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Forum Discussion: Truly Better Prognosis in the Developing World?


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In our Forum discussion “journal club” series, the editors of Schizophrenia Bulletin provide access to the full text of a recent article. A short introduction by a journal editor gets us started, and then it's up to our readers to share their ideas and insights, questions, and reactions to the selected paper. So read on…

Cohen A, Patel V, Thara R, Gureje O. Free Full Text Questioning an Axiom: Better Prognosis for Schizophrenia in the Developing World? Schizophr Bull. 2007 Sep 28; [Epub ahead of print]

View Comments By:
Digvijay Goel — Posted 17 October 2007
Amresh Shrivastava — Posted 24 October 2007
Nirmala Srinivasan — Posted 1 November 2007
Jonathan Burns — Posted 5 November 2007
Patricia Estani — Posted 20 November 2007
Arthur Kleinman — Posted 17 December 2007
John McGrath — Posted 21 December 2007
John Strauss — Posted 8 January 2008
Julian Leff — Posted 25 January 2008
Assen Jablensky, Norman Sartorius — Posted 31 January 2008
Evelyn J. Bromet — Posted 1 February 2008
Karl-Ludvig Reichelt — Posted 27 February 2008
Robert Lemelson — Posted 25 April 2012


Background Text
By William Carpenter, Maryland Psychiatric Research Center, and Editor, Schizophrenia Bulletin

The field should celebrate each time an important concept is challenged by data and modification of a theory or hypothesis is required. A nice recent example was John McGrath’s “data versus dogma” piece detailing variations in incidence and prevalence of schizophrenia across geographic location and other socio-demographic variables (McGrath, 2006). [Ed. Note: See also SRF Live Discussion led by McGrath.] Alex Cohen and colleagues now review 23 reports that challenge the view that schizophrenia has a more benign course in developing countries. The view that course of illness is better in developing countries emerged from the International Pilot Study of Schizophrenia (IPSS) where patient subjects in Nigeria, Colombia, and India fared better at 2- and 5-year follow-up than patient subjects in five developed countries (WHO, 1979). Taiwan was an exception, but also not easily classified in the developing/developed dichotomy. The IPSS could not address sampling bias (e.g., acute, florid psychoses may have better prognosis and may also be more likely to be admitted to a clinical facility in poor countries), but the subsequent Determinants of Outcome WHO study addressed sampling issues more effectively and again found better outcome in developing countries (Jablensky et al., 1992). Together with other reports from the WHO studies (Harrison et al., 2001; Hopper et al., 2007), many of us accepted the view that the interaction between environment and the disease was more favorable in the developing world. There were interesting and compelling hypothetical explanations. My favorite came from Lin and Kleinman (Lin et al., 1988), who suggested that the developing world was more likely to provide a sociocentric culture that would be less demanding and more accepting of disabilities associated with schizophrenia compared to the egocentric western, developed countries with emphasis on autonomy and individual accomplishment. Given the cognitive and motivational challenges associated with schizophrenia, a less demanding and more inclusive society would seem to have specific advantages.

Cohen and colleagues find a more textured landscape in the 23 studies they consider. Good and poor outcomes occur in the same nations. Explanations do not fit neatly into wealth, industrialized, urbanized, or other common explanations. Methodological issues may explain why some data suggest a more favorable course in developing countries. Other patterns emerge, and the authors identify seven questions to be addressed in future research.

The Schizophrenia Bulletin will carry a series of commentaries addressing selected critical issues from several vantages. These will also appear as “Comments” in SRF. The paper, Questioning an Axiom: Better Prognosis for Schizophrenia in the Developing World? is available through the Schizophrenia Research Forum and the Schizophrenia Bulletin Advanced Access page. Commentaries will appear online as they are accepted at Schizophrenia Bulletin.

References
McGrath, JJ. Variations in the incidence of schizophrenia: data versus dogma. Schizophr Bull. 2006;32:195–197. Abstract

WHO. Schizophrenia: an international follow-up study. Chichester: John Wiley and Sons; 1979.

Jablensky A, Sartorius N, Ernberg G, Anker M, Korten A, Cooper JE, Day R, Bertelsen A. Schizophrenia: manifestations, incidence and course in different cultures: a World Health Organization ten-country study. Psychological Medicine Monograph Supplement. 1992; 20; 20:1-97. Abstract

Harrison G, Hopper K, Craig T, Laska E, Siegel C, Wanderling J, Dube KC, Ganev K, Giel R, an der Heiden W, Holmberg SK, Janca A, Lee PW, Leon CA, Malhotra S, Marsella AJ, Nakane Y, Sartorius N, Shen Y, Skoda C, Thara R, Tsirkin SJ, Varma VK, Walsh D, Wiersma D. Recovery from psychotic illness: a 15- and 25-year international follow-up study. British Journal of Psychiatry. 2001;178:506-517. Abstract

Hopper K, Harrison G, Aleksandar J, Sartorious A. Recovery From Schizophrenia. Oxford University Press, New York, 2007.

Lin KM and Kleinman AM. Psychopathology and clinical course of schizophrenia: a cross-cultural perspective. Schizophr Bull. 1988;14(4):555-67. Abstract

Comments on Online Discussion
Comment by:  Digvijay Goel
Submitted 17 October 2007
Posted 17 October 2007

While the research issues raised by Cohen and colleagues are relevant/plausible, it is unlikely that any such study will ever be funded again. I am also unable to understand what will be gained by such research. Neither the pace, nor the direction of the social-economic-political changes taking place across the world are going to be influenced by psychiatric research, which has not been able to influence even mental health policy, as Norman Sartorius pointed out many years ago. This is an exercise in futility, and I am tempted to ask, so what?

The three reasons cited by the authors as justification for yet more, hugely costly, research in several repeatedly researched domains do not bear scrutiny. It is naive to believe that "identifying the processes that promote good prognosis," or "accurate information about the realities of the day-to-day lives of persons with schizophrenia" will ever inform national policy anywhere, least of all in low- and middle-income group countries where over a third of the population still live on less than a dollar a day and where the provision of safe drinking water and basic sanitation is still a distant dream. As Prof Jeffrey Sachs stated in his hard-hitting keynote address at the launch of the Lancet Series on Global Mental Health, London 3 September 2007, mental health care remains unsatisfactory even in the most developed countries, despite vast volumes of research-based “evidence.” Even more breathtaking is the authors' assumption that "detailed understandings about how sociocultural and psychiatric processes interact" will help "prevent or at least limit the potential harm that may result" from the impact of globalization! In 1939, a group of several hundred psychiatrists from 30 nations had signed a noble manifesto on the prevention of war: "We psychiatrists declare that our science is sufficiently advanced for us to distinguish between real, pretended and unconscious motives, even in statesmen." (1)

I do not pretend to have even a fraction of the authors' academic and research credentials. I am also aware that anecdotal experience, such as I have, does not count for much in this evidence-based age. Having practiced psychiatry in India (where the patient was invariably brought in by the family, who also took full responsibility for treatment, and where there was huge pressure to seek/resume gainful employment owing to economic compulsions) for nearly 4 decades, and now having had the experience of working in a “developed” OECD country (where the patient is invariably alienated from the family, with parents often obtaining legal orders prohibiting their progeny from coming within 500 meters of their house, where comorbid alcohol/substance misuse is common, and where liberal unemployment/sickness benefits act as disincentives to seek work) for the past 2 years, I have little difficulty in unpacking the “black box” of culture, or in subscribing to the impugned axiom, which has been subjected to a much more balanced analysis by Isaac et al. in a recent communication (2).

While working as Mental Health Adviser in the Ministry of Health in India, I and my colleagues had, inter alia, used Jablensky's 1992 paper (3) to convince the policymakers that increased funding for mental health made even better economic sense in developing countries like ours. The result was a sevenfold increase in the mental health outlay during the 10th Five Year Plan (2002-2007). Now this flip-flop: “Sorry we were wrong all along; schizophrenics fare much worse in India than in the west.” This is not to deny that questioning established dogma lies at the heart of the spirit of scientific inquiry. But the spirit of “consumerism,” which now seems to drive the research industry, feeds on a cannibalistic urge to erode the credibility of past research on the basis of ever-increasing methodological sophistry. This could eventually prove to be counterproductive and lose us whatever little clout we have at present with policymakers.

