Friday, 16 January 2009

Valproate, Lithium and Placebo.

Following on from the link from last night's post.

There has only been one long-term study on valproate (divalproex, Depakote, etc) versus placebo (A Randomized, Placebo-Controlled 12-Month Trial of Divalproex and Lithium in Treatment of Outpatients With Bipolar I Disorder - Charles L. Bowden, et al - Arch Gen Psychiatry. 2000;57:481-489.).

Here is the study: full text, or pdf (I personally found the pdf much easier to read, as the graphs etc are all in their proper places).

Here is the abstract (bear with me, I'll talk about it in a moment):

Background Long-term outcomes are often poor in patients with bipolar disorder despite treatment; more effective treatments are needed to reduce recurrences and morbidity. This study compared the efficacy of divalproex, lithium, and placebo as prophylactic therapy.

Methods A randomized, double-blind, parallel-group multicenter study of treatment outcomes was conducted over a 52-week maintenance period. Patients who met the recovery criteria within 3 months of the onset of an index manic episode (n=372) were randomized to maintenance treatment with divalproex, lithium, or placebo in a 2:1:1 ratio. Psychotropic medications were discontinued before randomization, except for open-label divalproex or lithium, which were gradually tapered over the first 2 weeks of maintenance treatment. The primary outcome measure was time to recurrence of any mood episode. Secondary measures were time to a manic episode, time to a depressive episode, average change from baseline in Schedule for Affective Disorders and Schizophrenia–Change Version subscale scores for depression and mania, and Global Assessment of Function scores.

Results The divalproex group did not differ significantly from the placebo group in time to any mood episode. Divalproex was superior to placebo in terms of lower rates of discontinuation for either a recurrent mood episode or depressive episode. Divalproex was superior to lithium in longer duration of successful prophylaxis in the study and less deterioration in depressive symptoms and Global Assessment Scale scores.

Conclusions The treatments did not differ significantly on time to recurrence of any mood episode during maintenance therapy. Patients treated with divalproex had better outcomes than those treated with placebo or lithium on several secondary outcome measures.

(Proportion of patients to relapse against time)

What is this actually saying in English?

There was no demonstrable benefit shown by taking divalproex or lithium for maintenance treatment over taking a placebo.

Less people taking the divalproex stopped taking it during a relapse than those on the placebo.

The side effects of divalproex were not as unpleasant as those of lithium, reflected in the lower drop out rate. In other words, the drug that is not doing anything effective has fewer unpleasant side-effects than the other drug that is not doing anything effective either.

If you read the main study, they explain the results by saying that due to ethical reasons they 'probably' had managed to screen out the really bad cases, and if they had been included, they 'probably' would have shown a better result in comparison to placebo:

Several factors may have contributed to the surprisingly good outcomes in the placebo group. Patients with mild forms of bipolar disorder may have been selected for the study because of the enrollment requirement that 2 consecutive GAS scores had to be above 60. Bias may also have been introduced by the requirement that remission of mania had to be achieved within 3 months of the manic episode, as failure to meet this criterion was a major reason for exclusion from randomization. Also, some patients were randomized whose manic episodes resolved without specific treatment. In addition, a number of study candidates with histories of severe illness were reluctant to enroll in the study because of the chance of receiving placebo for up to 1 year, with minimal use of rescue medications. Moreover, the index episodes of mania seemed to be more severe in patients who failed to qualify for randomization than in those randomized. Drug-placebo differences are known to be greater when patients with more severe forms of illness are studied.

But what does that mean, when we look beyond the self-deprecation of the study? If, instead of reading that as "oh, that's ok, the study's flawed anyway, therefore we can ignore the results", we look at the implication of those caveats?

It is saying that if the above is true, then the drugs do not prevent relapse apart from perhaps in the more severe or refractory cases.

What conclusions can be drawn? Valproate is definitely an effective anti-manic treatment. I can vouch for its efficacy. However, there is no decent evidence for it being of any use at all in maintenance treatment. Which begs the question, for me, personally, why put up with the damn side effects? Why not take it when needed, to knock down a high that is going too high, and when down again, come off sensibly.

I shall be taking these issues up with my psychiatrist with a voice of tumult and thunder next month, and yea! I shall smite his desk!


Terra Incognita said...

D, I highly recommend that you do take it up with your pdoc. It is the exact argument I had with my pdoc last summer when I was put on it and no longer needed it because I was all of a sudden a complete idiot on it. It is now considered in my "repetoire-as needed" (in other words, I can call my pharmacy and have it filled whenever I need it, but I probably won't because I find the S working quite well). And you know how I got to that point? This very way. RESEARCH. Print out what you know and take it with you. And good for you.

Lola Snow said...

I have mental images of you swooping in to the psychiatrists office with a file the size of the yellow pages, and a soapbox to read it to him on. Rather wish I could be a fly on the wall, could you stick it on youtube???

Hope you get it sorted though, bloody medication.

Lola x

LoopyKate said...

Smite you must...
BTW I've addd more comment to diffrentlysane's post, in part in respose to your comments.
I'm never sure whether it's worth it coz I'm never sure whether folk bother checking back..#so I thought I'd tell ya..
since it's been eating large morsels out my day..
How's the hole by the way - you surfaced yet?

Abysmal Musings said...

Thanks all. Yes, have popped my head out the hole and am frowning around. What is that Beckett play?

p.s. Yes, saw your comment, Kate, can't think of much more to add.

differentlysane said...

Good luck with the pdoc I second Lola and want to see it on youtube.