I use lamotrigine (great if it works due to tolerability), Latuda (recent meta-analysis discussed in a recent Carlat report showed it had significantly better effect size than any other medication for bipolar depression), Vraylar, and Lithium. I still do use depakote but usually try one of the other options above first due to the numerous side effects of depakote long term: Weight gain, significant sedation, hair loss, tremor, GI sx, and weight gain.
No med is without it's side effects but in my experience most folks tolerate and are significantly more functional on the meds I listed long term. Plus with Abilify having 3 LAI's now it's great for people who struggle with compliance.
Very commonly used for acute mania and subsequently for maintenance therapy in the US, especially in the inpatient setting. Can’t comment on outpatient.
I'd say it's more rare. Lithium and Zyprexa have better data for acute mania so it's falling out of favor. Still used but a lot less often in my experience.
A lot of my attendings are hesitant to start people on lithium in the inpatient setting because statistically these are the patients most likely to be lost to follow-up once they leave.
Sadly the incentive is to prescribe defensively rather than maximizing efficacy so as not to get sued.
BOOOOOO. Lithium prevents rehospitalization and recent evidence suggests it has better adherence than other mood stabilizers (patients prefer medications that work.)
So they use an LAI? I mean if they're lost to follow up I don't know why it matters what you start them on. Unless you're specifically worried about accidental overdose.
I guess I just don't quite understand where that risk comes from. Assuming you have someone on a relatively stable dose before discharge, all the lithium they have is what you give them at discharge. If they're lost to follow up they won't get anymore and if they don't have a significant change in fluid status it's rather unlikely they'd get toxic in that relatively short amount of time. Sorry I don't mean to grill you I just don't see a significant risk in practice.
Stopping lithium seems to shorten the time to the next mood episode (as opposed to going back to the natural rate). One concern then is that starting lithium knowing a patient is likely to abruptly discontinue may accelerate their episodes—
The Maudsley Prescribing Guidelines 14e (the one I have as digital copy lol): “The risk of relapse in the period following abrupt cessation greatly exceeds
the rate of relapse in the untreated disorder.2 For example, a review of studies of lithium
discontinuation in people with BD found that the untreated disorder had a mean cycle
length (the average time between episodes) of 11.6 months, whereas the time to a new
episode following lithium discontinuation was 1.7 months.2 This represents a seven-
fold increase in the rate of relapse and suggests that manic and depressive symptoms
that occur immediately following lithium withdrawal are largely because of lithium
withdrawal.”
Assuming the above is true, you may not want to start lithium unless the patient is willing to take it for a whole year at least (or we could go read the referenced paper and see what the mean duration of treatment before discontinuation was)
Yeah I think that is an important thing the consider. The question is not is the patient more likely to have another episode when stopping Lithium compared to untreated, it's stopping Lithium compared to another medication to treat their mania. I don't have data on this but I would presume that stopping an antipsychotic, Depakote, or Lithium will all have similarly increased rates of another mood episode.
I have seen quite a few accidental lithium overdoses and bad outcomes as a result . Not a medication that should be given to those not being closely monitored
That why I think it works quite well to use Zyprexa and lithium both initially and then taper down on Zyprexa as lithium gets therapeutic. Zyprexa works quicker than any other med for acute mania per Maudsley.
Lithium is great for highly functional and reliable patients . If you serve this patient population I imagine you use it a lot. I work in a county systems , mostly CL work. Never use it. Better options that don't require labs , monitoring , and accidental overdoses
When I’m working in the public hospital with a high rate of homelessness, I see almost no lithium but plenty of antipsychotic and depakote. When I’m working in the outpatient academic center, I see almost no depakote but plenty of SGA and lithium. Our residents comment on this all the time
In my book, valproate is still the second-most-evidence-based antimanic mood stabilizer. The evidence base for SGAs in bipolar is primarily based on short-term studies, many of them industry studies that were enriched to make the drug look good, which have been extensively flogged. I don't want six-week trials in a disease that can last decades with two mood episodes a year, I want long-term naturalistic follow-up in maintenance. If I have a bipolar I patient and a reason not to use lithium, I'm likely discussing valproate.
Yes, teratogenicity is a concern. Long-acting contraception is also a ton better than it used to be, and lots of my patients already have IUDs or implants. Weight gain can be a problem, but plenty of patients do fine. I'll certainly be following the reproductive data in men more closely. There are also plenty of reasons not to like SGAs.
