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There’s a huge gap between the claims made for “mood stabilising” drugs and the evidence for their safety and effectiveness. So why are we now dishing them out even to young children, asks psychiatrist David Healy, who helped uncover the suicide risks associated with modern antidepressants keel as signs of an illness that requires that anticonvulsants might stabilise moods by treatment. While it does not mention any a comparable “quenching” effect – in other dancing late into the night. “Your doctor never sees you like this,” a drugs, the website stresses the importance of voice-over says. The screen cuts to a shrunken, long-term medication. At the time the ad was anticonvulsants might prevent an episode of glum figure: “This is who your doctor sees.” aired, Eli Lilly's drug olanzapine (Zyprexa) had mood disorder “kindling” future episodes. Next we see the woman in active shopping just been approved by the US Food and Drug Although anticonvulsants had occasionally mode. “That is why so many people with Administration for treating periods of mania, been used for treating bipolar disorders, there and the company was running trials aimed at was at the time little evidence of a preventive depression and aren’t getting any better – establishing olanzapine as a “mood stabiliser”. effect to support this analogy. Nevertheless, because depression is only half the story.” We Before 1995, the term “mood stabilisers” the idea that some drugs might stabilise see the woman again depressed, looking at bills had barely been heard of. So what exactly moods appealed to doctors and their patients. that have arrived in the post, then cut to her are these drugs, and how effective and safe It was also very attractive to pharmaceutical energetically painting her apartment. “That companies, which were starting to take an fast-talking, energetic, quick-tempered, up-all- interest in the market for bipolar drugs.
night you,” says the voice-over, “probably manic-depressive illness were treated with Bipolar disorders entered the Diagnostic never shows up in the doctor’s office.” antidepressants, and the manias with the and Statistical Manual of Mental Disorders (DSM) in 1980. The criteria for bipolar I television in 2002. It encouraged viewers to doctors did not rush to take people off these disorder (classic manic-depressive illness) log onto bipolarawareness.com, which takes drugs after episodes of illness, many patients included an episode of hospitalisation for you to a website called the Bipolar Help remained on them for years. However, the mania. Since then, mood disorders that do not Center. Scroll down and you see the site only agent thought to prevent episodes of require hospitalisation have been described, belongs to pharmaceutical company Eli Lilly. Here you will find a “mood disorder questionnaire”. In the TV ad, we see our heroine filling in this questionnaire, and the ad encourages viewers to follow her example: of bipolar disorder in children. “Take the test you can take to your doctor, it can change your life… Getting a correct diagnosis is the first step in treating bipolar disorder. Help your doctor to help you.” such as bipolar II disorder, bipolar disorders This ad markets bipolar disorder. It can be permanent basis was lithium, a cheap trace seen as a genuine attempt to alert people who element, though it was not originally referred cyclothymia. With the emergence of these so- are unaware that they are suffering from one called “community” disorders, estimates for the prevalence of bipolar disorders have risen psychiatric diseases: manic-depressive illness, stabilisers” were anticonvulsants, a group from 0.1 per cent of the population to 5 per in which people undergo periods of extreme used for treating epilepsy. Epileptic fits can cent or more. Along with this expansion in emotional lows and periods of extreme highs cause changes in the brain that make future estimated prevalence – and in the market for fits more likely – an effect called “kindling” – drugs – have come new journals and a slew of The ad can also be seen as an example of bipolar societies and annual conferences, disease mongering: selling a disease so you anticonvulsants reduce or “quench” these many heavily funded by drug companies.
