SSRI's increase mania in BiPolar DO..

[DebDynamite]

Hey everyone.
I searched PubMed (not Cochrane- I'm @ a remote site this week) and can't seem to find one singular study that "proves" this. I'm wondering if there is one classic study that is generally referenced when Psych docs make this claim. Not that I'm refuting it- just curious about the EBM behind it. Anyone have a study they recommend I read? Thanks. (should I move this to the Montor forum?)

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[whopper]

Here's a few
http://www.neurotransmitter.net/admania.html

Buproprion tends to do it the least among the modern antidepressants.

I've read a few articles in the American Journal of Psychiatry showing SNRIs tend to do it more than SSRIs but I don't have those articles on me.

I did a pubmed search you like and I'm not finding much. However I have read several articles showing it. Unfortunately, after I read them a few times, I put them in the recycling bin.

 

[DebDynamite]

Thanks.
I was curious because- although intuition says it makes sense, one of my attendings challenged me to find "the definitive" article to prove it. This attending thinks they are generally good (and only stops them w/BP pts who are really getting manic) if the pt is in the depressed cycle. Which I can see.

 

[whopper]

Ouch,

I've read 3 major articles in the past few months (all of which I felt were well done & with very good measures), one published in the NEJM showing that antidepressants have pretty much no benefit in bipolar depression.

My own theory is there's 2 general types of depression in bipolar--one coming from the theory of subthreshold stimulation. The neurons that release happy NTs release too much (kinda like taking a hit of cocaine). Then like cocaine--because all the happy NTs (dopamine, NE, 5-HT) are all spent, antidepressants really wouldn't help the depression. In fact by the time the happy NTs are replenished, which antidepressants wouldn't help,--it could just encourage shifts into mania. The studies I read seem to back that theory.

The other theory is the other type of depression may be because the bipolar person may be depressed independent of their bipolar cycles--they may have for example suffered too many stressors. In effect, they have depression, similar to that of a major depressive DO person on top of their bipolar. In this case I figure antidepressants may help.

These are just my theories and I figured others have come up with this before me. I ought to check my Steven Stahl book on this but its at my apt, and I'm currently living at my parents house for the month for a 1 month elective.

 

[LM02]

To help narrow your search, Nassir Ghaemi has written some good, comprehensive reviews on the topic.

The NEJM paper that came out of STEP-BD, which whopper referenced, is a good resource, as well. But the focus of that analysis was on overall efficacy (and not on antidepressant-induced mania).

Off the top of my head, I believe that recent data suggest risk for treatment-emergent mania secondary to SSRI use in about 30% of patients with bipolar disorder (there's a semi-recent paper written by Leverich et al. that concludes this from the Stanley Network data).

 

[LAZYGUY]

scholar.google.com

It's much more friendly than pubmed or ovid. Did a quick 1 minute search, look through some others.

Am J Psychiatry 158:906-912, June 2001
© 2001 American Psychiatric Association

Article
Double-Blind, Placebo-Controlled Comparison of Imipramine and Paroxetine in the Treatment of Bipolar Depression
Charles B. Nemeroff, M.D., Ph.D., Dwight L. Evans, M.D., Laszlo Gyulai, M.D., Gary S. Sachs, M.D., Charles L. Bowden, M.D., Ivan P. Gergel, M.D., M.B.A., Rosemary Oakes, M.S. and Cornelius D. Pitts, R.Ph.
OBJECTIVE: This study compared the efficacy and safety of paroxetine and imipramine with that of placebo in the treatment of bipolar depression in adult outpatients stabilized on a regimen of lithium. METHOD: In a double-blind, placebo-controlled study, 117 outpatients with DSM-III-R bipolar disorder, depressive phase, were randomly assigned to treatment with paroxetine (N=35), imipramine (N=39), or placebo (N=43) for 10 weeks. In addition to lithium monotherapy, patients may have received either carbamazepine or valproate in combination with lithium for control of manic symptoms. Patients were stratified on the basis of trough serum lithium levels determined at the screening visit (high: >0.8 meq/liter; low: 0.8 meq/liter). Primary efficacy was assessed by change from baseline in scores on the Hamilton Rating Scale for Depression and the Clinical Global Impression illness severity scale. RESULTS: Differences in overall efficacy among the three groups were not statistically significant. For patients with high serum lithium levels, antidepressant response at endpoint also did not significantly differ from placebo. However, both paroxetine and imipramine were superior to placebo for patients with low serum lithium levels. Compared to imipramine, paroxetine resulted in a lower incidence of adverse events, most notably emergence of manic symptoms. CONCLUSIONS: Antidepressants may not be useful adjunctive therapy for bipolar depressed patients with high serum lithium levels. However, antidepressant therapy may be beneficial for patients who cannot tolerate high serum lithium levels or who have symptoms that are refractory to the antidepressant effects of lithium.


