Monday, October 11, 2010

Do Neuroleptics Increase an Aberrant Neurodegenerative Autoimmune Response?

Long, 2250 words, difficult, give yourself a chance. My conclusion is that the current approach to treating schizophrenia could very well be inducing neurodegeneration through an autoimmune mediated pathology. I examine this from the perspective of heat shock proteins, autoimmunity, and neuroimmunology. This raises very serious questions about the current emphasis on "pre treating" so called "pre-psychotic" individuals.

This recent news item caught my interest because it relates to a set of immune cells that play a cardinal role in autoimmunity and cancer prevention. The news item addresses gamma delta T cells, a set of T cells that respond to one of the most abundantly expressed stress proteins in our body, heat shock protein 60. This protein is very strongly associated with autoimmunity. While autoimmunity is typically associated with pathology it plays a fundamental role in our health by eliminating dangerous cells that could become cancerous or induce the release inflammatory mediators that initiate tissue damage.

For an overview of gamma delta T cells you can look at this Wiki entry but unfortunately it is sparse and overlooks one of the most important features of gamma delta T cells, that being that these cells are responsive to one of the most abundantly expressed stress proteins in our body - heat shock protein 60. One of the stranger but little known issues concerning schizophrenia is that schizophrenics have a reduced incidence of cancer and a heightened incidence of autoimmune diseases. The studies are certainly not conclusive but in schizophrenia there is evidence of an elevated response to heat shock protein 60. Thus ....
RESULTSTen (33%) of 30 patients with schizophrenia but only one (3%) of 31 healthy individuals showed immunoreactivity to HSP60 or HSP70. The authors found especially high anti-HSP70 titers in never-medicated patients. High anti-HSP60 titers were mainly found in patients who were being treated with neuroleptics.
Recently some have argued for an autoimmune component to schizophrenia. It is important to remember though that this does mean that schizophrenia is an autoimmune disease. Rather autoimmunity is a component of the condition. That is probably a moot point because in many pathological conditions some level of autoimmunity is involved. What is of interest is that in some studies the autoimmune response to both heat shock protein 60 and 70 were increased with drug treatment. Given that these heat shock proteins are typically associated with cell stress this raises the suggestion that the drugs are inducing neurodegeneration. Worryingly, this idea has been put to me by a Russian friend of mine and in the last few years Nancy Andreasen, former Prof of Psychiatry at Harvard and a world authority on schizophrenia, has asserted that the drug treatments for schizophrenia might be causing neurodegeneration. As she states in a New York Times article:

Another thing we’ve discovered is that the more drugs you’ve been given, the more brain tissue you lose. ...
A. Well, what exactly do these drugs do? They block basal ganglia activity. The prefrontal cortex doesn’t get the input it needs and is being shut down by drugs. That reduces thepsychotic symptoms. It also causes the prefrontal cortex to slowly atrophy.
I'm not happy with the "slowly atrophy" explanation. It is a stab in the dark explanation. Note my previous comment though, that the drugs used to treat schizophrenia seem to upregulate the levels of heat shock proteins 60 and 70. This will potentially induce a stronger immune response because these heat shock proteins are "danger signals" to the immune system. Heat shock protein 60 in particular can be expressed at very high levels and frequently is associated with autoimmunity, though a chicken and egg issue is involved there. At sufficiently high levels it will induce apoptosis. What does "sufficiently high levels" mean? In that study it was because hsp 60 was inducing apoptosis through Toll receptors. They claim that is the first report of the same but that can't be true because I have known about that for at least a decade. This activation of Toll receptors through hsp60 does not have to involve cell wall rupture, heat shock protein 60 "leaks out", can be pinocytosed(absorbed) by an immune cell, which will activate Toll receptors, the guardians of the inflammatory responses.

