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Depression or cancer: the choice between serotonin or melatonin?
Medical Hypotheses (1998) 50, 385-387 © Harcourt Brace & Co. Ltd 1998
Depression or cancer: the choice between serotonin or melatonin? A. PANZER Department of Physiology, University of Pretoria, PO Box 2034, Pretoria 0002, South Africa (phone: +27 12 3192137; Fax: +27 12 3192238; e-mail: [email protected])
Abstract - - Stress causes disturbances of monoamine functioning and may result in a serotonin deficiency which is manifested, as depression. In some humans, stress does not, however, cause depression. It is hypothesized that in these individuals, melatonin, which is normally a product of serotonin, may be converted back to its precursor and thus replenish serotonin stores. These people are thus not depressed and are characterized by their pleasant, unassertive nature. Their lowered melatonin levels may, however, signal an increased risk for cancer. It is therefore postulated that unresolved stress results in either depression (with low serotonin) or cancer (as a result of decreased melatonin), depending on individual personality traits and biochemistry.
Introduction
Monoamine metabolism and functions
The fact that psychological factors influence physical disease, has long been recognized in the well-known placebo effect. The interactions between the brain, endocrine, and immune systems have, however, only recently been explored. Studies of psychoneuroimmunology have validated anecdotal observations, for example that stress leads to an increased susceptibility to colds (1), that people with neoplasms have significantly fewer allergies (2), and that cancer patients tend to be more pleasant, appeasing and rational than average (3). The biochemical neurotransmitter link between personality traits and cancer development, has, however, not been explained. This paper alms to present an hypothesis to explain the link between personality and cancer by referring to serotonin and melatonin metabolism.
Melatonin is a product of serotonin metabolism, as seen in Fig. 1. In the biosynthesis of melatonin, the
Tryptophan $ 5-Hydroxytryptophan $ Serotonin J, N-acetyltransferase (NAT) N-acetylserotonin $ J, Hydroxyindole-O-methyl transferase (HIOMT) Melatonin $ 6-Hydroxymelatonin, 6-Sulfatoxymelatonin and other metabolites. Fig. ] Thebiosynthesisof me]atonin.
Received20 December1996 Accepted29 January 1997 385
386
MEDICAL HYPOTHESES
rate-limiting step is the conversion of serotonin to N-acetylserotonin, catalysed by N-acetyltransferase (4). It is fascinating that melatonin can also be converted back to N-acetylserotonin (5). The reason why melatonin should be metabolized to a product that is its own precursor, has not yet been elucidated. No studies have been done to indicate whether conversion of N-acetylserotonin to serotonin also occurs, but for the purposes of this argument it will be supposed to be possible, pending further research results. It is therefore conceivable that melatonin and serotonin are freely interconvertible. A deficiency of serotonin as neurotransmitter is thought to cause depression (6), and serotoninreuptake inhibitors, which increase the availability of this neurotransmitter in the synaptic cleft, alleviate the symptoms (7). Melatonin, the pineal hormone which is known best for its functions in synchronizing the circadian clock, has also been implicated in the pathogenesis of cancer. As a matter of fact, melatonin therapy has been shown to be effective in a wide variety of neoplasms (8-11). In spite of the close biochemical relationship, no link between serotonin and depression, on the one hand, and melatonin and cancer, on the other, has yet been found. In a recent review of the influence of psychological factors on disease (1), the authors conclude that evidence of depression influencing the onset and progression of cancer, is inconclusive and inconsistent.
Effects of stress on monoamine levels
Stress mediated through the hypothalamic-pituitaryadrenal axis produces disturbances seen in monoamine functioning (12). It is hypothesized that this stress may be manifested in two different ways, as shown in Fig. 2. Support for the hypothesis represented in Fig. 2a can be found in the clear association of deficient serotonin and depression (6,7), as well as the finding that depressed subjects have a normal Stress
~, Serotonin - -
Normal melatonin
$ Depression
$ No cancer
a
Stress
Normal serotonin
$ No depression
,l, Melatonin
$ Cancer
b
Fig. 2 Two different disturbances of monoamine functioning, resulting from stress.
