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Interactive Effects of Sex and 5-HTTLPR on Mood and Impulsivity During Tryptophan Depletion in Healthy People

      Background

      Serotonin (5-HT) plays a central role in mood regulation and impulsivity. We studied whether healthy men and women react differently on mood and impulsivity measures during acute tryptophan depletion (ATD). We also studied the relative contribution of a functional length triallelic polymorphism in the promoter region of the serotonin transporter, designated 5-HTTLPR, to the behavioral responses to ATD.

      Methods

      Thirty-nine men and 44 women participated in a randomized, double-blind, parallel group ATD study. Behavioral measures of impulsivity and mood were obtained.

      Results

      During ATD, women reported mood reduction and showed a cautious response style, which is commonly associated with depression. Men showed an impulsive response style and did not report mood reduction. The 5-HTTLPR influenced the mood response to ATD in women.

      Conclusions

      Healthy men became more impulsive, whereas healthy women showed mood reduction in response to ATD. This suggests that 5-HT could be one mechanism contributing to the sex differences in the prevalence of mood and impulsivity disorders. The influence of 5-HTTLPR on mood responses in women further substantiates the relevance of this variant in the pathophysiology of at least a subgroup of patients with major depressive disorder.

      Key Words

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      References

        • Sher L.
        • Oquendo M.A.
        • Galfalvy H.C.
        • Grunebaum M.F.
        • Burke A.K.
        • Zalsman G.
        • et al.
        The relationship of aggression to suicidal behavior in depressed patients with a history of alcoholism.
        Addict Behav. 2005; 30: 1144-1153
        • Oquendo M.A.
        • Galfalvy H.
        • Russo S.
        • Ellis S.P.
        • Grunebaum M.F.
        • Burke A.
        • et al.
        Prospective study of clinical predictors of suicidal acts after a major depressive episode in patients with major depressive disorder or bipolar disorder.
        Am J Psychiatry. 2004; 161: 1433-1441
        • Dumais A.
        • Lesage A.D.
        • Alda M.
        • Rouleau G.
        • Dumont M.
        • Chawky N.
        • et al.
        Risk factors for suicide completion in major depression: A case-control study of impulsive and aggressive behaviors in men.
        Am J Psychiatry. 2005; 162: 2116-2124
        • Asberg M.
        Neurotransmitters and suicidal behaviour.
        Ann N Y Acad Sci. 1997; 836: 158-181
        • Booij L.
        • Swenne C.A.
        • Brosschot J.F.
        • Haffmans P.M.J.
        • Thayer J.F.
        • Van der Does A.J.W.
        Tryptophan depletion affects heart rate variability and impulsivity in remitted depressed patients with a history of suicidal ideation.
        Biol Psychiatry. 2006; 60: 507-514
        • Ordway G.A.
        • Klimek V.
        • Mann J.J.
        Neurocircuitry of mood disorders.
        in: Davis K.L. Charney D. Coyle J.T. Nemeroff C. Neuropsychopharmacology: The Fifth Generation of Progress: An Official Publication of the American College of Neuropsychopharmacology. Lippincott Williams & Wilkins, Philadelphia2002: 1051-1065
        • Doland M.
        • Anderson I.M.
        • Deakin J.F.W.
        Relationship between 5-HT function and impulsivity and aggression in male offenders with personality disorders.
        Br J Psychiatry. 2001; 178: 352-359
        • Hibbeln J.R.
        • Umhau J.C.
        • Linnoila M.
        • George D.T.
        • Ragan P.W.
        • Shoaf S.E.
        • et al.
        A replication study of violent and nonviolent subjects: Cerebrospinal fluid metabolites of serotonin and dopamine are predicted by plasma essential fatty acids.
        Biol Psychiatry. 1998; 44: 243-249
        • Coccaro E.F.
        • Berman M.E.
        • Kavoussi R.J.
        • Hauger R.L.
