Pharmageddon. David Healy

led in the 1940s and 1950s to an astonishing development of truly novel and extremely effective agents, from the antibiotics and cortisone to the diuretics, antihypertensives, hypoglycemics, and psychotropic drugs, as well as the first chemotherapy for cancer. It seemed we were set on a course in which genuine developments would succeed each other for years to come. The era of snake oil was over. Academic understanding and medical research had developed as never before, laying the basis for real progress, and pharmaceutical companies had played a part in this progress. Besides, even with the change in what could be patented, the spirit of the patent laws and the expectations of the medical community at least notionally remained aimed at providing businesses with a period of monopoly but only in return for a genuine novelty that offered a distinct benefit to the public. Such an arrangement seemed to be an engine for harnessing commercial vigor to public purpose.

      It hasn't turned out that way. When assessing the patent application for a drug, the examining officer is supposed to look at whether the structure of a molecule is substantially different from compounds already on the market, and whether it provides a clear clinical benefit, a solution to a problem of medical care for which we have not previously had an answer.³² It is in the interest of a drug company, however, to argue that differences that may appear to be trivial are in fact substantial and innovative, as in some cases they are. But, if a country wishes to build up its pharmaceutical sector, as the United States was intent on doing in the postwar decades, one way to do so is to make it easy to take out patents. The notions of benefit to the community and of novelty can be shaved, so that companies might be awarded patents for trivial variations on a compound that does not clearly confer any benefit in terms of health or other public value.

      Against this background let us look at the patenting of Depakote. The American patent on Depakote was taken out in 1991 but the drug in fact came from a French anticonvulsant, sodium valproate, first produced in 1962. By the mid-1960s, it was known that the sedative effects of sodium valproate could be useful in the treatment of mania. When Abbott filed for a patent on semi-sodium valproate in 1991, it was on the basis that minimally reducing the amount of sodium in the compound, which was completely irrelevant to the mode of action of the drug, made it novel. Had Abbott proposed to test this compound, which was trivially different from sodium valproate, for a hitherto incurable disorder, such a stretching of the spirit of the patent law might have been warranted on the basis of clinical need. But all Abbot planned to do was to put it into trials for use in mania, with a result that was a foregone conclusion. That Depakote was granted a patent is indicative of how lax the application of American patent law had become. The reason to go to all this trouble was that sodium valproate was now off-patent—any company could make it—and without marketing exclusivity Abbott thought that it could make little or no money.

      Faced with an application for its use in mania, the FDA then licensed Depakote. Surely clinicians would not use the much more expensive on-patent semi-sodium valproate over the far less costly off-patent but essentially identical sodium valproate? Such a prediction ignores the power of the kind of branding that product patents made possible. Clinicians were faced with a brand new compound, a brand new class of drug—a mood stabilizer—and a brand new illness—bipolar disorder—and they fell hard for the package. Depakote became a billion dollar global blockbuster and manic-depressive illness was consigned to the dustbin of history, greatly increasing the costs of healthcare in the process. The success of Depakote lay entirely in Abbott's ability to distinguish between two drops of water—but it was the ability to take out a product patent with global reach that made it worth their while to do so.

      In the case of Zyprexa, an antipsychotic and mood stabilizer, the story is as extraordinary. The first generation of antipsychotics ran into problems in the 1970s with million-dollar legal settlements against their manufacturers for a disfiguring neurological side effect of treatment—tardive dyskinesia. This led to a period of almost twenty years when no new antipsychotic came on the market. The only antipsychotic that did not cause this problem was clozapine, but clozapine had been withdrawn in 1975 because it was associated with a higher rate of mortality than other antipsychotics.

      The way forward seemed to lie in producing a safe clozapine. There were two ways to attempt this. One was to develop a drug that bound to the key brain receptors that clozapine bound to; this method underpinned the patenting of Risperdal (risperidone) and Geodon (ziprasidone). Another way was to make minor adjustments to the clozapine molecule. Tweaking a molecule risks producing a compound with all the hazards and none of the benefits of the parent. This is what Lilly did: in 1974 the company produced a series of compounds that were all abandoned because of toxicity.

      As the patent life of that series ebbed away, Lilly had to decide whether to abandon the hunt. This was a company in serious financial trouble, facing potential takeover. On April 29, 1982, they opted to move forward with a compound from the original series that by definition was not novel—olanzapine, later branded as Zyprexa. To make Zyprexa commercially viable, they needed a new patent, which meant demonstrating some benefit not found with other antipsychotics. In 1991, the only novelty presented in the company's new patent application, which was approved, was a study in dogs in which Zyprexa produced less elevation of blood cholesterol levels than another never- marketed drug.

      Zyprexa has since turned out to be one of the drugs most likely in all of medicine to increase cholesterol levels in man. Lilly has settled over $2 billion worth of claims that Zyprexa has raised cholesterol and caused diabetes and other metabolic problems. There was arguably a better case to be made for patenting it to raise cholesterol than to treat psychosis.³³ Lilly's patent was declared invalid in Canada, though not in the United States or Europe. Despite this, Zyprexa has been one of the biggest selling drugs of all time, grossing $4–5 billion per annum from the late 1990s through 2010. There was no basis to think this drug was any more effective than dozens of others and a lot of reasons to think it was more problematic for patients, but the marketing power that came with its patented status enabled Lilly to hype its benefits and conceal its hazards and steer doctors to write enough Zyprexa prescriptions to save the company.

      In our brave new world, companies can make blockbuster profits out of a Depakote or Zyprexa. If these two compounds were exceptions, the price might be worth paying for a set of drugs that were otherwise innovative and were leading to treatments for serious conditions that previously went untreated. Many might sigh but most would reconcile themselves to the situation—this is the way the world works. But that world does not seem to be working anymore. Where there were a handful of new tranquilizers, antipsychotics, antidepressants, and stimulants introduced annually year after year from the 1950s onward, the flow of novel psychotropic drugs dried up in the mid-1980s.

      The decline of the antidepressants illustrates this all too well. The antidepressant drugs produced from 1958 to 1982 were used primarily for severe mood disorders and as such had a much smaller volume of sales than the benzodiazepine group of drugs, of which the best known, Valium and Librium, quite literally became household names—these were mother's little helpers. Valium and the other benzodiazepines were marketed as tranquilizers for anxiety from 1960 onward. In the 1980s, claims that they caused dependence led to a backlash against the benzodiazepines, leaving the market open for a new group of drugs which, however, could not be called tranquilizers as this term was now too closely linked to dependence and withdrawal. The strategy seemed clear to the major drug companies—to persuade doctors that behind every case of anxiety lay a case of depression. And to persuade them that a new group of drugs, the SSRIs (selective serotonin reuptake inhibitors), were both antidepressant and a therapeutic advance, when in fact the companies had almost consigned the SSRIs to the dustbin in the early 1980s as they were not as effective as either the tranquilizers or older antidepressants. They were also not especially novel, most of them being simple derivatives of preexisting antihistamines, many of which work as well as the SSRIs for nervous problems. Nevertheless this molecular group appeared to offer a modest but patentable amount of novelty and therapeutic benefit. The profits that came with the patent status, amounting to $15 billion per year for the group as a whole, provided the means to transform psychiatry's views of common nervous disorders—until the patent on these drugs expired soon after 2000 and clinicians had to be reeducated that the very same patients were now suffering from bipolar disorder and in reality needed a mood stabilizer.

      If the SSRIs had been a bridge to