Father forgive them. They know not what they do.

References:

1. Wedge B. Psychiatry and international affairs. Science. 1967;157:281-285. Abstract

2. Isaac MK, Chand P, Murthy P. Schizophrenia outcome measures in the wider international community. British Journal of Psychiatry. 2007;191 (suppl.5o): s71-s77

3. Jablensky A, Sartorius N, Ernberg G, Anker M, Korten A, Cooper JE, Day R, Bertelsen A. Schizophrenia: manifestations, incidence and course in different culture. A World Health Organisation Ten- Country Study. Psychological Medicine 1992, Monograph Supplement 20, Cambridge University Press, Cambridge.

View all comments by Digvijay GoelComment by:  Amresh Shrivastava
Submitted 19 October 2007
Posted 24 October 2007

Outcome of schizophrenia in India
Responding to the conclusion in the present meta-analysis, which questions that schizophrenia may not have a good prognosis in developing countries, I seem to agree with the evidence.

Before any other point, the question that needs to be examined is, what is “developing country” in the context of outcome? And why should the outcome be any different, considering the etiopathology of schizophrenia and available treatment?

India is, as we believe, a developing country and may figure by some criteria largely undeveloped, while by other criteria it is quite advanced. Western/developed countries also have seen good outcomes in schizophrenia recently, particularly in the areas of early psychosis studies and first episode psychosis.

We need to be careful about very old studies of schizophrenia conducted when the concept of diagnostic classification was evolving, whether that influenced the studies, and whether old and new studies are comparable at all.

Indian society is full of diversities and very complex. By and large, it is understood that awareness of mental illness is still poor, identification very late, treatment availability and accessibility continues to be a problem, manpower is short, psychosocial intervention is absent, and whether studies reflect ground reality is a major issue.

There is hardly any difference in recent studies of India and the West in terms of outcome after more advanced treatments are available.

To divide the world into developed and developing for studying outcome does not make much sense, because geographical location is not a determinant of disease in strict biological terms. Social changes and prevailing conditions do influence outcome, but Western countries do have their share of socially compromised populations. Homeless schizophrenics in the USA are not news. The question certainly needs to be examined, but by parallel, good, similar design studies, and not by comparing the non-comparables.

While people in Indian society may be more tolerant, supportive, and more involved, there is a high level of organizational and governmental support and care in the Western world for schizophrenia and mental illness. We can only compare if similar treatment facilities are put in place and the sample has a similar duration of untreated illness. And we should also study the parameters of social reintegration of the mentally ill.

View all comments by Amresh ShrivastavaComment by:  Nirmala Srinivasan
Submitted 24 October 2007
Posted 1 November 2007

I am delighted to share my comments on this topic in my dual capacity: as an activist from the caregiver consumer lobby, and also as a professional in social sciences person, with rich research experience. I am in ground zero and hence contact with reality is unavoidable. I know of families who can afford $300 to $400 a day for aftercare facilities—these may be the Rockefellers of India. At the other extreme, less-than-a-dollar-a-day families have no access to medication and wander homeless. I know of patients living in positive family environments but with very poor outcomes. The reverse is the amazing case of patients from highly dysfunctional families with fair if not good progress. So the genetic factors play a decisive role; while we must give due credits to other factors, we cannot use the myopic developed-developing dichotomy in a scenario characterized by global flow of capital. As a famous Marxist economist mentioned, we have circles of development engulfing the global economy.

In that sense, I appreciate the comments of Dr. Amresh Srivastava. Family is no doubt the backbone of support as of today. But due to compulsions of global economy, migration is affecting the Indian family system. Combined with lack of policies, public care institutions and supportive legal systems, the void left by the withering away of the family is going to take a heavy toll on our mental health status. Hence while the West is good for political backup, India is sitting on a time bomb with treatment not available to 90 percent of persons with mental illness. I had to file public interest litigation in the Supreme Court and in our Provincial Court to move the government to do what is its basic commitment to ensure right to life and health enshrined in the Constitution of India. There are a few patients who are able to afford imported depot injections of risperidone; many others live on local medicines at times beyond expiry dates. Who does better depends more on the genetic rather than on external support systems. For the genetic factors to be set on track, let us follow some public mental health care models followed in the West. The debate about patient outcomes in developing vs. developed countries is not only inconclusive but also redundant.

View all comments by Nirmala SrinivasanComment by:  Jonathan Burns
Submitted 2 November 2007
Posted 5 November 2007

Developing world poverty, inequality, violence, and social fragmentation are not good for outcome in schizophrenia!
The WHO studies concluded that course and outcome of schizophrenia was better in developing countries. This has become psychiatric lore. However, the reality is that significant political, social, and economic ills that characterize many countries in Africa, Latin America, and Asia constitute psychosocial stressors that mediate strongly against recovery. Economic and social underdevelopment translates into inadequate or even no access to mental health services for many patients with schizophrenia. In many regions, no services exist at all, or where they do exist, they are desperately poor. For example, throughout Africa the majority of patients have no ready access to novel antipsychotics and the prevalence of tardive dyskinesia is shockingly high. Stigma, too, abounds in the developing world—employers and communities are not tolerant and benevolent toward individuals with mental illness.

The belief that community and family life in the developing world is widely intact and that it provides a nurturing environment that facilitates recovery and promotes social and economic empowerment of the mentally ill is a myth. It is a dangerous and paternalistic myth. Continued idealization of the underdeveloped South as a haven for schizophrenia sufferers will only add to the already heavy burden experienced by these individuals, their families, and these societies in coping with this disabling disease.

If anyone is interested in putting together a collaborative multisite study of schizophrenia outcome in the developing world, e-mail me your suggestions.

View all comments by Jonathan BurnsComment by:  Patricia Estani
Submitted 3 November 2007
Posted 20 November 2007

I think it is mostly impossible to compare the two samples that the article’s study compared. The definition of the variables are poorly operative, so that the comparisons are confused. The most salient example is the variable of the relationships between the occupations of the patients, the outcomes of these patients and the occupations in the developed and in the developing countries.

The study mentions the occupational demands of the recovered patients with schizophrenia in the developed and in the developing countries. The article concluded that the outcomes of the patients are better in the developing countries because the occupational market is more favorable to these patients. But, this is not possible to conclude. The social and occupational market is less demanding in the developing countries. The subject is less occupied or the subject has less work, so the prognosis could be better in this wrong sense, but this is not really a better prognosis.

In this sense, this is not only NOT a measure of a good outcome, but is a measure of a very poor outcome. This is valid not only for patients with schizophrenia but also for any patient with any mental disorder. Thus, the conclusions are very weak and it is necessary to explain which type of variables the study is based on and if these variables really mean better outcomes or artificial better outcomes. More valid data must be included in these kinds of inter-social or inter-cultural studies, and I think these data must be more precise and experimental.

View all comments by Patricia EstaniComment by:  Arthur Kleinman
Submitted 17 December 2007
Posted 17 December 2007

Reprinted courtesy of Schizophrenia Bulletin
Kleinman A. Commentary on Alex Cohen et al.: "Questioning an Axiom: Better Prognosis for Schizophrenia in the Developing World" Schizophr Bull. 2007 Dec 3; [Epub ahead of print].

In the 1950s, ’60s, and ’70s, the field of cross-cultural (or transcultural) psychiatry provided what was largely Euro-American psychiatry with several useful alternatives. Based on limited research, it balanced the near hegemonic American and British research materials and conclusions with data from the non-Western world, and with new findings about established psychiatric disorders that challenged diagnoses, programs, and treatments. Cultural psychiatry still provides those contributions, but psychiatry itself has changed. We are now in an era of global psychiatry, where psychiatrists from Asia, Latin America, and Africa are contributing numerous studies on mental illness and mental health care, and these are now becoming part of psychiatric science. Not surprisingly, over the past few decades, studies of depression, suicide, psychosis, and substance abuse in a wide range of societies have greatly increased. One outcome of this increase is that we now have a much more detailed and complex view of these conditions in different socioeconomic, cultural, and political settings.

