Calcium-channel Blockers for Bipolar?

[kugel]

---

Members do not see this ad.

At various times in my training/career I've come across someone stating there is "some data" for CCB's in Bipolar (esp Verapamil), but that it's not pursued because there's no money in it for any drug company.

I decided to do a MDConsult/Medline search for "verapamil, bipolar" 1995-current, sorted for "relevance" and looked at the first 100 (after ~80, they lost all relevance). Below are the ones that looked interesting. I'm ordering these from the librarian, but...

wanted to know what some of you think about CCB's in bipolar, esp in manic pt's who can't/won't take lithium or valproate - or those in whom either/both have been ineffective.




CONCLUSIONS: These data provide evidence that verapamil is effective for mania. The response rate for mania compares favorably to that for other mood stabilizers. After decades of case reports and underpowered clinical trials, we must definitively study verapamil for efficacy and gender specificity in bipolar disorder.

Verapamil treatment for women with bipolar disorder.
Wisner KL - Biol Psychiatry - 1-MAY-2002; 51(9): 745-52


CONCLUSIONS: In this preliminary investigation, verapamil monotherapy did not demonstrate antimanic efficacy. By contrast, the combination of verapamil plus lithium was highly efficacious. Our findings thus suggest that verapamil may have potential utility as an adjunct to lithium. This effect may be mediated by additive actions on PKC inhibition, which may be an important mechanism for antimanic agents in general.

Verapamil augmentation of lithium treatment improves outcome in mania unresponsive to lithium alone: preliminary findings and a discussion of therapeutic mechanisms.
Mallinger AG - Bipolar Disord - 01-DEC-2008; 10(8): 856-66



While the data from earlier studies support the use of verapamil in treating bipolar mania. more recent better-controlled trials have not. This paper reviews the available body of data regarding CCAs in the treatment of bipolar disorder, concluding there is presently limited support for their efficacy.

Calcium channel antagonists for the treatment of bipolar disorder.
Levy NA - Bipolar Disord - 01-JUN-2000; 2(2): 108-19



Symptom and global severity was as well controlled with lithium as with verapamil. Lithium caused more side-effects than placebo and verapamil, but no more than carbamazepine or valproate. CONCLUSION: The clinical trial evidence suggests that lithium should remain the first line treatment for acute mania.

Systematic overview of lithium treatment in acute mania.
Poolsup N - J Clin Pharm Ther - 01-APR-2000; 25(2): 139-56



The authors compared the antimanic effects of a verapamil-magnesium oxide (V-M) combination with a verapamil-placebo combination (V-P) in patients pretreated with verapamil. BPRS scores and serum magnesium levels were compared. The V-M combination was found to be significantly more effective than V-P in reducing manic symptoms (P=0.015). Serum magnesium levels were significantly higher in the V-M group (P<0.04). These data suggest that magnesium may increase antimanic efficacy of verapamil by mechanisms which may operate at the intracellular level. The magnesium-verapamil combination may have clinical application as an adjunct to verapamil in the maintenance therapy of mania.

Magnesium oxide augmentation of verapamil maintenance therapy in mania.
Giannini AJ - Psychiatry Res - 14-FEB-2000; 93(1): 83-7



CONCLUSIONS: The investigators found no benefit of verapamil over placebo in treating acute mania.

Verapamil for the treatment of acute mania: a double-blind, placebo-controlled trial.
Janicak PG - Am J Psychiatry - 01-JUL-1998; 155(7): 972-3



CONCLUSION: This study suggests that lithium is superior to verapamil in the management of acute mania.

Superiority of lithium over verapamil in mania: a randomized, controlled, single-blind trial.
Walton SA - J Clin Psychiatry - 01-NOV-1996; 57(11): 543-6



1. The authors investigated the possible antimanic properties of a Calcium channel blocker, Verapamil, in 15 in-patients admitted consecutively to the female psychiatric ward at Pisa University for a manic episode. 2. The results showed that most of the patients presented a global improvement of the manic symptoms and, in some cases, even a complete clinical remission. 3. Although it was necessary to add chlorpromazine for the severe conditions of several patients, verapamil appeared to speed the positive outcome and to lead to a faster resolution of the symptoms. In addition, the association of verapamil and chlorpromazine did not produce any relevant side-effect. These preliminary findings thus indicate that verapamil by itself does not seem to be sufficient in the treatment of a severe affective episode, but it may constitute an alternative to lithium salts in association with neuroleptics.

