Richard Gosden

Abstract

The definition of schizophrenia is currently being extended to include a "pre-psychotic" phase. Pre-psychosis detection and intervention programs have already been established in Australia. These are intended to identify people "at-risk" for schizophrenia and treat them to prevent their transition into psychosis. However, analysis of leading research in this field shows high levels of arbitrariness in the selection of diagnostic indicators and a lack of convincing evidence about the efficacy of treatments. The favoured prophylactic treatment is atypical neuroleptic medication and sponsorship of research is providing manufacturers of these drugs with a ubiquitous presence in the field. Many risks are associated with atypical neuroleptics and adverse reactions include psychosis. Taken together these factors suggest that pre-psychotic intervention may be more concerned with expanding the market for atypical neuroleptics than with preventing schizophrenia.

In recent years psychiatric researchers have extended the definition of schizophrenia to include a "pre-psychotic" phase. Detection and intervention programmes have been implemented and neuroleptic medication prescribed in the belief that it can prevent the development of psychosis in people who are thought to be "at-risk" (Yung, McGorry, McFarlane, et al., 1996, p. 300). The pre-psychotic signs of schizophrenia are usually referred to as early psychosis or as prodromal symptoms of schizophrenia (Larsen & Opjordsmoen, 1996). These pre-psychotic symptoms, however, are only tentative and researchers themselves sometimes describe them as being "putative" (Yung & McGorry, 1996).

Promoters of the concept see pre-psychosis detection and intervention as a form of preventive medicine. They argue that if the incidence of schizophrenia can be reduced by early identification and treatment, as is the case for some somatic diseases, then community benefits will follow, such as cost savings, avoidance of personal trauma and family disruption (Jackson & Birchwood, 1996).

However, bio-medical, drug-based preventive medicine campaigns for abnormal or deviant behaviours such as "schizophrenia" may also be interpreted differently. Apart from the risks involved in the prophylactic use of neuroleptic drugs, so-called preventive medicine might be variously seen as an unnecessary expansion of social control, a threat to human diversity through the enforcement of hyper-normality, a violation of human rights, and a marketing ploy for the new generation of atypical neuroleptic drugs.

Early Psychosis Detection and Intervention

Early psychosis detection and intervention programs generally aim to reduce the duration of untreated psychosis (DUP). The DUP is the period preceding first treatment for schizophrenia during which symptoms and signs of an impending psychological crisis are present. Bio-medical psychiatrists argue that the DUP for most people who develop psychosis is much longer than it should be, often lasting for years (Larsen, McGlashan & Moe, 1996).

It has been claimed that "the cost of treatment for patients with a DUP greater than 6 months is twice the cost of those with a DUP less than 6 months" (McGlashan & Johannessen, 1996, p. 212). Some argue that brain damage is occurring during the DUP and that the longer it continues the less chance a person has of ultimate recovery: "most of the neurobiological damage is already accomplished by the time it is possible to make a valid DSM-IV diagnosis" (p. 209) and "applying existing schizophrenia treatment as soon as possible in the course of the disorder may slow or stop deterioration" (p. 201). But apart from the equivocal evidence of initial pilot studies (Pettegrew et al, 1991), no substantial findings support these contentions.

Nevertheless, despite the weak theoretical base, Falloon et al. (1996) claimed that when a program of early detection and intervention was put into place at Buckingham in the United Kingdom in the mid-1980s, the incidence of schizophrenia in the community was measurably reduced. These findings have not been replicated. This is not surprising as the Buckingham Project’s "diagnostic thresholds for functional psychotic disorders" appear to have been uniquely flexible (p. 279). This diagnostic flexibility is the most likely explanation for the supposedly "successful" outcome of the Project.

Yet despite this obvious flaw the claimed success of the Buckingham Project has been the basis for a growing body of literature and the initiation of early psychosis projects in other parts of the world. The promoters of these programs now face the task of reaching consensus on three points: (1) an inventory of easily recognisable pre-psychotic symptoms; (2) the design of a community-based catchment system that funnels at-risk people into a clinical setting; and (3) an appropriate pre-psychosis treatment program.