The review by Cohen et al. needs to be understood in this context of globalization. They show that the data about the course and outcome of schizophrenia are much more complicated for all societies, but especially for poor and middle income societies. They conclude that one of the conclusions of the past—namely that schizophrenia has a better outcome in those societies compared with rich nations—needs to be reconsidered. And they bring a substantial body of data to bear on that process of reassessment, along the way pointing to the deep processes of family responses, work conditions, stigma, and adult mortality, about which much more needs to be understood. I am persuaded by their comments and find their conclusion well reasoned and reasonable.

Cohen has made a career of criticizing World Health Organization (WHO) studies of schizophrenia. And many of his concerns are important. Readers need to balance the questions he and his distinguished colleagues raise with the conclusions of the WHO studies' authors. Given that we do not know the cause of schizophrenia, that many suspect it contains multiple distinctive conditions, that research on treatment has been controversial, and that the course of psychosis has been shown to be influenced by many factors, it is impressive to begin with that there is a strong cross-cultural hypothesis in the field. This hypothesis and this article's criticism have contributed, in my view, to move the field ahead conceptually and empirically. That there is still uncertainty, confusion, and controversy is a sign of how very much more we need to learn. But let us also celebrate how far we have come. What we now know about the course of schizophrenia appears to argue against any simple conclusion. The still dominant view in psychiatry that schizophrenia is a disorder of progressive, unrelenting deterioration is not supported by long-term outcome studies, even in North America. The view that schizophrenia has a more favorable outcome in poorer societies now also appears less certain. And this should lead to a more complex and sophisticated appreciation both of the biosocial course of the group of psychotic conditions that constitutes schizophrenia and of the diverse research perspectives in psychiatry that wrestle with how to make context as important as condition in the understanding of outcome.

This sense of progress in our cross-cultural understanding of mental illness can also be illustrated by other early formulations that have been proved inaccurate or inadequate. For example, when the first set of WHO studies concluded that outcome was better in low-resource societies, it was proposed that those societies were more sociocentric than psychocentric industrialized societies, and therefore outcome might reflect greater family and community support systems wrong. We have learned over the years that virtually all societies contain both strong interpersonal ties and individualistic orientations. While family connections may seem stronger in certain poor societies with powerful cultural supports for patriarchy, they have been shown to be as much a source of stress as support. The same holds for stigma. Stigma about serious mental illness seems to exist almost everywhere. Its sources and patterns may differ but its consequences for the mentally ill are terrible in rich and poor societies alike. Societies cannot be categorized as high support or low stigma. The social processes involved in the course of chronic illness are no more easily stereotyped than ethnicity is. No one can believe today that all Chinese act one way, all Americans another. Intraethnic and intrasocietal diversity is large. And this means, we need a more nuanced and complex modeling of social processes just as we require a more subtle and precise understanding of symptoms and syndromes. That recognition represents the kind of progress in cross-cultural psychiatric understanding that our improving understanding of course and outcome of schizophrenia also represents.

View all comments by Arthur KleinmanComment by:  John McGrath, SRF Advisor
Submitted 21 December 2007
Posted 21 December 2007

Reprinted courtesy of Schizophrenia Bulletin

Dissecting the heterogeneity of schizophrenia outcomes
Goethe believed that data are the natural enemy of hypotheses. As new data accumulate, only a few lucky hypotheses survive the fresh empirical onslaught. Over time, most hypotheses eventually need amendment or outright rejection. Schizophrenia epidemiology has been a particularly fertile field in recent years, with new data leading to the revision of several long-standing dogmatic beliefs (McGrath, 2005; McGrath, 2006; McGrath, 2007). The target article by Cohen and colleagues (Cohen et al., 2007) questions another of the oft-repeated tenets of schizophrenia epidemiology. After close inspection of the schizophrenia outcome studies based in low- and middle-income countries, the authors reject the notion that outcomes in these sites are superior to comparable published data from high-income countries (Hopper and Wanderling, 2000). It is curious that the hypothesis related to economic status captured the attention of the research community at the expense of the more general finding to emerge from the WHO study, which was that clinical outcomes varied widely within and between sites, regardless of economic status (Jablensky et al., 1992). The review by Cohen and colleagues reminds us that crude ecological variables related to national economic status do not seem to help untangle this heterogeneity.

In recent decades there has been a substantial research effort focused on the identification of the onset of psychotic disorders (Yung and McGorry, 1996; McGlashan, 1998). However, we still struggle to understand the offset of schizophrenia (Saha et al., 2005). Categorical outcome measures (e.g., recovered versus persistent illness) are not readily operationalized for chronic disorders such as schizophrenia. Dimensional symptom outcomes (e.g., positive or negative symptoms) and more “downstream” measures of disability (e.g., employment, social functioning) tend to fluctuate over time, and show divergent trajectories. Compared to measuring incidence, prevalence, and mortality, the assessment of clinical outcomes in schizophrenia is much more of a challenge (Hafner and An der Heiden, 2003; Andreasen et al., 2005).

Apart from the multidimensional nature of outcome measures, there are methodological concerns about how best to compare results from studies with different intake criteria, and different durations of follow-up. With respect to intake criteria, outcome studies can be based on (a) incident case or (b) mixed incident and prevalent cases. Prevalent cases are enriched with those with chronic illness and depleted of those who have died. The target article draws attention to the potential for differential between-site mortality to bias assessments of clinical outcomes. A recent systematic review of mortality in schizophrenia found prominent variation between sites; however, there was no significant difference in standardized mortality ratios between sites when sorted by economic status (Saha et al., 2007). While thought-provoking, these and related ecological analyses based on economic status (Saha et al., 2006) should be treated cautiously, because of the relative lack of data from low- versus higher-income nations.

With respect to duration of follow-up, studies can measure outcome at widely different time intervals (e.g., 5 versus 25 years). Outcome measures are usually provided as “percent recovered” or proportions describing other outcome-related measures. However, is it valid to compare “proportions recovered” between studies with different durations of follow-up? Solutions such as annualized remission rates are also suboptimal (e.g., if 20 percent of a sample achieves remission criteria at 10 years follow-up, the annualized remission rate = 2 percent). This derived measure assumes that the chance of recovery is evenly distributed over time, which is an unlikely scenario for any disease.

Because we do not expect that schizophrenia outcomes will obediently map onto geopolitical boundaries, within-nation differences should also be studied alongside between-nation differences. Sites can compare the relative influence of factors known to influence the chance of remission (e.g., sex, age of onset, duration of treated and untreated psychosis), and also explore the impact of risk factors such as urban birth and/or residence, migrant status, and neighborhood-level variables related to social capital. The contours of schizophrenia epidemiology within nations may be more informative than previously appreciated (McGrath, 2007).

The take-home message from the target article is that clinical outcomes in schizophrenia are heterogeneous (as is the case for incidence [McGrath et al., 2004], prevalence [Saha et al., 2005], and mortality [Saha et al., 2007]). The heterogeneity in these estimates mirrors the marked clinical and neurobiological heterogeneity of the disorder (Tamminga and Holcomb, 2005). Cultural and socioeconomic factors would contribute to the variability in outcomes via many different pathways. Less widely canvassed, underlying genetic differences between groups may also contribute to differences in both the risk of schizophrenia and the clinical outcome. The HapMap project has demonstrated that our species shows between-group genetic variations, and while there is substantial variation within geographically-defined populations, there remains between-group differences that reflect ancient geographical origin (Tishkoff and Kidd, 2004). Some of these variations have been linked to disease susceptibility (Balaresque et al., 2007; McGrath, 2006). With respect to clinical outcomes, evidence from other chronic disorders suggests that the genetic factors that predict recovering from an illness may differ from those genetic factors that increase susceptibility to that disorder (Spitz et al., 2005; Waters and Nicoll, 2005). This may also be the case for clinical outcomes in schizophrenia.

Finally, the paper by Cohen and colleagues is timely. Understanding the interactions between incidence, prevalence, mortality, and remission underpin the calculation of the Disability-Adjusted Life Year (DALY), a metric increasingly used to prioritize health service delivery (Murray and Lopez, 1996). Detailed population-based estimates for clinical outcomes will be required for the next Global Burden of Disease study (Lopez, 2005; Murray et al., 2007). The target article by Cohen and colleagues provides a useful resource for this exercise, and should galvanize more empirical research in the field of schizophrenia outcomes.

