My comments on “Is active psychosis neurotoxic?” by T. H. McGlashan” published in the Schizophrenia Bulletin (vol 32 no. 4 pp. 609-613).

First, I shall summarize the McGlashan article. In this article, he approaches the question, which has been taken as dogma by many in our field, is active psychosis, i.e., the presence of hallucinations and delusions, neurotoxic?  The prevailing viewpoint is that indeed it is and that neuroleptic agents, whether first- or second-generation, are neuroprotective: without their protective coverage, the “schizophrenic brain” will deteriorate further and that there exists a dose-response relationship between frequency of relapse and time to recovery, i.e., every psychotic relapse makes it that much more difficult for the person to achieve stability.  McGlashan orients us to the question by taking us on an abbreviated, but very relevant, tour of the history of biological psychiatry as applied to the schizophrenias, starting with the viewpoint of Emil Kraepelin on schizophrenia as an early form of dementia which is neurodegenerative.  Manfred Bleuler, son of Eugen Bleuler who gave us the term “schizophrenia,” decades later, presented us with a more benign view of the course and outcome of the disorder.  A review of retrospective data in chronic schizophrenia suggests that the deterioration is most apparent in the first three years of active illness.  McGlashan, in commenting on the neuroanatomical research, noted:

“The data that have been produced support a picture of reduced synaptic connectivity between brain neurons rather than a reduction in the number of neurons.  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 [axons, dendrites, etc.] without neuronal loss...Given the severity that schizophrenic 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” (p. 610).

The origins of the viewpoint that untreated psychosis, often referred to as DUP (duration of untreated psychosis), is neurotoxic and that neuroleptic agents, such as zyprexa, clozaril and risperdol, are neuroprotective can be traced back to the research of Richard Wyatt.  The latter concluded that antipsychotic agents treat active psychosis and prevent deterioration.  Untreated psychosis came to mean untreated with antipsychotic agents.  However, a research study by de Haan et al/ (2003) published in Schizophrenia Bulletin documented that withholding of psychosocial treatment can be equally, if not more, detrimental to psychotic patients (de Haan et al (2003).  Duration of untreated psychosis and outcome of schizophrenia: delay in intensive psychosocial treatment versus delay in treatment with antipsychotic medication.  Schizophrenia Bulletin, 29 (2), pp.341-348).

Research studies by Loebel et al. and Lieberman supported the view that there was a negative dose effect of active psychosis on long-term course, i.e., neurotoxicity.  DUP was made a strong focus of research thanks to the efforts of Pat McGorry and colleagues at the Early Psychosis Prevention and Intervention Center (EPPIC) in Melbourne.  Correlational data on the association between longer DUP and poorer outcome took on the weight of a causal relationship.

McGlashan gathers together a great deal of research evidence demonstrating that it could not be true that untreated active psychosis is neurotoxic.  The latter does not behave like typical neurodegenerative illnesses, e.g., the DUP effect plateaus (in fact the differences in outcome between a long and short DUP are minimal), we would not see neurodegenerative effects prior to the emergence of positive symptomatology, the relapse-dose effect would continue beyond the window of functional deterioration, etc.  If DUP were neurotoxic, we would expect to observe evidence of neuronal death and/or gliosis as a reaction to neuronal death.  The postmortem brains of persons with schizophrenia show neither gliosis nor loss of neuronal cell numbers for the most part.  McGlashan notes: “Once the plateau is reached, the positive symptoms of schizophrenia neither become more and more severe nor become harder to treat after each relapse” and “Neuropathology, like longitudinal course, does not support the hypothesis that untreated psychosis is neurotoxic”(p. 611).

McGlashan proposes an interesting alternative hypotheisis to neurotoxicity: psychosis as emerging from reduced connectivity.  This synaptic plasticity hypothesis centers on significantly reduced neuropil, i.e., the synaptic syncytium between neurons.  Hoffman and McGlashan (1993) demonstrated that such schizophrenic symptoms as auditory hallucinations can be simulated in computer models by reducing the connections within a putative neuronal network.  This model proposes that reduced connectivity precedes symptom formation and generates characteristic psychotic symptomatology.  McGlashan makes the bold claim that symptom formation, once present, can change levels of connectivity between neurons via positive and negative information feedback loops, e.g., could chronic preoccupation with delusions and/or hallucinations decrease the use of certain neural pathways leading to content-driven alterations in connectivity, i.e., disuse atrophy in some circuits and overuse hypertrophy in other circuits?  Now for the crux of his argument, McGlashan states:

