Lithium+Valproate combination in bipolar disorder

[thelastpsych]

I've seen a lot of psychiatrists in my neck of the woods prescribe lithium AND valproic acid to bipolar patients - usually in lower doses (i.e 600-900mg Lithium and 1g Depakote for a 160 pound male patient), which doesn't make a lot of sense to me - I'd rather just prescribe one in a higher dose and follow it up with serum concentration tests.
Having said that, are there situations where it is recommended to associate Lithium and Valproic Acid, instead of focusing on third of fourth line treatments in refractory patients? (Clozapine, for instance). I've searched PubMed, but could only find a 2013 Cochrane Metanalysis which found that combining Valproate with Lithium is better than Valproic Acid alone, but not better than Lithium alone.

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[wolfvgang22]

I'm not aware of any research evidence that recommends the combination of lower dose lithium and valproic acid at subtherapeutic concentrations. But, I know I've prescribed this way pragmatically before when I have had patients complain of side effects of higher doses of both despite low concentrations and the patient has also been unable to tolerate alternative medications for one reason or another. I have even had patients refuse to take a medication because they didn't like the color and no amount of motivational interviewing helped.

Controlled Bipolar symptoms on somewhat less than ideal polypharmacy has turned out to be preferable to medication non-adherance and repeat hospitalization. Perhaps that is the reason your colleagues have done this, also. Alternatively, they are just poor prescribers. If you don't have access to their rationale in a chart you could politely ask them by phone.

 

[forchinet121]

I mean at this point I think you should realize anything goes in the community and this shouldn’t really be surprising and seems reasonable given a specific clinical context

 

[Celexa]

I've seen a lot of psychiatrists in my neck of the woods prescribe lithium AND valproic acid to bipolar patients - usually in lower doses (i.e 600-900mg Lithium and 1g Depakote for a 160 pound male patient), which doesn't make a lot of sense to me - I'd rather just prescribe one in a higher dose and follow it up with serum concentration tests.
Having said that, are there situations where it is recommended to associate Lithium and Valproic Acid, instead of focusing on third of fourth line treatments in refractory patients? (Clozapine, for instance). I've searched PubMed, but could only find a 2013 Cochrane Metanalysis which found that combining Valproate with Lithium is better than Valproic Acid alone, but not better than Lithium alone.

I agree it's odd to see a frequent pattern of neither being in the commonly accepted therapeutic range. I would not find it strange necessarily if only one were in the therapeutic range and the other lower.

If this is occurring frequently in female patients of reproductive age as well as males, though, that would be a strong indication the person prescribing pretty clueless...

 

[thelastpsych]

I agree it's odd to see a frequent pattern of neither being in the commonly accepted therapeutic range. I would not find it strange necessarily if only one were in the therapeutic range and the other lower.

If this is occurring frequently in female patients of reproductive age as well as males, though, that would be a strong indication the person prescribing pretty clueless...

I've seen a lot of female patients in the community with 'bipolar disorder' that have clear borderline personality disorder - when you carefully interview them, most refer never have had maniac/hypomaniac symptoms for more than 3 days, and most say they are bipolar because their emotions oscilate a lot during the day (who would have guessed!).
To make things even worse, these same 'bipolar' patients are recieving SSRIs along with sub-therapeuthic doses of lithium and Valproate. Most don't even know the risks of congenital malformation using valproic acid during pregnancy.
I'm finding it shocking the gap between academic and community practices, being fresh out of residency - not trying to generalize ofc, as I've seen excellent community psychiatrists and horrible academic programs, but that seems to be the norm where I practice.

 

[splik]

It's a pretty common combination. the BALANCE study is the main one looking at this and found lithium and lithium+VPA seemed better than VPA alone as maintenance therapy. It is not uncommon for acutely manic pts to be started on both in inpatient settings. Akiskal used to recommend smaller doses of multiple medications as more tolerable. Conventional wisdom suggested a synergistic effect of using drugs in combination. many cases of bipolar disorder can be challenging to treat. The typical bipolar patient takes >4 medications in a given year (not necessarily all at the same time).

You could ask why lithium+VPA if BALANCE shows lithium monotherapy may be as good? Well, there are still unanswered questions but only 1 in 3 patients have a solid response to lithium monotherapy. Patients with mixed episodes and rapid cycling do not respond well to lithium monotherapy (and may not respond well to any monotherapy). Lithium does not combine so well with certain neuroleptics (e.g. haldol, risperidone) in that there can be severe neurotoxicity and in some cases demyelination and thus permanent brain damage.

