https://joannamoncrieff.com/2015/07/01/reasons-not-to-believe-in-lithium/
‘I don’t believe in God, but I believe in lithium’ is the title of
Jamie Lowe’s moving account of her manic depression (now usually
referred to as bipolar disorder) in the New York Times (
http://mobile.nytimes.com/2015/06/28/magazine/i-dont-believe-in-god-but-i-believe-in-lithium.html?referrer=).
The piece reminds us how devastating and frightening this condition can
be, so it is understandable that the author put her faith in the
miracle cure psychiatrists have been recommending since the 1950s:
lithium.
Lowe took lithium from the age of 17 for 20 years, until at the age
of 37 or thereabouts she was diagnosed with kidney failure, a direct
result of this treatment. She will need dialysis, and a kidney
transplant – a high price to pay for a really effective treatment. The
sad thing is, we have little evidence that lithium is a really effective
treatment, or even that it is effective at all. However, as I explain
below, once someone starts on lihium, there is evidence that there is a
high risk of having a relapse if they stop it. This is not the same as
showing that lithium is a good thing in the first place, but it does
mean that people who are already taking lithium have to be very careful
if they decide they want to come off.
Lithium is a neurotoxin. It inhibits the functioning of the nervous
system so that people typically feel drowsy, lethargic and slowed up.
These effects were observed in guinea pigs initially, and then in people
with mania by the Australian doctor, John Cade, who first proposed that
lithium might be a useful treatment for manic depression (1). In the 19
th
century lithium had been used for the treatment of gout, and became a
popular ingredient of tonics and even beer, until it was shown that it
did not dissolve the uric acid crystals that cause gout as had been
claimed (2).
The sedative and slowing effects of lithium, although usually
described as side effects, account for why lithium can help reduce
arousal and activity levels in people with acute manic symptoms. So
there is nothing magic or specific about lithium’s action in manic
depression. Lithium will exert its characteristic effects in anyone,
whether or not they have mania or manic depression. In theory, these
effects might suppress the emergence of a manic episode, as well as
reduce the severity of symptoms once an episode has started. The
evidence that long-term lithium treatment reduces the occurrence of
manic or depressive episodes is actually very weak, however.
The main problem with the evidence is that there is no study in which
people who have been started on lithium have been compared with people
who haven’t. Every randomised trial of lithium versus placebo starts
with people who are already on drug treatment of one sort or another,
often lithium itself. Now there is good evidence, accepted by leading
proponents of lithium (3;4), that withdrawing from lithium can
precipitate a relapse of manic depression, especially a manic episode.
Three studies have shown, for example, that people are more likely to
have a relapse after stopping lithium than they were before they started
it (5-7). No one knows the mechanism for this, but it is as if removing
the neurological suppression produced by lithium causes the nervous
system of a susceptible person to go into over-drive, precipitating a
manic relapse.
So demonstrating that people who stop lithium and start a placebo
have higher rates of relapse than people who continue on lithium does
not demonstrate that going onto lithium in the first place prevents
episodes. But all the placebo-controlled trials of lithium are like
this to at least some degree. The trial that established the idea of
long-term lithium treatment, for example, started with people who had
already been on lithium for many years (8). In more recent studies, not
all participants have been on lithium prior to enrolment, but those not
taking lithium were likely to be taking other sorts of sedative
medication. The first of these recent studies, the largest study up
until that point involving 372 participants, found no difference between
lithium, sodium valproate and placebo in terms of the rate of
recurrence of any type of mood episode (9). The second found a higher
rate of manic relapse in placebo-treated patients compared with those on
lithium, but the pattern with which relapses occurred was strongly
suggestive of a discontinuation effect. A large majority of relapses
occurred in the first few weeks after allocation to placebo, and none
occurred in the last few months of the study, suggesting that the point
of discontinuation of previous medication was associated with subsequent
relapses (10). In the final trial, rates of mania were higher in people
on placebo by about 14% (14% vs 28%), but 20% of participants were
taking lithium before randomisation, and still others were taking
Depakote or antipsychotics, all of which were stopped relatively
abruptly prior to the trial (11).
