A genetic predisposition to depression may be a potential risk factor in the development of depression. Although the neurobiological equivaLent of the predisposition remains unclear, it seems as though the brain serotonin (5-HT) system pLays an important mediating role. Therefore, individuals with a family history of depression (FH+) may be more likely to develop depression due to an innate vulnerability related to altered serotonergic neurotransmission in the brain. A major problem, however, is that the role of brain 5-HT in depression is complex and this serotonin-related innate vulnerability, by itself, is not sufficient enough to cause a depressive episode. In the search for additional factors, stress has received particular attention. Stressful life events influence and precede the onset of depression. Furthermore, depression is associated with stress hormone dysregulation and bidirectional interactions are thought to occur between stress-related changes in the neuroendocrine stress system and the 5-HT system. In the current review, we argue that healthy individuaLs with a positive family history of depression are more prone to develop depression due to a genetic 5-HT susceptibility, which deteriorates stress coping mechanisms and increases stress vulnerability.
Adell A. , Garcia-Marquez C. , Armario A. , Gelpi E. (1988) Chronic stress increases serotonin and noradrenaline in rat brain and sensitizes their responses to a further acute stress . J Neurochem50: 1678—1681
2.
Akiskal H.S. (2005) Mood disorders: historical introduction and conceptual overview. In Sadock B J , Sadock V A (eds), Kaplan & Sadock's Comprehensive Textbook of Psychiatry. Lippincott Williams & Wilkins , Philadelphia
3.
Arborelius L. , Owens M.J. , Plotsky P.M. , Nemeroff C.B. (1999) The role of corticotropin-releasing factor in depression and anxiety disorders . J Endocrinol160: 1—12
4.
Audenaert K. , Van Laere K. , Dumont F. , Slegers G. , Mertens J. , van Heeringen C. , Dierckx R.A. (2001) Decreased frontal serotonin 5-HT 2a receptor binding index in deliberate self-harm patients . Eur J Nucl Med28: 175—182
5.
Auerbach J. , Geller V. , Lezer S. , Shinwell E. , Belmaker R.H. , Levine J. , Ebstein R. (1999) Dopamine D4 receptor (D4DR) and serotonin transporter promoter (5-HTTLPR) polymorphisms in the determination of temperament in 2-month-old infants . Mol Psychiatry4: 369—373
6.
Bell C. , Abrams J. , Nutt D. ( 2001) Tryptophan depletion and its implications for psychiatry . Br J Psychiatry178: 399—405
7.
Benkelfat C. , Ellenbogen M.A. , Dean P. , Palmour R.M. , Young S.N. (1994) Mood-lowering effect of tryptophan depletion. Enhanced susceptibility in young men at genetic risk for major affective disorders . Arch Gen Psychiatry51: 687—697
8.
Bhatti T. , Gillin J.C. , Seifritz E. , Moore P. , Clark C. , Golshan S. , Stahl S. , Rapaport M. , Kelsoe J. (1998) Effects of a tryptophan-free amino acid drink challenge on normal human sleep electroencephalogram and mood . Biol Psychiatry43: 52—59
9.
Biegon A. , Grinspoon A. , Blumenfeld B. , Bleich A. , Apter A. , Mester R. (1990) Increased serotonin 5-HT2 receptor binding on blood platelets of suicidal men . Psychopharmacology (Berl) 100: 165—167
10.
Bondy B. , Erfurth A. , de Jonge S. , Kruger M. , Meyer H. (2000) Possible association of the short allele of the serotonin transporter promoter gene polymorphism (5-HTTLPR) with violent suicide . Mol Psychiatry5: 193—195
11.
Brown G.W. , Bifulco A. , Harris T.O. (1987) Life events, vulnerability and onset of depression: some refinements . Br J Psychiatry150: 30—42
12.
Carpenter L.L. , Anderson G.M. , Pelton G.H. , Gudin J.A. , Kirwin P.D. , Price L.H. , Heninger G.R. , McDougle C.J. (1998) Tryptophan depletion during continuous CSF sampling in healthy human subjects . Neuropsychopharmacology19: 26—35
13.
