Valproate for acute mania — under-dosing endemic
Is valproate under-dosed, in acute mania? Good evidence indicates that is the case; I am not alone in that view (1): I will proffer my opinion to explain why this is so.
When I was in practice I was an early adopter of high-dose valproate. The valproate regime I used was informed by my friend Professor Mervyn Eadie, a neurologist who was doing research on valproate around that time (2-8), and it was aimed at using the maximum tolerable dose. I therefore started with the objective of using 20 – 60 mg/kg per day, aiming at an initial dose in the middle of that range of 40 – 50 mg/kg, which is a daily dose of 2,500 mg for smaller persons (50 kg body wt.), and 5,000 mg for larger persons (100 kg body wt.).
I quickly settled on an initial dose of 1 g on admission (in the non-slow-release form in which it was then available, ‘Epilim’ tabs), followed by a further 1 g 4 to 6 hours later, usually escalating to 3 or 4 g the following day — most patients were able to tolerate 3 to 4 g daily without difficulty.
The T max is 1-2 hrs, T1/2 11-20 hrs (steady-state 3-4 days).
Vajda et al. (9) found human brain valproate levels were only a fraction of serum & CSF levels (6.8% to 27.9%).
Most ‘TDM’ serum level requests are inappropriate, and many are not taken at the correct time — at least eight hours after the last dose, and before a morning dose (10).
Using blood levels to guide dose is of uncertain value for several reasons, summarised by Eadie (5, 7, 11):
‘Therapeutic ranges of plasma concentrations of antiepileptic drugs are good servants in the management of epilepsy, but can become bad masters. The therapeutic range for valproate is rather wide, and some authors believe there is little correlation between plasma concentrations and antiepileptic effects of the drug (12).
In a recent review from the epilepsy field Patsalos et al. (13) highlight the value of ‘individual therapeutic concentration’, as opposed to reference ranges which, as Eadie said long ago, can become bad masters.
Patsalos et al. also, like Eadie, conclude that the evidence validating a useful predictable dose-effect relationship is poor (see also ‘toxicology’ below), and that due to individual variation many patients require concentrations outside the reference ranges. Management is best guided, at least for epilepsy, by determination of the ‘individual therapeutic concentration’ (the concentration needed for seizure freedom in a particular individual).
One possible explanation for the poor correlation between therapeutic benefit and serum levels in epilepsy is that different types of epilepsy have different sensitivities to the effects of valproate. I know of no analysis of the literature that has looked at this question, which was drawn to my attention by Prof Eadie. That point makes it even more relevant to assess the levels at which it is effective in mania separately, and not to rely only on pre-existing epilepsy data — see comment re Allen (14) below.
Twice daily administration of the standard preparation is a reasonable way to start therapy, and if blood tests are felt to be absolutely necessary they should be done before the morning dose.
Note that some Valproate SEs are not concentration-related (see toxicology below).
Until I undertook the research for this commentary I was unaware that the vast majority of trials, and other published accounts, of valproate in acute mania had utilised such low doses (viz. a maximum of 10 – 20 mg/kg). Despite this, they demonstrated a modest degree of efficacy, more or less equivalent to lithium and APs in most studies. The Cochrane review tabulates the details of the trials that were included (15), of which none used in excess of 20 mg/kg except Freeman (16), who used up to 3,000 mg, but only in a small number of patients, and Tohen (17) who used a max of 2,500 and used blood levels in a target range of 50 to 125 µg/ml.
In Druschky’s more recent European data (18) the mean dose was 1,500 mg daily.
A review by Vasudev et al. underlines the under-dosing problem (1).They found the mean valproate dose being given after the first week was 1,000 mg. The maximum, after one whole month, was only 1,500 mg. They concluded, understandably, that inadequate initial dosing and inadequate dose increments indicated that current practice is not evidence-based.
A small digression is relevant here, because this is an excellent example of how guidelines are a powerful negative self-fulfilling and circular exercise. Trials are often designed to show equivalent effectiveness to existing treatment, but with less side effects. The trials with the lowest doses demonstrating equi-effectiveness get published. Others get lost. Since no trials have utilised higher doses the guidelines will inevitably conclude that there is no evidence that higher doses are better — and they will therefore entrench and perpetuate that unfounded misconception, especially because more and more doctors now are unwilling to use non-guideline drugs and doses. This is exemplified by the UK NICE guidelines which are unhelpful, in more ways than one.