References:

McGrath JJ. Myths and plain truths about schizophrenia epidemiology--the NAPE lecture 2004. Acta Psychiatr Scand Jan 2005;111(1):4-11. Abstract

McGrath JJ. Variations in the incidence of schizophrenia: data versus dogma. Schizophr Bull Jan 2006;32(1):195-197. Abstract

McGrath JJ. The surprisingly rich contours of schizophrenia epidemiology. Arch Gen Psychiatry Jan 2007;64(1):14-16. Abstract

Cohen A, Patel V, Thara R, Gureje O. Questioning an Axiom: Better Prognosis for Schizophrenia in the Developing World? Schizophr Bull Sep 28 2007. Abstract

Hopper K, Wanderling J. Revisiting the developed versus developing country distinction in course and outcome in schizophrenia: results from ISoS, the WHO collaborative followup project. International Study of Schizophrenia. Schizophr Bull 2000;26(4):835-846. Abstract

Jablensky A, Sartorius N, Ernberg G, Anker M, Korten A, Cooper JE, Day R, Bertelsen A. Schizophrenia: manifestations, incidence and course in different cultures. A World Health Organization ten-country study. Psychol Med Monogr Suppl 1992;20:1-97. Abstract

Yung AR, McGorry PD. The prodromal phase of first-episode psychosis: past and current conceptualizations. Schizophr Bull 1996;22(2):353-370. Abstract

McGlashan TH. Early detection and intervention of schizophrenia: rationale and research. Br J Psychiatry Suppl 1998;172(33):3-6. Abstract

Saha S, Chant D, Welham J, McGrath J. A Systematic Review of the Prevalence of Schizophrenia. PLoS Med May 2005;2(5):e141. Abstract

Hafner H, An der Heiden W. Course and outcome of schizophrenia. In: Hirsch SR, Weinberger DR, eds. Schizophrenia. Cambridge: Cambridge University Press; 2003:101-141.

Andreasen NC, Carpenter WT, Jr., Kane JM, Lasser RA, Marder SR, Weinberger DR. Remission in schizophrenia: proposed criteria and rationale for consensus. Am J Psychiatry Mar 2005;162(3):441-449. Abstract

Saha S, Chant D, McGrath J. A systematic review of mortality in schizophrenia: is the differential mortality gap worsening over time? Arch Gen Psychiatry Oct 2007;64(10):1123-1131. Abstract

Saha S, Welham J, Chant D, McGrath J. Incidence of schizophrenia does not vary with economic status of the country: evidence from a systematic review. Soc Psychiatry Psychiatr Epidemiol May 2006;41(5):338-340. Abstract

McGrath J, Saha S, Welham J, El Saadi O, MacCauley C, Chant D. A systematic review of the incidence of schizophrenia: the distribution of rates and the influence of sex, urbanicity, migrant status and methodology. BMC Med Apr 28 2004;2(1):13. Abstract

Tamminga CA, Holcomb HH. Phenotype of schizophrenia: a review and formulation. Mol Psychiatry Jan 2005;10(1):27-39. Abstract

Tishkoff SA, Kidd KK. Implications of biogeography of human populations for 'race' and medicine. Nat Genet Nov 2004;36(11 Suppl):S21-27. Abstract

Balaresque PL, Ballereau SJ, Jobling MA. Challenges in human genetic diversity: demographic history and adaptation. Hum Mol Genet Oct 15 2007;16 Spec No 2:R134-139. Abstract

McGrath JJ. The romance of balancing selection versus the sober alternatives: let the data rule (Commentary on Keller and Miller),. Behavioural and Brain Sciences 2006;29(4):417-418.

Spitz MR, Wu X, Mills G. Integrative epidemiology: from risk assessment to outcome prediction. J Clin Oncol Jan 10 2005;23(2):267-275. Abstract

Waters RJ, Nicoll JA. Genetic influences on outcome following acute neurological insults. Curr Opin Crit Care Apr 2005;11(2):105-110. Abstract

Murray CJ, Lopez AD. The Global Burden of Disease. Boston: Harvard School of Public Health; 1996.

Lopez AD. The evolution of the Global Burden of Disease framework for disease, injury and risk factor quantification: developing the evidence base for national, regional and global public health action. Global Health Apr 22 2005;1(1):5. Abstract

Murray CJ, Lopez AD, Black R, et al. Global burden of disease 2005: call for collaborators. Lancet Jul 14 2007;370(9582):109-110. Abstract

View all comments by John McGrathComment by:  John Strauss
Submitted 8 January 2008
Posted 8 January 2008

Is Prognosis in the Individual, the Environment, the Disease, or What?
This wonderful title was suggested by Will Carpenter. It provides a perfect context for considering the problem of prognosis in general, and more specifically, the report by Cohen et al. on the question of cultural differences in prognosis.

Often unrecognized currently, prognosis has for centuries been one of the foundations of scientific medicine. Hippocrates, Sydenham, and in psychiatry, Kraepelin, utilized prognosis as the basis for identifying disease processes. This contrasted strongly with the tendency to use the clinical picture or ‘‘syndrome’’ at one moment in time as the basis for defining various diseases. In fact, Kraepelin put together three very different syndromes, considering them one disease (dementia praecox) because of what he believed to be their common inexorable downhill course. Aside from its use for identifying disease processes, prognosis also serves as a basis against which treatment effectiveness can be measured and for identifying healing processes. In fact, prognosis demonstrates how the use of a longitudinal perspective can provide one of the major ways of understanding many major aspects of disease and disorder.

And what a neat idea that is! In the medical world where the striking syndrome ‘‘dropsy’’ (generalized bodily swelling) was shown over time actually to represent several very different pathological processes involving the kidney, heart, or other organs, the dependence on syndromes alone to identify separate diseases was shown to be grossly inadequate and often misleading. Perhaps, it is because of the power of prognosis and its serving as a base for so many of our medical concepts that there has been so much resistance to recognizing that “schizophrenia” (derived from Kraepelin’s original concept of dementia praecox) in fact has a diverse range of courses and outcomes. Since our early report on this diversity over 30 years ago using measures of demonstrated reliability, there have been well over 20 studies carried out in many different centers showing the prognostic diversity of schizophrenia no matter the choice of diagnostic criteria, the measurement techniques for defining outcome, or the length of follow-up. Even Kraepelin who was an excellent observer raised a question about his theory at one point. Nevertheless, many mental health professionals continue to be taught and to believe that schizophrenia is invariably chronic and very often involves an inevitable deterioration. Incredible! No, the desire for a simple model of prognosis in schizophrenia, as laudable as that might be in the abstract, has not been confirmed by scientific study. So, where did we go wrong? And, more specifically regarding the report of Cohen et al., what can we learn from cross-cultural studies about the determinants of and the issues involved in understanding the course and outcome of schizophrenia?

To begin at the beginning, what might account for the diversity of outcome that has been found? Biological factors such as genetic differences of course may play a role. But there is little data to suggest exactly how that might operate. Environmental factors perhaps? And this is where the international studies have been particularly important with their suggestions regarding cultural differences.

Of course, once we let in cultural factors, the way is open for other environmental factors, social class as was suggested in the 1950s and 1960s, and another variable that became politically incorrect in the 1970s, family environmental factors. There are other potential environmental factors as well, such as the availability and efficacy of treatment and rehabilitation, programs focusing on ‘‘recovery’’ and reinsertion into the community, employment, and housing possibilities, etc.

One variable strikingly lacking from these more traditional biological and social considerations is the possible role of the individual in affecting the course and outcome of disorder. This variable, too, can be ‘‘politically incorrect’’ either from the point of view of the danger of ‘‘blaming the patient,’’ for example, if he or she does not improve or from the deviation involved in considering the patient’s role from a narrow, sometimes considered ‘‘more rigorous,’’ version of the medical model. That narrow version suggests that the disease, and perhaps treatment and environment, more or less alone are the key factors in determining prognosis. My own unrecognized acceptance of such a narrow version of the medical model was first severely challenged when a patient who was a subject in a longitudinal study we were conducting suddenly said to me, ‘‘Why don’t you ever ask me what I do to help myself?’’ Subsequently Alan Breier and Strauss (Breier and Strauss, 1984) began to try to answer that question, and it continues to be a focus of my efforts (e.g., Strauss, 1996; Strauss, 2007) because it appears to me to be such an important part of understanding of the processes of disorder and their prognosis.