Research in Australia

Australia has become a particularly active site for this type of research and in 1996 a National Early Psychosis Project was launched as "a collaborative endeavour between the Commonwealth, State and Territory governments of Australia to develop and promote a national model of best practice for early intervention in psychosis" (National Early Psychosis Project [NEPP], 1998a). This model of best practice is now embodied in the recently published Australian Clinical Guidelines for Early Psychosis (NEPP, 1998b). These guidelines extend the definition of psychosis to include "the period described as the prodrome" (p. 11).

The most advanced early psychosis program in Australia, consistently cited as a model, is run by the Early Psychosis Prevention and Intervention Centre (EPPIC) in Melbourne, Victoria (McGorry, Edwards, Mihalopoulos, Harrigan & Jackson, 1996). EPPIC assumed a leadership role in Australia after winning the government tender to establish the NEPP. Much of the policy development embodied in the Clinical Guidelines has come out of EPPIC research programmes.

A major problem with research into a prodromal phase of schizophrenia is a lack of consensus about pre-psychotic symptoms. The EPPIC team had at first intended to adopt the nine prodromal symptoms supplied in DSM-III-R (American Psychiatric Association [APA], 1987, pp. 194-195). However, when EPPIC conducted a community survey of Australian high school students to determine the prevalence of these symptoms in the general population of adolescents, they found that "nearly half the sample (49.2%) had two or more symptoms and hence met the criteria for DSM-III-R schizophrenia prodrome" (Yung et al., 1996, p. 289). This remarkably high figure caused the researchers to adjust the threshold for diagnosis by reducing the number of symptoms. Testing the restricted criteria on ordinary high school students found that only "10 to 15 percent of the sample met the criteria for schizophrenia prodrome" (p. 289).

Satisfied that the modified criteria could be used to correctly identify their target group, the EPPIC researchers went on to implement "a specialised outpatient service to monitor and care for young people thought to be at high risk for psychosis" ( Yung et al., 1996, p. 289). The new clinic was called PACE – Personal Assistance and Crisis Evaluation.

Initially, the PACE clinic targeted young people between 16 and 30 years of age. These were divided into three groups. Group 1 were people who met the complete DSM-III-R criteria for schizophrenia prodrome and who also had a first or second degree relative with a history of a DSM-III-R psychotic disorder or schizotypal personality disorder. Group 2 were people who had one or more of the DSM-III-R positive-only criteria for schizophrenia prodrome, (1) markedly peculiar behaviour; (2) digressive, vague, overelaborate, or metaphorical speech; (3) odd or bizarre ideation or magical thinking; (4) unusual perceptual experiences. Group 3 were "young people with a history of fleeting psychotic experiences that spontaneously resolved (called brief limited intermittent psychotic symptoms, or BLIPS) within 1 week" (Yung et al., 1996, p. 292).

To detect these types of people in the community and channel them into the PACE clinic, a public education campaign was launched, aimed particularly at general practitioners and other specialised professionals who are frequently in contact with young people – like school counsellors, teachers and youth workers. Treatment involved psychosocial therapy or neuroleptic medication, sometimes both. Of the patients treated "[t]he most frequently occurring DSM-III-R prodromal symptoms were magical thinking, perceptual disturbance, and impaired role function, present in 67.7, 54.8, and 54.8 percent of the subjects, respectively" (Yung et al., 1996, p. 293).

The fact that nearly 70% of these youngers were treated for "magical thinking" requires discussion. According to a description in the DSM-IV Glossary of Technical Terms magical thinking is not a particularly debilitating symptom:

The logic of schizophrenia prevention is that although some of the prodromal symptoms might not be serious handicaps in themselves they are, all the same, signs of underlying psychosis. However, this logic is transparently absurd when the EPPIC researchers apply it to magical thinking. This is because members of the EPPIC team had previously discovered in other research that 51% of normal Australian 16-year-olds experience magical thinking (McGorry & Edwards, 1997, p. 17). Having already rejected the possibility that half of all Australian teenagers are afflicted with the prodrome for schizophrenia, the EPPIC team should have realised that magical thinking is simply a part of normal adolescent psychology. To persist in treating magical thinking in these circumstances verges on the bizarre.

Nevertheless, by 1996 the EPPIC researchers were ready to claim success for the initial PACE programme: ".... it is possible to identify and follow possibly prodromal individuals in the community" (Yung et al., 1996, p. 299). But they were concerned that many of the patients monitored during the course of the programme did not make the transition to full psychosis. The transition rate to psychosis presents an interesting problem of interpretation. On the one hand, if most of the young people fail to cross the threshold into psychosis, it can be claimed that the preventive treatment was successful. But on the other hand, it might also indicate that the prodromal indicators were not accurate and that many false positives were included among the patients.