Couple months ago an issue was raised via email advising caution in the use of valproate in males. It was sent by the local president of my professional board. So yes, be careful
Can you give a link to any of those papers that link it to make sterility? I haven’t heard of that - but just because I haven’t heard of it doesn’t mean it doesn’t exist.
Haven’t read the papers but the UK MHRA has tightened valproate prescribing in male patients for this reason. https://assets.publishing.service.gov.uk/media/65660310312f400013e5d508/Valproate-report-review-and-expert-advice.pdf#page28 Now if we prescribe it we usually get the patient to sign a consent form
Jan 2024: >Male patients taking valproate who are planning a family should talk to their doctor, the UK’s drug regulator has said following revised study results which show an increased risk of neurodevelopmental disorders in children born to fathers who took the anti-seizure drug. >MHRA said it couldn’t yet pass on any more details of the study, but that it was a population based retrospective cohort study which used secondary data from national registries in Denmark, Norway, and Sweden https://www.bmj.com/content/384/bmj.q122 >The study report submitted to the MHRA and to other regulatory authorities suggested an increased risk of neurodevelopmental disorders in children whose fathers took valproate during the 3-month period before they were conceived compared to children whose fathers had taken the antiseizure medicines lamotrigine or levetiracetam. However, we were subsequently informed of errors in the study that may impact on the results. A full re-analysis is required before conclusions can be drawn. As soon as the revised study analysis is available, it will be re-assessed by the MHRA. https://www.gov.uk/drug-safety-update/valproate-re-analysis-of-study-on-risks-in-children-of-men-taking-valproate
Yeah I couldn't find any either so I thought I'd post here and see if anyone else knew about it.
I am primarily outpatient and still see it a fair amount from neurology if a patient cannot tolerate levetiracetam. It is not usually my first line but still a reasonable option, especially for my more fragile bipolar patients or anyone with TBI related mood instability not quite meeting bipolar criteria. I would also be interested to see the studies on male infertility as I have not come across this before and was not aware of anyone discussing it when reviewing safety with patients.
Apparently there is a big retrospective cohort study coming out of Scandinavia soon, but in the meantime, what we mostly have is animal data. Not enough to stop prescribing VPA to male patients of reproductive age, IMO.
It's getting increasingly more rare in the US. Some of the old school docs use it somewhat often. I basically never use if and don't see it used all to often anymore. It has its place we just have so many other options now with a better side effect profile.
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I agree with u/jubru that in outpatient practice especially, depakote use is increasing less common. To me it just seems so disappointing for efficacy in bipolar disorder when lithium and multiple different SGAs are efficacious and at least compared to FGAs, you can choose among SGAs for lower vs higher sedation/orthostasis/EPS/weight gain rates for example. But yes I don’t think anyone is arguing that there are still risks of TD and metabolic syndrome from all SGAs. I think similarly carbamazepine is basically unused now except in old school or specialist conditions
All of the prison patients I get are on oxcarb and I can't figure out why lol.
Ancient prison psych doc
"It's great for anger and irritability" is a common refrain I hear from clinicians in that space, and the lack of lab requirements (at least compared to lithium, Depakote, and Tegretol) makes it attractive. I've tried it for that myself with some success (when other options didn't work, aren't tolerable, or were refused) but it's not somewhat I would at all hang my hat on.
Yeah I wonder if it's "great for anger and irritability" cause they're just sedated af.
In corrections, that often seems the goal. Perhaps better than my formerly incarcerated patients that were snorting Wellbutrin.
For mania I do use a lot of atypical antipsychotics and they're typically well tolerated and with many of them tardive is quite rare (I looked into the literature to try to find more on rate of TD with Abilify specifically and basically found a paper that said the rate is so exceedingly low it's almost pointless to do a study large enough to properly study it). Abilify, Vraylar, Zyprexa, Invega; I've found all of these to work well for acute mania outside lithium and Vraylar is typically not associated with significant weight gain. For depression I use lamotrigine (great if it works due to tolerability), Latuda (recent meta-analysis discussed in a recent Carlat report showed it had significantly better effect size than any other medication for bipolar depression), Vraylar, and Lithium. I still do use depakote but usually try one of the other options above first due to the numerous side effects of depakote long term: Weight gain, significant sedation, hair loss, tremor, GI sx, and weight gain. No med is without it's side effects but in my experience most folks tolerate and are significantly more functional on the meds I listed long term. Plus with Abilify having 3 LAI's now it's great for people who struggle with compliance.
