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Updated 5 October 2006 E-mail discussion
Printable version

Forum Discussion: Is Active Psychosis Neurotoxic?


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In our Forum discussion “journal club” series, the editors of Schizophrenia Bulletin or Schizophrenia Research provide access to the full text of a new article. A short introduction by a journal editor, below, gets us started, and then it's up to our readers to share their ideas and insights, questions and reactions to the selected paper. So read on…

View Comments By:
Robert McClure — Posted 10 November 2006
Karl-Ludvig Reichelt — Posted 22 November 2006
Mariano Scolari — Posted 27 November 2006


Background Text
By Gunvant Thaker, Maryland Psychiatric Research Center, and Associate Editor, Schizophrenia Bulletin

In the latest issue of Schizophrenia Bulletin, Tom McGlashan raised an important question: Is active psychosis neurotoxic? (See McGlashan, 2006.) This has been a controversial issue for some time in our field and has tremendous implications for how we focus our treatment in our patients and our research activities to identify novel treatment strategies. The hypothesis originated based on an interesting paper by Wyatt on the effects of antipsychotic medications on the natural course of schizophrenia (Wyatt, 1991). Subsequent early intervention and first episode studies further supported the hypothesis. However, most of this supporting evidence is derived from correlational analyses where causal effects are impossible to infer, or from uncontrolled and/or observational studies where random assignment to different treatments didn’t occur. Tom McGlashan further points out that several predictions based on the neurotoxic hypothesis are not validated by the existing data. Controlled clinical trials of schizophrenia that used random assignment and placebo arm can be informative in this regard. John Bola recently reviewed these studies and concluded that there was no evidence of long-term harm to individuals whose psychosis remained untreated during the double-blind trial (Bola, 2005; SRF related news story).

The onset of schizophrenia is defined by the onset of psychotic symptoms (“first break”), whereas impairments in other domains such as cognitive and neurophysiological function, as well as social and occupational deterioration and negative symptoms, emerge at different times. Whether treatment of one domain of symptoms/impairments affects the emergence or the course of the other domains remains unknown. This question is as much relevant for identifying treatments for the neurophysiological and cognitive deficits of schizophrenia that frequently precede psychosis as it is for the early and aggressive treatment of psychosis.


Comments on Online Discussion
Comment by:  Robert McClure (Disclosure)
Submitted 10 November 2006 Posted 10 November 2006

In 2001, in an Archives of General Psychiatry paper, Danny Mathalon and colleagues expressed concern that the neurodevelopmental hypothesis was threatening to overshadow the neurodegenerative hypothesis of schizophrenia (Mathalon et al., 2001). They made this statement while publishing their MRI results, demonstrating longitudinal increases in cerebrospinal fluid and decreases in regional brain volumes in schizophrenic subjects, measured with MRI. Their findings were consistent with other MRI studies showing progressive longitudinal brain volume change in schizophrenia. Although the paper was excellent overall, and very well-executed, I took issue with their interpretation of the findings (Weinberger and McClure, 2002). Specifically, we disagreed with the idea that quantitative measures of CSF space and regional brain volume with MRI could constitute evidence that brain tissue has degenerated. Danny Weinberger and I also...  Read more


View all comments by Robert McClure

Comment by:  Karl-Ludvig Reichelt (Disclosure)
Submitted 17 November 2006 Posted 22 November 2006

Most of the evidence collected shows a considerable genetic disposition for schizophrenia (Onstad et al., 1991; Kendler and Diehl, 1993). This means there must be chemical changes secondary to some protein deviations. (If not, it is not genetic at all.) It is therefore not the psychosis which is toxic, but the psychosis is due to toxic/damaging substances affecting the brain. The increase in opioid receptor binding compounds of peptide nature (opioids) can explain this (Lindstrom et al., 1986; Reichelt et al., 1996), not the least because opioids induce Fos antigen in many of the key nuclei of the brain (Sun et al., 1999). Opioids have been shown to be trophic substances in brain development (  Read more


View all comments by Karl-Ludvig Reichelt

Comment by:  Mariano Scolari
Submitted 24 November 2006 Posted 27 November 2006

If active psychosis is neurotoxic, it is very important to find out the molecular mechanisms that promote it, because they would provide new therapeutic strategies for the treatment of schizophrenia. The question that arises is: What distinguishes a neurotoxic disease from a neurodegenerative one? Is it the processes implicated? The number of neurons lost with time? Maybe one could consider neurotoxicity as an acute process and neurodegeneration as a chronic event.

In light of the data reviewed in this interesting paper, it is probable that a change of terminology will be necessary. Consider the following fragments in the text: “Neuropathology, like longitudinal course, does not support the hypothesis that untreated psychosis is neurotoxic” and “…the theory assumes that reduced connectivity precedes symptom formation and is generative of characteristic symptoms.” These statements establish the necessity of distinguishing neurotoxicity and the loss of connectivity or synaptic contacts. Although both processes imply structural changes, in the case of neurotoxicity, these...  Read more


View all comments by Mariano Scolari
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