There are different types of dopamine receptors and the conventional neuroleptics under discussion have been shown to be most effective in blocking D2 receptors. But a new generation of neuroleptics, called ‘atypicals’, have recently become available which target other types of receptors as well. It is claimed that the atypicals will prove to be safer than the conventional neuroleptics and will reduce the incidence of neuroleptic-induced disorders. At this stage the evidence for this claim is equivocal since most of the atypicals are very new. It may take some years of usage before the problems become fully apparent.
However, one of the atypicals, clozapine, is not a new drug, and some of the major problems attached to its usage have been known for some time. In the early 1990s clozapine was the only atypical available, and for a time it had the aura of a wonder-drug. But its origins were a lot earlier and ‘clinical trials of clozapine were begun in the United States in 1972, but they were temporarily halted in 1975 following reports of clozapine-induced agranulocytosis’.[9] Agranulocytosis is ‘a life-threatening blood disorder that reduces the white blood cell count’,[10] and it was found that some 1–2 per cent of patients treated with clozapine were afflicted with this condition, and of these some 35 per cent died from it.[11]
Clozapine earned such a bad reputation from its early usage that a Reagan-era drug deregulation campaigner even blamed it for causing some of the legal restrictions that he claimed inhibit drug research. He described clozapine as being one of a number of ‘major tragedies which have created public alarm and fear and which have led to the condemnation of drugs’.[12]
By the end of the 1980s, however, as the accumulation of evidence about disorders induced by conventional neuroleptics began to overwhelm the psychiatric establishment in the United States, clozapine was still the only neuroleptic medication with an atypical profile which gave hope for a resolution to the EPSE problem. And so, in some desperation, clozapine was rehabilitated. It was approved for clinical use in the United States in 1990 after FDA-controlled trials which ‘lasted only six weeks’.[13]
When it first went back on the market, the manufacturer, Sandoz,[14] as a precautionary measure required that all the recipients undergo a weekly blood test conducted by the company’s laboratories. This procedure was very expensive and pushed up the price of treatment to about $9000 a year. Under pressure from the consumer lobby, however, Sandoz was forced to make some concessions about the rigour of these blood tests, and the cost of clozapine treatment was soon lowered to about $4000 a year in the US.[15]
The combination of agranulocytosis risk, the inconvenience of regular blood tests and excessive cost led to a situation in which clozapine was only being recommended for use with patients who did not respond to the traditional neuroleptics or who could not tolerate the adverse effects associated with these drugs. The clinical advice in the early 1990s was that ‘a patient who has been unsuccessfully treated with three different antipsychotic drugs from different classes in sufficient doses, each for a least two months, is probably a candidate for treatment with clozapine’.[16]
During the period of its banning in the US, clozapine remained available in some European countries, where it continued to earn a bad reputation with some psychiatrists. Peter Breggin, a US-based psychiatrist critical of drug treatments for schizophrenia, claimed: ‘Clinicians I have spoken to in Europe feel that clozapine produces a particularly profound lobotomy effect, adding to concern about long-term dangers of tardive psychosis and dementia.’[17]
This negative view, however, was not shared by all European psychiatrists with long-term experience of clozapine. Two Russian psychiatrists who emigrated to the United States claimed that the drug had been used successfully in their home country for more than twenty years where ‘it was not reserved for neuroleptic-resistant disorders but instead was used with some success as a first-line treatment in acute disorders’. However, they admitted that their information was largely anecdotal and that ‘the Russian studies did not include controlled clinical trials, standardised diagnostic criteria, random assignment, double-blind conditions, standardised rating instruments, and other methodological approaches that we associate with scientific rigour’.[18]
Clozapine survived the early scares and is now generally considered to be less dangerous than was first thought. However, there have been reports of severe problems when people try to stop taking clozapine.[19] Some people’s brain chemistry adjusts so that they become dependent on regular dosing with clozapine, and when the drug is withdrawn they rapidly slide into psychosis.
Unlike conventional neuroleptics, clozapine is claimed to reduce some of the negative symptoms of schizophrenia, which led some researchers to focus their work on the serotonin levels in the brains of schizophrenics. The new line of research helped to spawn a growing array of atypical neuroleptics to complement clozapine, which share similar features.
One of the more recently launched atypicals is olanzapine (Zyprexa), made by Eli Lilly. Although quite a lot is already known about the effects of olanzapine on chemical receptors in the brain, it is not known whether any of these known effects contribute in any way to the observed reduction in schizophrenic symptoms.
The binding properties of the atypicals are giving rise to wide speculation about the cause of schizophrenia which extend well beyond the old dopamine theory inspired by the conventional neuroleptics. Some researchers think the mechanisms of the atypicals will eventually make it possible to trace the cause of schizophrenic symptoms, while others disagree.
Despite the claimed benefits for schizophrenics from these drugs, the enthusiasm of pharmaceutical researchers might be best understood in economic terms. By the end of the 1980s, as patents for the conventional neuroleptics expired and generics became available, the continued reliance on conventional neuroleptics threatened to undermine pharmaceutical profits. As a result the quest for a new generation of schizophrenia drugs was driven at least as much by a need to ensure long-term drug profits as it was by the need to discover safer drugs which targeted the cause of schizophrenia more precisely. In fact when the cost of the atypicals is compared to that of conventional neuroleptics, and the equivocal nature of some claims for atypicals is borne in mind, then the significance of the economic factors is brought into perspective.
The table shows the cost to pharmacists in the United States for thirty days, treatment with usual dosage based on the average wholesale price in 1996 and January 1997.
COST OF SOME DRUGS FOR SCHIZOPHRENIA
Table adapted from: ‘Olanzapine For Schizophrenia’, Medical Letter on Drugs and Therapeutics, Vol. 38, No. 992, 17 January 1997, pp. 5–7.
Next: Uncertainties in Schizophrenia Research
[9] Moisey Wolf et al., ‘Clozapine Treatment in Russia: A Review of Clinical Research’, p. 256.
[10] Peter Breggin, Toxic Psychiatry, p. 106.
[11] Keltner et al., op.cit., p. 245.
[12] M. Weatherall, ‘An end to the search for new drugs’, p. 387.
[13] Breggin, op.cit., p. 447.
[14] Sandoz has since merged with Ciba-Geigy and the new conglomerate is named Novartis.
[15] Keltner et al., op. cit., pp. 245–6.
[16] Kaplan and Sadock, op.cit., p. 648.
[17] Breggin, op. cit., p. 105.
[18] Wolf et al., op. cit., pp. 256, 258.
[19] T. M. Shiovitz et al., ‘Cholinergic rebound and rapid onset psychosis following abrupt clozapine withdrawal’, pp. 591–5.