Advances in Biological Psychiatric Research

The 19th century writer Lewis Carroll wrote "Alice in Wonderland". In this children's classic was a delightful character called "The Mad Hatter". This strange character wore a 19th century hat. The character was based on an actual situation in the felt hat industry in England. It seems that the people who made felt hats were using mercury in the process and were getting mercury poisoning. Mercury is a heavy metal that poisons the brain causing madness.

But what does this tell us? For one thing, we need to be very careful about pollution. For another thing, a toxin is capable of poisoning the brain and therefore schizophrenia might be caused by an unknown toxin. Alcohol is an example of an exogenous toxin that poisons the brain. However, in schizophrenia an endogenous toxin may be at work. There even could be more than one toxin.

Catecholamines

The catecholamine theory is one of the most popular theories for schizophrenia and also one of the most logical. It takes into account the connection between schizophrenia and stress. Stress exacerbates schizophrenia as well as other psychiatric diseases. Ref. 1 describes one of the many catecholamine theories.

Dopamine is one of the suspects (2). It seems that neuroleptic drugs block dopamine receptors, which is why they produce Parkinsonian side effects. However, dopamione itself may not be the problem in schizophrenia. A toxic metabolite or metabolites may be the problem(s). Hoffer favors this theory, as did the late Dr. Osmond.

Axelrod was awarded a Nobel Prize for his work on this theory (4). Unfortunately he was never able to identify the toxin.

COMT

This very important enzyme metabolizes dopamine by methylation. Supposedly this deactivates dopamine, but there is a theory that abnormal methylation can produce a toxin (5, 6). A COMT inhibitor has been used as a treatment in Parkinson's disease (9). In theory it makes the dopamine last longer.

Drug Abuse

A lot can be learened about the brain when studying drug abuse (10). Many hallucinogens have chemical structures similar to metabolites of dopamine. Dopamine itself has no methyl or methoxy groups. The hallucinogens have either methyl groups or methoxy groups or both. Some hallucinogens have structures similar to serotonin. This may be a reason why so many SSRIs (selective serotonin reuptake inhibitors) are being used in psychiatry.

The class of hallucinogens similar to dopamine in structure is called "phenethylamines" (11). Amphetamines are classified by the chemical name phenylisopropylamines (12). An "amine" by definition contains the nitrogen atom.

Unfortunately some of these hallucinogens can lead to physical dependence (addiction). This is discussed in Ref. 13.

The serotonin theory goes back to Gaddum (16) and others. According to this theory there is an antagonism between serotonin and LSD. This led to the serotonin deficiency theory for schizophrenia. However, actual measurements of serotonin postmortem in schizophrenic brains did not support this theory. A similar theory was advocated for depression.

Drug abuse is such a vast topic that I can't do justice to it here. Perhaps I will write an article strictly about it, but even that won't do justice to it. I would have to write a whole series of articles on it like I have on schizophrenia.

Conclusions

My own theories are presented in Refs. 17-20. I believe that a toxin is created from dopamine by abnormal methylation. This abnormal metabolite could produce yet another abnormal metabolite. But what is the treatment? I am not at all satisfied with the drugs that we have now. I favor alternative medicine. I don't accept all types of alternative medicine, but orthomolecular medicine uses nutrition. That is real science.

Nutrition is safer than drugs and cheaper. Then again, I would not rule out drugs of the future. Maybe in the future they can do better than they have in the past.

References

1. Is COMT a Susceptibility Gene for Schizophrenia? Hywel J. Williams, Michael J. Owen, and Michael C. O'DonovanSchizophr Bull. 2007 May; 33(3): 635-641. Published online 2007 April 4. doi: 10.1093/schbul/sbm019. PMCID: PMC2526139.

2. Van Rossum JM. The significance of dopamine-receptor blockade for the mechanism of action of neuroleptic drugs. Arch Int Pharmacodyn Ther. 1966;160:492-49.

3. Davis KL, Kahn RS, Ko G, Davidson M. Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry. 1991;148:1474-1486.

4. Axelrod J, Tomchick R. Enzymatic O-methylation of epinephrine and other catechols. J Biol Chem. 1958;233:702-705.

5. Jeffery DR, Roth JA. Characterization of membrane-bound and soluble catechol-O-methyltransferase from human frontal cortex. J Neurochem. 1984;42:826-832.

6. Tunbridge EM, Weinberger DR, Harrison PJ. A novel protein isoform of catechol O-methyltransferase (COMT): brain expression analysis in schizophrenia and bipolar disorder and effect of Val158Met genotype. Mol Psychiatry. 2006;11:116-117.

7. Lachman HM, Papolos DF, Saito T, et al. Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics. 1996;6:243-250.

8. Lee SG, Joo Y, Kim B, et al. Association of Ala72Ser polymorphism with COMT enzyme activity and the risk of schizophrenia in Koreans. Hum Genet. 2005;116:319-328.

9. Gasparini M, Fabrizio E, Bonifati V, Meco G. Cognitive improvement during Tolcapone treatment in Parkinson's disease. J Neural Transm. 1997;104:887-894.

10. Fantegrossi WE, Ullrich T, Rice KC, Woods JH, Winger G. 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') and its stereoisomers as reinforcers in rhesus monkeys: serotonergic involvement. Psychopharmacology. 2002;161:356-364.

11. Sannerud CA, Kaminski BJ, Griffiths RR. Intravenous self-injection of four novel phenethylamines in baboons. Behav Pharmacol. 1996;7(4):315-323.

12. Fantegrossi WE, Woods JH, Winger G. Transient reinforcing effects of phenylisopropylamine and indolealkylamine hallucinogens in rhesus monkeys. Behav Pharmacol. 2004;15(2):149-57.

13. Balster RL, Woolverton WL. Continuous-access phencyclidine self-administration by rhesus monkeys leading to physical dependence. Psychopharmacology. 1980;70(1):5-10.

14. Moreton JE, Meisch RA, Stark L, Thompson T. Ketamine self-administration by the rhesus monkey. J Pharmacol Exp Ther. 1977;203(2):303-9.

15. Tanda G, Munzar P, Goldberg SR. Self-administration behavior is maintained by the psychoactive ingredient of marijuana in squirrel monkeys. Nat Neurosci. 2000;3(11):1073-4.

16. Gaddum JH. Antagonism between lysergic acid diethylamide and 5-hydroxytryptamine. J Physiol. 1953;121(1):15P.

17. www.associatedcontent.com/article/1680090/cuban_research_on_schizophrenia.html

18. www.associatedcontent.com/article/1680380/the_virus_theory_for_schizophrenia.html
19. www.associatedcontent.com/article/1676885/new_ideas_in_psychiatry.html
20. www.associatedcontent.com/article/1649109/mitochondrial_dysfunction_in_mental.html