29th December, 2009.
Dear Mr Horton,
I hope you are still editor of The Lancet. I have suspended my membership, for financial reasons, of the medical journalists' association. But this story is very important, and, because I rarely report anything clinical, I have decided that the safest thing to do for your newspaper is for me to reproduce exactly your PRESS RELEASE sent to me under embargo as a member of the press on your mailing list.
I would like to know what choice those involved in this trial had to decline to participate in this trial. Were they aware of the draconian powers of the mental health act? If any of these participants had ever been dehumanised by arrest or detention for medical reasons, ie by the Mental Health Act, I would argue they will have been declined a legal defence and that their diagnosis is deeply suspect. I would further argue that psychologically they ought to be viewed as possibly suffering from Stockholm syndrome and that they are likely to wrongly defend the medical profession and were vulnerable to abuse and incorrect diagnosis or diagnosis where there should have been none.
How did the participants in this trial die? How long had elapsed before anyone gave them a diagnosis, and how was it done and with what explanation? Were their denials dismissed as delusion or considered to be possibly correct and valid in the face of wrong diagnosis? Had any of them ever been wrestled to the ground by medical thugs to satisfy some do gooder arguing they should be forced to have the "opportunity" they were declining? Had anyone gone back to the beginning and explored in depth and in detail whether the original diagnosis ought ever to have existed? Had some total idiot decided to "save" them from prison by manipulating a diagnosis of mental illness rather than letting them be charged and be defended.
Freelance journalist and editor.
FROM The Lancet. These words are not available for advertising on this website.
COMBINED LITHIUM PLUS VALPROATE OR LITHIUM MONOTHERAPY BETTER AT PREVENTING RELAPSE IN BIPOLAR PATIENTS THAN VALPROATE MONOTHERAPY (BALANCE study)
Embargoed for 23.12.04
I noticed soon after publication I had written 04 and not 09. It should be 09. I posted on this website mid morning 29.12.09
For people with bipolar I disorder*, for whom long-term therapy is clinically indicated, both combination therapy with lithium plus valproate and lithium monotherapy are more likely to prevent relapse than is valproate monotherapy. This benefit seems to be irrespective of baseline severity of illness and is maintained for up to 2 years. These are the conclusions of the BALANCE study, published Online First (www.thelancet.com) and in an upcoming Lancet, written by Professor John R Geddes, Clinical Trials Unit for Mental Illness, University of Oxford, UK, and colleagues. However, BALANCE could not confirm or refute an advantage of combined therapy over lithium monotherapy.
Bipolar disorder is a disabling mental illness that is characterised by episodes of both elevated or irritable mood and depression. Although acute episodes can be succeeded by a period of remission, most patients have a recurrent or chronic illness, making bipolar disorder one of the most important causes of disability at ages 15-44 years. Many patients do not respond to monotherapy, and combinations of drugs are often recommended despite little evidence. Lithium plus valproate is often recommended after failure of first-line monotherapy. Should this combination have additive pharmacological effects and prove better than monotherapy, it could be an appropriate first-line therapy.
In the randomised BALANCE trial, 330 patients aged 16 years and older with bipolar I disorder from 41 sites in the UK, France, USA, and Italy were allocated to lithium monotherapy, valproate monotherapy, or both agents in combination after an active run-in** of 4-8 weeks on the combination. Patients were followed for up to 24 months, and the primary outcome was initiation of new intervention for an emergent mood episode.
The researchers found that 54% of people in the combination therapy group, 59% in the lithium group, and 69% in valproate group had a primary outcome event during follow-up. In terms of relative risk, those given combination therapy were 41% less likely to have a primary outcome event versus those given valproate; while those given lithium were 29% less likely to have an event than those given valproate. Both these findings were statistically significant. Patients given combination therapy were also 18% less likely to have an event versus those given lithium monotherapy, but this finding was not statistically significant. A total of 16 participants had serious adverse events after randomisation, that were judged not to be related to the trial treatments: seven receiving valproate monotherapy (three deaths); five lithium monotherapy (two deaths); and four combination therapy (one death).
The authors say: "The results of BALANCE show that for people with bipolar I disorder for whom long-term therapy is clinically indicated, combination therapy with lithium plus valproate is more likely to prevent relapse than is monotherapy with valproate. The 41% relative benefit is irrespective of baseline severity of illness, is maintained for up to 2 years, and is most apparent in prevention of manic relapse."
They conclude: "The main BALANCE findings have important implications for clinical decisions about long-term therapy for bipolar disorder. First, valproate monotherapy is recommended by clinical practice guidelines as a first-line option for long-term therapy. Our results suggest that patients should be advised that a better outcome would be likely with combination therapy with lithium plus valproate semisodium or lithium alone. Second, guidelines suggest that patients who have frequent relapses during treatment with lithium monotherapy could switch to valproate monotherapy. The results of BALANCE suggest that these patients would fare better if they changed to combination therapy."
In an accompanying Comment, Dr Rasmus W Licht, Mood Disorders Research Unit, Aarhus University Hospital, Denmark, says that the results of BALANCE, even without a placebo group, confirm the long-term efficacy of lithium, not only for the prevention of mania but also for prevention of depression.
He says: "On the basis of their overall results, the BALANCE group rightly challenges the recommendation by present clinical guidelines that valproate monotherapy is a first-line option for long-term treatment."
He concludes: "By a diligent balance of external and internal validity, BALANCE surely reflects its acronym. It is remarkable indeed that a clear signal could be detected despite the straightforward study procedures, including the allowance of co-medication, and there is no doubt that the trial sets the stage for future large-scale, simple, investigator-sponsored trials.