R. Ramasubbu (2001)
Dose-response relationship of selective serotonin reuptake inhibitors treatment-emergent hypomania in depressive disorders
Acta Psychiatrica Scandinavica 104 (3), 236–239.
doi:10.1034/j.1600-0447.2001.00383.x


Objective: The notion that antidepressant treatment-associated hypomania or mania being pharmacologically induced has been challenged. To determine whether selective serotonin reuptake inhibitors (SSRI) induced hypomania is secondary to medication effects, we examined the dose–response relationship of SSRI-induced hypomania in two patients with depressive disorder.
Method: Case study.
Result: Hypomanic symptoms emerged during treatment with sertraline at the dose of 300 mg per day in a 45-year-old male with major depression. Paroxetine treatment at the dose of 80 mg per day induced hypomania in a 37-year-old female with dysthymia and trichitillomania. These patients have no family or personal history of bipolar disorder. Hypomania resolved when sertraline was decreased to 200 mg per day and paroxetine to 40 mg per day. No hypomanic switch was observed during 18–24 months follow-up.
Conclusion: In the absence of risk factors for manic switch, SSRI-induced hypomania may be dose-dependent medication effects.

 

[cleareyedguy]

I think there is serious disagreement about whether antidepressants can precipitate mania, and if so, how often switching occurs.

There is less debate over the relatively poor results of antidepressants in treating bipolar depression.

 

[melvin]

Step- BD is great, but those pt's were on a mood stabilizer, not monotherapy anti-depressants. Look into the Stanley Foundation research. The group as a whole tended to be more rapid cyclers and there was switching, but not to the extent that we are led to believe by dogma. Sorry i don't have time to post the Stanley Foundation article

 

[whopper]

Unfortunately I don't have a list that can compare the numbers (is it in PDR? I don't have one on me right now), but I remember that out of the modern antidepressants...

Bupropion does it the least
SSRIs do it more than bupropion
SNRIs do it more than SSRIs.

Bottom line: if someone has bipolar depression, and you want to use an antidepressant, consider bupoprion 1st if you are worried about inducing mania.

However given what I've read in the studies I mentioned, I'd go with lamictal or seroquel first.

 

[MBK2003]

I was at the MGH Board Review course last month which emphasized the articles cited above as well as the strong emphasis by Sachs, Dording, et al on there being a lack of good evidence (aside from Symbyax) for the use of SSRIs/TCAs/Bup/SNRIs on top of a mood stabilizers in bipolar depression. They emphasized that this did not mean they were recommending Symbyax due to concerns about the metabolic side effects of Olanzapine compared with other mood stabilizers. I think the evidence from the larger studies, particularly Step-BD may point us in a different direction for treating bipolar depression, like using another mood stabilizer or even Modafanil (don't get me started on the problems with that study).

 

[whopper]

Modafanil (don't get me started on the problems with that study).

Problem with modafanil is 1 study I've seen points that its really no more effective than coffee.

And if you think about it, caffeine in coffee is a stimulant, and would pretty much have the same benefits. Harder core stimulants such as methylphenidate are more efficacious because they are much more potent in terms of the physiological mechansism (which are pretty much the same but much more potent with amphetamines.)

http://abcnews.go.com/2020/Story?id=2874922&page=3

Remember, caffeine for example does have benefits with ADHD. Remember it works along the same pathways as amphetamines, though is not as potent.

But if it is working pretty much just as well as coffee, why then not just tell the patient to take OTC caffeine pills than to get provigil for hundreds of dollars a month?