Carroll B.J. (1982) Use of the dexamethasone suppression test in depression . J Clin Psychiatry43: 44—50
14.
Caspi A. , Sugden K. , Moffitt T.E. , Taylor A. , Craig I.W. , Harrington H. , McClay J. , Mill J. , Martin J. , Braithwaite A. , Poulton R. (2003) Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene . Science301: 386—389
15.
Collier D.A. , Stober G. , Li T. , Heils A. , Catalano M. , Di Bella D , Arranz M.J. , Murray R.M. , Vallada H.P. , Bengel D. , Muller C.R. , Roberts G.W. , Smeraldi E. , Kirov G. , Sham P. , Lesch K.P. (1996) A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders . Mol Psychiatry1: 453—460
16.
Davis S. , Heal D.J. , Stanford S.C. (1995) Long-lasting effects of an acute stress on the neurochemistry and function of 5-hydroxytryptaminergic neurones in the mouse brain . Psychopharmacology (Berl) 118: 267—272
17.
De Kloet E.R. , Versteeg D.H. , Kovacs G.L. (1983) Aldosterone blocks the response to corticosterone in the raphe-hippocampal serotonin system . Brain Res264: 323—327
18.
De Kloet E.R. , Joels M. , Holsboer F. (2005) Stress and the brain: from adaptation to disease . Nat Rev Neurosci6: 463—475
19.
De Kloet E.R. , Kovacs G.L. , Szabo G. , Telegdy G. , Bohus B. , Versteeg D.H. (1982) Decreased serotonin turnover in the dorsal hippocampus of rat brain shortly after adrenalectomy: selective normalization after corticosterone substitution . Brain Res239: 659—663
20.
Delgado P.L. , Charney D.S. , Price L.H. , Aghajanian G.K. , Landis H. , Heninger G.R. (1990) Serotonin function and the mechanism of antidepressant action. Reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan . Arch Gen Psychiatry47: 411—418
21.
Delgado P.L. , Price L.H. , Miller H.L. , Salomon R.M. , Aghajanian G.K. , Heninger G.R. , Charney D.S. (1994) Serotonin and the neurobiology of depression. Effects of tryptophan depletion in drug-free depressed patients . Arch Gen Psychiatry51: 865—874
22.
Delgado P.L. , Miller H.L. , Salomon R.M. , Licinio J. , Krystal J.H. , Moreno F.A. , Heninger G.R. , Charney D.S. (1999) Tryptophan-depletion challenge in depressed patients treated with desipramine or fluoxetine: implications for the role of serotonin in the mechanism of antidepressant action . Biol Psychiatry46: 212—220
23.
Dinan T.G. (1994) Glucocorticoids and the genesis of depressive illness; a psychobiological model . Br J Psychiatry164: 365—371
24.
Dinan T.G. (1996) Serotonin and the regulation of hypothalamic-pituitary-adrenal axis function . Life Sci58: 1683—1694
25.
Drevets W.C. , Frank E. , Price J.C. , Kupfer D.J. , Holt D. , Greer P.J. , Huang Y. , Gautier C. , Mathis C. (1999) PET imaging of serotonin 1A receptor binding in depression . Biol Psychiatry46: 1375—1387
26.
Eley T.C. , Sugden K. , Corsico A. , Gregory A.M. , Sham P. , McGuffin P. , Plomin R. , Craig I.W. (2004) Gene—environment interaction analysis of serotonin system markers with adolescent depression . Mol Psychiatry9: 908—915
Fulford A.J. , Harbuz M.S. (2005) An introduction to the HPA axis. In Steckler T , Kalin N H , Reul J M H M (eds), Handbook of Stress and the Brain. Elsevier B.V., Amsterdam
29.
Fuller R.W. (1996) Serotonin receptors involved in regulation of pituitary-adrenocortical function in rats . Behav Brain Res73: 215—219
30.