Inventing the Diagnostic Criteria

The EPPIC researchers decided to interpret the low transition rate of their patients as indicating that a substantial fraction were false positives (Yung et al., 1996, p. 299). They promptly began a new prospective study of at-risk individuals using updated diagnostic criteria. The same 16 to 30 years age group was targeted, with the same division of the subjects into three groups. This time, however, the DSM-III-R prodromal symptoms were replaced with DSM-IV symptoms for Schizotypal Personality Disorder.

DSM-IV specifies nine symptoms for this condition and a diagnosis normally requires the presence of five or more. But the researchers at the PACE clinic decided that only one symptom would be sufficient to indicate the presence of the schizophrenia prodrome. This completely disregards the DSM-IV view that "Schizotypal Personality Disorder has a relatively stable course, with only a small proportion of individuals going on to develop Schizophrenia or another Psychotic Disorder" (APA, 1994, p. 643). If this is true about people who meet the normal diagnostic criteria by having five or more symptoms, what is to be assumed about the real risk of psychosis for people who meet the PACE diagnostic criteria by only having one symptom?

Defying reasonable expectations, the PACE research found that 48% of the people inducted into the program using the diluted schizotypal indicators became psychotic within 12 months. The transition rate to psychosis at 6 months was 40%. But even these results still raised ethical questions about treatment of the non-psychotic majority: "because over 50% of cases do not develop psychosis within twelve months routine treatment of this group would result in many young people being subject to unnecessary treatment and labelling" (Yung et al., 1998, p. 28).

It should be noted here that a serious gap exists in the material published about the PACE programme regarding the effectiveness of prophylactic treatments: nothing has yet been published to indicate whether a particular kind of prophylactic treatment might have helped to prevent psychosis or whether, on the other hand, another kind of treatment might actually have induced psychosis.

Although heavily influenced in its developmental stage by the EPPIC researchers, the Australian Clinical Guidelines for Early Psychosis do not recommend the use of the schizotypal symptoms. Instead a 16-item list of "Prodromal Symptoms and Signs" of psychosis is provided:

The authors of the Guidelines acknowledge that "these signs and symptoms are not usually indicative of a developing psychosis." This is apparently said to prevent over-zealous usage and to minimise the alarm that might arise in normal people who encounter this list and reflect on themselves. The Guidelines advise that these signs are only meant to be used as symptoms of impending psychosis when "they occur in individuals who have been identified as ‘at-risk’ of psychosis".

A separate table with a list can be used to identify those who are "at-risk". The idea is to first narrow down the field before using the prodromal symptoms and signs. The narrowed field focuses on adolescents and young people. There is a fairly extraordinary mixture of further risk factors that range from the relatively specific "Family history of psychotic disorder" to the equivocal "Season of birth", to the thoroughly non-specific "Life events" and "Subjective/functional change in the person" (NEPP, 1998b, p. 12). The risk factors seem tailored to fit almost any young person who is a bit worrisome to parents, school teachers or other authority figures.

Some of the risk factors listed in the Guidelines are based on hypotheses of aetiology for schizophrenia that remain unconfirmed. One of these, "Season of birth", is a hypothesis of doubtful merit based on observations that records in some countries indicate a slight increase in winter/spring births for schizophrenics (Kendell & Adams, 1991). Season of birth might be a useful adjunct to aetiological research but to use it as a diagnostic indicator is ludicrous: most people who develop schizophrenic symptoms are born outside the supposed "risk season" while the vast majority of those born within the "risk season" are obviously not at any risk of developing schizophrenia.

These anomalies indicate a certain level of carelessness by the compilers of the Clinical Guidelines. Indeed both the list of "risk factors" and the list of "symptoms and signs" were not originally devised for the Clinical Guidelines but were adopted without comment from a publication called the Early Psychosis Training Pack (McGorry & Edwards, 1997). The principal authors of this training pack are the Director and Assistant Director of EPPIC but the document was produced by Gardiner-Caldwell Communications, a British public relations company specialised in pharmaceutical marketing. The training pack was funded by an "educational grant" from the pharmaceutical company Janssen-Cilag, which manufactures risperidone, an atypical neuroleptic.