        Relationship of prolactin response to d-fenfluramine to behavioral and questionnaire assessments of aggression in personality-disordered men.
        Biol Psychiatry. 1996; 40: 157-164
        • Virkkunen M.
        • Rawlings R.
        • Tokola R.
        • Poland R.E.
        • Guidotti A.
        • Nemeroff C.
        • et al.
        CSF biochemistries, glucose metabolism, and diurnal activity rhythms in alcoholic, violent offenders, fire setters, and healthy volunteers.
        Arch Gen Psychiatry. 1994; 51: 20-27
        • Young S.N.
        • Leyton M.
        The role of serotonin in human mood and social interaction.
        Pharmacol Biochem Behav. 2002; 71: 857-865
        • Carpenter L.L.
        • Anderson G.M.
        • Pelton G.H.
        • Gudin J.A.
        • Kirwin P.D.
        • Price L.H.
        • et al.
        Tryptophan depletion during continuous CSF sampling in healthy human subjects.
        Neuropsychopharmacology. 1998; 19: 26-35
        • Williams W.A.
        • Shoaf S.E.
        • Hommer D.
        • Rawlings R.
        • Linnoila M.
        Effects of acute tryptophan depletion on plasma and cerebrospinal fluid tryptophan and 5-hydroxyindoleacetic acid in normal volunteers.
        J Neurochem. 1999; 72: 1641-1647
        • Nishizawa S.
        • Benkelfat C.
        • Young S.N.
        • Leyton M.
        • Mzengeza S.
        • De Montigny C.
        • et al.
        Differences between males and females in rates of 5-HT synthesis in human brain.
        Proc Natl Acad Sci U S A. 1997; 94: 5308-5313
        • Neumeister A.
        • Konstantinidis A.
        • Stastny J.
        • Schwarz M.J.
        • Vitouch O.
        • Willeit M.
        • et al.
        Association between serotonin transporter gene promoter polymorphism (5HTTLPR) and behavioral responses to tryptophan depletion in healthy women with and without family history of depression.
        Arch Gen Psychiatry. 2002; 59: 613-620
        • van der Veen F.M.
        • Evers E.A.T.
        • van Deursen J.A.
        • Deutz N.E.P.
        • Backes W.H.
        • Schmitt J.A.J.
        Acute tryptophan depletion reduces activation in the right hippocampus during encoding in an episodic memory task.
        Neuroimage. 2006; 31: 1188-1196
        • Evers E.A.T.
        • van der Veen F.M.
        • Jolles J.
        • Deutz N.E.P.
        • Schmitt J.A.J.
        Acute tryptophan depletion improves performance and modulates the BOLD response during a Stroop task in healthy females.
        Neuroimage. 2006; 32: 248-255
        • Neumeister A.
        • Hu X.
        • Luckenbaugh D.A.
        • Schwarz M.
        • Nugent A.C.
        • Bonne O.
        • et al.
        Differential effects of 5-HTTLPR genotypes on the behavioral and neural responses to tryptophan depletion in patients with major depression and healthy controls.
        Arch Gen Psychiatry. 2006; 63: 978-986
        • Neumeister A.
        • Nugent A.C.
        • Waldeck T.
        • Geraci M.
        • Schwarz M.
        • Bonne O.
        • et al.
        Neural and behavioral responses to tryptophan depletion in unmedicated patients with remitted major depressive disorder and controls.
        Arch Gen Psychiatry. 2004; 61: 765-773
        • Neumeister A.
        Tryptophan depletion, serotonin, and depression: Where do we stand?.
        Psychopharmacol Bull. 2003; 37: 99-115
        • Smith K.A.
        • Fairburn C.G.
        • Cowen P.J.
        Relapse of depression after rapid depletion of tryptophan.
        Lancet. 1997; 349: 915-919
        • Van der Does A.J.W.
        • Booij L.
        Cognitive therapy does not prevent a response to tryptophan depletion in patients also treated with antidepressants.
        Biol Psychiatry. 2005; 58: 913-915
        • Ellenbogen M.A.
        • Young S.N.
        • Dean P.
        • Palmour R.M.
        • Benkelfat C.
        Mood response to acute tryptophan depletion in healthy volunteers: Sex differences and temporal stability.