Gessa G.L. , Biggio G. , Fadda F. , Corsini G.U. , Tagliamonte A. (1974) Effect of the oral administration of tryptophan-free amino acid mixtures on serum tryptophan, brain tryptophan and serotonin metabolism . J Neurochem22: 869—870
31.
Gillespie N.A. , Whitfield J.B. , Williams B. , Heath A.C. , Martin N.G. (2005) The relationship between stressful life events, the serotonin transporter (5-HTTLPR) genotype and major depression . Psychol Med35: 101—111
32.
Gonda X. , Juhasz G. , Laszik A. , Rihmer Z. , Bagdy G. (2005) Subthreshold depression is linked to the functional polymorphism of the 5HT transporter gene . J Affect Disord87: 291—297
33.
Gonda X. , Rihmer Z. , Zsombok T. , Bagdy G. , Akiskal K.K. , Akiskal H.S. (2006) The 5-HTTLPR polymorphism of the serotonin transporter gene is associated with affective temperaments as measured by TEMPS-A . J Affect Disord91: 125—131
34.
Grabe H.J. , Lange M. , Wolff B. , Volzke H. , Lucht M. , Freyberger H.J. , John U. , Cascorbi I. (2005) Mental and physical distress is modulated by a polymorphism in the 5-HT transporter gene interacting with social stressors and chronic disease burden . Mol Psychiatry10: 220—224
35.
Greenberg B.D. , Tolliver T.J. , Huang S.J. , Li Q. , Bengel D. , Murphy D.L. (1999) Genetic variation in the serotonin transporter promoter region affects serotonin uptake in human blood platelets . Am J Med Genet88: 83—87
36.
Hariri A.R. , Drabant E.M. , Munoz K.E. , Kolachana B.S. , Mattay V.S. , Egan M.F. , Weinberger D.R. (2005) A susceptibility gene for affective disorders and the response of the human amygdala . Arch Gen Psychiatry62: 146—152
37.
Hariri A.R. , Mattay V.S. , Tessitore A. , Kolachana B. , Fera F. , Goldman D. , Egan M.F. , Weinberger D.R. (2002) Serotonin transporter genetic variation and the response of the human amygdala . Science297: 400—403
38.
Heils A. , Teufel A. , Petri S. , Stober G. , Riederer P. , Bengel D. , Lesch K.P. (1996) Allelic variation of human serotonin transporter gene expression . J Neurochem66: 2621—2624
39.
Heim C. , Nemeroff C.B. (2001) The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies . Biol Psychiatry49: 1023—1039
40.
Holsboer F. (2000) The corticosteroid receptor hypothesis of depression . Neuropsychopharmacology23: 477—501
41.
Holsboer F. , Gerken A. , von Bardeleben U. , Grimm W. , Beyer H. , Muller O.A. , Stalla G.K. (1986) Human corticotropin-releasing hormone in depression—correlation with thyrotropin secretion following thyrotropin-releasing hormone . Biol Psychiatry21: 601—611
42.
Holsboer F. , Lauer C.J. , Schreiber W. , Krieg J.C. (1995) Altered hypothalamic-pituitary-adrenocortical regulation in healthy subjects at high familial risk for affective disorders . Neuroendocrinology62: 340—347
43.
Joiner T.E. Jr , Johnson F. , Soderstrom K. , Brown J.S. (2003) Is there an association between serotonin transporter gene polymorphism and family history of depression ? J Affect Disord77: 273—275
44.
Kaufman J. , Yang B.Z. , Douglas-Palumberi H. , Houshyar S. , Lipschitz D. , Krystal J.H. , Gelernter J. (2004) Social supports and serotonin transporter gene moderate depression in maltreated children . Proc Natl Acad Sci U S A101: 17316—17321
45.
Kelsoe J.R. (2005) Mood disorders: genetics. In Sadock B J , Sadock V A (eds), Kaplan & Sadock's Comprehensive Textbook of Psychiatry. Lippincott Williams & Wilkins, Philadelphia
46.