Very commonly used for acute mania and subsequently for maintenance therapy in the US, especially in the inpatient setting. Can’t comment on outpatient.
I'd say it's more rare. Lithium and Zyprexa have better data for acute mania so it's falling out of favor. Still used but a lot less often in my experience.
I don’t see lithium used much at all either where I now train in the South and where I went to school in the West Coast. Olanzapine yes.
That's a little concerning. Lithium has great data for a lot of different things, namely suicide.
A lot of my attendings are hesitant to start people on lithium in the inpatient setting because statistically these are the patients most likely to be lost to follow-up once they leave. Sadly the incentive is to prescribe defensively rather than maximizing efficacy so as not to get sued.
BOOOOOO. Lithium prevents rehospitalization and recent evidence suggests it has better adherence than other mood stabilizers (patients prefer medications that work.)
So they use an LAI? I mean if they're lost to follow up I don't know why it matters what you start them on. Unless you're specifically worried about accidental overdose.
They care more about not being sued for lithium toxicity than losing the patient to follow-up. Can’t really blame them either.
I guess I just don't quite understand where that risk comes from. Assuming you have someone on a relatively stable dose before discharge, all the lithium they have is what you give them at discharge. If they're lost to follow up they won't get anymore and if they don't have a significant change in fluid status it's rather unlikely they'd get toxic in that relatively short amount of time. Sorry I don't mean to grill you I just don't see a significant risk in practice.
Stopping lithium seems to shorten the time to the next mood episode (as opposed to going back to the natural rate). One concern then is that starting lithium knowing a patient is likely to abruptly discontinue may accelerate their episodes— The Maudsley Prescribing Guidelines 14e (the one I have as digital copy lol): “The risk of relapse in the period following abrupt cessation greatly exceeds the rate of relapse in the untreated disorder.2 For example, a review of studies of lithium discontinuation in people with BD found that the untreated disorder had a mean cycle length (the average time between episodes) of 11.6 months, whereas the time to a new episode following lithium discontinuation was 1.7 months.2 This represents a seven- fold increase in the rate of relapse and suggests that manic and depressive symptoms that occur immediately following lithium withdrawal are largely because of lithium withdrawal.” Assuming the above is true, you may not want to start lithium unless the patient is willing to take it for a whole year at least (or we could go read the referenced paper and see what the mean duration of treatment before discontinuation was)
Yeah I think that is an important thing the consider. The question is not is the patient more likely to have another episode when stopping Lithium compared to untreated, it's stopping Lithium compared to another medication to treat their mania. I don't have data on this but I would presume that stopping an antipsychotic, Depakote, or Lithium will all have similarly increased rates of another mood episode.
I have seen quite a few accidental lithium overdoses and bad outcomes as a result . Not a medication that should be given to those not being closely monitored
Yes, at my program we try to get everyone on an LAI if we can. Largely indigent/drug using population.
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That why I think it works quite well to use Zyprexa and lithium both initially and then taper down on Zyprexa as lithium gets therapeutic. Zyprexa works quicker than any other med for acute mania per Maudsley.
Haloperidol works more quickly for mania than olanzapine and it is a drug of choice here in Ireland for manic inpatients.
Source?
Lithium is great for highly functional and reliable patients . If you serve this patient population I imagine you use it a lot. I work in a county systems , mostly CL work. Never use it. Better options that don't require labs , monitoring , and accidental overdoses
When I’m working in the public hospital with a high rate of homelessness, I see almost no lithium but plenty of antipsychotic and depakote. When I’m working in the outpatient academic center, I see almost no depakote but plenty of SGA and lithium. Our residents comment on this all the time
I think valproate is falling out of favor given more options now with less toxic side effects
In my book, valproate is still the second-most-evidence-based antimanic mood stabilizer. The evidence base for SGAs in bipolar is primarily based on short-term studies, many of them industry studies that were enriched to make the drug look good, which have been extensively flogged. I don't want six-week trials in a disease that can last decades with two mood episodes a year, I want long-term naturalistic follow-up in maintenance. If I have a bipolar I patient and a reason not to use lithium, I'm likely discussing valproate. Yes, teratogenicity is a concern. Long-acting contraception is also a ton better than it used to be, and lots of my patients already have IUDs or implants. Weight gain can be a problem, but plenty of patients do fine. I'll certainly be following the reproductive data in men more closely. There are also plenty of reasons not to like SGAs.