Therefore, few doctors gain the experience that would contradict that, because they feel constrained to follow the guidelines. Furthermore, so few psychiatrists have knowledge of the pharmacology and toxicology of valproate, that they do not have the confidence to try higher doses.
In this instance, that is despite scientific evidence that under dosing is occurring, and that higher doses are safe and more effective (see below).
Vasudev’s paper leaves me profoundlyperplexed regarding the kind of difficulty in thinking and decision-making that allows a clinician to take a month to do something so simple, like to adjust the dose of the drug above the minimum effective dose. This is especially so because it is being given for an acute condition which carries significant morbidity.
This frequent failure of ‘good-clinical-management’ of treatment, in relation to dose-escalation, duration, and response, is a theme which permeates most of psychiatric therapeutics, and is given insufficient attention in guidelines, if it is mentioned at all (see the comments in my AD algorithm). This seems to relate to several factors: the poor critical-thinking skills of psychiatrists, the inattention to teaching competent decision-making during their training, and poor confidence, resulting largely from poor pharmacological knowledge.
Rapid control of acute/severe mania
Valproate is relatively unusual in that the intravenous and oral doses are equivalent (i.e. bio-availability is 100%): therefore, blood levels and effectiveness are similar when equivalent IV/oral doses are administered (19). Generally speaking, in manic patients, it will be easier to give drugs orally, than attempt to manage intravenous infusions, which would in any case have no advantages.
Valproate has now been in use for over 50 years, and it has become clear that doses of up to 140 mg per kilogram (per day) are safe. Trials in epilepsy indicate that doses of 40 to 60 mg per kilogram well-tolerated and many patients have little by way of side-effects or significant adverse effects even when levels are above 100 mg/kg (see also ‘toxicology’).
Typical guidelines for the treatment of epilepsy advise doses up to a maximum of 60 mg/kg.
The above information helps to put the low doses of around 10 mg per kilogram, which are typically used in mania, into perspective.
A conservative dose range was simply adopted from pre-existing common practice in epilepsy patients. It is unlike most other psychiatric drugs, which gained approval specifically for a treatment indication in psychiatry: those were subjected to dose response studies, prior to the clinical-trial phase of experimentation.
It is worth noting that no proper dose-ranging study has ever been done concerning the use of valproate in acute mania, or any other psychiatric condition — but see Allen (14) regarding evidence that higher levels are better. They produced evidence of a pronounced and clear improvement in benefit showing a linear trend that did not plateau-out even at serum levels of > 100 μg/ml.
Carlat sums it up as ‘very effective for acute mania, and rapidly so, usually quelling manic symptoms within a week’. ‘Trials’, and hence guidelines, suggest it is equally effective as lithium and APs; I take Carlat’s above comment to infer the opinion that it is better, much better. That is the view I propound.
However, it seems to be used in only a proportion of cases, like about 50% (18): although this frequency of usage will inevitably vary from place to place and is probably often in combination with the so-called’ ‘atypical’ APs.
Incidentally, it appears lamotrigine is used surprisingly frequently in acute mania despite complete lack of evidence for its effectiveness.
Relative safety vs AEDs and APs
Druschky’s review (18) indicates, as previous reports and data suggest, that valproate is the safest of all the AEDs, and it is safer and much more ‘patient-friendly’ than APs. It has the lowest rate of adverse drug reactions rated as severe, compared to other AEDs (18).
It has low day-to-day mild side-effects compared to alternatives, and the lowest rate of treatment cessation from all causes, including SEs (a contrast to quetiapine where in some studies up to 50% of recipients cease it within 4 weeks).
Dose-related SEs most frequently seen appear to be: asthenia, diarrhoea, vomiting anorexia, but even in patients on high doses these rarely required treatment discontinuation (20). Note other SEs are not dose-related.
It has a wide margin of safety as the toxicology data demonstrates.