Kendler K.S. , Gardner C.O. (2001) Monozygotic twins discordant for major depression: a preliminary exploration of the role of environmental experiences in the aetiology and course of illness . Psychol Med31: 411—423
47.
Kendler K.S. , Kuhn J.W. , Vittum J. , Prescott C.A. , Riley B. (2005) The interaction of stressful life events and a serotonin transporter polymorphism in the prediction of episodes of major depression: a replication . Arch Gen Psychiatry62: 529—535
48.
Klaassen T. , Riedel W.J. , van Someren A. , Deutz N.E. , Honig A. , van Praag H.M. (1999) Mood effects of 24-hour tryptophan depletion in healthy first-degree relatives of patients with affective disorders . Biol Psychiatry46: 489—497
49.
Lefebvre H. , Contesse V. , Delarue C. , Feuilloley M. , Hery F. , Grise P. , Raynaud G. , Verhofstad A.A. , Wolf L.M. , Vaudry H. (1992) Serotonin-induced stimulation of cortisol secretion from human adrenocortical tissue is mediated through activation of a serotonin4 receptor subtype . Neuroscience47: 999—1007
50.
Lesch K.P. , Balling U. , Gross J. , Strauss K. , Wolozin B.L. , Murphy D.L. , Riederer P. (1994) Organization of the human serotonin transporter gene . J Neural Transm Gen Sect95: 157—162
51.
Lesch K.P. , Bengel D. , Heils A. , Sabol S.Z. , Greenberg B.D. , Petri S. , Benjamin J. , Muller C.R. , Hamer D.H. , Murphy D.L. (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region . Science274: 1527—1531
52.
Lieb R. , Isensee B. , Hofler M. , Pfister H. , Wittchen H.U. (2002) Parental major depression and the risk of depression and other mental disorders in offspring: a prospective-longitudinal community study . Arch Gen Psychiatry59: 365—374
53.
Maes M. , Meltzer H.Y. (1995) The serotonin hypothesis of major depression. In Bloom F E , Kupfer D J (eds), Psychopharmacology: The Fourth Generation of Progress. Raven Press, New York
54.
Maes M. , Minner B. , Suy E. ( 1991) The relationships between the availability of L-tryptophan to the brain, the spontaneous HPA-axis activity, and the HPA-axis responses to dexamethasone in depressed patients . Amino Acids1: 57—65
55.
Malison R.T. , Price L.H. , Berman R. , van Dyck C.H. , Pelton G.H. , Carpenter L. , Sanacora G. , Owens M.J. , Nemeroff C.B. , Rajeevan N. , Baldwin R.M. , Seibyl J.P. , Innis R.B. , Charney D.S. (1998) Reduced brain serotonin transporter availability in major depression as measured by [123I]-2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane and single photon emission computed tomography . Biol Psychiatry44: 1090—1098
56.
Mann J.J. , Huang Y.Y. , Underwood M.D. , Kassir S.A. , Oppenheim S. , Kelly T.M. , Dwork A.J. , Arango V. (2000) A serotonin transporter gene promoter polymorphism (5-HTTLPR) and prefrontal cortical binding in major depression and suicide . Arch Gen Psychiatry57: 729—738
57.
Markus C.R. (2003) Food, stress and mood. In Wadson D , Dodds F (eds), Performance Functional Foods. Woodhead Publishing Limited , Cambridge
58.
Markus C.R. , Panhuysen G. , Tuiten A. , Koppeschaar H. , Fekkes D. , Peters M.L. (1998) Does carbohydrate-rich, protein-poor food prevent a deterioration of mood and cognitive performance of stress-prone subjects when subjected to a stressful task?Appetite31: 49—65
59.
Markus R. , Panhuysen G. , Tuiten A. , Koppeschaar H. (2000a) Effects of food on cortisol and mood in vulnerable subjects under controllable and uncontrollable stress . Physiol Behav70: 333—342
60.
