Sue
You're right to be skeptical, but this issue is getting very difficult. As
you point out, the only decent study on relating valproate concentration to
response in mania (Bowden et al. Am J Psych 1996 15: 765-70) found that
patients with bipolar disorder who have valproate concentrations between 45
mg/L and 100-125 mg/L are much more likely to have efficacious and
well-tolerated responses than patients with concentrations outside this
range.
However, the study did not address the crucial question of whether plasma
level is a better predictor than dose is. It's important also to note that
the work is based on fasting trough valproate concentrations.
Unfortunately, the subtleties of the message have been missed by people who
write guidelines, and both the American and Canadian guidelines for the
management of bipolar disorder now recommend monitoring of valproate (and
carbamazepine, if used).
An article in the College of Psychiatrists Psychiatric Bulletin in 1997
(21: 221-3) discusses the evidence for what dose to use. Their
recommendation for valproate is 'aim for plasma levels >50 mg/L (>750
mg/day)' - which rather begs the question of a link between dose and plasma
level. However, a lot of psychiatrists are now demanding concentration
measurements on the basis of this article. Bowden's patients were on a
standard regime (250 mg tds increased to 1000 mg/day on days 3-5, levels
taken on day 5). On this regime, 16/65 (25%) of patients had day 5 levels
below 45 mg/L.
After a constructive discussion with our psychiatrists, during which I
learned more about psychiatry and they learned more about drug monitoring,
we've agreed to provide the service in patients who are receiving adequate
dose regimes (>750 mg/day), to confirm that adequate levels are being
achieved. We will review the evidence when we've been running it for a bit.
On the basis that if something is worth doing, it's worth doing properly,
we agreed that only fasting trough samples would be acceptable, since that
is what the literature relates to, and the variation in concentration
across the dose interval is substantial for valproate. In passing, this
move alone has reduced the number of requests!!
Hope that's helpful. I have a short Powerpoint presentation on valproate
monitoring in bipolar disorder which you (or anyone else) is welcome to if
it's any use.
Mike Hallworth
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