In considering the possibility of cross-cultural factors in the report by Cohen et al., we focus on the social realm of the triad, biologic, social, and personal. The report demonstrates that in understanding social factors, the problem begins with measurement and the interpretation of that measurement. In the International Pilot Study of Schizophrenia (IPSS), which marked one of the earliest systematic cross-cultural investigations, anthropologists who consulted to the study such as William Caudill were concerned that we were not paying sufficient attention to the assessment of cultural variations even at the syndrome level. The primary goal of the IPSS, however, was to discover whether we could identify ‘‘similar’’ manifestations of a disorder schizophrenia, suggesting that such a disorder actually existed in different cultures. For the organizers led by the principal investigator Tsung-yi Lin, it seemed reasonable to focus on that goal and to recognize that one could not do everything in one project. Thus, the exploration of diversity would have to await other research efforts.

Even in that project, however, certain problems in comparing clinical status across cultures signaled potential difficulties for future research attempting to reach specific cross-cultural conclusions about epidemiology and the status of patient functioning. In terms of comparing prognosis, there were issues of sampling (e.g., do the less florid [the more ‘‘process’’] patients who also tend to have poorer prognosis, tend not to come to the attention of mental health professionals in developing countries?). There were also issues of interpretation of longitudinal functional status. For example, there was a patient in a developing country who at follow-up was ‘‘working full-time’’ guarding the cattle. When we asked a person from the village what that meant in terms of work, the response was that it was not real work because that was usually a job reserved for young children. In another developing country, there was the statement that there was less stigma around mental illness than in developed countries. When we inquired in more detail, however, we were told that of course family members would not let it be known that one of the sons had mental illness because it would then be impossible for the daughters to get married. These are only anecdotes, of course, but they suggested that making certain cross-cultural comparisons may need a sophisticated approach to sampling and inquiry to assure the validity of conclusions.

These considerations, here focusing on one aspect of the social domain, indicate the complex context within which an understanding of the diversity of prognosis in schizophrenia exists. But even the recognition of issues in each of the three individual domains, the biological, environmental, and personal, is incomplete. More than likely, interactions between two or [among] all three of these domains will be important influences on course and outcome, for example, the interaction between the efforts of a person to get better, a case worker who assists him in that process, the availability of a helpful job and of useful medication. Often in medical research, we try to focus on one variable that can account for a huge amount of the variance in a certain problem. Occasionally, we meet with relative success, as with the pneumococcus, for example, as a major variable in one type of pneumonia. For schizophrenia, however, as is seen in the report by Cohen et al., even a focus on only one of the three domains involves considerable complexity in research design, data collection, data analysis, and interpretation. Such complexity is nothing new, of course, for medical research. Very often, the crucial factors involved in aspects of illness are extremely complex. In the study of schizophrenia, there is increasing evidence that the diversity of prognosis is the result of a complex interaction between the disorder, the environment including the culture, and the characteristics of the person afflicted. Only by considering such a model are we likely to develop an accurate picture of the prognostic processes.

References:

Breier A, Strauss JS. The role of social relationships in the recovery from psychotic disorder. Am J Psychiatry. 1984;141:949–955. Abstract

Strauss JS. Subjectivity. J Nerv Ment Dis. 1996;184:205–212. Reprinted as Subjektivitet. Dialog 1999;9:37–50. Translated into Norwegian by Rimestad S. Abstract

Strauss JS. La réalité et le concept de maladie mentale. Psychiatr Sci Hum Neurosci. 2007;125–130.

View all comments by John StraussComment by:  Julian Leff
Submitted 25 January 2008
Posted 25 January 2008

Reprinted courtesy of Schizophrenia Bulletin

Methodological issues
I agree with the authors’ criticism of the use of the dichotomy between developed and developing countries, partly because of the difficulty in defining these terms and partly due to the myriad different social, cultural, and economic factors subsumed by them. While ‘‘low income’’ and ‘‘middle income’’ can be reasonably accurately defined, they also encompass a great diversity of factors, both within and between countries. In addition, the authors have aggregated 23 studies including prevalence and incidence samples and prospective and retrospective designs. They acknowledge that a meta-analysis is ruled out by this diversity of sampling procedures and methods but nevertheless proceed to treat these studies as providing equally informative findings. An incidence study is likely to miss a small proportion of individuals fulfilling the selection criteria—11 percent in the AESOP study (Morgan et al., 2006), which used case finding procedures based on those in the International Studies of Schizophrenia (ISoS) research. However, a prevalence study will fail to include a high proportion of people who experience an acute first onset of schizophrenia from which they recover completely, thus introducing a bias toward chronicity. The International Pilot Study of Schizophrenia was based on prevalence samples because its aim was to determine whether it was possible to train psychiatrists from different countries to use assessment instruments in a reliable way, to establish whether schizophrenia exists in all the cultures studied, and to determine whether an international collaborative study in psychiatry was achievable. The success of this venture paved the way for the Determinants of Outcome of Severe Mental Disorders (DOSMeD), the main strength of its design being the collection of an epidemiologically based incidence sample followed prospectively in each center using the same instruments. Cohen and colleagues have taken a step backwards in conflating results from both incidence and prevalence studies. These authors state that ‘‘Except for the China ISoS site, sampling in all the WHO studies relied on a variety of help-seeking agencies to identify potential subjects.’’ I am particularly familiar with the Chandigarh site from the DOSMeD study because I visited it several times and went on field trips to the rural areas with the researchers. The city of Chandigarh has a highly literate population, 70 percent during the period of the study, and a Postgraduate Medical Institute of considerable sophistication in which the psychiatric facility was sited. The proportion of incident cases derived from help-seeking agencies would consequently be minimal. By contrast, the rural areas around the city have populations with a low level of literacy, 30 percent at the time, and limited access to medical facilities. To deal with this problem, Professor Wig, the director of the center, established a mobile team of psychiatric professionals who made regular circuits of the rural areas, holding outpatient clinics to identify and treat potential subjects for the study. This procedure increased the likelihood that all incident cases were identified.

It is noteworthy that the data from the Nigerian center in Ibadan were given less weight than those from other centers in the ‘‘developing’’ countries because the case finding procedures, compared with those in Chandigarh, were not considered to be sufficiently comprehensive.

The role of families
More prospective first-onset studies have been conducted in India than in any other low-income country, and the clinical, social, and occupational outcomes are consistently good.

For this reason, the family study incorporated in the Chandigarh center’s research is of particular interest. Two aspects of the findings need emphasis: the contrast between the prevalence of relatives’ expressed emotion (EE) in the city and in the rural areas and the contribution made by the generally low levels of EE to the good clinical outcome of the patients in this center. The local field workers in the Chandigarh center were trained to assess EE to an acceptable level of inter-rater reliability. The proportion of urban relatives of first-onset patients with schizophrenia who were rated as high EE was found to be 30 percent, while the comparable proportion for rural relatives was only 8 percent. At the 1-year follow-up, levels of EE had dropped in both groups: 12.5 percent of urban relatives were rated as high EE, but not a single rural relative (Leff et al., 1990). This latter finding has no precedent among relatives in high-income countries. A comparison across a wide variety of countries has shown that the prevalence of high EE households is greatest among the most industrialized and urbanized societies and least among rural agrarian societies (Leff and Warner, 2006). A comparison was made between the Chandigarh sample of first contact patients and a sample of London patients admitted for the first time with a diagnosis of schizophrenia, both groups being assessed with the same instruments. The proportion of high EE relatives was 47 percent in the London sample and 23 percent in the total Chandigarh sample (P <0.005). The relapse rates at 1-year follow-up showed the same pattern: 29 percent and 14 percent, respectively (P<0.05). A log linear analysis of these data revealed that the better outcome for the Chandigarh patients was wholly predicted by the lower level of EE (Kuipers and Bebbington, 1988). I would be cautious about generalizing from these results to the other Indian centers, let alone to all low-income countries, but the explanatory power of relatives’ EE is such (Butzlaff and Hooley, 1998) that it merits incorporation in further studies of variation in outcome across countries and cultures. Recent research indicates that socio-environmental factors are implicated in the etiology of schizophrenia as well as influencing its course (Morgan et al., 2007). However, the role of these factors is unlikely to be elucidated at the national level. Focusing research on the local social environment for specific groups, particularly at the familial level, will prove more productive. The EE studies provide an example of the level of analysis that is likely to advance our understanding of cross-national differences in outcome.