Markus C.R. , Olivier B. , Panhuysen G.E. , Van Der Gugten J. , Alles M.S. , Tuiten A. , Westenberg H.G. , Fekkes D. , Koppeschaar H.F. , de Haan E.E. (2000b) The bovine protein alpha-lactalbumin increases the plasma ratio of tryptophan to the other large neutral amino acids, and in vulnerable subjects raises brain serotonin activity, reduces cortisol concentration, and improves mood under stress . Am J Clin Nutr71: 1536—1544
61.
Modell S. , Yassouridis A. , Huber J. , Holsboer F. (1997) Corticosteroid receptor function is decreased in depressed patients . Neuroendocrinology65: 216—222
62.
Modell S. , Lauer C.J. , Schreiber W. , Huber J. , Krieg J.C. , Holsboer F. (1998) Hormonal response pattern in the combined DEX—CRH test is stable over time in subjects at high familial risk for affective disorders . Neuropsychopharmacology18: 253—262
63.
Moja E.A. , Rocchi E. , Benedetti F. , Paolillo F. , Casalgrandi G. , Ponz de Leon M. (1991) Decrease in plasma tryptophan after a tryptophan-free amino acid solution. A comparison between cirrhotic and control subjects . Life Sci48: 409—418
Neumeister A. , Konstantinidis A. , Stastny J. , Schwarz M.J. , Vitouch O. , Willeit M. , Praschak-Rieder N. , Zach J. , de Zwaan M. , Bondy B. , Ackenheil M. , Kasper S. (2002) Association between serotonin transporter gene promoter polymorphism (5-HTTLPR) and behavioral responses to tryptophan depletion in healthy women with and without family history of depression . Arch Gen Psychiatry59: 613—620
66.
Neumeister A. , Young T. , Stastny J. (2004a) Implications of genetic research on the role of the serotonin in depression: emphasis on the serotonin type 1A receptor and the serotonin transporter . Psychopharmacology (Berl) 174: 512—524
67.
Neumeister A. , Bain E. , Nugent A.C. , Carson R.E. , Bonne O. , Luckenbaugh D.A. , Eckelman W. , Herscovitch P. , Charney D.S. , Drevets W.C. (2004b) Reduced serotonin type 1A receptor binding in panic disorder . J Neurosci24: 589—591
68.
Nishizawa S. , Benkelfat C. , Young S.N. , Leyton M. , Mzengeza S. , de Montigny C. , Blier P. , Diksic M. (1997) Differences between males and females in rates of serotonin synthesis in human brain . Proc Natl Acad Sci U S A94: 5308—5313
69.
Nuller J.L. , Ostroumova M.N. (1980) Resistance to inhibiting effect of dexamethasone in patients with endogenous depression . Acta Psychiatr Scand61: 169—177
70.
Owens M.J. , Nemeroff C.B. (1994) Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter . Clin Chem40: 288—295
71.
Pandey G.N. , Pandey S.C. , Janicak P.G. , Marks R.C. , Davis J.M. (1990) Platelet serotonin-2 receptor binding sites in depression and suicide . Biol Psychiatry28: 215—222
72.
Porter R.J. , Gallagher P. , Watson S. , Young A.H. (2004) Corticosteroid-serotonin interactions in depression: a review of the human evidence . Psychopharmacology (Berl) 173: 1—17
73.
Reich T. , Van Eerdewegh P , Rice J. , Mullaney J. , Endicott J. , Klerman G.L. (1987) The familial transmission of primary major depressive disorder . J Psychiatr Res21: 613—624
74.
Richell R.A. , Deakin J.F. , Anderson I.M. (2005) Effect of acute tryptophan depletion on the response to controllable and uncontrollable noise stress . Biol Psychiatry57: 295—300
75.
Rihmer Z. , Angst J. (2005) Mood disorders: epidemiology. In Sadock B J , Sadock V A (eds), Kaplan & Sadock's Comprehensive Textbook of Psychiatry. Lippincott Williams & Wilkins, Philadelphia
76.
Roiser J.P. , Cook L.J. , Cooper J.D. , Rubinsztein D.C. , Sahakian B.J. (2005) Association of a functional polymorphism in the serotonin transporter gene with abnormal emotional processing in ecstasy users . Am J Psychiatry162: 609—612
77.