All of this is to say that there is nothing eyebrow raising about combining the two, even at lower doses. Though in my own training VPA was really hated on, I never really used it at all until I was an attending though used it more for delirium and catatonia than bipolar.

 

[psych_0]

It's a pretty common combination. the BALANCE study is the main one looking at this and found lithium and lithium+VPA seemed better than VPA alone as maintenance therapy. It is not uncommon for acutely manic pts to be started on both in inpatient settings. Akiskal used to recommend smaller doses of multiple medications as more tolerable. Conventional wisdom suggested a synergistic effect of using drugs in combination. many cases of bipolar disorder can be challenging to treat. The typical bipolar patient takes >4 medications in a given year (not necessarily all at the same time).

You could ask why lithium+VPA if BALANCE shows lithium monotherapy may be as good? Well, there are still unanswered questions but only 1 in 3 patients have a solid response to lithium monotherapy. Patients with mixed episodes and rapid cycling do not respond well to lithium monotherapy (and may not respond well to any monotherapy). Lithium does not combine so well with certain neuroleptics (e.g. haldol, risperidone) in that there can be severe neurotoxicity and in some cases demyelination and thus permanent brain damage.

All of this is to say that there is nothing eyebrow raising about combining the two, even at lower doses. Though in my own training VPA was really hated on, I never really used it at all until I was an attending though used it more for delirium and catatonia than bipolar.

I had never heard of Depakote for catatonia. Thanks for this. If anyone else is interested, I found this algorithm on a meta analysis.

 

[vanfanal]

I've seen a lot of female patients in the community with 'bipolar disorder' that have clear borderline personality disorder - when you carefully interview them, most refer never have had maniac/hypomaniac symptoms for more than 3 days, and most say they are bipolar because their emotions oscilate a lot during the day (who would have guessed!).
To make things even worse, these same 'bipolar' patients are recieving SSRIs along with sub-therapeuthic doses of lithium and Valproate. Most don't even know the risks of congenital malformation using valproic acid during pregnancy.
I'm finding it shocking the gap between academic and community practices, being fresh out of residency - not trying to generalize ofc, as I've seen excellent community psychiatrists and horrible academic programs, but that seems to be the norm where I practice.

You know, sometimes it feels like I’m the only one seeing these things and thinking this way. And when you discuss with the patient, they make me think like I’m crazy because several psychiatrists have told them the same thing. I take a lot of reassurance from this. Thank you 🙏🏽

 

[thelastpsych]

It's a pretty common combination. the BALANCE study is the main one looking at this and found lithium and lithium+VPA seemed better than VPA alone as maintenance therapy. It is not uncommon for acutely manic pts to be started on both in inpatient settings. Akiskal used to recommend smaller doses of multiple medications as more tolerable. Conventional wisdom suggested a synergistic effect of using drugs in combination. many cases of bipolar disorder can be challenging to treat. The typical bipolar patient takes >4 medications in a given year (not necessarily all at the same time).

You could ask why lithium+VPA if BALANCE shows lithium monotherapy may be as good? Well, there are still unanswered questions but only 1 in 3 patients have a solid response to lithium monotherapy. Patients with mixed episodes and rapid cycling do not respond well to lithium monotherapy (and may not respond well to any monotherapy). Lithium does not combine so well with certain neuroleptics (e.g. haldol, risperidone) in that there can be severe neurotoxicity and in some cases demyelination and thus permanent brain damage.

All of this is to say that there is nothing eyebrow raising about combining the two, even at lower doses. Though in my own training VPA was really hated on, I never really used it at all until I was an attending though used it more for delirium and catatonia than bipolar.

Thank you for you answer splik, I've also read that bipolar patients with SUD also benefit more from VPA than from lithium, has it been empirically true for you? From my limited experience, VPA seems to fare better in these cases (better impulse control?). Never heard of VPA for catatonia, I'll keep that in mind.