Recent papers relating to higher doses of valproate
Trinka (21):Efficacy and safety of intravenous valproate for status epilepticus: a systematic review. … 15 and 45 mg/kg in bolus (6 mg/kg/min) followed by 1-3 mg/kg/h infusion. Safety studies of intravenous VPA administration in patients with status epilepticus showed a low incidence of adverse events overall (<10%), mainly dizziness, thrombocytopenia, and mild hypotension, which was independent of infusion rates. Of note, good cardiovascular and respiratory tolerability was observed in these studies, even at high doses and fast infusion rates (up to 30 mg/kg at 10 mg/kg/min), despite multiple morbidities or other antiepileptic drugs.
Georgoff (22): The maximum tolerated dose of intravenous valproate in healthy subjects was 140 mg/kg; significantly higher than the previously established maximum tolerated dose of 60-75 mg/kg. Adverse events were mild and no drug-related abnormalities were seen in clinical laboratory tests, ECG, and cognitive testing.
Case reports of interactions and toxicity can be highly misleading, as they are in my field of serotonin toxicity. The same, unsurprisingly, applies to valproate, which has, as a result of misleading case-reports, unjustifiably gained a reputation for high toxicity and a narrow therapeutic index.
More comprehensive data from large series of carefully observed overdoses from toxicology units strongly contradicts that impression (23, 24). In a nutshell, valproate is relatively benign in overdose: mostly producing only drowsiness, tachycardia, and gastrointestinal effects (vomiting). In Isbister’s series ‘in 8 of the 15 valproate alone poisonings, greater than 200 mg kg-1 (14 g) was ingested, none of these had any major abnormalities except drowsiness in two cases ingesting 20 g and 25 g.’ Just as there is little correlation between SEs and serum levels at therapeutic doses, so Isbister found there is no correlation in ODs between serum levels and severity: they concluded, ‘more than half of the valproate-alone overdoses ingested greater than 200 mg kg-1 with little effect. Drowsiness was seen in two patients ingesting 300– 400 mg kg-1.
These data are from Prof Whyte’s prospective toxicology database, that I have a connection with, because that is where most of the ST data have come from. It is high-quality data from a top research group. Lastly, they also noted how much more toxic was carbamazepine.
Only limited, and poor quality, evidence supports the efficacy of valproate in the long-term treatment of bipolar disorder. As Ciprianiet al. state (25): ‘Clinicians and patients should consider acceptability and tolerability profile when choosing between lithium and valproate, their combination, or other agents, as long-term treatment for bipolar disorder’.
Valproate is under-used and greatly under-dosed in acute mania. Mono-therapy with high-dose valproate is the first-choice preference by a wide margin.
It has less side effects and a wider margin of safety than any of the other relevant drugs. It is much less expensive than almost any other option.
If adequately dosed, is almost certainly much more effective, despite the paucity of evidence for this from RCTs. That simply speaks to the fact that RCTs are frequently unhelpful, and as Parker has said (26), they ‘produce clinically meaningless results’.
It is therefore important for clinicians to develop and trust their clinical judgement, and stop deferring too readily and too often to the sometimes mis-informed conclusions promulgated by the committees that produce these guidelines — for a discussion of the extensive problems with guidelines see my recent commentary.
It reminds me of one of the factors that speeded my departure from the National Health Service in the UK many years ago. The more competent a clinician you were, the more of the actual work you finished up doing, whilst the people who were less capable sat on committees telling you how you should be doing the work! I was not very tolerant of being told how to do my job by a bunch of grannies.
There has been little useful new basic research on valproate for some years now — all the money is in new APs! But there is more data on dosing and toxicology, showing valproate has a substantially better profile than any other AEDs.
No dose ranging study has been done concerning the use of valproate in acute mania, a rather conservative dose-range was simply adopted uncritically from then-current epilepsy practice. The re-examination of those data above supports the safety, and theoretical rationale, and effectiveness, for administering much larger doses.
Accordingly, I would urge clinicians to give careful consideration to higher dosages of valproate in acute mania (30 – 60 mg/kg/day, or more): that means, even for a little (50 kg) patient a minimum dose of 1,500 mg per day (30 mg/kg) and for a larger person (100 kg) a minimum dose of 3,000 mg per day.
It is probable that the immense amount of money put into the marketing of new so-called ‘atypical’ antipsychotic drugs for the treatment of mania has obscured the profile and usefulness of valproate. As if it were needed, this is yet another example of the distorting effect on good clinical practice, produced by the huge dollar influence in sales and marketing from big Pharma, acting on the rather half-hearted and hesitant profession of psychiatry.
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