Rybakowski J.K. , Twardowska K. (1999) The dexamethasone/corticotropin-releasing hormone test in depression in bipolar and unipolar affective illness . J Psychiatr Res33: 363—370
78.
Sapolsky R.M. (1992) Stress, the Aging Brain, and the Mechanism of Neuron Death. MIT Press, Cambridge, MA
79.
Sargent P.A. , Kjaer K.H. , Bench C.J. , Rabiner E.A. , Messa C. , Meyer J. , Gunn R.N. , Grasby P.M. , Cowen P.J. (2000) Brain serotonin1A receptor binding measured by positron emission tomography with [11C]WAY-100635: effects of depression and antidepressant treatment . Arch Gen Psychiatry57: 174—180
80.
Seckl J.R. , Fink G. ( 1991) Use of in situ hybridization to investigate the regulation of hippocampal corticosteroid receptors by monoamines . J Steroid Biochem Mol Biol40: 685—688
81.
Stahl S.M. (1998) Mechanism of action of serotonin selective reuptake inhibitors. Serotonin receptors and pathways mediate therapeutic effects and side effects . J Affect Disord51: 215—235
82.
Steckler T. , Holsboer F. , Reul J.M. (1999) Glucocorticoids and depression. BaillieresBest Pract Res Clin Endocrinol Metab13: 597—614
83.
Sullivan P.F. , Neale M.C. , Kendler K.S. (2000) Genetic epidemiology of major depression: review and meta-analysis . Am J Psychiatry157: 1552—1562
84.
Ursin H. , Olff M. ( 1993) The stress response. In Stanford S C , Salmon P (eds), Stress: From Synapse to Syndrom. Academic Press , London , 4—20
85.
Van derDoes A.J. (2001) The effects of tryptophan depletion on mood and psychiatric symptoms . J Affect Disord64: 107—119
86.
Van Praag H.M. (2004) Can stress cause depression ? Prog Neuropsychopharmacol Biol Psychiatry28: 891—907
87.
Van Praag H.M. , de Kloet E.R. , Van Os J. (2004) Stress, the brain and depression. Cambridge University Press, Cambridge
88.
Von Bardeleben U , Holsboer F. (1989) Cortisol response to a combined dexamethasone-hCRH challenge in patients with depression . J Neuroendocrinol1: 485—488
89.
Wilhelm K. , Mitchell P.B. , Niven H. , Finch A. , Wedgwood L. , Scimone A. , Blair I.P. , Parker G. , Schofield P.R. (2006) Life events, first depression onset and the serotonin transporter gene . Br J Psychiatry188: 210—215
90.
Williams W.A. , Shoaf S.E. , Hommer D. , Rawlings R. , Linnoila M. (1999) Effects of acute tryptophan depletion on plasma and cerebrospinal fluid tryptophan and 5-hydroxyindoleacetic acid in normal volunteers . J Neurochem72: 1641—1647
91.
Williams R.B. , Marchuk D.A. , Gadde K.M. , Barefoot J.C. , Grichnik K. , Helms M.J. , Kuhn C.M. , Lewis J.G. , Schanberg S.M. , Stafford-Smith M. , Suarez E.C. , Clary G.L. , Svenson I.K. , Siegler I.C. (2003) Serotonin-related gene polymorphisms and central nervous system serotonin function . Neuropsychopharmacology28: 533—541
92.
Willis-Owen S.A. , Turri M.G. , Munafo M.R. , Surtees P.G. , Wainwright N.W. , Brixey R.D. , Flint J. (2005) The serotonin transporter length polymorphism, neuroticism, and depression: a comprehensive assessment of association . Biol Psychiatry58: 451—456
93.
Wurtman R.J. (2005) Genes, stress, and depression . Metabolism54: 16—19
94.
Young S.N. , Smith S.E. , Pihl R.O. , Ervin F.R. (1985) Tryptophan depletion causes a rapid lowering of mood in normal males . Psychopharmacology (Berl) 87: 173—177