The possibility that relapses in the placebo groups in these trials
are induced by withdrawal of previous medication would make sense of the
fact that it has proved impossible to demonstrate that people receiving
modern drug treatment for manic depression do any better than those who
don’t, or didn’t. In fact, overall, they seem to do slightly worse.
Two important studies have examined rates of relapse in people with
classical manic depressive symptoms prior to the 1950s. American
psychiatrist George Winokur found the records of 100 patients admitted
to a psychiatric hospital between 1934 and 1944 with an episode of mania
and then followed them up through their hospital records. He found that
48% had a relapse requiring hospitalisation over an average follow-up
duration of 3.2 years. For comparison purposes this equates to a relapse
rate of 15% per year (12). Margaret Harris, David Healy and colleagues
did the same for patients admitted to the North Wales asylum in the
1890s. They found that, on average, patients had 4 relapses over the
subsequent 10 years, equating to a relapse rate of 20% a year. In
comparison, during the 1990s, people with manic depression (most of whom
we can assume were on drug treatment) were having an average of 6.3
admissions in 10 years, or 31% per year, for example (13). That’s over
10% higher than the rate of admission for people in the 1890s!
Relapse rates among patients taking lithium in randomised trials that
have started with patients experiencing a manic episode (as the
historical studies did) are uniformly higher too. In the comparison
between lithium, Divalproex (Depakote) and placebo, for example, the
lithium group relapsed at a rate of 31% a year (9). In the comparison
between lithium, lamotrigine and placebo in people with mania it was 26%
a year (10). Admittedly these figures include all relapses, and not
just those severe enough to require hospitalisation. A large study
conducted in the 1970s, however, found that rates of hospital admission
for relapse were 21.5% per year in the lithium group (14).
Several ‘naturalistic’ studies have tracked the progress of people
taking lithium and other treatments. The vast majority of these studies
also show high relapse rates among those on lithium, even though most
studies highly compliant populations and we know that people who are
compliant with any treatment (including placebo) have better outcomes
than those who are not. One study of patients who were known to be
compliant with their lithium treatment for at least a year, for example,
found a rate of relapse of 40% a year over a 6 year follow-up (15).
In my view the evidence that lithium helps prevent episodes of manic
depression is far too weak to outweigh the harms it can cause (which
commonly include thyroid damage, kidney damage, and acute neurological
toxicity at doses very close to those used in practice, hence the need
for blood monitoring). Manic depression is a highly variable condition.
Some people have many episodes, some people few, and the pattern of
episodes varies throughout life as well. Long periods of remaining well
are not necessarily evidence of a treatment’s effectiveness. What we
would need to demonstrate the efficacy and value of lithium is a
prospective randomised trial in which people who had not previously been
on long-term drug treatment were randomly allocated to start lithium or
placebo. At present, my view is that the evidence that lithium
might be effective is not strong enough to justify such a trial, given the health risks associated with it.
As Jamie Lowe eloquently expresses, manic depression can be a
terrifying condition, and I know that people will say therefore ‘if not
lithium, then what?’. But the evidence that any long-term drug
treatment is better than nothing is not strong (1). Many doctors and
patients are very uncomfortable with that conclusion, and feel there
just has to be something. And if people want to try some sort of drug
treatment, like antipsychotics or anticonvulsants, then I feel that
doctors should help them take it as safely as possible, at as low a dose
as possible. But doctors should be honest about the state of the
evidence and for lithium, I am not convinced there are any circumstances
that justify the risks it entails.
In 1957 a pharmacologist bemoaned the fashion for treatment ‘by
lithium poisoning’ (16). One day, I believe, we will wake up and realise
his concern was spot on!
Reference List
(1) Moncrieff J. The Myth of the Chemical Cure: a critique of
psychiatric drug treatment. Basingstoke, Hampshire, UK: Palgrave
Macmillan; 2008.
(2) Johnson FN. The History of Lithium Therapy. London: Macmillan; 1984.
(3) Franks MA, Macritchie KAN, Young AH. The consequences of
suddenly stopping psychotropic medication in bipolar disorder. Bipolar
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