You know, sometimes it feels like I’m the only one seeing these things and thinking this way. And when you discuss with the patient, they make me think like I’m crazy because several psychiatrists have told them the same thing. I take a lot of reassurance from this. Thank you 🙏🏽

It's so strange, I think some older psychiatrists use very simplified heuristic to diagnose patients ("emotional instability = bipolar"; "hearing voices = schizophrenia"), and keep raising dosages and adding medications on top of one another, without questioning their diagnosis or assumptions. I've started to feel that a very careful interview, with a lot of focus on psychopathology and phenomenology, is THE primary skill that differentiates good from bad psychiatrists . Also knowing what can and can't be treated with medications is becoming more and more a strong priority for me.

 

[Celexa]

Thank you for you answer splik, I've also read that bipolar patients with SUD also benefit more from VPA than from lithium, has it been empirically true for you? From my limited experience, VPA seems to fare better in these cases (better impulse control?). Never heard of VPA for catatonia, I'll keep that in mind.


It's so strange, I think some older psychiatrists use very simplified heuristic to diagnose patients ("emotional instability = bipolar"; "hearing voices = schizophrenia"), and keep raising dosages and adding medications on top of one another, without questioning their diagnosis or assumptions. I've started to feel that a very careful interview, with a lot of focus on psychopathology and phenomenology, is THE primary skill that differentiates good from bad psychiatrists . Also knowing what can and can't be treated with medications is becoming more and more a strong priority for me.

Not just older ones, unfortunately.

I agree, diagnosis is THE most important skill we have. And I don't mean just identifying DSM diagnoses; I mean the careful process of building a full picture of what a patient is experiencing and why. Outpatient, this could be over months.

The amount of time I spend teaching my residents that "anxiety" without further description is utterly meaningless alone is formidable. Don't tell me the patient is anxious! Tell me what is actually going on!

 

[vanfanal]

It's so strange, I think some older psychiatrists use very simplified heuristic to diagnose patients ("emotional instability = bipolar"; "hearing voices = schizophrenia"), and keep raising dosages and adding medications on top of one another, without questioning their diagnosis or assumptions. I've started to feel that a very careful interview, with a lot of focus on psychopathology and phenomenology, is THE primary skill that differentiates good from bad psychiatrists . Also knowing what can and can't be treated with medications is becoming more and more a strong priority for me.

I agree, diagnosis is THE most important skill we have. And I don't mean just identifying DSM diagnoses; I mean the careful process of building a full picture of what a patient is experiencing and why. Outpatient, this could be over months.

All very true. As others have said, it’s easy to be a ****ty psychiatrist. It’s very hard to be a good one. And I guess my conflict is with the fact that it’s hard to practice that kind of good psychiatry these days; it takes time, mutiple opt sessions as mentioned and certainly doesn’t lend itself to the kind of volume and productivity that other specialties have like looking at 10+ skin lesions or radiographs in an hour.

As I free associate…I remember a patient I saw in clinic once. Very bright young man; was responding to all my questions with metaphors. I didn’t think he was psychotic, just very psychodynamically defended. He was my last appointment of the day and I spent two hours with him. I didn’t feel compelled to prescribe a medication to relieve my own helplessness. I do think we connected because he was tearful, a good sign of affect expression I think. Anyway, I couldn’t see him again but we agreed that psychodynamic therapy would be good for him. I think the skill and expertise of that session is equal that if a radiologist reading a complex scan, but I didn’t get paid (monetarily) as such, though I don’t know if radiologists remember scans like I remember this patient.

Others have really touted private practice as they golden ticket. That feels to be a while for way as I’m in my career infancy.

 

[annoyedpsychiatrist]

I've seen a lot of psychiatrists in my neck of the woods prescribe lithium AND valproic acid to bipolar patients - usually in lower doses (i.e 600-900mg Lithium and 1g Depakote for a 160 pound male patient), which doesn't make a lot of sense to me - I'd rather just prescribe one in a higher dose and follow it up with serum concentration tests.
Having said that, are there situations where it is recommended to associate Lithium and Valproic Acid, instead of focusing on third of fourth line treatments in refractory patients? (Clozapine, for instance). I've searched PubMed, but could only find a 2013 Cochrane Metanalysis which found that combining Valproate with Lithium is better than Valproic Acid alone, but not better than Lithium alone.

This is one of the issues. Depending on the area you live in, finding a clozapine prescriber may be exceedingly difficult. I used to do it but the logistical burden became too great and now that I dont have direct access to a lab its just not practical. Even the community mental health center here doesnt do it. Great medication, just a pain in the ass to prescribe tbh

 

[docksan]

Things work in the community because it's largely a volume based practice and you're encouraging adherence. That doesn't mean it's appropriate just because it appears to be effective. The teratogenic potential of these two alone should preclude regular use.