output of melatonin (13). The hypothesis represented in Fig. 2b is corroborated by both retrospective and prospective studies which suggest that persons who have a tendency to repress emotions and therefore do not feel 'depressed', even during severe stress, are more prone to cancer (14). It is suggestive that cancer patients on the whole tend to be pleasant, trying to act rationally in spite of negative feelings (3). These personality traits are so common in cancer patients, that a personality type, called type C, has been proposed which is characterized by cooperative, appeasing, unassertive, patient and pleasant behaviour (15). This is clearly incompatible with a diagnosis of depression. Furthermore, melatonin levels have been found to be decreased in cancer patients (16,17). Conclusion
The appropriate biochemical coping mechanism for unresolved stress, may thus be decreased serotonin with resultant depression. If depression is averted by replenishing serotonin from conversion of melatonin, the benefit of feeling good and being nice may not outweigh the risk for cancer development. References 1. Cohen S, Herbert T B. Health psychology: psychological factors and physical disease from the perspective of human psychoneuroimmunology [Review]. Annu Rev Psychol 1996; 47: 113-142. 2. Petroianu A, Chaves D N, De Oliveira O Jr. Comparative incidence of allergy in the presence or absence of cancer. J Int Med Res 1995; 23(5): 358-363. 3. van der Ploeg H M, Kleijn W C, Mook J, van Donge M, Pieters A M, Leer J W. Rationality and antiemotionality as a risk factor for cancer: concept differentiation. J Psychosom Res 1989; 33(2): 217-225. 4. Reiter R J. Pineal melatonin: cell biology of its synthesis and of its physiological interactions. Endocrine Rev 1991; 12(2): 151-180. 5. Young I M, Leone R M, Francis P, Stovell P, Silman R E. Melatonin is metabolized to N-acetyl serotonin and 6-hydroxymelatonin in man. J Clin Endocrinol Metab 1985; 60(1): 114--119. 6. Baldwin D, Rudge S. The role of serotonin in depression and anxiety [Review]. Int Clin Psychopharmacol 1995; 9(Suppl 4): 41--45. 7. Wong D T, Bymaster F P. Development of antidepressant drugs: fluoxetine (Prozac) and other selective serotonin uptake inhibitors [Review]. Adv Exp Med Biol 1995; 363: 77-95. 8. Lissoni P, Barni S, Fossati V e t al. A randomized study of neuroimmunotherapy with low-dose subcutaneous interleukin2 plus melatonin compared to supportive care alone in patients with untreatable metastatic solid tumour. Support Care Cancer 1995; 3(3): 194-197. 9. Lissoni P, Meregalli S, Fossati V e t al. A randomized study of immunotherapy with low-dose subcutaneous interleukin-2 plus melatonin vs chemotherapy with cisplatin and etoposide as
DEPRESSION OR CANCER: SEROTONIN OR MELATONIN?
10.
11.
12. 13.
first-line therapy for advanced non-small cell lung cancer. Tumori 1994; 80(6): 464--467. Lissoni P, Meregalli S, Nosetto Let al. Increased survival time in brain glioblastomas by a radioneuroendocrine strategy with radiotherapy plus melatonin compared to radiotherapy alone. Oncology 1996; 53: 43-46. Lissoni P, Ardizzoia A, Barni S e t al. A randomized study of tamoxifen alone versus tamoxifen plus melatonin in estrogen receptor-negative heavily pretreated metastatic breast cancer patients. Oncology Reports 1995; 2: 871-873. Dinan T G. Noradrenergic and serotonergic abnormalities in depression: stress-induced dysfunction? [Review]. J Clin Psychiatry 1996; 57(Suppl 4): 14-18. Kennedy S H, Brown G M. Effect of chronic antidepressant treatment with adinazolam and desipramine on melatonin
387 output. Psychiatry Res 1992; 43(2): 177-185. 14. Hilakivi-Clarke L, Rowland J, Clarke R, Lippman ME. Psychosocial factors in the development and progression of breast cancer [Review]. Breast Cancer Res Treat 1994; 29(2): 141-160. 15. Temoshok L. Personality, coping style, emotion and cancer: towards an integrative model [Review]. Cancer Surv 1987; 6(3): 545-567. 16. Bartsch C, Bartsch H, Jain A K, Laumas K R, Wetterberg L. Urinary melatonin levels in human breast cancer patients. J Neural Transm Suppl 1981; 52(4): 281-294. 17. Bartsch C, Bartsch H, Maestroni G J M. Conti A, Reiter R J, eds. Melatonin secretion in oncological patients: current results and methodological considerations. In: Advances in Pineal Research. London: John Libbey, 1994: 283-301.