There is evidence that during neuropathologies gamma delta T cells are increased in number. That these cells are in larger numbers in the cerebral spinal fluid of multiple sclerosis patients is hardly surprising. The possibility of a gamma delta T cell response driven by heat shock protein 60 was recognised in 1994.
 The speculation is reiterated that the demise of the oligodendrocyte in MS may occur late in lesion formation and may be in part related to the expression of heat shock proteins (specifically, members of the hsp 60 family), potent stimulators of T-cell receptor-gamma delta T cells that have been claimed to have cytolytic activity and that have been located in chronic active MS lesions.
Heat shock protein 60 is an early warning indicator of cellular stress, it is expressed under a wide variety of cellular stresses and as the below extract indicates it can initiate immune responses. As the below extract indicates, plasma membrane expression of heat shock protein 60 is not only common but can persist beyond the period of direct insult.
Although we know neither how the subcellular distribution of hsp60 is regulated nor the biological significance of plasma membrane-associated hsp60, there are several possible expla-nations. Increased hsp60 on cell surfaces could simply be an indicator of cellular stress, possibly produced directly by infec-tion or indirectly by cytokines and fever. Production and repair of proteins increase during stress and infection, and hsp60 is necessary to these processes (15). hsps also have long half-lives, and so it is possible that hsp60 is transported to the cell surface as a way to eliminate excess hsp. If hsp60 is expelled from the cell, hsp60-derived peptides would then become dis-played on the surfaces of professional APCs. Considering that hsp60 is a major immunogen of many bacterial pathogens (26, 27) and that there is a high level of homology between bacterial and mammalian hsp60 (28), this process could sustain acti-vated T cells primed to respond to a number of pathogens, as well as contribute to autoimmune disease.
Another possibility is that surface hsp60 acts as a signal of stressed, activated, or damaged cells, targeting them for clear-ance by cytotoxic cells or macrophages as part of the tissue repair process. In our infectious disease model hsp60 could be expressed on preapoptotic or apoptotic cells. Increased levels of hsp60 expression have been detected on membranes of cells induced to undergo apoptosis by treatment with dexametha-sone (40) and also in apoptotic cells isolated directly from AIDS patients (40). T cells undergoing antigen-triggered apo-ptosis

Plasma Membrane Expression of heat shock protein 60 in vivo in response to infection.

Multiple Sclerosis is an interesting case because the cells the produce myelin, oligdendrocytes, have some characteristics which increase susceptibility to immunological assault. Whereas most cells require some level of stress to express heat shock protein 60 at the cells surface, oligodendrocytes may be consistently demonstrating this quality.
We have demonstrated that such gamma delta T cells can induce in vitro lysis of human adult-derived OGC.
Constitutive expression of HSP60 could be discerned on the surface of all OGC under non-stressed culture conditions. Only some astrocytes demonstrated minor punctate surface HSP60 staining, whereas the remainder did not express HSP60 constitutively. 
Differential Expression of heat shock proteins by Human Glial Cells.

This constitutive expression of the heat shock protein 60 family in oligodendrocytes is also found here. Interestingly, in this study on cardiomyocytes, plasma membrane expression of heat shock protein correlated with apoptosis(programmed cell death). It is generally accepted that females have higher rates of autoimmune conditions than males, this study, highlighting how during certain phases of the menstrual cycle gamma delta T cell proliferation occurs, offers some insight into this susceptibility. Given this study highlighting the increased numbers of gamma delta T cells across a range of neurologic disorders, especially, and mysteriously, Cerebral Palsy, and that white matter pathology figures prominently in many dementias, there is the suggestion that at the most fundamental level an "autoimmune response" is cardinal to many chronic inflammatory states. This is not just a matter of inducing apoptosis, there is also evidence of an inflammatory response being initiated by these cells.  How far we have come from the self - nonself model!

I have focused on gamma delta T cells and heat shock protein 60 because long ago I encountered:
14 of 32 (44%) otherwise healthy patients with schizophrenia had antibodies to a neuroblastoma protein of molecular weight 60 kDa. By partial sequence analysis, this protein was identified as the 60 kDa human heat-shock protein (hsp) ... 
Of 100 normal subjects or disease controls, antibodies to hsp60 were found in only 8 patients, all of whom had active infectious or inflammatory disease. Our results support the presence of abnormal immune reactivity involving hsp60 in a subset of patients with schizophrenia. The immune response may be related to the pathogenesis of the disease.
AND ..
RESULTS: Ten (33%) of 30 patients with schizophrenia but only one (3%) of 31 healthy individuals showed immunoreactivity to HSP60 or HSP70. The authors found especially high anti-HSP70 titers in never-medicated patients. High anti-HSP60 titers were mainly found in patients who were being treated with neuroleptics.
That last sentence is very important. High anti-HSP60 titers strongly suggests that in a subset of schizophrenics there is an elevated autoimmune response, probably of the Th 1 inflammatory mediated autoimmune variety. The literature often interprets this elevation of heat shock protein 60 and 70 as a protective response arising from the neuroleptic treatment, an interpretation of unalloyed optimism. The exact opposite could be the case, pointing to an immunologically mediated process of the cerebral atrophy that Nancy Andreasen asserts is happening with neuroleptic treatment.