“In such a system, any treatment (including antipsychotics) that reduces psychotic symptoms might also release the brain from its aberrant, symptom generating, wiring, and reengage the patient in a cognitive dialogue with the real world as opposed to a world of psychotic creations.  Reunion with reality reestablishes a richer fabric of complimentary neuronal connectivity...Time and degree of immersion in a mental state of psychosis is the culprit here, leading to atrophy of wordly-wise judgment and skills and to atrophy of the synaptic connections underpinning these skills...Antipsychotic medication works...by reengaging the patient in the world on a more complex level with greater investment and cathexis, not by being ‘neuroprotective.’  The process mediating these changes, both destructive and ameliorative, is the process of learning, i.e., changing synaptic plasticity, not changing neuronal number” (p. 611).

For McGlashan the problem in schizophrenia is significantly attenuated synaptic plasticity secondary to withdrawal from the daily commerce of living.  Therefore, efficacious treatment must minimize psychotic distortions with medications and asylum firstly, and then attempt to maximize reengagement with reality via medications and outreach strategies which “...together preserve salience and promote real world investment” (p. 612).  Minkowski (1927), like Eugen Bleuler (1911), was impressed by the nature of schizophrenic autism, the patient’s impaired vital contact with her or his world and incapacity to resonate, to establish meaningful emotional bonds with others.  Gallese (2003b), mirror neuron researcher, commented on the patient’s difficulties in establishing a precognitive, intuitive interpersonal bond with an other in schizophrenia.  It is McGlashan’s emphasis on withdrawal from the daily commerce of living which is a zone of convergence for the PostKleinian psychoanalytic viewpoint of Franco De Masi (“Psychotic withdrawal and the overthrow of psychic reality” published in the International Journal of Psychoanalysis in 2006, vol. 87 pp 789-807).  I would like to make some points which differentiates my position from McGlashan’s.

For almost two decades I have been calling attention to the fact that the neuroscience of severe mental illness overlaps significantly with the neuroscience of profound stress/fear/anxiety and the neuroscience of social isolation, exclusion and defeat.  I have written many papers demonstrating this at the level of molecular biology, as well as at more macro levels of systems neurobiology and psychobiology.  I do believe that psychotropic agents which reduce excessive cortisol levels, as do certain antipsychotic and anxiolytic agents and glucocorticoid antagonists, can potentially be neuroprotective, particularly if used in nonreductionistic ways.  There is research data demonstrating that benzodiazepines can be very beneficial, e.g., minimizing stress-induced exacerbations of psychosis (Wolkowitz, 1996) as well as being effective when used as the sole agent in the treatment of schizophrenia (9 out of 14 double-blind studies demonstrated this, resulting in many authors claiming that BZs even when used alone may have mild antipsychotic efficacy in some patients.  Yrjö Alanen, retired professor at the University of Turku, reported that approximately 50% of their newly diagnosed psychotic patients did not have neuroleptic exposure due to their emphasis on psychotherapy and the use of anxiolytic medications for sleep and agitation.  Parenthetically, psychologist Jaako Seikkula and colleagues using their psychosocial treatment intervention called Open Dialogue Treatment (ODT), an approach which does not emphasize pharmacotherapy and focuses instead on developing a social network of family and helpers and involving the patient in all treatment decisions (something I never witnessed in my work in city and state psychiatric hospitals), in ongoing research in Finland, has shown that over 80% of those treated with this approach return to work and over 75% show no residual signs of psychosis.  Official government statistics comparing 22 health districts in Finland found that Dr. Seikulla’s district was the only one not to have any new chronic hospital patients in a two year period and led the National Research and Development Center for Welfare and Health to award a prize for his ten years of ongoing care of psychiatric patients.

Unlike McGlashan, I see a significant role of sociocultural factors not only in the course and outcome, but also, in the initiation of the schizophrenic and bipolar disorders.  There is emergent data demonstrating this (see Jane Boydell, Jim van Os and Robin Murray 2004, in their “Is there a role for social factors in a comprehensive developmental model for schizophrenia?”contained in an excellent volume Neurodevelopment and Schizophrenia edited by Matcheri Keshavan, James Kennedy and Robin Murray in 2004 for Cambridge University Press and the psychosocial research on bipolar disorder has been summarized in “Psychosocial predictors of symptoms” by Sheri Johnson and Björn Meyer in Psychological Treatment of Bipolar Disorder edited by Sheri Johnson and Robert Leahy in 2004 for The Guilford Press).

