Various Theories for Schizophrenia and Depression

One of the most popular theories in psychiatry is the tryptophan theory (1). There are variations of this theory for schizophrenia, depression, and bipolar disorder. Both Ref. 1 & 2 report increased metabolism on tryptophan in schizophrenia. This is in contradiction to a drug company theory of supposedly decreased serotonin. Ref. 2 reported serotonin to be high in all patients.

Depression

It seems that the drug interferon, which is used to treat hepatitis and cancer, induces depressive symptoms. This drug increases tryptophan metabolism (3, 4).

ADHD

Ref. 5 discusses ADHD.

Biological Markers

Refs. 6-10 report biological markers in depression and schizophrenia. Let us first discuss depression because the results have been the most consistent for depression..

Depression

Cytokines have been linked to depression (11). They cause increased tryptophan metabolism. It seems that the drug interferon induces depression as a side effect. Interferon is used to treat cancer and also hepatitis. This drug causes increased tryptophan metabolism. It may be the increasd tryptophan metabolism that is causing the depression side effect. This gives us a very important clue to the cause of depression. Further support for this theory comes from Refs. 12-14. Ref. 15 also supports this thesis.

Schizophrenia

Ref. 16 supports the cytokine theory for schizophrenia. This appears to suggest that schizophrenia and depression are closely related from a biochemical point of view.

Ref. 17 reports increased metabolites of tryptophan in the cerebrospinal fluid of schizophrenics. Ref. 18 appears to support this if too much tryptophan is flooding the brain cells.

Bipolar Disorder

Ref. 19 supports a similar theory for bipolar disorder.

Conclusions

It appears that the major forms of mental illness all involve excessive tryptophan metabolism, particularly in the brain. This might be also true in Huntington's chorea and Alzheimer's disease (2). This author favors a diet very low in tryptophan as a treatment. This diet should be supplemented with niacin so as to avoid pellagra. Tryptophan is high in animal foods. It is relatively low in plant foods.

References

1. Miller CL, Llenos IC, Dulay JR, Barillo MM, Yolken RH, Weis S. Expression of the kynurenine pathway enzyme tryptophan 2,3-dioxygenase is increased in the frontal cortex of individuals with schizophrenia. Neurobiol Dis. 2004;15:618-629. [PubMed]

2. Tryptophan and tyrosine catabolic pattern in neuropsychiatric disorders. Ravikumar A, Deepadevi KV, Arun P, Manojkumar V, Kurup PA. Neurol India. 2000 Sep;48(3):231-8.

3. Tryptophan kynurenine metabolism as a common mediator of genetic and environmental impacts in major depressive disorder: the serotonin hypothesis revisited 40 years later. Oxenkrug GF.Isr J Psychiatry Relat Sci. 2010;47(1):56-63.

4. Int J Neuropsychopharmacol. 2010 Jul 29:1-7. [Epub ahead of print] Depressive symptoms following interferon-alpha therapy: mediated by immune-induced reductions in brain-derived neurotrophic factor? Kenis G, Prickaerts J, van Os J, Koek GH, Robaeys G, Steinbusch HW, Wichers M.

5. Todd RD, Botteron KN. Is attention-deficit/hyperactivity disorder an energy deficiency syndrome? Biol Psychiatry. 2001;50:151-158. doi: 10.1016/S0006-3223(01)01173-8.

6. J Child Psychol Psychiatry. 2010 Aug;51(8):935-43. Epub 2010 Apr 12. The possible role of the kynurenine pathway in adolescent depression with melancholic features. Gabbay V, Klein RG, Katz Y, Mendoza S, Guttman LE, Alonso CM, Babb JS, Hirsch GS, Liebes L.

7. Connor TJ, Leonard BE. Preskorn SH, Feighner JP, Stanga C, Ross R, editors. Biological markers for Depression. 2004. pp. 117-148. Handbook of Experimental Pharmacology. Antidepressants. Past, Present and Future (Volume 157). Springer, New York.

8. Domenici E, Muglia P. The search for peripheral markers in psychiatry by genomic and proteomic approaches. Exp Opin Med Diagn. 2007;1:235-251.

9. Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 2006;27:24-31.

10. Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry. 2009;65:732-741

11. Motivala SJ, Sarfatti A, Olmos L, Irwin MR. Inflammatory markers and sleep disturbance in major depression. Psychosom Med. 2005;67:187-194.

12. Mossner R, Mikova O, Koutsilieri E, Saoud M, Ehlis AC, Muller N, et al. Consensus paper of the WFSBP Task Force on Biological Markers: Biological markers in depression. World J Biol Psychiatry. 2007;8:141-174.

13. Musselman DL, Lawson DH, Gumnick JF, Manatunga AK, Penna S, Goodkin RS, et al. Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med. 2001;344:961-966.

14. Capuron L, Gumnick JF, Musselman DL, Lawson DH, Reemsnyder A, Nemeroff CB, et al. Neurobehavioral effects of interferon-alpha in cancer patients: Phenomenology and paroxetine responsiveness of symptom dimensions. Neuropsychopharmacology. 2002;26:643-652.

15. Reichenberg A, Yirmiya R, Schuld A, Kraus T, Haack M, Morag A, et al. Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry. 2001;58:445-452.

16. Cytokine hypothesis of schizophrenia pathogenesis: evidence from human studies and animal models. Watanabe Y, Someya T, Nawa H. Psychiatry Clin Neurosci. 2010 Jun;64(3):217-30.

17. Increased Levels of Kynurenine and Kynurenic Acid in the CSF of Patients With Schizophrenia. Linderholm KR, Skogh E, Olsson SK, Dahl ML, Holtze M, Engberg G, Samuelsson M, Erhardt S. Schizophr Bull. 2010 Aug 20.

18. Decreased plasma tryptophan and tryptophan/large neutral amino acid ratio in patients with neuroleptic-resistant schizophrenia: Relationship to plasma cortisol concentration. Lee M, Jayathilake K, Dai J, Meltzer H.Psychiatry Res. 2010 Aug 9.

19. Elevated levels of kynurenic acid in the cerebrospinal fluid of patients with bipolar disorder. Olsson SK, Samuelsson M, Saetre P, Lindström L, Jönsson EG, Nordin C, Engberg G, Erhardt S, Landén M. J Psychiatry Neurosci. 2010 May;35(3):195-9.