can sell treatments for it. It encourages people changes. In the 1980s, Robert Post of the US In the industry’s hands, the growth of to view any variations from an even emotional National Institute of Mental Health suggested awareness of “mood stabilisation” has been 38 | NewScientist | 15 April 2006
sensational. It started in 1995, the year the FDA be applied to some antipsychotic drugs as well antipsychotics as a long-term treatment for granted Abbott Laboratories a licence to use as to anticonvulsants like sodium valproate. bipolar disorder, and scant evidence of their (Depakote) to treat periods of mania. In the antipsychotics had sought a licence for using onwards, Eli Lilly, Janssen and AstraZeneca, US, approval allows companies to advertise these drugs as a “maintenance” treatment. the makers of the antipsychotics olanzapine, drugs for the licensed purpose, and in its ads What’s more, academic review articles make it risperidone (Risperdal) and quetiapine for doctors Abbott described valproate as a clear that there is still no consensus among (Seroquel) respectively, marched in on this “mood stabiliser” – a label that may have psychiatrists on what a “mood stabiliser” is.
new territory and began the process of getting encouraged many to think it could do more There has always been a rationale to using approval for using these drugs not just to treat antipsychotics to treat the periods of mania mania but as long-term “mood stabilisers”.
By 2001, this term featured in the titles or that people with bipolar disorder go through. The result of these trends is that people abstracts of more than 100 scientific papers a with a bipolar disorder are now routinely year (see Graph, page 40), and it has started to prescribed a cocktail of expensive drugs on 15 April 2006 | NewScientist | 39
a permanent basis. Drug companies, often stem in part from difficulties in conducting with the enthusiastic support of psychiatrists, trials that last more than a few weeks for have managed to firmly establish the idea conditions as complex as manic-depressive illness. However, the existing evidence of preventive medication, not merely treatment benefit for one agent (lithium) and possible for episodes of mania or depression.
benefit for one more (olanzapine) must be For instance, Eli Lilly’s Bipolar Help Center weighed against the dangers. The potential website states: “Staying on medication over toxicity of lithium is well known, and a the long haul is critical. Without it, symptoms consistent body of evidence shows that people will reappear and the illness will get worse.” undergoing regular, long-term treatment with Similarly, information available from Janssen, antipsychotics have an increased risk of death. the maker of Risperdal, states: “Medicines are antipsychotics do not show up in the relatively bipolar disorders. Studies over the past twenty short-term trials aimed at demonstrating years have shown beyond the shadow of doubt treatment effects in psychiatry. There is also that people who receive the appropriate drugs evidence from trials of antipsychotics for are better off in the long term than those who schizophrenia that there are significantly There is, however, much less evidence than active drug than those on placebo.
many might think to support these claims. In being pulled into the manic-depressive net, demonstrated in clinical trials translate there is almost none at all, as drug trials have into therapeutic efficacy. In north Wales a patients given an active drug. No suicides and century ago, patients with bipolar I disorder person-years of exposure) occurred in 418 patients on placebo. Based on these figures, I lithium for bipolar I disorder, no randomised improvements in services and treatment with calculate that suicidal acts are 2.2 times as controlled trials show that patients with the very latest drugs, bipolar I patients are likely in those taking “mood stabilisers” bipolar disorders who receive drugs do better admitted four times as often (History of in the long term than those who receive no Psychiatry, vol 16, p 423). This is not ordinarily If the efficacy of “mood stabilisers” is medicine. Eli Lilly’s olanzapine was approved what happens when treatments “work”, but by the FDA for the long-term treatment of quite often is what happens when treatments include an increased risk of suicide, we should bipolar I disorder in January 2004 on the basis have side effects.
surely be very cautious about expanding their of a randomised, placebo-controlled trial. But use. Yet in the US there is now a surge of this trial essentially lasted only a year, and diagnoses of bipolar disorder in children Fearsome toll
most apparent relapses occurred just after despite the facts that these children do not patients stopped taking olanzapine, which Those selling bipolar disorder stress the meet the usual criteria for bipolar I disorder suggests that they were in fact suffering disorder’s fearsome toll in terms of suicides. and that until recently the general wisdom withdrawal symptoms. Even in the case of was that it was very rare for manic-depressive lithium, there is some dispute over what has antidepressants in triggering suicide has been illness to start in the pre-teen years. This trend is exemplified by the book The It is true that this lack of evidence may diagnosis: if the doctor had only realised the Bipolar Child by Demitri and Janice Papolos. patient was bipolar, the argument goes, they Published in 2000, it sold 70,000 hardback copies in six months in the US. As the Star- antidepressant. Because of this suicide risk, Telegram newspaper in Fort Worth, Texas, most psychiatrists would find it difficult not reported in July 2000, The Bipolar Child made to prescribe drugs for any person with bipolar all the difference to a local girl, Heather Norris, disorder. Yet as real as this risk is, the best then aged 2. Heather had been diagnosed with available evidence shows that medication attention deficit hyperactivity disorder making her worse. After reading The Bipolar Child, her mother challenged her doctor to change the diagnosis – and the medication.