        Neuropsychopharmacology. 1996; 15: 465-474
        • Smith K.A.
        • Clifford E.M.
        • Hockney R.A.
        • Clark D.M.
        • Cowen P.J.
        Effect of tryptophan depletion on mood in male and female volunteers: A pilot study.
        Hum Psychopharmacol. 1997; 12: 111-117
        • Benkelfat C.
        • Ellenbogen M.A.
        • Dean P.
        • Palmour R.M.
        • Young S.N.
        Mood-lowering effect of tryptophan depletion: Enhanced susceptibility in young men at risk for major affective disorders.
        Arch Gen Psychiatry. 1994; 51: 687-697
        • Young S.N.
        • Smith S.E.
        • Pihl R.O.
        • Ervin F.R.
        Tryptophan depletion causes a rapid lowering of mood in normal males.
        Psychopharmacology (Berl). 1985; 87: 173-177
        • Smith S.E.
        • Pihl R.O.
        • Young S.N.
        • Ervin F.R.
        A test of possible cognitive and environmental influences on the mood lowering effect of tryptophan depletion in normal males.
        Psychopharmacology (Berl). 1987; 91: 451-457
        • Bell C.J.
        • Hood S.D.
        • Nutt D.J.
        Acute tryptophan depletion.
        Aust N Z J Psychiatry. 2005; 39: 565-574
        • Booij L.
        • Van der Does W.
        • Benkelfat C.
        • Bremner J.D.
        • Cowen P.J.
        • Fava M.
        • et al.
        Predictors of mood response to acute tryptophan depletion: A reanalysis.
        Neuropsychopharmacology. 2002; 27: 852-861
        • Booij L.
        • van der Does A.J.
        • Haffmans P.M.
        • Spinhoven P.
        • McNally R.J.
        Acute tryptophan depletion as a model of depressive relapse: Behavioural specificity and ethical considerations.
        Br J Psychiatry. 2005; 187: 148-154
        • Cadoret R.J.
        • Langbehn D.
        • Caspers K.
        • Troughton E.P.
        • Yucuis R.
        • Sandhu H.K.
        • et al.
        Associations of the serotonin transporter promoter polymorphism with aggressivity, attention deficit, and conduct disorder in an adoptee population.
        Compr Psychiatry. 2003; 44: 88-101
        • Walderhaug E.
        • Lunde H.
        • Nordvik J.E.
        • Landrø N.I.
        • Refsum H.
        • Magnusson A.
        Lowering of serotonin by rapid tryptophan depletion increases impulsiveness in normal individuals.
        Psychopharmacology (Berl). 2002; 164: 385-391
        • Holden C.
        Sex and the suffering brain.
        Science. 2005; 308: 1574-1577
        • Kessler R.C.
        • Berglund P.
        • Demler O.
        • Jin R.
        • Walters E.E.
        Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the national comorbidity survey replication.
        Arch Gen Psychiatry. 2005; 62: 593-602
        • Khan A.
        • Brodhead A.E.
        • Schwartz K.A.
        • Kolts R.L.
        • Brown W.A.
        Sex differences in antidepressant response in recent antidepressant clinical trials.
        J Clin Psychopharmacol. 2005; 25: 318-324
        • Moreno F.A.
        • Rowe D.C.
        • Kaiser B.
        • Chase D.
        • Michaels T.
        • Gelernter J.
        • et al.
        Association between a serotonin transporter promoter region polymorphism and mood response during tryptophan depletion.
        Mol Psychiatry. 2002; 7: 213-216
        • Roiser J.P.
        • Blackwell A.D.
        • Cools R.
        • Clark L.
        • Rubinsztein D.C.
        • Robbins T.W.
        • et al.
        Serotonin transporter polymorphism mediates vulnerability to loss of incentive motivation following acute tryptophan depletion.
        Neuropsychopharmacology. 2006; 31: 2264-2272
        • Hu X.
        • Oroszi G.
        • Chun J.
        • Smith T.L.
        • Goldman D.
        • Schuckit M.A.
        An expanded evaluation of the relationship of four alleles to the level of response to alcohol and the alcoholism risk.
        Alcohol Clin Exp Res. 2005; 29: 8-16
        • Caspi A.
        • Sugden K.
        • Moffitt T.E.
        • Taylor A.
