Claim: Biological Toxicity by Not Using Anti-psychotic Medication for Psychosis
Fact: Read Below
Dr. Toby Watson, PsyD

There was a hypothesis that Richard Wyatt put forward in 1991 that psychotic psychosis, in and of itself, could be neurotoxic and damaging to the brain, whereby, not medicating a patient with antipsychotic medications would cause harm. There were numerous studies conducted in the 90’s showing that the average length of time from initial onset for psychosis to medical treatment was approximately 1-2 years.

Despite unfounded claims of damage following Wyatt’s hypothesis, Wyatt, Carpender and other researchers admitted they did not believe it was actually supported by postmortem examination or empirical evidence.  Nevertheless, legal journals began raising the issue of whether it was unacceptable for medication-free research to occur with patients exhibiting psychosis. This was mirrored by psychiatric researchers writing a series of articles discussing the ethical or unethical nature of supporting the use of unmedicated subjects in research studies , despite the lack of actual evidence showing any harm being caused by not using antipsychotic medication.

To combat the ever growing misinformation being put forth, researchers tried to make it clear that the psychosis-is-toxic to the brain theory was “only speculative” and not supported by the evidence.

The Evidence:

Evidence often used to support the hypothesis that not giving antipsychotic medication to a person with psychosis stems from several areas of study: biological and outcome of functioning.  However, these studies are plagued with significant methodological and conclusionary flaws.  In the case of Wyatt’s summary of research, Carpenter noted conclusions were being based largely on “uncontrolled” studies with “myriad confounds” that undermined the “relevance to understanding drug treatment effects on long term course.”  Of particular interest, there was no cohorts randomized to drug vs no drug comparison groups.  


Postmortem histopathologic investigations found reduced spine densities and smaller dendritic arbors on the pyramidal cells of the cortex in schizophrenia. The most replicated postmortem finding has been increased neuronal density in the cortex resulting from reduced neuropil without neuronal loss.  These postmortem findings for schizophrenia are milder than the findings for real neurodegenerative disorders such as Alzheimer’s, with its neuronal cell loss and reactive gliosis. Given the severity that schizophrenic clinical deterioration can reach, the telltale signs of outright neurodegeneration were assumed to exist and were sought for time and again, but to no avail, leading experts in the field to conclude that postmortem neuropathology of schizophrenia yields no specific cell phenotype, no gliosis, and little to no cell loss.

Duration of Untreated Psychosis (DUP) can correlate with longer periods of poorer outcomes.  Lieberman noted in the same DUP sample that the number of relapses into active psychosis post onset was associated with greater treatment resistance, longer time to remission and positive clinical response with each subsequent treatment. Researchers noted the DUP being neurotoxic to the brain hypothesis is “reasonable...but must be based on more than a correlation.”  Testing a causal hypothesis, as in the above hypothesis requires disproving alternate hypothesis (i.e. that a person who is genetically and neurobiologically vulnerable to a more severe form of schizophrenia also develops the overt disorder in ways that lead to DUP; individuals who present with longer DUP also have family dynamics that lead to worsening of symptoms that are unrelated to neurobiology but more related to secondary avoid-treatment behaviors).

In order to rule out these other hypotheses that are equally valid for drawing a causal link conclusion, one would need to test this alternate hypothesis  (i.e. vulnerability or family dynamics related to psychosis severity may determine DUP rather than vice versa).  This is methodologically challenging in that it requires the prospective prediction of schizophrenia severity and of DUP by measures of premorbid prognosis in nonsymptomatic samples.  In essence, it requires long-term follow along of a very large prospective birth cohort sample. Because it would take many years and many subjects, a controlled, randomly assigned study has never been conducted.  In contrast, replicating the DUP-outcome correlation,  requiring an interview to measure only 2 variables (DUP and some outcome), has given rise to a tidal wave of ‘‘DUP studies.’’  

Structural and functional scan studies measuring mass brain, cortical, frontal and temporal gray matter volumes have often been found to be smaller in unmedicated patients when compared to controls; however, these studies all have one major confounding variable in that individuals who are diagnosed with schizophrenia are under much greater stress than the controls being used.

It is commonly accepted in the medical literature that individuals under high stress produce more glucocorticoid (cortisol) than their non-highly stressed controls.  Patients experiencing psychosis have higher levels of stress than their counterpart non-diagnosed controls, and increased cortisol levels produce brain atrophy (i.e. shrinkage of the brain).  Thus, any mass or subpartal differences in size of brain matter can be accounted for by normal brain responses to stress.  Thus, non-pharmacologically treated individuals with differing brain volumes may have these differences simply due to a normal hypothalamic-pituitary-adrenal (HPA) response system.

[This understanding about chronic elevations in cortisol levels also may explain some of cognitive deficits schizophrenia patients often exhibit, as both acute and chronic cortisol elevations do in fact produce cognitive deficits. High cortisol levels can cause weight gain, osteoporosis, digestive problems, hormone imbalances, cancer, heart disease, diabetes, exhaustion, mood swings, poor sleep, impaired attention.  Cortisol stress hormone has been called “Public Enemy No. 1.” ]

Researchers also attempt to conclude brain damage by acknowledging that lateral ventricles are enlarged with patients who have not been given anti-psychotic medications; however, this too fails to take into account the research demonstrating that one of the functions of the lateral ventricles is to support overall brain movement (i.e. to ensure the brain does not slosh around in the skull).  When an individual is under stress, cortisol is produced, the brain shrinks, the lateral ventricles increase to ensure the brain does not move about.  Thus, again what is being portrayed as neurocognitive damage is really a normal response to high stress.  

Further, when individuals are given anti-psychotic medications, this phenomena is exaggerated even greater, as gray matter can be reduced and destroyed approximately 5% per year.  This loss of overall brain tissue is cumulative, meaning that after 5 years of continual antipsychotic medication usage, upwards of 25% of the matter has been destroyed.  This in turn also leads to greater brain atrophy and increasing lateral ventricles.

Further, neuroscientific researchers have known for years about the toxic effects of significant stress and prolonged cortisol elevations, as they have found reductions in hippocampal volume and deficits in hippocampus-dependent memory tasks when compared to non-high stressed or high cortisol leveled individuals.   

In a MRI study, Fannon et al. examined 37 never or minimally treated patients with a first episode of psychosis (schizophreniform disorder, schizophrenia, or schizoaffective disorder) and 25 matched normal comparison subjects. Patients had a relatively short (31-week) average duration of psychosis (retrospectively determined). Confirming the results of previous reports, the authors found that the patients with psychosis revealed significantly smaller whole brain volumes and smaller cortical and temporal gray matter volumes and significantly larger lateral and third ventricle volumes than comparison subjects. However, no relationship between the duration of prior psychosis and any regional brain volumes was detected.

Uncompleted review…

Dr. Watson

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