Schizophrenia is not a progressive brain disease

DSC_0072 1 (2)Despite Emil Kraepelin’s early characterization of dementia praecox, the disorder or disorders that we now call schizophrenia are not characterized by dementia, or inevitable loss of cognitive ability and function. Dr. Robert B. Zipursky, Professor of Psychiatry and Behavioural Neurosciences at McMaster University in Hamilton, Ontario, said that psychiatrists may share Kraepelin’s impression of a malignant illness because of the clinician’s illusion, which arises from the biased sample of patients that psychiatrists treat, i.e. people with chronic, relapsing illness and multiple co-morbidities who come to hospitals (1). According to Professor Zipursky, who spoke at the 9th Annual Pacific Psychopharmacology Conference in Coquitlam, BC on September 18, 2015, available studies indicate that about 70% of people with first-episode psychosis will achieve remission within a year; he defined remission as having positive symptoms no greater that mild in severity and negative symptoms no greater than moderate in severity.

First-episode psychosis includes patients with various diagnoses including bipolar disorder, schizoaffective disorder, brief psychotic disorder as well as schizophrenia. Patients who achieve functional recovery, however, represent a smaller group, especially in those confirmed to have schizophrenia. In long-term outcome research, 20% or fewer of people with schizophrenia meet criteria for recovery defined as sustained remission of symptoms and success in social relations and competitive employment.
Some psychiatrists have concluded that this long-term functional impairment is due to progressive cognitive deterioration which may occur with untreated or chronic positive psychotic symptoms. A related hypothesis is the “neurotoxicity of psychosis” which posits that persisting psychosis leads to ongoing loss of cerebral tissue as manifested by enlarged ventricles and cortical atrophy on neuroimaging, accompanied by worsening deficits on neuropsychologic testing. Consequently, many clinicians working in first episode psychosis accept that the duration of untreated psychosis is an important determinant of long-term outcome.

While he acknowledged that deficits in grey matter volumes observed with MRI are more prominent in chronic patients, Dr. Zipursky asserted that many factors may contribute to this such as sampling bias; concurrent substance use including cannabis, tobacco and alcohol; lack of physical activity; and chronic antipsychotic therapy. The latter is controversial, but he cited a meta-analysis of longitudinal MRI studies in which change in grey matter volumes was correlated with antipsychotic exposure but not illness duration or severity (2). However, he emphasized that relieving suffering and improving function are the goals of treatment, not specifically increasing cerebral volume, which is affected by various factors mentioned before. Furthermore, Dr. Zipursky showed compelling evidence that following a first episode of schizophrenia, antipsychotic discontinuation is by far the most important cause of relapse.

Duration of untreated psychosis (DUP) has a small correlation with treatment outcome, likely accounting for less than 5% of the variance in clinical outcome measures, and questionable association with cognitive functioning and structural brain measures, according to Dr. Zipursky. He presented evidence that it is a risk marker for poor outcome in schizophrenia as opposed to a causative risk factor. “It’s not certain that it relates to improving outcomes, but it does relate to reducing suffering,” Zipursky said.
He concluded that to improve outcomes and promote functional recovery, antipsychotic medication is crucial but so are psychosocial interventions to manage substance use, educate families, provide adequate housing and income support when needed, and engage patients in vocational rehabilitation and supported employment.


Zipursky RB, Reilly TJ, Murray RM. The myth of schizophrenia as a progressive brain disease. Schizophr Bull. 2013;39:1363-1372. Full text

Fusar-Poli P, Smieskova R, Kempton MJ, Ho BC, Andreasen NC, Borgwardt S. Progressive brain changes in schizophrenia related to antipsychotic treatment? A meta-analysis of longitudinal MRI studies. Neurosci Biobehav Rev. 2013;37:1680-1691. Full text