        • Craig I.W.
        • Harrington H.
        • et al.
        Influence of life stress on depression: Moderation by a polymorphism in the 5-HTT gene.
        Science. 2003; 301: 386-389
        • Zalsman G.
        • Huang Y.Y.
        • Oquendo M.A.
        • Burke A.K.
        • Hu X.Z.
        • Brent D.A.
        • et al.
        Association of a triallelic serotonin transporter gene promoter region (5-HTTLPR) polymorphism with stressful life events and severity of depression.
        Am J Psychiatry. 2006; 163: 1588-1593
        • Covault J.
        • Tennen H.
        • Armeli S.
        • Conner T.S.
        • Herman A.I.
        • Cillessen A.H.N.
        • et al.
        Interactive effects of the serotonin transporter 5-HTTLPR polymorphism and stressful life events on college student drinking and drug use.
        Biol Psychiatry. 2007; 61: 609-616
        • Courtet P.
        • Picot M.-C.
        • Bellivier F.
        • Torres S.
        • Jollant F.
        • Michelon C.
        • et al.
        Serotonin transporter gene may be involved in short-term risk of subsequent suicide attempts.
        Biol Psychiatry. 2004; 55: 46-51
        • Bayle F.J.
        • Leroy S.
        • Gourion D.
        • Millet B.
        • Olie J.P.
        • Poirier M.F.
        • et al.
        5HTTLPR polymorphism in schizophrenic patients: Further support for association with violent suicide attempts.
        Am J Med Genet B Neuropsychiatr Genet. 2003; 119: 13-17
        • Steiger H.
        • Joober R.
        • Israel M.
        • Young S.N.
        • Ng Ying Kin N.M.K.
        • Gauvin L.
        • et al.
        The 5HTTLPR polymorphism, psychopathologic symptoms, and platelet [3H-] paroxetine binding in bulimic syndromes.
        Int J Eat Disord. 2005; 37: 57-60
        • Gorwood P.
        • Batel P.
        • Ades J.
        • Hamon M.
        • Boni C.
        Serotonin transporter gene polymorphisms, alcoholism, and suicidal behavior.
        Biol Psychiatry. 2000; 48: 259-264
        • Hu X.Z.
        • Lipsky R.H.
        • Zhu G.
        • Akhtar L.A.
        • Taubman J.
        • Greenberg B.D.
        Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder.
        Am J Hum Genet. 2006; 78: 815-826
        • Praschak-Rieder N.
        • Hussey D.
        • Wilson A.A.
        • Carella A.
        • Lee M.
        • Dunn E.
        • et al.
        Tryptophan depletion and serotonin loss in selective serotonin reuptake inhibitor-treated depression: An [(18)F] MPPF positron emission tomography study.
        Biol Psychiatry. 2004; 56: 587-591
        • Murphy F.C.
        • Smith K.A.
        • Cowen P.J.
        • Robbins T.W.
        • Sahakian B.J.
        The effects of tryptophan depletion on cognitive and affective processing in healthy volunteers.
        Psychopharmacology (Berl). 2002; 163: 42-53
        • Cornblatt B.A.
        • Lenzenweger M.F.
        • Erlenmeyer-Kimling L.
        The continuous performance test, identical pairs version: II.
        Psychiatry Res. 1989; 29: 65-85
        • Dougherty D.M.
        • Mathias C.W.
        • Marsh D.M.
        • Papageorgiou T.D.
        • Swann A.C.
        • Moeller F.G.
        Laboratory measured behavioral impulsivity relates to suicide attempt history.
        Suicide Life Threat Behav. 2004; 34: 374-385
        • Dougherty D.M.
        • Marsh D.M.
        Immediate & Delayed Memory Tasks (IMT/DMT 2.0): A Research Tool for Studying Attention, Memory, and Impulsive Behavior.
        Neurobehavioral Research Laboratory and Clinic, University of Texas Health Science Center at Houston, Houston2003
        • Swets J.A.
        • Tanner W.P.
        • Birdsall T.G.
        Decision processes in perception.
        Psychol Rev. 1961; 68: 301-340
        • Davies D.R.
        • Parasuraman R.
        The Psychology of Vigilance.
        Academic Press, London1982
        • Conners C.K.
        • Epstein J.N.
        • Angold A.
        • Klaric J.
        Continuous performance test performance in a normative epidemiological sample.
