“Despite the substantial evidence and compelling rationale of the neurodevelopmental theories [in that schizophrenia adheres to a developmental model in which the primary developmental defect gives rise to pathologic ramifications iteratively through the various stages of neurobiological development], there are certain aspects of schizophrenia that are not adequately explained. Among these are the long latency period and the heterogeneous but commonly deteriorating clinical course of the illness. Another important factor that is central to the arguments to follow is the apparent ability of treatment to modify the course of the illness. Thus, although there can be little doubt that the neurodevelopmental factors play an important role in the diathesis from which schizophrenia arises, other pathophysiologic processes may also be involved. Chief among these is the potential role of neurodegeneration suggested by the original observations of Kraepelin (1919), who characterized schizophrenia (dementia praecox) by its progressive and deteriorating course” (Lieberman, 1999).

Since the 1990s, scientists in the field of schizophrenia research have heatedly argued over whether schizophrenia is a neurodegenerative or neurodevelopmental condition. Even the eminent psychiatrist, Emil Kraepelin, noted that the cognitive abilities of individuals with schizophrenia often progressively deteriorated. However, both genetics and teratogenic studies have shown conclusively that prenatal risk factors do play a role in schizophrenia’s occurrence.

The German psychiatrist, Emil Kraepelin, famous for studying “dementia praecox” aka schizophrenia.

While there appear to be few scientists today who disbelieve the important role the prenatal environment and genetic predisposition play in schizophrenia, there is still debate and a genuine lack of consensus as to whether schizophrenia is also a neurodegenerative condition.

A study published last August in JAMA by Kubota et al. (2015) adds to the ever-growing yet still inconclusive evidence of neurodegeneration in schizophrenia. As is a common finding in various neurodegenerative conditions, the team reports strong evidence of cortical thickness and volume loss as well as ventricular enlargement in schizophrenia in relation to cognitive decline.

So why do so many scientists still not view schizophrenia as both a neurodevelopmental and neurodegenerative condition? The most likely culprit is rooted in semantics. In the traditional sense, “neurodegeneration” is defined not only by symptomatology but ultimately by histopathology. You’ve probably heard, for instance, that Alzheimer’s can’t be diagnosed definitively without a postmortem brain examination? Well, this is somewhat similar– except in schizophrenia’s case, there is no obvious evidence of gliosis, which is a staged reaction of glial cells to a brain injury, and necrosis in which the cell basically explodes. There is however evidence of apoptosis, which, in contrast to necrosis, is a more orderly form of cellular suicide and tends to result in less damage to the surrounding tissue.

So, we have cell loss at the microscopic level, we have volume reductions at the larger tissue level, and we have a group of people whose cognition and behaviors often deteriorate over time. But schizophrenia isn’t definitively neurodegenerative?

As I’ve talked about in previous posts on cell stress and the Unfolded Protein Response (UPR), and as I’m also starting to suspect exists within a subset of the autism spectrum as well, I believe what we have in schizophrenia– if perhaps only in a distinctive subset– is a genuine neurodegenerative condition and what is lacking in science is a fuller understanding of the spectrum of neurodegenerative disorders. In support of this interpretation, the use of nonsteroidal anti-inflammatories (NSAID) which are known to relieve (or sometimes unfortunately exacerbate) the UPR and decrease cellular stress have been used with some success in early trials in treating both positive and negative symptoms in schizophrenia [1].

Is schizophrenia akin to Alzheimer’s or Huntington’s or Parkinson’s? No. Those conditions all share a sharp and definitive decline in abilities, ultimately leading to death. But that most likely is just the tip of the neurodegenerative ice berg, so to speak. On the other milder end, we may have conditions whose deteriorations are milder and may even wax, wane, or cease altogether. After all, different developmental time periods tend to have different ceilings for risk that change with age. Febrile seizures, for instance, occur typically within the middle infancy-to-toddler ages and then significantly decrease once a person hits childhood– and yet the same stimulus, the fever, occurs sporadically throughout the lifetime. Why else would the severity of schizophrenic psychotic episodes typically reduce by middle age if not for a changing risk “ceiling”?

In fact, when considering endoplasmic reticular stress and the UPR, even prolonged anxiety could be considered an extremely mild form of neurodegeneration as it would cause a similar, albeit ameliorated, response and trigger the same downstream set of events, leading to structural loss and regrowth depending on the brain region studied [2].

Though I’m not a scientist who actively studies schizophrenia and am by no means an expert on the literature in that area, as an outsider scientist looking in, it seems blaringly obvious to me that many features of schizophrenia SCREAM neurodegeneration and is no doubt why the question has been ask and re-asked so often. True, the flavor of the neurodegeneration may be weaker compared to conditions like Lewy Body Dementia making it more difficult to spot, but there’s still a common underlying theme.