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					Doses of carbamazepine and valproate in bipolar affective disorder
David Taylor and Denise Duncan
Psychiatric Bulletin 1997, 21:221-223.
Access the most recent version at DOI: 10.1192/pb.21.4.221

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                                                                  DRUG INFORMATION QUARTERLY

Doses of carbamazepine and
valproate in bipolar affective
David Taylor and Denise Duncan

Carbamazepine and valproate are now well             patients with milder forms of BAD and other
established treatments for bipolar affective dis     disorders.
order (BAD).Both drugs are used in the acute           The doses of carbamazepine used were
treatment of mania and, more frequently, as          somewhat higher than those recommended by
longer-term mood stabilisers. The British Na         the BNF: mean daily doses ranged from
tional Formulary (BNF, Vol. 32, 1996) provides       614 mg to 1400 mg. Indeed, in practices where
                                                     a target plasma level of 7-12 mg/1 is used,
information on the use of carbamazepine in and
'prophylaxis of manic depressive illness' the        daily doses average 1000 mg (Gerner & Stan-
suggests that the 'usual range' of doses is          ton, 1992).
between 400 mg and 600 mg daily. No guidance            With the exception of the Jacobsen study,
on the use ofvalproate in BADis given in the BJVF    patients in valproate trials usually received
because the drug is not licensed for this            doses considerably in excess of 750 mg/day. In
indication in the UK.                                a selection of smaller trials reviewed by McElroy
   Perhaps because of the absence of firm            and co-workers (1992), valproate doses were of a
prescribing advice for either drug, the doses of     similar magnitude and the authors felt strongly
carbamazepine and valproate seen in practice         that 50 mg/1 was the threshold plasma level for
vary considerably. In general, low doses appear      response.
to be most frequently prescribed and daily              The heterogeneity of the studies, subjects
doses above 600 mg of either drug are not often      and conditions described in Table 1 makes
seen. Doses seem to be only rarely titrated to       any meaningful conclusion difficult. In addi
maximise efficacy. This is possibly because the      tion, few of these trials attempted to discover
evaluation of efficacy in preventing mood            the minimum plasma level or dose necessary
changes (prophylaxis) takes months or even           for efficacy. Nevertheless, one can conclude
years.                                               that plasma levels of above 7 mg/1 are
   It is apparent that more specific guidance on     robustly associated with response to carba
the dosing of carbamazepine and valproate            mazepine, corresponding to daily doses of
would prove valuable and so we have examined         above 600 mg. For valproate, plasma levels
pertinent research data in an attempt to develop     above 50 mg/1 appear to produce acceptable
more useful advice.                                  efficacy. These levels correspond to doses of
   Table 1 lists details of important trials of      750 mg/day or (much) greater. It is interesting
carbamazepine and valproate in mania and             to note that, in the United States, where
BAD (retrieved from MEDLINE     search, July 1996    valproate (as divalproex) is licensed for the
and examination of reference sections of these       treatment of BAD, an initial dose of 750 mg/
papers). It can be seen that plasma level            day is recommended, followed by titration to
monitoring was used in all studies. With carba       give a plasma level of between 50 and 125 mg/
mazepine, levels above 7 or 8 mg/1 were gen          1. As if to confirm this, advertisements for
erally associated with efficacy. With valproate,     divalproex state that 90% of patients in trials
levels within the range 50-100 mg/1 appear to be     were treated with doses above 1000 mg/day.
related to response. There are two exceptions to        These findings have important implications
these general observations. Stuppaeck et al          for prescribers. In the absence of data
(1990) noted that a mean level of 5.7 mg/1           supporting the use of low doses or low
carbamazepine gave an 80% response rate in           plasma levels, the doses and plasma levels
their cohort, but it is noteworthy that only seven   recommended here should be aimed for. This
of 25 patients had true BAD. Jacobsen (1993)         means that if our informal observations are a
showed that low levels of valproate (mean            true reflection of prescribing practice, whole
32.5 mg/1) produced a sustained response in          sale change in practice is called for.

