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The shock wave hit when they broke thecode. It was January 2005, nearly fouryears since the start of a clinical trial to

definitively compare schizophrenia therapies.The US$43-million trial, involving nearly 1,500patients at 57 clinical sites in the United States,was testing whether a raft of anti-psychoticdrugs introduced in the 1990s and hailedas transformational was any better than a50-year-old pill called perphenazine, one ofa generation of drugs that left patients withhorrible side ef fects. Until investigatorsunblinded the trial, codes concealed who wasreceiving which drug.

As it turned out, it didnt matter. The ClinicalAnti-psychotic Trials of Intervention Effective-ness (CATIE) made it clear that the new thera-pies were barely different from the old1. Theywere just as good as perphenazine at controlling

psychosis hallucinations and delusions. Butpatients taking the new drugs remained con-fused, socially withdrawn and bereft of drive,just as they did on perphenazine. And the newantipsychotics were not even convincinglyfreer of side effects overall, three-quartersof patients abandoned their drug during the18-month treatment regime, regardless of whichdrug they took.

That was frustrating and humbling for theresearch community, says Jeffrey Lieberman, apsychiatrist at Columbia University, New York,and the trials principal investigator. And it hada chilling effect on the pharmaceutical indus-

try. Within a few years, under intensifying

pressure to rein in costs, several large companies,including London-headquartered AstraZenecaand GlaxoSmithKline, chose to pull out ofpsychiatric pharmacology altogether.

Chastened researchers also had to regroup.It became a case of back to the drawing board,says Shitij Kapur, head of Kings College Lon-dons section on schizophrenia, imaging andtherapeutics. Scientists needed to learn muchmore about the diseases biology. They had toensure that whatever they learned would betranslated more smoothly to the clinic, by wayof better animal models, biomarkers and clini-cal trials. And they wanted to develop drugs totarget not just psychosis, but also the negativesymptoms such as impaired cognition, bluntedemotions and lack of initiative the types of

trait that render most people with schizophreniaincapable of holding down a job.

The scale of the work to be done was toodaunting for individual labs. So in recentyears, researchers working in the public andprivate sectors have decided to share moreideas and resources. Few expect a single mol-ecule to do the entire job. Fifteen years ago,we were naively optimistic, says Kapur. Now,there is still optimism but with a hefty dose

of pragmatism thrown in.No one questions the transformational

impact of the first antipsychotic drugs whenthey were introduced in the 1950s. Psychiat-ric hospitals could, for the first time, releaselarge numbers of patients with schizophreniawho would otherwise have spent their livesincarcerated. The prototype, chlorpromazine,spawned a whole class of drug known as typi-cal anti-psychotics, including perphenazine.

MOVING TARGETBut the price of that freedom was high. Typi-cal antipsychotics exert their effect by blockingthe dopamine type 2 (D2) receptor, modify-ing dopamine neurotransmission. But thesesilenced receptors also provoked distressingside effects such as twitching and jerking,leading to the misconception that movement

disorders and antipsychotic efficacy wereinextricably linked.

So entrenched was this idea that when, in the1960s, industrial pharmacologists discovereda promising antipsychotic drug candidate thatdid not disrupt movement in animal tests, theyhad difficulty persuading their sceptical man-agers to develop it. Sandoz, a company based inBasel, Switzerland, that is now part of Novartis,eventually introduced clozapine to the marketin 1971. As well as acting on D2 receptors, itblocked the 5-HT2A receptor of the mood-modulating neurotransmitter serotonin, whichseems to temper the movement side effects.

The drug proved so much better that desperate

B y A l I s O N A B B O T T

SCHIZOPHRENIASearch for origins and treatments

nature.com/schizophrenia

The iology istoo complicated.

Pharacopaniesare quitting.

Where areschizophreniadrugs going tocoe fro?

THE DRUGDEADLOCK

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psychiatrists lobbied for its reinstatement afterSandoz withdrew it from the market in 1975when its own rare side effect became apparent:a susceptibility to life-threatening infections.

The US Food and Drug Administration(FDA) relicensed clozapine in 1989 for treat-ment-resistant cases, in conjunction withregular blood tests. Within years, other drug

companies had launched their own atypicals(see Schizophrenia drug sales), all with aclozapine-like pharmacology but intended tobe safer. Yet some serious side effects, such asmetabolic problems, emerged. By this point,clinicians were starting to question whetherthese new, and more expensive, drugs were anyimprovement on their predecessors. CATIEconfirmed their worst fears.

A sElf-fulfIllING pROphECyA re-examination of the pharmacological pro-files after the trial showed that although theatypical antipsychotics hit both D2 and 5-HT2A

receptors, the D2 blockadeseemed to be responsible fortheir clinical effects. That isnot surprising in retrospect,given that the animal mod-els used to test the drugswere all designed to pick upD2-receptor blockade, saysMark Tricklebank, a behav-ioural pharmacologist anddirector of the Lilly Centrefor Cognitive Neurosciencein Windlesham, UK. It wasall very circular, a self-fulfill-ing prophecy, he says. Wedbeen tuning the engine, whenwhat we really needed was anew engine.

