Arguments for and against heterogeneity in the aetiology of schizophrenia

Abstract

Phenotypic variability and likely extensive genetic heterogeneity have been confounding the search for the causes of schizophrenia since the inception of the diagnostic category. The inconsistent results of genetic linkage and association studies using the diagnostic category as the sole schizophrenia phenotype suggest that the current broad concept of schizophrenia does not demarcate a homogeneous disease entity. Approaches involving subtyping and stratification by covariates to reduce heterogeneity have been successful in the genetic study of other complex disorders, but rarely applied in schizophrenia research. This article reviews past and present attempts at delineating schizophrenia subtypes based on clinical features, statistically derived measures, putative genetic indicators, and intermediate phenotypes, highlighting the potential utility of multidomain neurocognitive endophenotypes.

Keywords:

Schizophrenia, heterogeneity, pleiotropy, subtypes, genetics, endophenotypes

Top of page

Introduction

More than a century since the delineation of dementia praecox by Kraepelin,¹ the aetiology, neuropathology, and pathophysiology of schizophrenia remain elusive. Despite the availability of criteria^{2, 3} allowing reliable diagnostic identification, schizophrenia essentially represents a broad clinical entity defined by subjective symptoms, behavioural signs, and patterns of course. Research has marked out numerous biological indicators tentatively associated with the disorder, including neurocognitive dysfunction, brain dysmorphology, and neurochemical abnormalities. Yet none of these variables has to date been definitively proven to possess the sensitivity and specificity expected of a diagnostic test. Genetic linkage and association studies have targeted multiple candidate loci and genes, but failed to demonstrate that any specific gene variant, or a combination of genes, is either necessary or sufficient to cause schizophrenia.^{4, 5, 6} Thus, the existence of a specific brain disease underlying schizophrenia is still a hypothesis, for which no conclusive proof or refutation has yet been produced.

The paradox of an ever increasing volume of research data, and the apparent stalemate of the search for causes of the disorder, has fuelled doubts about the validity of the schizophrenia construct, some leading to proposals to discard the category^{7, 8} or to replace it with a pre-Kraepelinian notion of a unitary 'psychosis'.⁹ Given the protean nature of the symptoms of schizophrenia and the poor coherence of the clinical and biological findings, such doubts are not without reason. However, simply dismantling the concept is unlikely to beget an alternative model that would account for the host of clinical phenomena and research data consistent with a disease hypothesis of schizophrenia. A well replicated epidemiological finding is that, on average, about 1% of the population develop schizophrenic disorders in their lifetime.^{10, 11} Further evidence that schizophrenia is not an arbitrary construct comes from the relative invariance of its clinical presentation and incidence across populations and over time, established by field research conducted by the World Health Organization (WHO) in over 20 diverse populations and cultures.¹²

In this article, we survey the evidence for phenotypic variation and likely aetiological heterogeneity as major sources of inconsistent findings and argue that, like other complex disorders, schizophrenia is not a nosological monolith. We review past and present attempts at delineating subtypes based on clinical features, statistically derived measures, putative genetic indicators, and endophenotypes. The end point is that conceptual and methodological constraints, well articulated in the genetics of complex disorders, have not been adequately considered in schizophrenia research.

Top of page

Arguments for and against heterogeneity in the aetiology of schizophrenia

The debate on heterogeneity and the likely existence of aetiologically distinct subtypes has waxed and waned in the schizophrenia literature without ever reaching a closure. Over 10 years ago, the editors of Schizophrenia Research invited researchers to state reasons for and against schizophrenia being a homogeneous single disease.¹³ In summary, the arguments were as follows.

Date: 2016-04-22; view: 845