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The Infection Question and other triggers
For Professionals: Highlights of Orthomolecular Health Conferences, 2008 and 2005

The Infection Question and other triggers

 

Exactly what is the problem being treated when a physician gives a patient an antipsychotic medication? Is it bipolar mania or Lyme (or other) encephalopathy. The usual answer is that the medication stops the action of excessive transmitters by blocking their receptors. But that may not be the whole story, or, as Paul Harvey would say, the "rest of the story."  There is something else that antipsychotic medications do that is rarely acknowledged by physicians, or even drug representatives from the pharmaceutical companies that make the drugs. These medications bind with calmodulin (calcium modifier). This leads to a series of events that reduce the amount of  an enzyme called protein kinase C (PKC). Also, they reduce the very viruses and bacteria that may have started the cascade leading to excessive PKC and excessive neurotransmitters in the first place! PKC is an enzyme (10 different ones) that are known to play a major role in mania and schizophrenia. If the above is true, as I intend to demonstrate on this page, then would the targeted treatment of specific infections be preferable  to chronically giving medications that inhibit, but do not decisively treat the trigger? If the mania is triggered by infection, such a strategy  would seem to be a logical way to cure the infection and neutralize that trigger for mania. True Example: A homeless women walks the streets for years carrying the label of schizophrenia. She is hospitalized for a medical condition, tested for Lyme disease, found to be positive, treated, and is now no longer diagnosed as "schizophrenic."

In Too Good to be True? Nutrients Quiet the Unquiet Brain, I discuss the role of infections in triggering what we call psychiatric disorders and curative treatments for those infections. Here is a summary of some of the current research. Even though some of these references are highly technical,  the relevant conclusions are highlighted so the main point is more easily understood. #

First, however, here is a relatively easy to understand summary. Event "A"  triggers "B" which activates" C." "B" and "C" combine to trigger "D."  "D" is implicated in both mania and schizophrenia. If this is a true sequence of events, it would appear to make sense to stop event "A" from happening.  If reducing "B" or "C" reduces "A" and "D," one might get symptomatic relief but would this really fix the problem? This would require the person to be on "B" and "C" binding drugs the rest of their life. "A" would still be there.   Taking the logic a bit further, if one were to stop "A" would "E" be sufficient to correct the genetic deficits in protein expression that predispose to excessive PKC?  If you have the patience to read this page, continue on to the end (Simple Summary) and find the key to ABCDE.

Before reading the following it might be useful to understand the terms agonist and antagonist.

1. When an antigen such as the flu, toxoplasmosis, Borna virus or Lyme disease enters the body, there is activation of B-cell and T-cell receptors. This activation generates two major signals, an increase in intracellular calcium (Ca2+) and a cascade of protein kinases, including Protein Kinase C (PKC).               

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=138649

bullet PKC is dependent on Ca2+ and calmodulin. A Google search on these topics will show dozens of articles on "Ca2+/calmodulin dependent kinases," including PKC.
bulletFor example, with anthrax, increased intra cellular Ca2+activates calmodulin  which binds with four calcium ions. For more details the article below see the last paragraph page 273 of the article below.

          http://www.nature.com/nature/journal/v415/n6870/pdf/415373.pdf 

2.  Ca2+/calmodulin dependent PKC is one biomarker for mania. Lithium, Depakote, and Tamoxifen, the chemotherapy drug all reduce PKC, and mania.

bullet Click here for a collection of papers on this subject. Note that interventions are targeted towards the PKC itself,not the precursors to PKC.
bullet Husseini K. Manji, FRCPC, Gregory J Moore, PhD and Guang Chen, PhD, "Bipolar disorder: leads from the molecular and cellular mechanisms of action of mood stabilisers," British Journal of Psychiatry (2001) 178:s107-s119

3. Low levels of PKC are associated with teen suicide.

bullet Ghanshyam N. Pandey,PhD; Yogesh Dwivedi, PhD; Hooriyah S. Rizavi, MS; Xinguo Ren, MD; Robert R Conley, MD, "Decreased Catalytic Activity and Expression of Protein Kinase C Isozymes in Teenage Suicide Victims, a Postmortem Brain study," Arch Gen Psychiatry. 2004;61:685-693

