The future of schizophrenia

Schizophrenia is a major public health problem. Affecting almost 1% of the world's population, it takes an enormous economic and social toll in addition to the distress, dysfunction, disability and mortality for those afflicted with this disease. Elements of the disease are present from birth, other aspects emerge during developmental years, and the illness becomes fully expressed in early adulthood with long-lasting implications for most patients.

Schizophrenia, which is seen as the paradigmatic psychiatric illness, presents different symptoms in multiple domains, whereby positive and negative phenomena can be separated (Falkai et al., 2005): Positive (psychotic) symptoms in a broader sense include delusions or delusional ideation, hallucinations, disturbance of association, catatonic symptoms, agitations as well as feelings of alien influence and suspiciousness. Negative symptoms include restricted range and intensity of emotional expression, limited thought and speech productivity, social withdrawal, and reduced initiation of goal-directed behaviour. These negative components are typically characterised as affective flattening, alogia, diminished drive, anhedonia and avolition. Furthermore, schizophrenia is associated with cognitive impairment, disorganised speech and behaviour, as well as poor attention. The primary advance in pharmacological treatment of schizophrenia was in 1952 with the introduction of dopamine antagonist antipsychotic drugs.

Paradigm shift in schizophrenia research: from single-disease entity to the paradigm of multiple domains

A century of work has been based on designs that conceptualise schizophrenia as a single disease entity, despite recognition that schizophrenia must have scientific status of a syndrome in the absence of proof of a single disease process (Carpenter et al., 1999). The implications are profound. Research based on the presumption that a single disease is present has produced weak findings that frequently fail confirmation in replication studies. The heterogeneity of patients receiving this diagnosis is substantial. Causal and neuropathological findings valid for some patients will not be found in others. Illness manifestations vary substantially between patients, and symptomatic components of illness are only weakly related to each other within individuals.

Efforts in Europe during the mid-20th Century to reduce this heterogeneity by separating ´true´ or nuclear schizophrenia from other psychotic disorders became the international standard with DSM-III (Diagnostic and Statistic Manual of Mental Disorders) in 1979. The criteria for diagnosing schizophrenia had changed radically from the original Kraepelian concept of avolition combined with dissociative pathology (Kraepelin, 1896). This was replaced by reality distortion pathology with hallucinations and delusions being prominent.

Rather than a more homogeneous disease entity being defined by nuclear schizophrenia, a syndrome with substantial heterogeneity was found. Separate domains of pathology have been defined, each with its own life history and only loosely linked with the other domains (Carpenter, 2004). First six, then three domains were viewed as critical: positive psychotic symptoms, negative symptoms, and pathology observed in the interpersonal context. A paradigm shift was proposed, moving the focus of aetiological, pathophysiological and therapeutic study away from schizophrenia as a disease entity onto specific domains of pathology (Strauss et al., 1974). This indicated a shift in schizophrenia research away from the syndrome level toward study designs that aimed to identify more homogenous entities (Carpenter et al., 1999).