Brian Koehler PhD
Postdoctoral Faculty
New York University
80 East 11 Street #339
New York NY 10003
212.533.5687

From Grace Jackson, M.D. 061221
Hi Brian --

I appreciate your thoughtful review of the McGlashan paper. I have just a few reflections to add to your erudite remarks:

First:  The data on postmortem brain findings is not entirely correct.

Jellinger (1977) published the postmortem findings of 28 patients diagnosed with a variety of conditions, all of whom were exposed to neuroleptics for as long as 5 yrs. 

The postmortem findings were significant for reactive gliosis in the basal ganglia of 47% of these patients.  This was a very significant finding, given the fact that only 4% of non-neuroleptized patients with similar diagnoses demonstrated the same kind of scarring (gliosis), and only 2% of a group of neurological control patients manifested the same changes.

In the 1960s, Roizin published several papers which demonstrated autopsy findings of reactive gliosis throughout the brains of patients exposed to neuroleptics.  Gershon documented the same changes in guinea pigs exposed to chlorpromazine and reserpine.

Neuronal dropout has been evidenced in the frontal cortex of postmortem schizophrenic patients exposed to neuroleptics ------ many times, these changes are missed because research teams employ different staining methods or different stereological procedures.  Also, the changes are not necessarily uniform throughout the layers of cortical tissue.

Finally, it is important to realize that neuronal loss may occur without inflammatory reactions, as p53 may be activated early on to induce DNA repair, and phosphatidylserine may not be flipped to the outer leaflet of cell membranes to generate inflammatory responses by T-cells and other members of the immune system.

Since a large body of evidence demonstrates how and why neuroleptics ---old and new -- induce apoptosis [which is distinguished from necrosis by the lack of inflammatory reaction] -- it would be premature to suggest that DUP  does NOT  lead to degenerative change, based solely upon the lack of  reactive gliosis.    One would have to simultaneously measure the rates of apototic cell LOSS ,  along with the rates of neuronal proliferation AND differentiation.  at this time, there are no technological methods which permit simultaneous determination of these
three processes (rates of change).

I am not aware of any study that has compared autopsy findings from the brains of UNTREATED new psychotics  ---  in the present Zeitgeist, it has become all but illegal for youngish (40s) physicians such as myself to participate in neuroleptic free treatment.   Perhaps there is more freedom in other countries, but it is professional suicide in the USA to fight the HERD mentality/Group Think which mandates the use of neuroleptics and other drugs in all patients, usually for life.

I would LOVE to live in a country where a doctor COULD participate in neuroleptic free treatment, without living in TERROR that his or her license is about to be seized, or where the same doctor could actually enjoy an academic appointment, or even -- God forbid -- the respect of one's peers.  Such a freedom does not exist for physicians in the United States of America in the year 2006.

I am not as enthusiastic about the use of corticotrophin antagonists, CRH blockers,  or anxiolytics as you are,  perhaps because I am more fearful of the unintended consequences of these interventions --  such as, allostatic load which leads the human body to REACT to the interventions with opposite or worse  adaptations [i.e, UPREGULATION of cortisol receptors]; and an epidemic of Addison's disease.

In the case of CRH antagonists and cortisol/corticosterone inhibitors/blockers, we must remember that the human organism was created to USE these chemical transmitters and hormones for the fight or flight response ---- when we artifically induce a "shut off" or disabling of these same systems, we will render the recipient of these pills (or in 20 years, the gene therapies)  entirely  helpless when it comes to possessing the necessary response mechanisms which promote survival

[one can already predict the future military applications of nanotechnologies ---deliver the CRH antagonists into the food or water supply ofyour worst enemy, and see what happens.................................

As for benzos as an effective tool for diminshing psychotic anxiety: yes, I believe Loren Mosher generated similar responses by using antihistamines in the Soteria cohorts.  When he said that half of the patients were able to get through the initial psychosis without neuroleptics, he also mentioned in his public lectures that some of the folks received antihistamines.

Unfortunately, neither Mosher nor the Finnish folks seem to have contemplated the long term toxicities associated with benzos or antihistamines.

The human organism is wired for certain responses --- indeed, the evolutionary psychologists would suggest that psychosis is a genetically programmed adaptive response to stress overwhelm --and not until psychiatry/psychology as a whole understands WHY those responses are called into play will there be a rational approach to  reversing them

Best,
Grace