Depression or cancer: the choice between serotonin or melatonin? A. PANZER Department of Physiology, University of Pretoria, PO Box 2034, Pretoria 0002, South Africa (phone: +27 12 3192137; Fax: +27 12 3192238; e-mail: [email protected])
Abstract - - Stress causes disturbances of monoamine functioning and may result in a serotonin deficiency which is manifested, as depression. In some humans, stress does not, however, cause depression. It is hypothesized that in these individuals, melatonin, which is normally a product of serotonin, may be converted back to its precursor and thus replenish serotonin stores. These people are thus not depressed and are characterized by their pleasant, unassertive nature. Their lowered melatonin levels may, however, signal an increased risk for cancer. It is therefore postulated that unresolved stress results in either depression (with low serotonin) or cancer (as a result of decreased melatonin), depending on individual personality traits and biochemistry.
Introduction
Monoamine metabolism and functions
The fact that psychological factors influence physical disease, has long been recognized in the well-known placebo effect. The interactions between the brain, endocrine, and immune systems have, however, only recently been explored. Studies of psychoneuroimmunology have validated anecdotal observations, for example that stress leads to an increased susceptibility to colds (1), that people with neoplasms have significantly fewer allergies (2), and that cancer patients tend to be more pleasant, appeasing and rational than average (3). The biochemical neurotransmitter link between personality traits and cancer development, has, however, not been explained. This paper alms to present an hypothesis to explain the link between personality and cancer by referring to serotonin and melatonin metabolism.
Melatonin is a product of serotonin metabolism, as seen in Fig. 1. In the biosynthesis of melatonin, the
Tryptophan $ 5-Hydroxytryptophan $ Serotonin J, N-acetyltransferase (NAT) N-acetylserotonin $ J, Hydroxyindole-O-methyl transferase (HIOMT) Melatonin $ 6-Hydroxymelatonin, 6-Sulfatoxymelatonin and other metabolites. Fig. ] Thebiosynthesisof me]atonin.
Received20 December1996 Accepted29 January 1997 385
386
MEDICAL HYPOTHESES
rate-limiting step is the conversion of serotonin to N-acetylserotonin, catalysed by N-acetyltransferase (4). It is fascinating that melatonin can also be converted back to N-acetylserotonin (5). The reason why melatonin should be metabolized to a product that is its own precursor, has not yet been elucidated. No studies have been done to indicate whether conversion of N-acetylserotonin to serotonin also occurs, but for the purposes of this argument it will be supposed to be possible, pending further research results. It is therefore conceivable that melatonin and serotonin are freely interconvertible. A deficiency of serotonin as neurotransmitter is thought to cause depression (6), and serotoninreuptake inhibitors, which increase the availability of this neurotransmitter in the synaptic cleft, alleviate the symptoms (7). Melatonin, the pineal hormone which is known best for its functions in synchronizing the circadian clock, has also been implicated in the pathogenesis of cancer. As a matter of fact, melatonin therapy has been shown to be effective in a wide variety of neoplasms (8-11). In spite of the close biochemical relationship, no link between serotonin and depression, on the one hand, and melatonin and cancer, on the other, has yet been found. In a recent review of the influence of psychological factors on disease (1), the authors conclude that evidence of depression influencing the onset and progression of cancer, is inconclusive and inconsistent.
Effects of stress on monoamine levels
Stress mediated through the hypothalamic-pituitaryadrenal axis produces disturbances seen in monoamine functioning (12). It is hypothesized that this stress may be manifested in two different ways, as shown in Fig. 2. Support for the hypothesis represented in Fig. 2a can be found in the clear association of deficient serotonin and depression (6,7), as well as the finding that depressed subjects have a normal Stress
~, Serotonin - -
Normal melatonin
$ Depression
$ No cancer
a
Stress
Normal serotonin
$ No depression
,l, Melatonin
$ Cancer
b
Fig. 2 Two different disturbances of monoamine functioning, resulting from stress.