Effectiveness of the combination verapamil and chlorpromazine in the treatment of severe manic or mixed patients.
Lenzi A - Prog Neuropsychopharmacol Biol Psychiatry - 01-MAY-1995; 19(3): 519-28

 

[whopper]

Wow, though I'm not surprised.

CCBs can affect the firing of neurons if that medication could cross the blood-brain barrier. Calcium after all is an ion.

So, why hasn't anyone done any more work into this? This is very very interesting.

Off on the side, a buddy of mine who I've known for years, though only see about once a year at a convention (model-building) just told me recently he has bipolar and he controls it through the eating of dark chocolate.

Of course I was doubftul, but he went down the list of symptoms he's had including occasional hallucinations when manic. He said he was put on psychotropics and while they worked, he felt he was over-medicated. He said he believed his psychiatrists did not listen to his over-medication concerns so he gave up and didn't see another one.

Then, factor that chocolate is known to have some psychotropic effects. Could some of them affect bipolar? I don't know.

I of course told my friend to try another psychiatrist, and I couldn't back his dark chocolate idea, but it did leave me wondering there might be something to it.

 

[Sneezing]

That would be awesome if there was evidence behind chocolate. Imagine being able to tell a patient, well, I'm sorry, but now you have to consume 1/2 pound of chocolate a day. People's eyes would light up with joy! Although, chocolate would still carry a hefty metabolic syndrome risk.

 

[billypilgrim37]

Although, chocolate would still carry a hefty metabolic syndrome risk.

I bet some folks would still gain less than they would on Zyprexa.

 

[OldPsychDoc]

That would be awesome if there was evidence behind chocolate. Imagine being able to tell a patient, well, I'm sorry, but now you have to consume 1/2 pound of chocolate a day. People's eyes would light up with joy! Although, chocolate would still carry a hefty metabolic syndrome risk.

I hear that Lilly is researching a class of cacao-ergic agonists which deliver greater efficacy with no weight gain. 😉

 

[kugel]

I hear that Lilly is researching a class of cacao-ergic agonists which deliver greater efficacy with no weight gain. 😉

It is a QuickMelt tab with a cacao mixture layered top and bottom with an olanzapine center layer. brand name = Andes.

"But if you eat a sensible diet and get regular exercise (which should be possible now that the illness is being effectively treated) there should not be any clinically significant weight gain."
- barely fictitious Lilly internal sales-force training memo


And now back to our regularly scheduled program about
CALCIUM-CHANNEL BLOCKERS

 

[Red Beard]

So, why hasn't anyone done any more work into this? This is very very interesting.

If it had the potential to make someone rich, then maybe someone would be ponying up the money to take a good hard look.

The unfortunate state of affairs in psychiatric research.

 

[whopper]

That's what I was thinking.

E.g. Wellbutrin, the study that found it could cause seizures on a significant level was flawed. In fact the PDR cites it's odds of causing a seizure as less than that of an SSRI. Yet to remove the black box warning will cost an arm and a leg. (Why should it cost anything if the data is already there?).

Which puts us in an uncomfortable spot if you have someone with depression and seizure disorder where the wellbutrin actually helps and was started by someone who didn't know wellbutrin has a seizure warning. Do you continue it knowing the seizure the data is flawed or do you stop it?

 

[OldPsychDoc]

That's what I was thinking.

E.g. Wellbutrin, the study that found it could cause seizures on a significant level was flawed. In fact the PDR cites it's odds of causing a seizure as less than that of an SSRI. Yet to remove the black box warning will cost an arm and a leg. (Why should it cost anything if the data is already there?).

Which puts us in an uncomfortable spot if you have someone with depression and seizure disorder where the wellbutrin actually helps and was started by someone who didn't know wellbutrin has a seizure warning. Do you continue it knowing the seizure the data is flawed or do you stop it?