4. Various antagonists to calmodulin reduce PKC and infections. These antagonists are cytotoxic, that is, destructive to cells.

bullet Stelazine is an antagonist to calmodulin. It reduces infection as evidenced by an increased survival rate of Vibrio.vulnificus-infected mice treated with an antibiotic and Stelazine compared to those treated with antibiotic alone. http://iai.asm.org/cgi/content/abstract/72/10/6157
bulletThorazine, the original major tranquilizer was derived from a treatment for killing internal parasites in horses, not for any neurotransmitter binding properties. Too Good to be True? Nutrients Quiet the  Unquiet Brain - a Four Generation Bipolar Odyssey p. 273. It is still used today by vets to deworm animals.
bulletE.coli infection causes an increase in intracellular calcium.  Calmodulin antagonists Thorazine, Stelazine, calcium channel blockers inhibits the action of an E.coli infection. http://mmi.creighton.edu/faculty/knoop.html
bulletHaldol blocks infection of B L-ymphocytes by Epstein-Barr virus, by binding to calmodulin and it also reduces symptoms of manic psychosis. Too Good to be True? Nutrients Quiet the Unquiet Brain - a Four Generation Bipolar Odyssey p. 273
bullet Ehrlichia risticii (a Lyme coinfection) replication was inhibited with calmodulin antagonists Thorazine and Stelazine and Ca2+  antagonist calcium channel blocker verapamil. Calmodulin and Ca2+ are essential for ehrlichial internalization, replication, and spreading in macrophages.

"Replication of Ehrlichia risticii was inhibited in P388D1 cells and murine peritoneal macrophages when a calmodulin antagonist (W-7, chlorpromazine, or trifluoperazine); a Ca2+ channel blocker (verapamil, diltiazem, nifedipine, or flunarizine); ...  was added after internalization of the organism at 3 h postincubation. ....  These results indicate that calmodulin and Ca2+ are essential for ehrlichial internalization, replication, and spreading in macrophages...."

Y Rikihisa, Y Zhang, and J Park, Role of CA2+ and calmodulin in ehrlichial infection in macrophages, Infect Immun. 1995 June; 63(6):2310-2316

bulletCalcium and Calmodulin antagonists reduce malaria parasites.

L W Scheibel, P M Colombani, A D Hess, M Aikawa, C T Atkinson, and W K Milhous, "Calcium and calmodulinantagonists inhibit human malaria parasites (Plasmodium falciparum): implications for drug design, Proc Natl Acad Sci USA. 1987 October;84(20):7310-7314

bullet
Thorazine inhibits candida species. (Yeast infections are implicated in autism, leaky gut, psychosis.)

"Chlorpromazine was tested for antifungal activity by using Candida albicans and standard assays. The MIC of chlorpromazine was 35 micrograms/ml; the minimal fungicidal concentration was also 35 micrograms/ml. The minimal effective concentration was 2.2 to 3.5 micrograms/ml (using assays based on quantitative cultures and growth). There was a slight positive interaction between chlorpromazine and amphotericin B but no interaction between chlorpromazine and rifampin. Chlorpromazine also inhibited C. krusei, C. parapsilosis, C. tropicalis, and Torulopsis glabrata. We conclude that phenothiazines have direct anti-Candida activity and that these drugs appear to have a broad antimicrobial spectrum." (Note: While the concentration was less that a normal human dose, the fact that brain concentrations are 70% higher, suggests antimicrobial action in the brain.)

Wood, NC, Nugent, KM, Inhibitory effects of Chlorpromazine on Candida species, Antimicrob Agents Chemother. 1985 May; 27(5):692-4

 
bulletCalmodulin activity has been identified in retroviruses. This is particularly important because as stated in the book, retroviruses are now implicated in schizophrenia.