Psychiatric Bulletin(1997), 21, 221-223                                                          221
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222                                                                                                                                                                          Taylor & Duncan
                                                                                       DRUG INFORMATION QUARTERLY

Recommendations                                                     JACOBSEN, F. M. (1993) Low-dose valproate:                 a new
                                                                       treatment      for cyclothymia,       mild    rapid     cycling
Carbamazepine - aim for plasma level > 7 mg/1                          disorders,    and premenstrual       syndrome.      Journal of
(> 600mg/day). Start at 200 mg BD; use mod                              Clinical Psychiatry, 54, 229-234.
ified release tablets; increase slowly.                             JOYCE. P. R (1988) Carbamazepine        in rapid cycling bipolar
                                                                       affective disorder, /ntemational Clinical Psychopharma-
Valproate - aim for plasma level of > 50 mg/1                          cology. 3. 123-129.
                                                                    LERER, B.. MOORE. N.. MEYENDORFF.E., et al (1987)
(>750 mg/day). Start at 500 mg OD; use mod                             Carbamazepine        versus lithium in mania: a double-
ified release tablets; increase slowly.                                blind study. Journal of Clinical Psychiatry. 48. 89-93.
                                                                    LuszNAT. R. M.. MURPHY,D. P. & NUNN, C. M. H. (1988)
All samples for plasma levels should be taken                          Carbamazepine         us lithium in the treatment            and
immediately before the next scheduled dose.                            prophylaxis of mania. British Journal of Psychiatry,
                                                                        153, 198-204.
                                                                    MCELROY,S. L., KECKJR. P. E.. HARRISON, .. et al (1992)
                                                                       Valproate     in the treatment        of bipolar      disorder:
                                                                       Literature review and clinical guidelines. Journal of
                                                                        Clinical Psychopharmacology,      12. 42S-52S.
References                                                                                        !
                                                                    OKUMA, T.. YAMASHITA... TAKAHASHI.R., et al (1990)
BOWDEN,C. L.. BRUGOER.A. M.. SWANN,A. C., et al (1994)                 Comparison         of     the    antlmanic       efficacy      of
                                                                       carbamazepine       and lithium carbonate of double-blind
     Efficacy of divalproex vs lithium and placebo in the              controlled study. Pharmacopsychiatry.        23. 143-150.
     treatment of mania. Journal of the American Medical
     Association, 271, 918-924.                                                                                F
                                                                    PLACIDI.G. F.. LENZI, A., LAZZERINI, .. et al (1986) The
—¿ JANICAK,P. G.. ORSULAK,P., et al (1996) Relation of               comparative      efficacy and safety of carbamazepine
                                                                       versus lithium: a randomized,           double-blind      3-year
     serum valproate concentration       to response in mania.
     American Journal of Psychiatry, 153, 765-770.                     trail in 83 patients. Journal of Clinical Psychiatry. 47,
BROWN,R. (1989) U.S. experience with valproate in manic
     depressive illness: a multicenter trial. Journal of Clinical   POPE. JR. H. G.. MCELROY.S. I.. KECKJR. P. E., et al (1991)
     Psychiatry. 50 (Suppl 3). 13-16.                                  Valproate In the treatment of acute mania. Archines of
                                                                        General Psychiatry. 48. 62-68.
CALABRESE. . R. & DELUCCHI,G. A. (1990) Spectrum of
     efficacy of valproate in 55 patients with rapid-cycling        SMALL.J. G.. KLAPPER.M. H.. MILSTEIN,V.. et al (1991)
     bipolar disorder. American Journal of Psychiatry, 147,            Carbamazepine compared with lithium in the treatment
                                                                       of mania. Archives of General Psychiatry. 48. 915-921.
—¿ MARKOVTTZ. J., KIMMEL, . E., et al (1992) Spectrum of
   ,               P.            S                                  STUPPAECK,C.. BARNAS, C., MILLER. C., et al (1990)
     efficacy of valproate in 78 rapid-cycling bipolar patients.       Carbamazepine       in the prophylaxis of mood disorders.
     Journal of Clinical Psychopharmacology,       12, 53S-56S.        Journal of Clinical Psychopharmacology.        10. 39-42.
FRANKENBURG. R, TOKEN.M., COHEN.B. M., et al (1988)
     Long-term response to carbamazepine:         a retrospective   'David Taylor, Chief Pharmacist; and Denise
     study. Journal of Clinical Psychopharmacology.       8. 130-   Duncan, Senior Drug Information Pharmacist,
      132.                                                          Pharmacy   Department,   Maudsley   Hospital.
GERNER. R H. & STANTON, . (1992) Algorithm for patient
     management of acute manic states: lithium, valproate,          Denmark Hill London SES 8AZ
     or carbamazepine?     Journal of Clinical Psychopharma
     cology. 12. 57S-63S.                                           •¿Correspondence

Doses of carbamazepine and valproate                                                                                              223

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