The schizophrenia drug-treatment paradox: pharmacological treatment based on best possible evidence may be hardest to practise in high-income countries

Most people with schizophrenia live in low- and middle-incomecountries in which clinicians/policy makers are not the firsttargets of marketing. Because it is years after a drug is firstlaunched that the full effects become known with confidence,the evidence upon which to base practice in low- and middle-incomecountries may be less biased than that in richer nations.

INTRODUCTION

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INTRODUCTION

The number of trials relevant to people with schizophrenia producedby any one country depends neither on the national populationof those with the illness nor on the country’s technicalsophistication. It is, with a few notable exceptions, muchmore closely correlated with the gross wealth of the nation,which in itself may be a proxy for the national activity ofthe pharmaceutical industry (Moll et al, 2003). In the pasthalf-century, industry’s research activity has led toinnovations and revolutions in the care of people with schizophrenia(Freeman, 1958) and has never stood still. Since 1953, theyear of the advent of chlorpromazine, many different antipsychoticmedications and drug preparations have become available. Drugs,however, have never stopped schizophrenia from being an illnessthat, for most, seems to require lifelong treatment. This hasgenerated enormous income for companies (IMS Health Inc., 2006).Of course this income and power can be misused (Montgomery et al, 2004;Heres et al, 2006); nevertheless, industry invests more inresearch and development than all ‘independent’sources, and this is likely to remain the case.

Relentless industry marketing – whether in the form of advertisements, research articles, teaching events, opinionleader talks, guideline lobbying, media seeding, visiting salesrepresentatives or even that not-so-free pizza (Moynihan, 2003a,b) – fosters hope of the new being better than the old.For about two decades after their patenting, new drug treatmentsare expensive. Even in countries where generic manufacturingof new drugs occurs through the legal loophole of the ‘processpatent’ – where it is only the process of manufacturethat is recognised as patented, allowing the manufacture ofa patented drug by altering the process even in a minor way – distribution may not be wide and the drugs can remaininaccessible. For example, owing to loopholes in current patentlaw, more than 20 brands of olanzapine and risperidone areavailable in India at a fraction of ‘Western’ prices.In Bihar, one poor state in India, there are more people withschizophrenia than in the whole of North America. Nevertheless,even these cheaper preparations are not affordable for the poor in Bihar and distribution through the state healthcare systemis variable. In any case the World Trade Organisation and theGeneral Agreement on Tariffs and Trade are ensuring that thisloophole is being closed and countries are less readily ableto exploit the current situation. In Brazil, for example, atypicalantipsychotic drugs remain expensive and are only generally affordable if paid for by the state, and this provision varies.Four-fifths of the world’s population of people withschizophrenia live in low- or middle-income countries; nevertheless,global marketing relentlessly promotes a collective guilt wherebyto advise the use of older, inexpensive drugs is, somehow,to give a second-class service.

COMMERCIAL INTERESTS AND CLINICAL EVIDENCE

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COMMERCIAL INTERESTS AND...

It is hard to know the ‘objective’ facts about theeffects of these treatments, and it may be impossible duringthe period in which large pecuniary interests are heavily involved.As time passes, more complete data from known trials beginto emerge and less-positive studies that had been previouslyunknown come to light (Easterbrook et al, 1991; Gilbody et al, 2000).In addition, once a drug is off patent, companies may well bemore generous with data. Whether or not this is as it shouldbe, it seems likely that this situation will change only slowly (Chalmers, 2006).

Rich countries develop and evaluate the new drugs, and thesesame nations are the first focus of the initial decades ofmarketing. As the battle of the companies is fought out inhigh-income countries, clouds of dust from marketing obscurethe view. Unless effects are dramatic, it takes decades for the dust to settle. For example, in the past 20 years millionsof people with schizophrenia in these high-income countrieshave been caught up in the struggle between companies producingdifferent new antipsychotic drugs. Inevitably there are winnersand losers. Many win. Everyone has been forced to be more thoughtfulabout prescribing, and new compounds have their own effect profilesand are welcome additions to the management of this difficultand damaging illness. On the other hand, some in the rich nationssuffer as a result of ill-publicised effects of the new drugs,and have to be compensated (McGough & Abboud, 2005). However,many more are not remunerated for the major or minor ill effectsthey suffer, save only in the knowledge that evidence of theproblems they encountered may be commonly known by the timethe medications become available to the other 80% of the world’spopulation.

During this period many in the lower-income countries have toobserve the battle from afar and they are forced to use olderdrugs. On the other hand, much is known about these familiarcompounds. The battles that did rage for the first-generationdrugs are long over, and much positive and negative data areavailable. As time passes and newer medication is becoming accessiblein less-affluent nations, the second generation of battleshave lost some of their urgency and aggression.

THE SCHIZOPHRENIA TREATMENT PARADOX

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THE SCHIZOPHRENIA TREATMENT...

Here is the schizophrenia drug treatment paradox. Evidence-basedpractice is the judicious use of the best available evidencein patient care or policy making (Sackett et al, 1997). Judicioususe of best available evidence for the care of people withschizophrenia is possible everywhere. However, by the time drugs are widely accessible in lower-income nations the ‘bestavailable evidence’ may well be better in these poorcountries than was the case when the drugs were first marketedin rich nations.

Recent findings from larger pragmatic and independently fundedstudies reinforce this argument (Lieberman et al, 2005; Lewis et al, 2006).If new drugs are compared with haloperidol, an antipsychoticparticularly associated with obvious adverse effects, the new experimental compound can hardly fail to seem beneficial interms of adverse effects (Joy et al, 2001). If, however, newercompounds are compared with more benign older drugs there isa consistent finding that there is little to choose betweenold and new medications, even on adverse effect outcomes. Soshocking are these results to a subspecialty convinced by marketingthat the trialists themselves are surprised and perplexed atthe messages to give, and journals may fail to encourage publicationof important results.

In both rich and poor countries, there is no need for collectiveguilt about use of older treatments. Use of these tried andtested drugs has more chance of being based on really goodevidence than that of newcomers for which marketing interestsobfuscate fact. There is, however, an enormous need for moreindependent, well-designed, conducted and reported pragmaticrandomised trials in this area. In order to offer people inrich countries more protection from being unofficial participantsin enormous post-licensing studies, these pragmatic randomisedtrials should take place before widespread introduction ofthe drugs.

REFERENCES

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