Public Relations Assisted Research

It may be worth noting that Gardiner-Caldwell also publishes a web-based journal entitled Influenza Bulletin (Gardiner-Caldwell Communications, 1998) for an organisation called the European Scientific Working-Group on Influenza (ESWI). ESWI receives funding from a number of pharmaceutical companies – including Solvay Pharma and SmithKline Beecham, both of whom manufacture influenza vaccines. Gardiner-Caldwell may have developed a public relations specialty whereby they provide promotional assistance for medical researchers which, at the same time, helps to expand the potential markets for their pharmaceutical sponsors. The Early Psychosis Training Pack may be considered in this light, which raises questions as to why the clinical guidelines for early psychosis "best practice" in Australia use material from the training pack without explanation.

A popular hypothesis among schizophrenia researchers about the season of birth postulates a link between influenza infection of mothers in the second trimester of pregnancy and schizophrenia in offspring. A review of the evidence shows this hypothesis to be doubtful (Weinberger, 1995). Still, some psychiatric researchers have called for an influenza vaccination programme for all women of child-bearing age to prevent mental illness (Livingston, Adams & Bracha, 1993). It is an interesting speculation to consider whether Gardiner-Caldwell’s public relations work to expand the market for influenza vaccines might have some linkage to the specification in the Training Pack and the Clinical Guidelines of season of birth as a risk factor for early psychosis. Is it possible Gardiner-Caldwell might be using their influence with early psychosis researchers to position the season of birth hypothesis so that a perceived need for influenza vaccination of child-bearing age women can be made a part of future "best practice" in preventive medicine for schizophrenia?

This type of public relations activity on behalf of drug companies does seem to play a role in other early psychosis research. Most often, the public relations work is on behalf of companies that manufacture the newer neuroleptics. A community education programme supporting a new two-step program for early intervention in first episode psychosis at the London Health Sciences Centre, London, Ontario, is being sponsored by Zeneca (Anonymous, 1996). It involves teaching doctors, parents, school teachers, college teachers and guidance counsellors how to identify the signs and symptoms of early psychosis in young people and where to direct them for psychiatric intervention. Zeneca manufacture quetiapine, an atypical neuroleptic.

The Western Psychiatric Institute and Clinic (WPIC) in Pittsburg, Pennsylvania is running a Program for Assessment and Care in Early Schizophrenia (PACES) (WPIC, 1998). To facilitate this research WPIC educates primary health care suppliers and educational professionals in their catchment area about the early signs of psychosis. Part of the research in conjunction with this program aims to test the efficacy of three new atypical neuroleptics, with funding provided by the manufacturers of the drugs – Janssen-Cilag, Eli Lilly and Pfizer.

A recently established programme in the United States aims to increase the awareness of schizophrenia by emphasising the importance of early intervention and detection. "The SOS programme – known in full as ‘SOS - Signs of Schizophrenia: What To Look For, What To Do’ – was set up by the National Mental Health Association in conjunction with Janssen Pharmaceutica in the USA" (Anonymous, 1998).

In Australia, EPPIC’s preventive treatment centre for young people, PACE, also receives drug company funding from Janssen-Cilag (EPPIC, 1998). This may have paid off handsomely for the company. The EPPIC researchers have established a leadership role in early psychosis research and treatment in Australia, as was apparent in the organisation of NEPP and the Clinical Guidelines that emerged from the Project. It may not be coincidental that a half page of the Clinical Guidelines is dedicated to dosage recommendations for using risperidone in first-episode psychosis (NEPP, 1998b, p. 28). The Clinical Guidelines do not extend these dosage recommendations to include other schizophrenia drugs and the recommendations for risperidone give the appearance of an official endorsement of the drug.

Drug-Sponsored Conferencing

Drug company involvement was particularly evident in the organisation of the Second National Conference on Early Psychosis – "Realising the Potential" – hosted by EPPIC at Hobart Tasmania in early September 1998. The conference was principally sponsored by Pfizer, with additional sponsorship coming from Janssen-Cilag, Eli Lilly and Novartis (manufacturer of clozapine). The conference was held at the Hobart casino and the foyer of the conference venue was given a carnival atmosphere by the presence of stalls set up by the four drug companies. As this author was able to observe, during intervals between conference sessions barkers from the drug company stalls competed with one another for the attention of conference delegates, with public relations teams distributing literature, coffee, and various gifts like pens, tea-towels, writing pads and rubber balls. Sponge-rubber brains from Eli Lilly were very popular.