        J Abnorm Child Psychol. 2003; 31: 555-562
        • Spreen O.
        • Strauss E.
        A Compendium of Neuropsychological Tests.
        2nd ed. Oxford University Press, New York1998
        • Halperin J.M.
        • Sharma V.
        • Greenblatt E.
        • Schwartz S.T.
        Assessment of the Continuous Performance Test: Reliability and validity in a nonreferred sample.
        Psychol Assess. 1991; 3: 603-608
        • Phillips L.H.
        • Rabbitt P.M.A.
        Impulsivity and speed-accuracy strategies in intelligence test performance.
        Intelligence. 1995; 21: 13-29
        • Rutschmann J.
        • Cornblatt B.
        • Erlenmeyer-Kimling L.
        Sustained attention in children at risk for schizophrenia.
        Arch Gen Psychiatry. 1977; 34: 571-575
        • Epstein J.N.
        • Erkanli A.
        • Conners C.K.
        • Klaric J.
        • Costello J.E.
        • Angold A.
        Relations between continuous performance test performance measures and ADHD behaviors.
        J Abnorm Child Psychol. 2003; 31: 543-554
        • Johnson M.H.
        • Magaro P.A.
        Effects of mood and severity on memory processes in depression and mania.
        Psychol Bull. 1987; 101: 28-40
        • McNair D.
        • Lorr M.
        • Droppleman L.
        POMS: Profile of Mood States.
        EITS/Educational and Industrial Testing Service, San Diego1992
        • Richell R.A.
        • Deakin J.F.W.
        • Anderson I.M.
        Effect of acute tryptophan depletion on the response to controllable and uncontrollable noise stress.
        Biol Psychiatry. 2005; 57: 295-300
        • Van der Does A.J.W.
        The effects of tryptophan depletion on mood and psychiatric symptoms.
        J Affect Disord. 2001; 64: 107-119
        • Knapp T.R.
        • Kimble L.P.
        • Dunbar S.B.
        Distinguishing between the stability of a construct and the stability of an instrument in trait/state measurement.
        Nurs Res. 1998; 47: 60-62
        • Gelernter J.
        • Kranzler H.
        • Cubells J.F.
        Serotonin transporter protein (SLC6A4) allele and haplotype frequencies and linkage disequilibria in African- and European-American and Japanese populations and in alcohol-dependent subjects.
        Hum Genet. 1997; 101: 243-246
        • Stein M.B.
        • Seedat S.
        • Gelernter J.
        Serotonin transporter gene promoter polymorphism predicts SSRI response in generalized social anxiety disorder.
        Psychopharmacology (Berl). 2006; 187: 68-72
        • Soubrie P.
        Reconciling the role of central serotonin neurons in human and animal behavior.
        Behav Brain Sci. 1986; 9: 319-335
        • Praschak-Rieder N.
        • Wilson A.A.
        • Hussey D.
        • Carella A.
        • Wei C.
        • Ginovart N.
        • et al.
        Effects of tryptophan depletion on the serotonin transporter in healthy humans.
        Biol Psychiatry. 2005; 58: 825-830
        • Salomon R.M.
        • Miller H.L.
        • Krystal J.H.
        • Heninger G.R.
        • Charney D.S.
        Lack of behavioral effects of monoamine depletion in healthy subjects.
        Biol Psychiatry. 1997; 41: 58-64
        • Miller E.
        • Lewis P.
        Recognition memory in elderly patients with depression and dementia: A signal detection analysis.
        J Abnorm Psychol. 1977; 86: 84-86
        • Corwin J.M.
        • Peselo E.
        • Feenan K.
        • Rotrosen J.
        • Fieve R.
        Disorders of decision in affective disease: An effect of beta-adrenergic dysfunction?.
        Biol Psychiatry. 1990; 27: 813-833
        • Sjoberg R.L.
        • Nilsson K.W.
        • Nordquist N.
        • Ohrvik J.
        • Leppert J.
        • Lindstrom L.
        • et al.
        Development of depression: Sex and the interaction between environment and a promoter polymorphism of the serotonin transporter gene.
        Int J Neuropsychopharmacol. 2006; 9: 443-449
        • Evenden J.L.