References:

Morgan C, Dazzan P, Morgan K, Jones P, Harrison G, Leff J, Murray R, Fearon P, . First episode psychosis and ethnicity: initial findings from the AESOP study. World Psychiatry. 2006 Feb 1;5(1):40-6. Abstract

Leff J, Wig NN, Bedi H, Menon DK, Kuipers L, Korten A, Ernberg G, Day R, Sartorius N, Jablensky A. Relatives' expressed emotion and the course of schizophrenia in Chandigarh. A two-year follow-up of a first-contact sample. Br J Psychiatry. 1990 Mar 1;156():351-6. Abstract

Leff J, Warner R. Social Inclusion of People with Mental Illness. Cambridge: Cambridge University Press; 2006:12–13.

Kuipers L, Bebbington P. Expressed emotion research in schizophrenia: theoretical and clinical implications. Psychol Med. 1988 Nov 1;18(4):893-909. Abstract

Butzlaff RL, Hooley JM. Expressed emotion and psychiatric relapse: a meta-analysis. Arch Gen Psychiatry. 1998 Jun 1;55(6):547-52. Abstract

Morgan C, Kirkbride J, Leff J, Craig T, Hutchinson G, McKenzie K, Morgan K, Dazzan P, Doody GA, Jones P, Murray R, Fearon P. Parental separation, loss and psychosis in different ethnic groups: a case-control study. Psychol Med. 2007 Apr 1;37(4):495-503. Abstract

View all comments by Julian LeffComment by:  Assen JablenskyNorman Sartorius
Submitted 31 January 2008
Posted 31 January 2008

Comment by Assen Jablensky and Norman Sartorius

Reprinted courtesy of Schizophrenia Bulletin

What did the WHO studies really find?
The article by Cohen et al. raises important issues and provides a useful synopsis of published studies on schizophrenia outcomes in 11 low- and middle-income countries. The authors use of this material to challenge what they claim to be an ‘‘axiom’’ (i.e., a self-evident proposition requiring no proof) of better course and outcome in developing countries which has been ‘‘embraced’’ by international psychiatry. They impute the origin of this belief primarily to World Health Organization (WHO)-led international collaborative research conducted over the past 30 years (WHO, 1973; WHO, 1979; Jablensky et al., 1992; Harrison et al., 2001) and caution that the publication of the final report from the International Study of Schizophrenia (ISoS) (Hopper et al., 2007) might even further bolster convictions in the ‘‘better prognosis’’ hypothesis. Based on evidence from research conducted outside the WHO studies, they conduct a reexamination of the axiom. Having been directly involved with the WHO schizophrenia research program over decades, we wish to point out that Cohen et al. have misunderstood key aspects of the design and conclusions of the WHO studies. They claim that ‘‘the sampling methods utilized in the WHO studies may have resulted in overly optimistic perceptions of course and outcome’’ because ‘‘case-finding methods which focus exclusively on help-seeking agencies will miss large proportions of seriously ill, poor prognosis individuals.’’ They state, mistakenly, that the WHO studies provide no evidence allowing an evaluation of ‘‘the quality of family and social interactions,’’ and impute to them by implicating a view that ‘‘scarcity’’ of care resources is responsible for better outcomes. Because these claims repeat an earlier critique of the WHO 10-country study (Determinants of Outcome of Severe Mental Disorders [DOSMeD] [Jablensky et al., 1992]) by Edgerton and Cohen in 1994 (Edgerton and Cohen, 1994), which was answered by us in a publication (Jablensky et al., 1994) not quoted in the present article, we summarize briefly the relevant features, findings, and conclusions of that study. An unexpected finding of the follow-up stage of the WHO International Pilot Study of Schizophrenia (IPSS) (WHO, 1979) was a markedly better overall outcome of schizophrenia patients in India and Nigeria at 2-year and 5-year follow-up. Because the IPSS cohort was not necessarily representative and the finding could be an artifact of selection, a second, epidemiologically designed study was launched in the early 1980s. DOSMeD (Jablensky et al., 1992) was the first large-scale study in which a unified design, stringent methods, and standardized instruments were concurrently applied to first-episode incident cohorts (total study population = 1379) at 12 research sites in diverse sociocultural settings (Colombia, Czechoslovakia, Denmark, India, Ireland, Japan, Nigeria, Russia, United Kingdom, and United States). The cohorts were recruited by 2-year active case finding within defined geographical areas, aiming to intercept all new onsets at all kinds of facilities—not just mental health services, but including primary care, police/prisons, traditional healers, and religious shrines (notably, 28 percent of the cases in India and Nigeria were recruited through such ‘‘alternative’’ care sources). For 86 percent of the cases, the duration of untreated psychosis was less than 1 year, and only 10 percent had been prescribed antipsychotic drugs prior to entry into the study. Repeated ‘‘leakage’’ checks on the completeness of case finding found that only a handful of incident cases had been missed by this technique, thus categorically ruling out an ascertainment bias favoring inclusion of milder or good prognosis cases. Patients and key informants were interviewed at baseline and at 1-year and 2-year follow- up (78.2 percent of the cohort), and a large proportion of the original cohort was traced and assessed again at 15 years (as part of the ISoS) (Hopper et al., 2007) in 8 of the 12 field research centers. Throughout the study, high intra- and intercenter reliability of assessment using the Present State Examination (PSE) (Wing et al., 1974) was maintained by joint rating of live and prerecorded interviews. Diagnostic stringency was ensured by processing of the PSE data using a computerized diagnostic algorithm (Wing et al., 1974). During the first 2 years, nested studies were conducted on the impact of potential precipitants of psychotic relapse: stressful life events (Day et al., 1987) (in 10 of the centers) and expressed emotion (Leff et al., 1990) (in Chandigarh, India). These studies did provide important information on family and social interactions. Operationally defined measures of course and outcome included one categorical index (pattern of course) and six quantitative dimensions (cumulative percentages): estimated follow-up time in psychotic episodes, in complete or incomplete remissions, duration of unimpaired community functioning, time in hospital, and time on antipsychotic medication. In all centers, disability and social functioning were evaluated using the WHO-Disability Assessment Schedule interview. Importantly, our analysis did not conflate measures of clinical status and measures of social functioning. Analysis of predictors of outcome was based on log-linear models (log-odds) which tested 25 potential predictors against the seven outcome variables. The essence of the findings and conclusions of the study are best conveyed by quoting from the DOSMeD final report (Jablensky et al., 1992). The study demonstrated clearly a diversity of outcomes but ‘‘did not identify any particular pattern in the course and outcome of schizophrenic illnesses which could be regarded as specific to a given area or culture.’’ The outcome of patients in the developing countries was not uniformly better, as compared to the outcome in developed countries. While high rates of complete clinical remission were significantly more common in developing country areas (37 percent) than in developed countries (15.5 percent), the proportions of continuous unremitting illness (11.1 percent and 17.4 percent) did not differ significantly across the two types of setting. Patients in developing countries experienced significantly longer periods of unimpaired functioning in the community, although only 16 percent of them were on continuous antipsychotic medication (compared with 61 percent in the developed countries). Across all centers, the best predictors (P <.001) of outcome were type of onset (insidious vs. acute) and type of setting (developed vs. developing country), followed by marital status (P <.01) gender (P <.05), social isolation (P <.05), and drug abuse (P <.05). Neither type of family household (extended vs. nuclear) nor experienced avoidance by others (a putative marker of stigma) reached statistical significance as predictor of outcome. Having excluded a number of potential confounders, we concluded that ‘‘it is unlikely that the variation in course and outcome could be reduced to a single variable’’ and considered ‘‘the possibility that the clinical conditions meeting the inclusion criteria of the study in the 2 types of setting may be heterogeneous and include varying proportions of etiologically and genetically different disorders which may be indistinguishable from one another at the level of the phenotype. This possibility exists but it cannot be properly examined or tested at the present time, in the absence of established genetic markers, indicators of etiology, or other underlying mechanisms of disease.’’ Nevertheless, ‘‘a strong case can be made for a real pervasive influence of a powerful factor which can be referred to as ‘culture,’ as the context in which gene-environment interactions shape the clinical picture of human disease. The contribution of the present study is not in providing the answer but in clearly demonstrating the existence of the question’’ (Jablensky et al., 1992). Cohen et al. cite and review a number of non-WHO studies in low- and middle-income countries as providing evidence that is contrary to the ‘‘presumed wisdom’’ allegedly promoted by the WHO reports. Yet they note the ‘‘heterogeneity in types of samples, follow-up periods, and outcome measures’’ used in those studies, acknowledge that no meta-analyses were possible, and base their reasoning on ‘‘reading of the research reports, tabulations of the available data, and interpretations of the evidence.’’ Using the same method in our perusal of Tables 3 and 5 in the target article, we are unable to find in this literature evidence contradicting any of the DOSMeD and ISoS findings and conclusions. In fact, notwithstanding the heterogeneity of the data due to design, methods, and power, nearly all studies report extraordinarily high proportions of ‘‘complete recovery,’’ ‘‘no or minimal psychotic symptoms,’’ ‘‘no psychotic episodes,’’ ‘‘no impairment,’’ ‘‘good to excellent social functioning,’’ etc. We agree that mortality is an important measure of outcome and that wherever standardized mortality ratios (SMRs) are available, people with schizophrenia tend to have elevated rates, compared with the general population. In the ISoS study, five SMRs were calculated for six schizophrenia cohorts in developing countries and 12 cohorts in developed countries. Of the 13 SMR values significant at P <.05, four were in developing countries and nine in developed countries. All the five highest values (SMR >4.0) were in developed countries. Had Cohen et al. included in their review comparable data from course and outcome studies in high-income countries, the contrast between the two groups of settings would be striking. We do not argue that the prognosis of schizophrenia in developing countries is groupwise uniformly milder or that the existing huge gaps in mental health service provision between high- and low-income countries are irrelevant to the lives of millions of people affected by this disorder. On the contrary, the erosion of social support systems, likely to be associated with the processes of globalization (Chisholm et al., 2007), should be a matter of grave concern. The sobering experience of high rates of chronic disability and dependency associated with schizophrenia in high-income countries, despite access to costly biomedical treatment, suggests that something essential to recovery is missing in the social fabric. Thus, the existence of outcome differentials between populations and cultures is not ‘‘presumed wisdom’’ but a real, complex issue which should be addressed with standards of precision and rigor that are customary in scientific research and discourse.