As this study indicates, though the linkage is weak, is that neuroleptics do increase the presence of autoantibodies to hsp60. This study found ...

Autoantibodies against 60-kDa heat shock protein in schizophrenia.
 In 10% of the drug-free but in 20% of the medicated schizophrenics, especially in females, we observed immunoreactivity against HSP60, high levels of IgG in CSF and a blood-brain barrier impairment. The high HSP antibody titres correlated with high levels of sIL-2R and sICAM-1. Only one of the controls showed antibodies against HSP60. Our results suggest that the observed immunological alterations are more pronounced during neuroleptic treatment than in the drug-free state. Whether or not this differential response to treatment with altered antibody production represents a subgroup of patients has yet to be determined.
The reference to the increased incidence in females is interesting because as that earlier studied I cited indicated during the menstrual cycle there can proliferation of gamma delta T cells. That only one control demonstrated antibodies to hsp 60 does suggest that the presence of antibodies to hsp60 is a marker of cell stress occurring somewhere in the body.

What I am suggesting is that this elevation in heat shock proteins is increasing the rates of apoptosis in the cerebral cortex, and it is that increase which is driving the acceleration of cell loss in schizophrenia. Given studies showing increased levels of autoantibodies to heat shock protein 60 in shizophrenia, there is the inference that heat shock protein 60 levels are sufficiently high to induce an aberrant immunological response that initiates apoptosis. This increase in "danger signals" AND the reduction of activity in the prefrontal cortex, which implies a reduction in activity dependent neurotrophic factor, are the likely causative suspects. Some months I wrote to my Russian friend asserting that the cell loss in schizophrenia is immunologically driven. He asked for evidence correlating the age of onset of psychosis with immunological function. It is generally accepted that psychotic symptoms typically occur during adolescence. Good question and as it turns out the onset of puberty does tend to increase immunological activity. Gamma Delta T cell numbers keep increasing up to puberty and slightly beyond but with age the numbers decrease, but that is on the basis of only one study I found. I find that interesting because spontaneous recovery does occur in schiozphrenia.

Strange as it may seem there is evidence of an inflammatory component in schizophrenia. This idea has been around a long time, at least since David Horrobin(1999). He makes the assertion that dopamine D2 receptors are the primary drivers PLA2 synthesis in the central nervous system, the implication being that as PLA2 is a potent intra cellular inflammatory mediator and that neuroleptic treatment is very much about the blockade of Dopamine D2 receptors, this blockade reduces inflammation and hence reduces psychotic symptoms. As this study indicates, there is evidence of an ongoing inflammatory state occurring in schizophrenia. A recent news article even reported that aspirin can be effective as an adjunct treatment in shizophrenia. The abstract concludes ...
CONCLUSION: Aspirin given as adjuvant therapy to regular antipsychotic treatment reduces the symptoms of schizophrenia spectrum disorders. The reduction is more pronounced in those with the more altered immune function. Inflammation may constitute a potential new target for antipsychotic drug development.
New!? Horrobin has been harping on about that for decades! While orthomolecular Therapy for schizophrenia never gained widespread support, there were many reports that some first time psychotics did respond well to this therapy. I remember reading that the success of orthomolecular therapy was very contingent on treatment occurring at the first psychotic episode. From an immunological perspective that makes a good deal of sense, if the inflammatory response can be quickly mitigated that will play a major role in preventing an ongoing change in the neurodegenerative immune response by limiting gamma delta T cell clonal expansion.

The incredible irony is that the current drug treatments of shizophrenia may be facilitating an autoimmune response that is part of the pathogenesis of schizophrenia. While looking for data I did come across references indicating that a rather large percentage of schizophrenics, as high as 25%, spontaneously recover. In these days though there is a very pronounced attempt to identify even "pre-psychotic" individuals, with a new classification for that sub-group in the latest DSM. It is as if the lessons of Szasz and Rosenhan have been completely forgotten. This new therapeutic trend, together with the research of Nancy Andreasen asserting the drugs induce neurodegeneration, and the data indicating a relatively high spontaneous recovery rate, raises very serious questions about the current philosophy behind our mental health strategies. It is frightening enough to think that the drugs used to treat schizophrenia probably are facilitating the neurodegeneration, but it is terrifying to contemplate that the emphasis on early intervention could entail the medicalising of individuals which will induce neurodegeneration and thus prevent spontaneous recovery. I'd call it madness but not too loudly because they might come and lock me away.

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