In the final plenary session of the conference this author asked a question of the assembled delegates: "Why were early psychosis programmes taking off now – and why was it happening in Australia – when there does not seem to have been a breakthrough in knowledge about the aetiology of schizophrenia and Australia does not normally lead the world in mental health initiatives?" The delegates became animated as they questioned one another for the answer, with none provided. In the end one may propose the working hypothesis argued presently, that early psychosis research and intervention programs are driven by funding and lobbying from the pharmaceutical companies that have recently launched atypical neuroleptics onto the market.

The objective of these pharmaceutical companies is to expand the market for the new drugs. The size of the existing market for palliative treatment of the psychotic and post-psychotic stages of schizophrenia is limited by diagnostic conventions. The size of the market for prophylactic treatment of pre-psychotic schizophrenia is potentially much larger. This is the expanded market these companies are plausiby seeking to create. Australia figures prominently in this strategy because it is being used as a proving ground for the idea of preventive medicine for schizophrenia. This may be in preparation for the introduction of full-scale preventive medicine campaigns in the much larger drug markets of North America and Europe.

Atypical Neuroleptics as Prophylactic Treatment

Prophylactic treatment with neuroleptic medication of people who have not manifested a psychological crisis, and who are currently coping, carries an enormous burden of ethical responsibility. This is because of the severe risks of drug induced diseases incurred by taking neuroleptic drugs. There is an extraordinary range of these drug-induced diseases and sometimes the warnings in advertisements published in psychiatric journals run to two pages of extremely small type. It is well-known that these warnings do not always list all of a drug’s known adverse effects (Breggin, 1993). Those that are listed should therefore be taken very seriously.

The more serious adverse reactions identified in the warnings, like agranulocytosis (Novartis, 1998, p. 8) and neuroleptic malignant syndrome (Janssen, 1998, p. 1124), may cause sudden death. The advertisements also warn about laboratory evidence which indicates the new drugs are carcinogens (Eli Lilly, 1998, p. 310) and mutagens (Zeneca, 1998, p 284). Despite the claims from some quarters that tardive dyskinesia is not a problem with atypicals most of the advertisements warn that these drugs do cause the disease. An advertisement for Risperdal (risperidone) warns clearly of this risk (Janssen, 1998).

The manufacturers also warn about the possibility of adverse mental and behavioural reactions. Many of these psychiatric reactions are the very disorders that prophylactic treatment with the drugs is intended to prevent. An advertisement published by Zeneca Pharmaceuticals, for instance, after warning about an extraordinary variety of ways their new atypical quetiapine can induce ill-health, identifies "Other Adverse Events Observed During the Pre-Marketing Evaluation of Seroquel". These include:

A Clozaril (clozapine) advertisement also warns about the risk of a variety of drug-induced negative and positive symptoms like loss of speech, amentia, delusions/hallucinations and paranoia (Novartis, 1998). If treatment with atypical neuroleptics can sometimes induce psychosis, hallucinations and delusions, as is frankly being admitted in advertisements for the drugs, questions most definitely arise about the application of these drugs as prophylactics against psychosis. In the long term, will prophylactic treatment actually increase the incidence of psychosis? This question does not seem to have been considered in the literature.

Another question to be addressed concerns how to interpret the significance of transition to psychosis by a person who has been receiving prophylactic treatment. Given traditional thinking in the field, such an event will probably be taken to indicate accuracy in the diagnosis of prodromal symptoms but ineffectiveness in the prophylactic treatment. Since drug approaches predominate, it might nonetheless encourage the prescription of increased doses of prophylactic drug treatment for other patients. Of course, such an event could simply indicate an adverse drug reaction. In that case it would be better to take other patients off their prophylactic medication altogether, rather than increase the dosage. Once again these lines of discussion are not arising in the literature.