 

[Sushirolls]

Thank you for you answer splik, I've also read that bipolar patients with SUD also benefit more from VPA than from lithium, has it been empirically true for you? From my limited experience, VPA seems to fare better in these cases (better impulse control?). Never heard of VPA for catatonia, I'll keep that in mind.


It's so strange, I think some older psychiatrists use very simplified heuristic to diagnose patients ("emotional instability = bipolar"; "hearing voices = schizophrenia"), and keep raising dosages and adding medications on top of one another, without questioning their diagnosis or assumptions. I've started to feel that a very careful interview, with a lot of focus on psychopathology and phenomenology, is THE primary skill that differentiates good from bad psychiatrists . Also knowing what can and can't be treated with medications is becoming more and more a strong priority for me.

Don't worry, the next week your patient will message you distraught, because their therapist says they don't have Borderline PD, but XYZ, and should be random med that is lower on the preference list for XYZ.

Or your patient you have been slowly chipping away at XYZ, messages you a week or few later, "I want to be tested for ADHD" my therapist thinks I have a ADHD.

This malarkey is enough of a reason I think at times of expanding and brining on my psychologist or Masters level therapists into a clinic to control quality just a pinch.

 

[ObsequiousAplomb]

Things work in the community because it's largely a volume based practice and you're encouraging adherence. That doesn't mean it's appropriate just because it appears to be effective. The teratogenic potential of these two alone should preclude regular use.

Teratogenic profile of lithium? Nah, it's safe and appropriate for use in women of childbearing age. Stop fear mongering. Undoubtedly safer than the Zyprexa or Seroquel you'd peddle in its place.

 

[Celexa]

Teratogenic profile of lithium? Nah, it's safe and appropriate for use in women of childbearing age. Stop fear mongering. Undoubtedly safer than the Zyprexa or Seroquel you'd peddle in its place.

I use lithium without hesitation in women of childbearing age with bipolar, but strictly speaking from a teratogenic perspective, I believe the SGAs do have a superior safety profile. From an overall health perspective i agree there's no reason to favor seroquel or olz.

 

[docksan]

Teratogenic profile of lithium? Nah, it's safe and appropriate for use in women of childbearing age. Stop fear mongering. Undoubtedly safer than the Zyprexa or Seroquel you'd peddle in its place.

Combining them? Everyone knows you don't worry as much about Ebstein with Lithium as you do about NTDs but are you really going to take a risk with both and say it's negligent when you get sued by the patient?

Edit: also be real, evidence for antipsychotics being now teratogenic is weak.

 

[calvnandhobbs68]

Teratogenic profile of lithium? Nah, it's safe and appropriate for use in women of childbearing age. Stop fear mongering. Undoubtedly safer than the Zyprexa or Seroquel you'd peddle in its place.

Safer from a teratogenic standpoint? I mean lithium isn't as teratogenic as people thought but it definitely seems more teratogenic than 2nd gen antipsychotics. Cardiac malformation risk seems to be around 2% overall which is about double the 1% baseline risk.

 

[ObsequiousAplomb]

Safer from a teratogenic standpoint? I mean lithium isn't as teratogenic as people thought but it definitely seems more teratogenic than 2nd gen antipsychotics. Cardiac malformation risk seems to be around 2% overall which is about double the 1% baseline risk.

My point is that really everything I prescribe that isn't an anti-epileptic is safe in pregnancy. Obviously I avoid Depakote in women of childbearing age and I don't prescribe Tegretol.

I'm not advocating for combining low dose Depakote and lithium in pregnancy.

APs are also pretty safe in pregnancy. From an overall health perspective though I would prefer lithium in women of childbearing age, provided it's indicated. As discussed in other threads, most of the actions people take during pregnancy are actually not evidence based (like stopping the depakote or whatever drug during the second trimester).

 

[docksan]

You could avoid a lot of that by just using Lamictal. Why even do both? It's not even teratogenicity you worry about at that point. There are tons of other side effects.

 

[ObsequiousAplomb]

You could avoid a lot of that by just using Lamictal. Why even do both? It's not even teratogenicity you worry about at that point. There are tons of other side effects.

Probably because lamictal would have different indications than Depakote + lithium or AP mono therapy or AP + lithium. The takehome in this thread is that one size fits all is silly