Continue it. With informed consent.
That's why we are physicians, licensed to prescribe stuff, and not trained monkeys following algorithms.

(Ditto for occasional bulimics without electrolyte disturbances.)

 

[Red Beard]

CONCLUSIONS: In this preliminary investigation, verapamil monotherapy did not demonstrate antimanic efficacy. By contrast, the combination of verapamil plus lithium was highly efficacious. Our findings thus suggest that verapamil may have potential utility as an adjunct to lithium. This effect may be mediated by additive actions on PKC inhibition, which may be an important mechanism for antimanic agents in general.

Verapamil augmentation of lithium treatment improves outcome in mania unresponsive to lithium alone: preliminary findings and a discussion of therapeutic mechanisms.
Mallinger AG - Bipolar Disord - 01-DEC-2008; 10(8): 856-66

This study has an excellent design, if it could be repeated with 3-4x the number of patients that would be pretty amazing.

 

[whopper]

Continue it. With informed consent.
That's why we are physicians, licensed to prescribe stuff, and not trained monkeys following algorithms.

True--given what I mentioned. I had a case where something similar happened. A patient with a seizure DO was placed on several SSRIs, all of which gave her hyponatremia. They had to be stopped. Someone else placed her on Wellbutrin. By the time I got her, she wanted to be on Wellbutrin, but when I informed her that there was a seizure disorder black box warning, which by the way was based on a study that was bogus, which by the way the FDA will not take off the black box warning even though the study was bogus----

Well let's just say she didn't understand. She didn't understand why the FDA would keep the black box warning on. I tried to explain it to her, she still didn't understand, so then I explained to her about the flaws of the study that she did not understand, and then she said...

"doctor, should I take it or not?"

I told her I thought she should take it, but I needed to know she understood why the seizure risk was over-inflated.

She never got to the point where she understood which was understandable given the situation. After all-we tell patients all the time that a med is safe because the FDA approves it. They don't know the politics, the bureaucracy that goes on, and here I am giving her something which could literally lead to a 15 hour homework assignment.

Is that informed consent? IMHO it is not. She walked out of there with a copy of a study, not truly understanding why it's flawed, and not truly understanding why the FDA would not take off the black box waring.

It was good enough for the attending psychiatrist (I was a resident at the time), but IMHO informed consent was not achieved.

 

[kugel]

Is that informed consent? IMHO it is not. She walked out of there with a copy of a study, not truly understanding why it's flawed, and not truly understanding why the FDA would not take off the black box waring.

It was good enough for the attending psychiatrist (I was a resident at the time), but IMHO informed consent was not achieved.

People generally hear me c/o docs not providing enough informed consent (e.g. no PCP has ever discussed risks/benefits/alternatives with me or any member of my family before handing out a medicine - and I'm talking about before I went to Med School). However, I think perhaps the example you gave is a bit overboard. I'm thinking Informed Consent (IC) does not mean that you have to explain all the ins/outs as to why some "experts" believe this medicine has a particular side effect, or even that there is a "black box". I honestly believe that the intent of IC is that the pt knows what the potential/reasonable risks are - not all the reasons why people believe those risks exist. When I tell people about the seizure risk in Wellbutrin, I tell them something like:

"Anyone walking down the street has a some very low risk of having a seizure in the next year. There are several things that put a person at higher than avg risk of a seizure. The first, of course, is a history of seizures or a strong family history of seizures. Do you have either one of those? No? Never had a seizure? No? Good.
Now people who have severe imbalances of sodium/potassium/chloride/bicarbonate may end up with higher risk for seizures if taking Wellbutrin. Have you ever had anything like that? No? Good.
So it's still possible that Wellbutrin will put you at slightly higher risk for seizures - but you don't have any of the risk factors that would make me scared to give you Wellbutrin. What questions do you have about Wellbutrin or the risk of seizures? None? You understand that there is still some possibility that Wellbutrin could increase your risk for seizures? Okay, that's fine."

That may look like a big speech, but it's no more than 50 seconds (yes, I'm such a geek that I timed it).