Perhaps the most insidious of the ethical burdens for the promoters of the prophylactic use of atypicals comes from the growing body of evidence that withdrawal from some of these drugs can sometimes cause a psychotic reaction. Withdrawal reactions from typical neuroleptics have also long been documented (Breggin, 1993; Cohen, 1997). It seems that the brain chemistry of some people treated with atypicals is changed in a way that makes them dependent on continued treatment. When atypical neuroleptic treatment is withdrawn from them they experience an immediate psychotic reaction that can only be rectified by recommencement of treatment (Stanilla, deLeon & Simpson, 1997).

The ethical burden for psychiatrists treating the supposed prodrome of schizophrenia will include resisting the temptation to interpret psychosis induced by atypical withdrawal as merely being evidence that the person was correctly diagnosed in the first place. As has probably occurred with typical neuroleptics psychiatrists will be tempted to argue that it was the prophylactic treatment which, up to the point of withdrawal, prevented the person from entering psychosis. In this way the original diagnosis and prophylactic treatment could easily be vindicated, when in fact they might both be at fault.

Conclusion

It is perhaps too obvious to point out the commercial advantages that might accrue to pharmaceutical companies from an expansion of the definition of schizophrenia to include a pre-psychotic phase. A preventive medicine campaign based on the type of prodromal symptoms and risk factors specified in the Australian Clinical Guidelines for Early Psychosis potentially defines the whole generation of young people as being at risk and in need of treatment.

It is hard to tell what the PACE research really indicates without details of symptoms, treatment and transition to psychosis for individual patients. The most benign interpretation would be that about 50% of their patients had false positive diagnoses and were therefore given unnecessary treatment. However, it is entirely possible that all or most of their patients had unnecessary diagnoses and that any transitions to psychosis were only adverse reactions to treatment.

Beyond the familiar signs of dubious psychiatric research and commercial opportunism there are other matters to consider. The intention of a preventive medicine campaign for schizophrenia is to link relatively benign signs and symptoms with an impending psychiatric emergency. The existence of this linkage can then be used to justify intrusive and coercive intervention in the lives of young people in whom the signs are detected. However, since there is no convincing evidence that the linkages are accurate or that the interventions are effective, the long-term result of such a campaign is fairly apparent. The threshold of social intolerance for deviations in thought, belief and behaviour by young people will be dramatically lowered. That threshold is currently marked by the florid displays of a psychotic break. The new threshold is to be marked by far less disruptive traits like a shortage of friends, irritability, or an interest in telepathy. If this new level of conformity is enforced on a large scale the mainstream of society should be more psychologically homogenous but this might not necessarily indicate an improvement in the collective well being.

Finally, perhaps the most certain indication of unsoundness in judgment among the promoters of pre-psychosis detection and intervention is the repeated references in their research and advocacy papers (Yung et al., 1996; Wyatt et al., 1998) to the original source of their idea – a 1938 article by D. Ewen Cameron. D. Ewen Cameron is the Canadian psychiatrist who became infamous in the 1980s after it was revealed he had performed cruel and brain-damaging experiments on his patients in the 1950s and 1960s with funding from the CIA (Breggin, 1993, pp. 249-251).

Patrick McGorry, the Director of EPPIC, is particularly determined to credit Cameron with the original idea of preventive treatment for schizophrenia. So determined is McGorry that he headed his introductory essay to a special early psychosis supplement he edited of the British Journal of Psychiatry (McGorry, 1998) with a paragraph from Cameron’s article. In the quote Cameron "calls for new ideas on the social problems involved in bringing the early schizophrenic promptly under treatment" (Cameron, 1938).

McGorry might not have done his research properly. In a Discussion section attached to Cameron’s original article no less a figure than Harry Stack Sullivan categorically rejects Cameron’s theory of an identifiable pre-psychotic phase of schizophrenia. Sullivan is scornfully dismissive of Cameron’s suggestion that people should "be rushed through treatment with insulin, metrazol and camphor on the chance that they might otherwise have developed schizophrenia" (Sullivan, 1938, p. 579). Sullivan continued, "I privately have a suspicion that [preventive treatment] might have a distinctly unfavourable effect on the general intelligence level and so on of the community."

Sullivan’s scorn in 1938 apparently helped to knock out the idea of schizophrenia prevention for almost sixty years. But what are we to make of its recent resurrection? Cameron, the originator of the idea, is now widely recognised as an infamous monster. Yet the current promoters use his name in the apparent belief that it lends authority to their own research.

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