output of melatonin (13). The hypothesis represented in Fig. 2b is corroborated by both retrospective and prospective studies which suggest that persons who have a tendency to repress emotions and therefore do not feel 'depressed', even during severe stress, are more prone to cancer (14). It is suggestive that cancer patients on the whole tend to be pleasant, trying to act rationally in spite of negative feelings (3). These personality traits are so common in cancer patients, that a personality type, called type C, has been proposed which is characterized by cooperative, appeasing, unassertive, patient and pleasant behaviour (15). This is clearly incompatible with a diagnosis of depression. Furthermore, melatonin levels have been found to be decreased in cancer patients (16,17). Conclusion
The appropriate biochemical coping mechanism for unresolved stress, may thus be decreased serotonin with resultant depression. If depression is averted by replenishing serotonin from conversion of melatonin, the benefit of feeling good and being nice may not outweigh the risk for cancer development. References 1. Cohen S, Herbert T B. Health psychology: psychological factors and physical disease from the perspective of human psychoneuroimmunology [Review]. Annu Rev Psychol 1996; 47: 113-142. 2. Petroianu A, Chaves D N, De Oliveira O Jr. Comparative incidence of allergy in the presence or absence of cancer. J Int Med Res 1995; 23(5): 358-363. 3. van der Ploeg H M, Kleijn W C, Mook J, van Donge M, Pieters A M, Leer J W. Rationality and antiemotionality as a risk factor for cancer: concept differentiation. J Psychosom Res 1989; 33(2): 217-225. 4. Reiter R J. Pineal melatonin: cell biology of its synthesis and of its physiological interactions. Endocrine Rev 1991; 12(2): 151-180. 5. Young I M, Leone R M, Francis P, Stovell P, Silman R E. Melatonin is metabolized to N-acetyl serotonin and 6-hydroxymelatonin in man. J Clin Endocrinol Metab 1985; 60(1): 114--119. 6. Baldwin D, Rudge S. The role of serotonin in depression and anxiety [Review]. Int Clin Psychopharmacol 1995; 9(Suppl 4): 41--45. 7. Wong D T, Bymaster F P. Development of antidepressant drugs: fluoxetine (Prozac) and other selective serotonin uptake inhibitors [Review]. Adv Exp Med Biol 1995; 363: 77-95. 8. Lissoni P, Barni S, Fossati V e t al. A randomized study of neuroimmunotherapy with low-dose subcutaneous interleukin2 plus melatonin compared to supportive care alone in patients with untreatable metastatic solid tumour. Support Care Cancer 1995; 3(3): 194-197. 9. Lissoni P, Meregalli S, Fossati V e t al. A randomized study of immunotherapy with low-dose subcutaneous interleukin-2 plus melatonin vs chemotherapy with cisplatin and etoposide as
DEPRESSION OR CANCER: SEROTONIN OR MELATONIN?
10.
11.
12. 13.
first-line therapy for advanced non-small cell lung cancer. Tumori 1994; 80(6): 464--467. Lissoni P, Meregalli S, Nosetto Let al. Increased survival time in brain glioblastomas by a radioneuroendocrine strategy with radiotherapy plus melatonin compared to radiotherapy alone. Oncology 1996; 53: 43-46. Lissoni P, Ardizzoia A, Barni S e t al. A randomized study of tamoxifen alone versus tamoxifen plus melatonin in estrogen receptor-negative heavily pretreated metastatic breast cancer patients. Oncology Reports 1995; 2: 871-873. Dinan T G. Noradrenergic and serotonergic abnormalities in depression: stress-induced dysfunction? [Review]. J Clin Psychiatry 1996; 57(Suppl 4): 14-18. Kennedy S H, Brown G M. Effect of chronic antidepressant treatment with adinazolam and desipramine on melatonin
387 output. Psychiatry Res 1992; 43(2): 177-185. 14. Hilakivi-Clarke L, Rowland J, Clarke R, Lippman ME. Psychosocial factors in the development and progression of breast cancer [Review]. Breast Cancer Res Treat 1994; 29(2): 141-160. 15. Temoshok L. Personality, coping style, emotion and cancer: towards an integrative model [Review]. Cancer Surv 1987; 6(3): 545-567. 16. Bartsch C, Bartsch H, Jain A K, Laumas K R, Wetterberg L. Urinary melatonin levels in human breast cancer patients. J Neural Transm Suppl 1981; 52(4): 281-294. 17. Bartsch C, Bartsch H, Maestroni G J M. Conti A, Reiter R J, eds. Melatonin secretion in oncological patients: current results and methodological considerations. In: Advances in Pineal Research. London: John Libbey, 1994: 283-301.