I do something similar for the risk of suicidal behavior in antidepressants, i.e. talk about the fact that some people think antidepressants cause suicidal behavior, but "I think that's a mis-reading of the data, and most all the studies since then have indicated antidepressants DEcrease suicidal risk. If you want, I'll explain why people might have thought that. But's it's more important to me to know who you would call or where you would go for extra help if YOU have suicidal thoughts that don't go away quickly or if you start thinking you might act on suicidal thoughts.

 

[whopper]

First off, sorry for detracting from the original topic because it is a very interesting one.

I disagree and agree that I went overboard (If that makes any sense).

Legally, informed consent requires that medical decisions be knowingly, intelligent and voluntary (KIV).
The point is no matter how dumbed-down I described it, she didn't understand why the FDA could keep a black-box warning that in reality was bogus.
To understand why requires one to understand all the tedious data I mentioned.

Giving the data that allows patients to take a medication under informed consent guidelines flows so easily when the FDA guidelines are all in sync and it's not bogus.

In the pure sense, I don't think I went overboard if you actually look at informed consent (IC) under the guidelines of the KIV standard. A patient with a seizure should be told of contraindications of a medication if they have a condition that is in that category which opens the trap I brought up. Practically speaking, yes I did go overboard because I just could have told her the medical truth-and kept mum on the bogus medical politics.

But as for IC, most doctors I know don't even follow it--hence all the bogus psychiatry consults one may receive because a patient refused a medical procedure and that patient was not told of the risks and benefits of the procedure, why they needed it or the alternatives. The patient refuses because they're not given enough information, so then the medical doctor demands a psychiatry consult to determine their capacity to make medical decisions.

 

[kugel]

The standard is to follow FDA warnings. In this particular case, I was asking a patient to defy that---arguably defy the standard of care, though in this rare particular case the standard was wrong. If you got 10 doctors, probably all ten would believe the wellbutrin seizure bogus data. That's the standard my friend in the eyes of the law.

It's okay w/me if we disagree. That's part of what these boards are for.

But the several Risk Mgt lawyers I've consulted say that's not the standard or the law. There is no law saying that. And the "standard" is precisely the issue of informed consent that we are discussing. The standard for Informed Consent is that the pt is provided with info about risks/benefits/alternatives, and that the decision is voluntary and reasoned (not "intelligent").

Always a good discussion, Whopper.
Thank You

There is no Black Box warning about seizures in the prescribing info for Wellbutrin (http://us.gsk.com/products/assets/us_wellbutrin_tablets.pdf pg. 10-11 ), though the warning is in bold. The only clear statement about what to do (PDR statements rarely say "what to do") is
"WELLBUTRIN should be discontinued and not restarted in patients who experience a seizure while on treatment."
Did your pt have a seizure while on Wellbutrin?

The lawyers tell me that as long as you document that you explained that there is such a risk, explained why you think the risk of DIScontinuing is Greater in THIS pt at this time, explained the alternatives, and document that the pt expressed an agreement to continue the treatment, then you have NOT violated any standard of care.

When we had a C-L pt with active Stevens-Johnson Syndrome (inpt medicine, sores all over incl corneas) from Lamictal, we asked her clearly every single day why she wanted to continue the Lamictal, and every day we documented her response that her Bipolar disorder was so bad and so intractable to everything except Lamictal that DIScontinuing Lamictal was a much greater threat to her life. Psych consulted the Risk Mgt lawyer, Medicine consulted the lawyer, the Pharmacy consulted the lawyer - and we all got the same answer. If you document the info provided and the clear message about the risks and the pt's decision is "reasoned" (that is, that there are reasons they can explain - whether you would decide the same way or not), then you HAVE met the requirements of Informed Consent.
That's a truly extreme situation, but illustrative I think.

Now, I should note that in Calif, the term "Informed Consent" has been written into many documents and some laws with the meaning of "written consent" for psychotropics. In CA, you want to be sure your consent for psychotropics is Written - but that is a separate and additional meaning to the usual meaning of "informed consent," since only psychotropics carry that additional burden under CA law - but all the other elements of the usual medico-legal meanings of "informed consent" must also be met.

