The idea that schizophrenia is a progressive brain disease was a prominent aspect of the disease concept when defined as Dementia Praecox
by Kraepelin at the end of the 19th century (1896–1899).1
While hallucinations, delusions, formal thought disorder, and disturbances in affect have been described since ancient times,2
thinking about their origins did not seem to occur in the literature until close to Kraepelin's time. As he wrote in his 1899 textbook: “ …. In view of the clinical and anatomical facts known so far I can not doubt we are dealing with serious … and only partially reversible damage to the cerebral cortex … 75% of cases reach higher grades of dementia and sink deeper and deeper ….”1
He then further described what he considered the neuropathology of schizophrenia and illustrated it in his 1919 volume, as “nerve cells diseased in high degree filled with lipoid products of disintegration.”3
On the other hand, Eugen Bleuler, also an influential thinker about the psychoses, who coined the term “schizophrenia” during this same era, only partially supported this notion and considered the possibility that these were not conditions due to brain damage, rather a “splitting of the mind” that could recover and that there were several possibilities for outcome, not only a progressive deteriorating one.4
Another contemporary of Kraepelin and Bleuler, Karl Jaspers, seemed to adopt the concept that this was a biological brain disorder, but did not address the issue of progression because his interest was more in the phenomenology itself.5,6
Thus, the concept of progression was focused on mainly by Kraepelin at that time and was certainly controversial from its beginnings.
Kraepelin's writings were followed in the early 1900s by a few large pneumoencephalographic studies7–11
describing evidence of brain ventricular enlargement in chronic schizophrenia. The few patients who had second follow-up studies a few years later also appeared to have further ventricular enlargement and thus evidence of a progressive brain disease (see ).
Pneumoencephalographic Evidence of Progressive Ventricular Brain Enlargement in Chronic Schizophrenia
Later in the 1900s, however, because the infectious and neoplastic disorders of the brain were separated from “psychiatric illness,” schizophrenia became a diagnosis of exclusion that was by definition thought to have no “organic” cause and thus related to the psychological environment that one was born into. It was acceptable in the mid-1900s for these patients to be treated with long-term psychoanalysis12–14
and family therapy15–17
and described as having schizophrenigenic mothers and bad family communication, despite the accumulation from twin and family studies that an inherited component increased risk for illness more substantially. There were 2 main discoveries that seemed to turn the tide back toward uncovering biological origins to schizophrenia, ie, the large effect of neuroleptics in suppressing symptoms of illness and the family adoption studies that showed it was not the environment, but rather inheritance that determined who did or did not develop schizophrenia.
It was not, however, until the 1970s when schizophrenia began again to be considered a biological disorder, that the previous pneumoencephalographic studies were confirmed using computerized tomography (CT). In initially a small cohort by Johnstone et al18
in 1976 and then a considerably larger one in 1978 by Weinberger et al19
, significantly increased ventricular size was reported in people with chronic schizophrenia compared with age-corrected controls that did not appear to be associated with years of illness or pharmacologic treatment. This is perhaps the most replicated finding in schizophrenia research today, more than 30 years later.
The nature of what is heritable is currently being investigated worldwide applying the newly emerged methods now available in molecular biology. What most investigators agree upon is that the inherited component has an effect on brain development and homeostasis. Although, specific genes or genetic pathways have not yet been definitively elucidated, a new field of “imaging the genome” has arisen from studies recently combining an examination of brain structure and function with genetic variation in such interesting brain-expressed genes as brain-derived neurotrophic factor (BDNF) and catechol-O-methyl transferase.20
Certainly, if there is a progressive component to the disorder, this could also be a characteristic of the genetic pathology, as is with other neurodegenerative disorders, such as Huntington Chorea or Alzheimer disease. One recent preliminary report even provides data suggesting that variation in the BDNF gene contributes to progressive brain change in schizophrenia.21
While if true, this could be an important finding that leads to considerable progress in understanding schizophrenia, it will need clear replication before time is invested further in a focused attempt to develop treatments that will combat the effects of inheriting this variation.
Once definitive genes for schizophrenia are established, it will be important to determine whether and how they could produce progressive brain changes. This will only be relevant, however, if the observed progressive component is central to the illness process, rather than due to secondary environmental effects (treatment or stress that accompanies the chronic illness course). Even if progression is central to the illness process, some investigators may propose that it is separate from the genetic vulnerability and represents a second so-called “hit” that leads to illness that could be environmentally or epigenetically induced (ie, such as stress, substance abuse, and hormonal disregulation, eg, Pantelis et al22
The evidence that currently exists for progressive brain change is thus discussed in the following review; the where, why, and when of progression are suggested based on existing knowledge; and future research needed to clarify the concept of progressive change and its relevance for understanding and treating schizophrenia are proposed.