To break out of this viciouscircle, scientists realized thatthey needed some fresh thinking in basic andtranslational science. Clinical trials had beenmostly focused on treating psychosis, but therewas increasing recognition that cognitive def-icits poor memory, inability to maintainattention and poor problem solving werea fundamental aspect of the disease. In 2005,Steve Hyman, then director of the US NationalInstitute of Mental Health in Bethesda, Mary-

land, launched Measurement and TreatmentResearch to Improve Cognition in Schizo-phrenia (MATRICS). The forum aimed tobring together academics, industry and theFDA to generate consensus about how best todesign clinical trials to test drugs targeted atthese cognitive deficits and later extendedto negative symptoms through a battery ofspecially designed tests2,3.

Guided by the MATRICS recommendations,several cognitive enhancers are already in early-phase clinical trial as potential add-ons to stand-ard antipsychotic therapies. Also in clinical trialare several candidate drugs acting on recep-

tors of the neurotransmitter glutamate the

only approach to have shifted focus away fromdopamine. But the glutamate circuitry in thebrain may prove hard to manipulate safely.And for the scientific community, the realchallenge lies in understanding the system theyare tinkering with. We dont even understandschizophrenia at the biological level, saysThomas Laughren, the FDAs director of psychi-

atric drugs, voicing a frustration felt by many.A European collaboration of researchersknown as Novel Methods Leading to NewMedications in Depression and Schizophre-nia (NEWMEDS) is throwing every cutting-edge technology available at the problem ina very unusual publicprivate collaboration.Launched last year, the five-year, 20-million(US$28-million) effort funded by the Euro-pean Commission includes seven academicpartners, nine pharmaceutical companies(including AstraZeneca) and a few biotechcompanies. One of these is Icelandic genom-ics company deCODE genetics, which in 2008

identified in a large population study threevariable genetic regions called copy numbervariations (CNVs), which, although very rare,confer a high risk of schizophrenia4.

Scientists from industry say that it was ini-tially hard to convince their companies of thevalue of sharing information in NEWMEDS.But they did and to their evident glee,industrial pharmacologists can for the first

time discuss openly, at least within the con-sortium, their individual approaches in psychi-atric disease. Academic members, in turn, aregleeful about access to some of the industrialresources now on the table. They have pooledextensive information and material includingdata from many clinical trials in schizophrenia,sometimes with associated blood samples. Wenow have the biggest database ever on this dis-ease more than 10,000 patients, says TineBryan Stensbl, a pharmacologist at the Dan-ish pharmaceutical company H. Lundbeck andthe coordinator of NEWMEDS.

In a joint project led by geneticist Hreinn

Stefansson of deCODE genetics, psychiatrist

Andreas Meyer-Lindenberg from the CentralInstitute of Mental Health in Mannheim, Ger-many, and neuroscientist Michael Brammerfrom Londons Institute of Psychiatry analysedmagnetic resonance imaging data from 500people identified by deCODE genetics as hav-ing the high-risk CNVs, as well as 500 controlsubjects. They hope that the study will identify

brain structures that are disrupted by abnor-mal genetic signatures and might eventuallypoint to new therapeutic targets. We wouldntbe doing this without the NEWMEDS initia-tive, says Meyer-Lindenberg.

An essential but admittedly less glamor-ous task for NEWMEDS is to determine therobustness of methods used to test drug candi-dates, particularly the animal and human testsof memory, attention and other aspects of cog-nition that are notorious for their sensitivityto tiny differences in environment. Unreliabletests may explain why drug candidates thatlook hopeful in animals fail in the clinic. Indus-

trial and academic scientistsare now using standardizedprotocols in their own labs,then comparing results andtrying to understand whysome may vary.

The consortium is alsoadopting rodent touch-screen technology, in whichanimals in behavioural teststap a screen with their noseto get a reward for perform-ing the experimental tasks,rather than press a lever orpoke their noses into a hole.Being automated, it does notneed constant observation.And crucially, results fromsuch tests are potentially eas-ier to translate into human

psychology testing, which is increasingly basedon touching screens.

The new concerted strategies could renewindustrys optimism, even if there are few con-crete signs of it just yet. With up to 1% of theworlds population estimated to be affected bythe disease, schizophrenia represents a hugepotential market for any company that can finda new drug that genuinely improves any symp-

toms particularly given that most patientsdevelop the disease in their early twenties, andcould be on daily therapy for the rest of theirlives.

Maybe, after all, a shock wave was just whatthe field needed.

Alison Abbott is Natures senior Europeancorrespondent.

1. Lieberman, J. A. et al. N. Engl. J. Med.353,12091223 (2005).

2. Buchanan, R. W. et al. Schizophr. Bull.31, 519(2005).

3. Kirkpatrick, B., Fenton, W. S., Carpenter, W. T. Jr &Marder, S. R. Schizophr. Bull.32, 214219 (2006).

4. Steffanson, H. et al. Nature455, 232236 (2008).

SCHIZOPHRENIA DRUG SALES

The worldwide market for schizophrenia drugs has grown tenfold since the introduction ofatypical antipsychotics such as Risperdal. Annual prescriptions have also risen dramatically.

Typical antipsychotics PrescriptionsAtypicals

Drug

sales(US$

billion) Pre

scriptions(millions)

60

50

40

30

20

10

0

12

10

8

6

4

2

01996199519941993 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

Abilifylaunch

Zyprexalaunch

Risperdallaunch

Geodonlaunch

Seroquellaunch

SouRCe:IMS

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