"Several viruses have been shown to require calcium for their function, and to bind calcium at specific sites. However, the nature of the calcium binding molecule on viruses has not been established. One possibility is the ubiquitous calcium-binding protein calmodulin. Our studies were designed to determine whether feline leukemia virus contained calmodulin. Accordingly, we tested purified feline leukemia virus for the presence of calmodulin-like activity. The virus, like authentic calmodulin, activated cyclic AMP phosphodiesterase. The ability of the virus to activate the enzyme was blocked in the presence of the known calmodulin inhibitors trifluoperazine and W-7. This indirect evidence for the presence of calmodulin was confirmed by radioimmunoassay. Several other retroviruses were also tested using radioimmunoassay and found to contain calmodulin. Our results indicate that the calcium binding site in retroviruses may be calmodulin."

Lewis, MG, Chang, JY, Olsen, RG, Fertel, RH, Identification of calmodulin activty in purified retroviruses, Biochem Biophys Res Commun. 1986 Dec 30;141(3):1077-83

bullet Like Lyme disease, Toxoplasma gondii is more prevalent in psychiatric patients than the general population. Further, drugs used in the treatment of schizophrenia and bipolar disorder inhibit the replication of Toxoplasma gondii.

Jones-Brando L, Torrey EF, Yolken R. Psychopathology in first-episode schizophrenia and antibodies to Toxoplasma gondii, Psychopathology 2005 Mar-Apr;38(2):87-90R.

"The exact mechanisms of action of some antipsychotics and mood stabilizers have not been elucidated. Response to these medications can vary among individuals. Recent studies indicate that infection with the parasite Toxoplasma gondii may contribute to the symptoms of schizophrenia in some individuals. We investigated commonly used antipsychotic and mood stabilizing medications for their ability to inhibit the replication of this organism. We employed a system for testing compounds for in vitro activity against T. gondii. Human fibroblasts (HFF) were treated with test compounds and then exposed to Toxoplasma that has been genetically modified to express cytoplasmic beta-galactosidase. Inhibition by the drugs was determined by spectrophotometric analysis of colorimetric reactions. We tested 12 neuroleptic compounds and found that of these, the antipsychotic haloperidol and the mood stabilizer valproic acid most effectively inhibit Toxoplasma growth in vitro. Valproic acid inhibited the parasite at a concentration below that found in the cerebrospinal fluid and blood of individuals being treated with this medication and displayed synergistic activity with haloperidol and with trimethoprim, an antibiotic commonly used to treat Toxoplasma infections. Several medications used to treat schizophrenia and bipolar disorder have the ability to inhibit the in vitro replication of T. gondii."

Jones-Brando L, Torrey EF, Yolken R., Drugs used in the treatment of schizophrenia and bipolar disorder inhibit the replication of Toxoplasma gondii, Schizophr Res. 2003, Aug 1;62(3):237-44.
 

5. Intravenous calcium replacement can cause mania; calcium supplementation can increase mania; calcium channels blockers reduce mania.

bullet Groat, R.D., Mackenzie, T.B., "The appearance of mania following intravenous calcium replacement," Nerv Ment Dis. 1980 Sep;168(9):562-3
 
bullet Pollack, M., Rosenbaum, J., Hyman, S., "Calcium channel blockers in psychiatry
Psychosomatics 28: 356-369, 1987

6. Besides infection, stress and insecticides can increase intracellular Ca2+, leading to production of PKC and changes in synaptic function such as excessive neurotransmitter production.

bullet"An errant enzyme linked to bipolar disorder, in the brainís prefrontal cortex, impairs cognition under stress, an animal study shows. The disturbed thinking, impaired judgment, impulsivity, and distractibility seen in mania, a destructive phase of bipolar disorder, may be traceable to over activity of protein kinase C (PKC), suggests the study, funded by the National Institutes of Healthís (NIH) National Institute of Mental Health (NIMH) and National Institute on Aging (NIA), and the Stanley Foundation. It explains how even mild stress can worsen cognitive symptoms, as occurs in bipolar disorder, which affects two million Americans."

             Stress impairs thinking via mania- linked enzyme - National Institute of Health in Innovations Report

bullet"Permethrin did cause an up regulation of serotonin transport, but required a 30-fold greater dose than that effective on dopamine uptake. Other evidence of specificity was found in transmitter release assays, where heptachlor and deltamethrin released dopamine from striatal terminals with greater potency than other transmitter types. These findings confirm that insecticides possess specificity for effects on striatal dopaminergic neurotransmission." Evan, E. Matsumura, F., 1993 "Activation of phosphoinositide/protein kinase C pathway in rat brains by Pyrethroids" Biochemical Pharmocol 45(3):703-710. 