On a separate note, I would think that in this particular case there is significant risk that some other physician is likely to have a knee-jerk response of stopping the Wellbutrin, or that a pharmacist knowing about her seizure hx will refuse to fill the script (I've had that happen). Therefore, in this case I would seriously consider another antidepressant, like Remeron or Effexor because helping her manage a cross-taper off the Wellbutrin and onto something else may be better for her than leaving her open to being stripped off her Wellbutrin w/o notice by the next doc or pharmacist.

As for the original question about knowledge or experience using CCB's for mania - I guess I'm going to assume SDN has nothing particularly useful for me. When I've read the articles, I'll update this thread with whatever (no matter how little) I've learned.

 

[whopper]

WELLBUTRIN should be discontinued and not restarted in patients who experience a seizure while on treatment."
Did your pt have a seizure while on Wellbutrin?

Possibly. Wow--what a grey/murky case.

She frequently experienced pseudo-seizures in addition to real seizures.

She wasn't on the video-EEG 24/7 7 days a week, 365 days a year. She had several seizure like episodes that almost everyone believed were pseudo-seizures.

1) thanks for the clarification. You legitimately corrected some points I brought up.

2) I editted my post, and you brought up content I editted out because I was trying to make my verbose post cleaner. I have no problem with you doing that, however. The point I brought up is one of valid debate. You were probably working on your post while I was editting mine.

3) I actually do agree with you. If I were on a jury, and this case went to court, I'd very much back your side. I still though am frustrated by that situation because I could very well see jury members going against your side as well.

My bottom line is I don't like it when doctors are put into a medical catch-22 because of the inaccuracies and bureacracies of the FDA or other organizations. The cataracts issue for Seroquel for example is another issue. If I really wanted to, I could get a lawyer and start rounding up people who got cataracts while on Seroquel in their 40s or above. While you and I would know that they most likely didn't get cataracts from Seroquel, there's the FDA warnings and manufacturer's recommendation that the patient see an opthamologist (which no one does). Any doctor could be cross examined and asked...

1) did you tell your patient of the risk of cararacts on seroquel? (the overwhelming majority would say no).
2) did you refer your patient to an eye doctor? (most will say no).
3) Did you continue your patient on Seroquel despite them not going to an eye doctor? yes
4) did your patient get caratacts? yes.

"Ladies and gentlemen of the jury, My client developed cataracts while on Seroquel. There is a warning against it which this doctor is supposed to have known about, and the manufacturer even recommends the patient be seen by an eye doctor. The doctor here did nothing to make that referall or even warn my patient."

While it will most likely not happen, it very well could. The Wellbutrin situation IMHO is similar.

At least in the seroquel case, the standard of care defends the doctor, because most doctors know the cataracts issue is likely bogus. In the wellbutrin issue, most doctors aren't aware that the study linking seizures to wellbutrin was flawed.

Anyway, despite my comments, I'm not really in spirit disagreeing with you since I understand where you are coming from. This is a grey issue and I think it is highly possible for ambulance-chasers to manipulate the presentation of what could happen, which is leading to my mixed agreement-disagreements with you.

If you document the info provided and the clear message about the risks and the pt's decision is "reasoned" (that is, that there are reasons they can explain - whether you would decide the same way or not), then you HAVE met the requirements of Informed Consent.

That's the problem I mentioned. Part of the issue with the wellbutrin was that I needed to provide the patient with a decent amount of information to meet the IC standard, and that issue, depending on the source, contradicts--which is confusing for the patient.

You are right. It would've been just easier to switch her to something else. I was a resident and the attending wanted to keep it Wellbutrin.

Again, sorry to detract from the OT!

 

[Anasazi23]

CCB's were a hot topic in psychiatry back even in the late 90's for mood lability.

I had remembered looking into such data back in residency, was underwhelmed, and shelved it until more reasonable data was available.

I presume the initial theory was that anti htn's, like the beta blockers, had some role in reducing acutely manic or hyperactive behavior in a clonidine-esque fashion.

 

[whopper]

Any of us at SDN have a desire to pursue a grant and further research this?

I'm going to keep an eye on my bipolar patients who are on a CCB and ask them if they've noticed any improvements on a CCB.

 

[kugel]

attached are some of the articles @ Verapamil in Mania, more to come