controlled, double-blind, randomised trials of The book’s authors have senior positions in “mood stabilisers” for the prevention of a charity called the Juvenile Bipolar Research manic-depressive episodes submitted to the board between 1997 and 2003 (The American company Novartis. The charity’s FAQ on what Journal of Psychiatry, vol 162, p 799). They it calls “early onset” bipolar disorder states: compared the suicide risk in patients on various drugs with those on placebo. Two intense moods for weeks or months at a time, but children appear to experience such rapid person-years of drug exposure) and eight suicide attempts (1969 per 100,000 person- 40 | NewScientist | 15 April 2006
If we consider adults alone for a moment, there is already potential for creating an children were solely for research purposes, “epidemic” of bipolar disorder because people there might be little problem. However, drugs are being diagnosed based on criteria that such as olanzapine and risperidone are now depend upon subjective judgements rather being given to preschoolers in the US.
than any objective criterion of disability, such Some research on the subject is adding fuel as hospitalisation or being off work for a to the fire. What might once have been thought month. With children, the risk is even greater of as sober institutions, such as Massachusetts because diagnosis is based mainly on the General Hospital in Boston, have run trials of reports of parents, with little scope in most olanzapine and risperidone on children with clinical practice for critical scrutiny of the social an average age of 4. The hospital recruited forces influencing parenting. For instance, in participants by running TV ads stating that an age in which both parents often have to difficult and aggressive behaviour in children work long hours and childcare centres reject aged 4 and up can stem from bipolar disorder. “difficult” children, medication may be the The ad does more than recruit children with a easiest way to deal with behavioural problems. clear disorder: it suggests that everyday Experts who appear willing to go so far as behavioural difficulties may be better seen in to accept the possibility that the first signs of terms of a disorder. Given that bipolar disorder in children is all but unrecognised outside the proportion of these children will not meet the conventional criteria for bipolar I disorder. It is all but impossible for a short-term trial of sedative agents for treating any sort of state that involves periods of overactivity not to show some rating-scale changes that can be regarded as beneficial. This research thus appears predestined to validate the diagnosis and thus increase the pressure for treatment.
diagnosed with bipolar disorder, the original rationale for mood stabilisation was greatly weakened by the results of the largest ever randomised trial of immediate versus deferred anticonvulsant therapy for people who had experienced a single seizure. The trial found that although immediate anti-epileptic drug treatment reduces the occurrence of seizures in the next one to two years, such treatment does not affect long-term remission in individuals with single or infrequent seizures. Yet the entire concept of “mood stabilisation” was based on an analogy with epilepsy, not on any demonstrations of long-term benefit of any particular drug.
The use of “mood stabilisers” as a long- term maintenance treatment for bipolar disorders is based more on wishful thinking than on a solid theoretical or empirical basis. There is good evidence that these drugs threaten the health and lives of adults taking them – who knows what lies in store for the growing number of young children given these complex agents? Only the health of drug companies’ profit margins appears assured. ● David Healy is a psychiatrist at the North Wales
Department of Psychological Medicine, Cardiff
University, UK. This is an edited version of an essay
in PLoS Medicine, one of a series of articles on
disease mongering available at http://collections.
plos.org/diseasemongering-2006.php
15 April 2006 | NewScientist | 41

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