Bloomquist,JR, Barlow, RL, Gillette, JS, LiW, Kirby ML, "Selective effects of insecticides on nigrostriatal dopaminergic nerve pathways, Neurotoxicology. 2002 Oct; 23(4-5):537-44

Technical Summary:  Calmodulin antagonists and calcium channel blockers inhibit a wide range of microbes, including the Lyme coinfection Ehrlichia.  Could they even inhibit Borrelia burgdorferi? A reduced microbial load retards the cascade leading to excessive PKC.  So, if intervening midstream with either a calmodulin antagonist like Haldol or a calcium channel blocker like Verapamil can be effective against manic psychosis provoked by infection, and it can inhibit the infection itself, wouldn't intervention further upstream directed at the infection prevent the excessive PKC in the first place?  A more efficient upstream intervention for a specific kind of immune mediated pathology, what we might call the infection-mediated- calmodulin-calcium-dependent PKC would be to directly treat the total microbial antigenic load, whether it be the flu, Lyme disease, bartonella, toxoplasmosis, cytomegalovirus and/or mycoplasmas.  I searched for "infection + calmodulin" on Google and found 46,000 references. Searching for "calmodulin-dependent PKC" led to 50,000 references. Searching for infection mediated- calcium-calmodulin dependent PKC led to only 51 sites.

If the stressor is an insecticide like Permethrin then it would be important to avoid exposure. If it is psychological stress it would be important to avoid it to the extent possible or learns ways of quieting the fight/flight reflex. Supplements discussed in the book may provide the resources for the brain to maintain a better level of homeostasis so that less, or even no medications are needed.

PKC facilitates the movement of neurotransmitters from vesicles to the synaptic cleft and plays a role in learning and memory. Therefore, one might expect a limited period of enhanced learning, more reciprocal give and take, and a heightened lucidity just before the transition to manic behavior when the PKC levels are not yet problematic. This has certainly been the case in our family where feedback that our son is doing great is a warning of pending disaster.

Lastly, an area for further research would be to see how nutritional supplementation alters the genetic expression of proteins, particularly PKC.  Since we know that infection, insecticide, and stress can trigger increased neurotransmitter uptake, one idea would be to test the PKC response of rats to different triggers and amounts of E. M. Power and other supplements. Since nutritional status plays a significant role in the body's defense against infections, it would appear in some cases that healthy nutritional status and targeted biological treatment of infections would be a more useful treatment than chronic administration of antipsychotic medications which don't definitively cure the infection.  A second avenue for study would be to compare effectiveness of various calmodulin antagonists in reducing PKC and the underlying infections.

The above suggests that it may be necessary to conceptualize bipolar disorder not as a monolithic "psychiatric"  disorder, but as a collection of heterogeneous biological disorders that can be individually identified and treated. Infection-mediated-excessive PKC may be one such disorder.

Simple Summary:  "A" is infection. "B" is Ca2+.. "C" is calmodulin. "D" is PKC. "E" is E. M. Power. As stated on the home page,  I have no business relationship with E. M. Power (Truehope) and simply used it as a representation of one nutritional solution.  Now you know the rest of the story.

# Disclaimer: The purpose of this page is to stimulate new thinking about mental illness.   The above description does not do justice to the complexity of processes involved.  It describes only one process involving a biomarker of mania,  excessive PKC.   While PKC is a major player, there is no single explanation for the mechanisms of mania. In fact, there are many up and down regulated proteins in the brains of those who have bipolar disorder, suggesting that no single explanation is sufficient to account for manic symptoms. Any treatment decisions require the consultation of medical professionals. This page is an expansion of ideas introduced in the book Too Good to be True? Nutrients Quiet the Unquiet Brain. While there is a definite a role of infections in severe mental illness  unique genetically and environmentally provoked immune responses to infections also play a role. For more information on current research in this area visit the Stanley Foundation Website.

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