        Varieties of impulsivity.
        Psychopharmacology (Berl). 1999; 146: 348-361
        • Barkley R.A.
        Behavioral inhibition, sustained attention, and executive functions: Constructing a unifying theory of ADHD.
        Psychol Bull. 1997; 121: 65-94
        • Sergeant J.A.
        • Oosterlaan J.
        • van der Meere J.
        Information processing and energetic factors in attention-deficit/hyperactivity disorder.
        in: Quay H.C. Hogan A.E. Handbook of Disruptive Behavior Disorders. Kluwer, New York1999
        • Sagvolden T.
        • Johansen E.B.
        • Aase H.
        • Russell V.A.
        A dynamic developmental theory of attention-deficit/hyperactivity disorder (ADHD) predominantly hyperactive/impulsive and combined subtypes.
        Behav Brain Sci. 2005; 28: 397-419
        • Evers E.A.T.
        • van der Veen F.M.
        • van Deursen J.A.
        • Schmitt J.A.J.
        • Deutz N.E.P.
        • Jolles J.
        The effect of acute tryptophan depletion on the BOLD response during performance monitoring and response inhibition in healthy male volunteers.
        Psychopharmacology (Berl). 2006; 187: 200-208
        • Clark L.
        • Roiser J.P.
        • Cools R.
        • Rubinsztein D.C.
        • Sahakian B.J.
        • Robbins T.W.
        Stop signal response inhibition is not modulated by tryptophan depletion or the 5-HT transporter polymorphism in healthy volunteers: Implications for the 5-HT theory of impulsivity.
        Psychopharmacology (Berl). 2005; 182: 570-578
        • Gallagher P.
        • Massey A.E.
        • Young A.H.
        • McAllister-Williams R.H.
        Effects of acute tryptophan depletion on executive function in healthy male volunteers.
        BMC Psychiatry. 2003; 3: 10
        • Hughes J.H.
        • Gallagher P.
        • Stewart M.E.
        • Matthews D.
        • Kelly T.P.
        • Young A.H.
        The effects of acute tryptophan depletion on neuropsychological function.
        J Psychopharmacol. 2003; 17: 300-309
        • Park S.B.
        • Coull J.T.
        • McShane R.H.
        • Young A.H.
        • Sahakian B.J.
        • Robbins T.W.
        • et al.
        Tryptophan depletion in normal volunteers produces selective impairments in learning and memory.
        Neuropharmacology. 1994; 33: 575-588
        • Wood R.M.
        • Rilling J.K.
        • Sanfey A.G.
        • Bhagwagar Z.
        • Rogers R.D.
        Effects of tryptophan depletion on the performance of an iterated Prisoner’s Dilemma game in healthy adults.
        Neuropsychopharmacology. 2006; 31: 1075-1084
        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders DSM-IV-TR.
        4th ed. American Psychiatric Press, Washington, DC2000
        • Gater R.
        • Tansella M.
        • Korten A.
        • Tiemens B.G.
        • Mavreas V.G.
        • Olatawura M.O.
        Sex differences in the prevalence and detection of depressive and anxiety disorders.
        Arch Gen Psychiatry. 1998; 55: 405-413
        • Schwartz A.J.
        College student suicide in the United States: 1990–1991 through 2003–2004.
        J Am Coll Health. 2006; 54: 341-352
        • van Praag H.M.
        Faulty cortisol/serotonin interplay.
        Psychiatry Res. 1996; 65: 143-157
        • Rihmer Z.
        • Pestality P.
        • Pihlgren H.
        • Rutz W.
        ‘Anxiety/aggression-driven depression’ and ‘male depressive syndrome’: Are they the same?.
        Psychiatry Res. 1998; 77: 209-210
        • LeMarquand D.G.
        • Benkelfat C.
        • Pihl R.O.
        • Palmour R.M.
        • Young S.
        Behavioral disinhibition induced by tryptophan depletion in nonalcoholic young men with multigenerational family histories of paternal alcoholism.
        Am J Psychiatry. 1999; 156: 1771-1779
        • Crean J.
        • Richards J.B.
        • de Wit H.
        Effect of tryptophan depletion on impulsive behavior in men with or without a family history of alcoholism.
        Behav Brain Res. 2002; 136: 349-357