References:

Cohen A, Patel V, Thara R, Gureje O. Questioning an Axiom: Better Prognosis for Schizophrenia in the Developing World? Schizophr Bull. 2007 Sep 28; [Epub ahead of print] Abstract

WHO. Report of the International Pilot Study of Schizophrenia, Volume I. Geneva, Switzerland: World Health Organization; 1973.

WHO. Schizophrenia: An International Follow-up Study. Chichester, UK: John Wiley & Sons; 1979.

Jablensky A, Sartorius N, Ernberg G, Anker M, Korten A, Cooper JE, Day R, Bertelsen A. Schizophrenia: manifestations, incidence and course in different cultures. A World Health Organization ten-country study. Psychol Med Monogr Suppl. 1992 Jan 1;20():1-97. Abstract

Harrison G, Hopper K, Craig T, Laska E, Siegel C, Wanderling J, Dube KC, Ganev K, Giel R, An Der Heiden W, Holmberg SK, Janca A, Lee PW, León CA, Malhotra S, Marsella AJ, Nakane Y, Sartorius N, Shen Y, Skoda C, Thara R, Tsirkin SJ, Varma VK, Walsh D, Wiersma D. Recovery from psychotic illness: a 15- and 25-year international follow-up study. Br J Psychiatry. 2001 Jun 1;178():506-17. Abstract

Hopper K, Harrison G, Janca A, Sartorius N (eds). Recovery from Schizophrenia: An International Perspective. New York, NY: Oxford University Press; 2007.

Edgerton RB, Cohen A. Culture and schizophrenia: the DOSMD challenge. Br J Psychiatry. 1994;164:222–231. Abstract

Jablensky A, Sartorius N, Cooper JE, Anker M, Korten A, Bertelsen A. Culture and schizophrenia. Criticisms of WHO studies are answered. Br J Psychiatry. 1994;165:434–436. Abstract

Wing JK, Cooper JE, Sartorius N. Measurement and Classification of Psychiatric Symptoms. Cambridge, UK: Cambridge University Press; 1974.

Day R, Nielsen JA, Korten A, Ernberg G, Dube KC, Gebhart J, Jablensky A, Leon C, Marsella A, Olatawura M. Stressful life events preceding the acute onset of schizophrenia: a cross-national study from the World Health Organization. Cult Med Psychiatry. 1987 Jun 1;11(2):123-205. Abstract

Leff J, Wig NN, Bedi H, Menon DK, Kuipers L, Korten A, Ernberg G, Day R, Sartorius N, Jablensky A. Relatives' expressed emotion and the course of schizophrenia in Chandigarh. A two-year follow-up of a first-contact sample. Br J Psychiatry. 1990 Mar 1;156():351-6. Abstract

Chisholm D, Flisher AJ, Lund C, Patel V, Saxena S, Thornicroft G, Tomlinson M; Lancet Global Mental Health Group. Scale up services for mental disorders: a call for action. Lancet. 2007;370:1241–1252. Abstract

View all comments by Assen Jablensky
View all comments by Norman SartoriusComment by:  Evelyn J. Bromet
Submitted 1 February 2008
Posted 1 February 2008

Reprinted courtesy of Schizophrenia Bulletin

Cross-national comparisons: problems in interpretation when studies are based on prevalent cases
Cohen et al. challenge the belief, stemming largely from the World Health Organization (WHO) schizophrenia research program, that ‘‘schizophrenia has a better course and outcome in countries of the developing world’’ compared with developed countries. They thus examine findings on illness course, mortality, and social and occupational outcomes across an array of studies conducted in low- or middle-income countries throughout the world. They consider findings from all follow-up studies of schizophrenia conducted in these countries, without regard to case identification specification or length of follow-up. The outcome results across the studies identified by Cohen et al. were variable, and in some cases, the samples fared very poorly indeed. Because none of the studies had control groups, cross-national disparities in the social and occupational trajectories of the patients with schizophrenia compared with counterparts from the same source populations are unknown. Cohen et al. suggest that there is a need for more outcome studies of ‘‘incident and prevalent cases.’’ Clearly, outcome studies of incident cases, defined as first episode, first contact with a provider, or first hospitalization, can potentially provide insights about the course and outcome of schizophrenia, and they are, unfortunately, fairly rare. On the other hand, follow-up studies of consecutive admissions to psychiatric inpatient and outpatient facilities, or prevalent cases, appear with great regularity. However, their findings are largely uninterpretable. As Cohen and Cohen (1984) elegantly delineated nearly 25 years ago, many forms of selection bias creep into prevalent samples, particularly chronicity and comorbidity, creating an illusion about the nature and correlates of illness course. Studies with variable lengths of time between illness onset and outcome determination, such as those reviewed by Cohen et al., create ambiguity about the course of schizophrenia rather than shed light on the process and its mechanisms across time and place. Thus, additional prevalent studies in low- and middle-income countries are unlikely to improve our understanding of cross-national differences in the course of schizophrenia.