The link here shows its price
http://www.drugstore.com/pharmacy/prices/drugprice.asp?ndc=63459010101&trx=1Z5006

This last post may deserve its own thread. I feel that often times, we as doctors give out the prescription med when there's an OTC that does the same and is much cheaper for our patients. (E.g. benadryl vs seroquel when all the doctor's shooting for is the antihistamine effect)

 

[Laughatmw]

I hope I am not intruding as a non doc, but I could not resist throwing my two cents into this thread. From my own research on PubMed as well as other sources it is my understanding that all SSRI medications are equally likely to induce mania in a bipolar patient, but certain SSRI meds, such as Zoloft are more likely to trigger disphoric mania then others. Instead of searching for an overall pattern with all SSRI medications I suggest doing research on their individual names.

 

[whopper]

Instead of searching for an overall pattern with all SSRI medications I suggest doing research on their individual names.

There are publications/presentations where all the modern antidepressants are neatly presented with a comparison. Unfortunately I can't find it this moment. Comparative data is expected to be known for exams. E.g. on a past PRITE, it asks which antidepressant to give to a bipolar depressed patient--and the answer was bupropion because it induces mania the least. Several other antidepressants were listed as other choices.

 

[DebDynamite]

This has been an educational thread. Not sure if I made myself clear, but my attending is augmenting a mood stabilizer with SSRI's and/or Buproprion. Regardless, I sent him some of the links in this thread. I also found this:

http://www.psicomag.com/biblioteca/2000/Bipolar_2000.pdf
Specifically parts 5 &6 seem to be what this attending is doing. I'm not surprised, he's really into giving more than one or two meds most of the time.

 

[Anasazi23]

I've had some bad luck lately in 'switching' patients. I'm still working in the outpatient clinic (6th month) and work in two other settings as a moonlighter. In the one moonlighting gig in particular, which has much higher functioning patients than my other two gigs, it has happened to me 3 times in the past 3 months. Luckily, nothing dangerous or outrageous occurred, but there was definately a switch with which I (and presumably the patient) was uncomfortable. All the patients to which this happened were relatively young (30's) - one with a signficant eating disorder.

It wasn't a case of failing to recognizing bipolar from the history, or adding an SSRI for no reason, but the depressive components were worrying, and two of the three cases included intermittent suicidal ideation. None of them consented to VPA or Li, and one had already been on an atypical.

The one case of switching (which I'm still wondering if it's my fault), involved him spending thousands of dollars on various "stupid stuff" as he calls it and were quite impulsive in nature. One involved a spur-of-the-moment decision to get a bike to trek around NYC which was $1000, not including the $500 of accessories to go with it. I saw him a week after he bought the bike at which time he reported, that "he doesn't even like riding bikes."

The next large purchase which occurred that same week included another spur-of-the-moment decision to organize a paint-ball extravaganza, which necessitated him buying a $400 paint-ball gun, and equipment totaling over another thousand dollars. This patient was inherited on a therapeutic dose of quetiapine and zoloft, which I increased from 150mg to 200mg, which appeared to cause the shift. Further visits are revealing, however, that this type of thing is in his history more than I might have realized in my initial visits with him.

The other case in particular is more complicated and involves an eating-disordered model.

 

[deleted77919]

One involved a spur-of-the-moment decision to get a bike to trek around NYC which was $1000, not including the $500 of accessories to go with it. I saw him a week after he bought the bike at which time he reported, that "he doesn't even like riding bikes."

He's not around 5'10" is he? I'm in NYC and getting tired of doing 60 mile rides on my old mountain bike, in the market for a nice road bike . . . I mean, since he is probably looking at selling it and all . . .

 

[MBK2003]

Not sure if I made myself clear, but my attending is augmenting a mood stabilizer with SSRI's and/or Buproprion.

What evidence does your attending present that this is expected to be an effective strategy? Can he/she point to a well-controlled study demonstrating efficacy in bipolar depression?

 

[DebDynamite]

What evidence does your attending present that this is expected to be an effective strategy? Can he/she point to a well-controlled study demonstrating efficacy in bipolar depression?

No quite the opposite- s/he admits freely that the EBM behind it is lacking,
yet s/he does it when thinking it will work with certain pts.