A prevalent sample is a mixture of recent onset and chronically ill patients. The specific composition of the mix will influence the findings and the inferences that are ultimately to be drawn. In our chapter on the epidemiology of psychosis, we showed that in a single mixed sample, the 5-year outcome was significantly better for the incident (first-admission) patients than for the prevalent (rehospitalized) patients in the group (Bromet et al., 1995). Among the incident cases, 22 percent experienced no relapse, 35 percent had one or more relapses with minimal or no impairment, and 43 percent were impaired throughout the 5 years. Among the prevalent cases, only 10 percent had no impairment, whereas 29 percent had multiple episodes with no/minimal impairment, and 60 percent were impaired with no return to normality. The more general point is that prevalent (consecutive admission) samples are biased by chronicity, thus overrepresenting the most severe and intractable forms of the illness. In contrast, incident samples, even when ascertained from clinical services, are less biased by chronicity, although they, too, contain patients with variable durations of untreated or undertreated illness. Population-based incident samples identified from cohort studies, such as birth cohorts, are the most representative and contain the least bias.

A useful way to think about follow-up studies of schizophrenia is to conceptualize them as clinical cohort studies (Susser et al., 2006). The design requirements then become very clear. A cohort is a group with a common experience that is observed in a standardized fashion over time. Thus, a clinical cohort is a group with a uniform starting point (the closer to the actual onset, the better for minimizing lead time bias), a transparent and systematic method of case ascertainment, and a reliable method of assessment and assignment of diagnosis. By their nature, well-designed clinical cohort studies yield findings that are readily interpretable. The WHO first-contact study was designed with these basic principles in mind (Jablensky et al., 1992). As Cohen et al. point out, the cross-cultural application was not without its problems, but the ability to make comparisons was greatly enhanced by the design. Two recent North American studies were also designed with the same goals (Bromet and Fennig, 1999; Erickson et al., 1998). Thus, in countries where ‘‘ideal’’ epidemiologic samples, such as birth cohorts, are not available or feasible, the clinical cohort design offers the next best alternative. The bottom line is that Cohen et al. argue that the ‘‘better prognosis’’ hypothesis is not correct for all poor and middle-income countries because both good and bad outcomes are found in socioeconomically deprived regions of the world. In deciding about studies to include in their review, the distinction between incident and prevalent cases was noted but was not considered particularly germane. It is important to emphasize that the WHO investigators did not claim that all patients in developing countries had good outcome trajectories. Instead, they found that on average, the incident cohorts from developing countries fared better than those from richer countries. (As an aside, the World Mental Health Consortium, a series of population-based morbidity surveys, also found higher rates of psychiatric disorder in wealthy countries like the United States compared with poor countries like Nigeria [Demyttenaere et al., 2004]) From an epidemiologic perspective, the biases in prevalent samples cannot be ignored when evaluating and comparing prognosis across studies. It is simply not possible to judge whether the differences in the outcomes reported in this review, including mortality, or the differences in the prognostic factors, represent methodological artifacts, true differences among the populations associated with culture or genetics, or a bit of both. This commentary is not intended as a tutorial. Our textbook on psychiatric epidemiology has several chapters devoted to the design of clinical cohort studies and considerations in specifying the criteria for selecting cases and controls for clinical research (Susser et al., 2006). Rather, I would like to suggest a method for undertaking new clinical cohort studies in resource-poor environments so that we can extend our understanding of cross-national differences in illness course with relative expedience. Specifically, an economical method that can be implemented in poor settings with stable population bases is the historical cohort design, as exemplified by the classic studies of Ciompi (Ciompi, 1980), Huber (Huber, 1997), and Bleuler (Bleuler, 1978). This strategy requires that the initial presentation of the illness is carefully documented in a record, which is often the case, and also that the likelihood of locating the patients for follow-up is not biased by whether they remain in treatment. For example, one of the most influential studies in the field of psychiatry was Deviant Children Grown Up, a historical cohort study of children evaluated for behavior problems in 1924–1929 who were systematically assessed 30 years later, along with classmate controls (Robins, 1966). The richness of the original records allowed the investigator to determine the childhood predictors of adult antisocial behavior and mood/anxiety disorders. Historical cohort studies from rich, middle-income, and poor countries of the world could provide important evidence about relative differences in the psychosocial trajectories of schizophrenia and their risk factors, particularly if they employ similar methodologies and measures.

I fully agree with the conclusion of Cohen et al. that ‘‘clinical, epidemiological, and ethnographic’’ strategies are needed to identify the processes that promote good outcome in different settings. There is no debate among epidemiologists about how to design an informative clinical cohort study, and such designs can be implemented around the world. Hopefully, the next generation of schizophrenia outcomes research will fully integrate the three domains mentioned by Cohen et al. as well as biologic, genetic, and treatment moderators.

References:

Cohen P, Cohen J. The clinician’s illusion. Arch Gen Psychiatry. 1984;41:1178–1182. Abstract

Bromet EJ, Dew MA, Eaton W. Epidemiology of psychosis with special reference to schizophrenia. In: Tsuang M, Tohen M, Zahner G, eds. Textbook in Psychiatric Epidemiology. New York, NY: Wiley-Liss, Inc.; 1995:283–300.

Susser E, Schwartz S, Morabia A, Bromet EJ. Psychiatric Epidemiology: Searching for the Causes of Mental Disorders. New York, NY: Oxford University Press; 2006.

Jablensky A, Sartorius N, Ernberg G, Anker M, Korten A, Cooper JE, Day R, Bertelsen A. Schizophrenia: manifestations, incidence and course in different cultures. A World Health Organization ten-country study. Psychol Med Monogr Suppl. 1992 Jan 1;20():1-97. Abstract

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View all comments by Evelyn J. BrometComment by:  Karl-Ludvig Reichelt (Disclosure)
Submitted 19 February 2008
Posted 27 February 2008

One of the dominant differences between the developed world and developing world is food types. Already Prof. F Dohan pointed out that schizophrenia was rare where grains are rare (Dohan et al., 1984) Rice and maize are staple foods in large parts of the developing world. In other parts manioc, kasawa, etc., have a substantial role in the countryside. This could explain the faster recovery when patients in these countries are returned to their native villages (Lehtinen, 1987). Also, the acculturation following transition to grain-based diet makes sense (Lorenz, 1990). Thus, the increased rate when poor people move from developing countries to developed countries where grains and milk products are the cheaper foods.

It would also fit our data on the levels of exorphins in schizophrenic patients (Reichelt et al., 1996). (See also an example of data on intervention with diet [Singh and Kay, 1976]). Since one molecule of glutenin contains 15 exorphin sequences, it is clear that the strictness of dietary intervention is critical. Given the trophic changes of the brain, negative experiments on chronic and heavily drugged cases are not very useful. I doubt very much that developed societies are more egocentric than developing countries, and do not find much evidence for this at all. During the Second World War in Asia, this was definitely not my experience.

References:

Dohan FC, Harper EH, Clark MH, Rodrigue RB, Zigas V. Is schizophrenia rare if grain is rare? Biol Psychiatry. 1984 Mar 1;19(3):385-99. Abstract

Lehtinen V. [The epidemiology of schizophrenia] Nord Med. 1987 Jan 1;102(4):112-3, 26. Abstract

Lorenz K. Cereals and schizophrenia .Adv Cereal Sci. Technol. X 1990: 435-469.

Reichelt KL, Seim AR, Reichelt WH. Could schizophrenia be reasonably explained by Dohan's hypothesis on genetic interaction with a dietary peptide overload? Prog Neuropsychopharmacol Biol Psychiatry. 1996 Oct 1;20(7):1083-114. Abstract

Singh MM, Kay SR. Wheat gluten as a pathogenic factor in schizophrenia. Science. 1976 Jan 30;191(4225):401-2. Abstract

View all comments by Karl-Ludvig ReicheltComment by:  Robert Lemelson
Submitted 23 April 2012
Posted 25 April 2012

Our film series "Afflictions: Culture and Mental Illness in Indonesia" is the first film series on serious mental illness in the developing world. Three of the films in the series directly address issues of differential outcome for thought disorders/schizophrenia, issues raised by the IPSS and DOSMD studies. The series has won a number of awards, and should be useful for anyone teaching transcultural psychiatry, psychiatric anthropology, and related fields. Information on the series is available here.

View all comments by Robert Lemelson