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

doi:10.1016/j.biopsych.2007.02.012

Biological Psychiatry

Volume 62, Issue 6, 15 September 2007, Pages 593-599

https://doi.org/10.1016/j.biopsych.2007.02.012 Get rights and content

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.

Section snippets

Participants

The participants were normal students recruited at the University of Oslo. Following a telephone screening, 86 participants arrived for further evaluation. After all the participants had provided written informed consent, they underwent a semistructured interview based on the DSM-IV criteria to rule out participants with evidence of major psychiatric diagnoses. Those with any past or present psychiatric diagnosis, including substance abuse, were excluded. Alcohol use was not permitted 24 hours

Effects of ATD on Tryptophan Levels

As predicted, ATD significantly decreased plasma concentrations of total [t(41) = 37, p < .001] and free [t(39) = 23, p < .001] tryptophan. Sham depletion significantly increased the concentrations of total [t(40) = 9, p < .001] and free [t(40) = 9, p < .001] tryptophan (Table 1). Genotype and sex did not influence the outcome.

Effects of ATD on Mood

Analyses of the mood response to ATD in our sample of healthy men and women showed a significant main effect of sex [F(1,70) = 9.8, p = .003], a trend toward significance

Discussion

The present study is, to our knowledge, the first to study sex differences between normal men and women in response to the effects of ATD on impulsivity and mood. Tryptophan-depleted men adopted an impulsive response style and showed no signs of mood reduction. Tryptophan-depleted women adopted a cautious response style associated with depression and reported a substantial drop in mood on the POMS. The sex difference in mood was evident in the triallelic L/L group, and the effect of 5-HT

References (89)

L. Sher et al.
The relationship of aggression to suicidal behavior in depressed patients with a history of alcoholism
Addict Behav
(2005)
L. Booij et al.
Tryptophan depletion affects heart rate variability and impulsivity in remitted depressed patients with a history of suicidal ideation
Biol Psychiatry
(2006)
J.R. Hibbeln 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)
E.F. Coccaro et al.
Relationship of prolactin response to d-fenfluramine to behavioral and questionnaire assessments of aggression in personality-disordered men
Biol Psychiatry
(1996)
S.N. Young et al.
The role of serotonin in human mood and social interactionInsight from altered tryptophan levels
Pharmacol Biochem Behav
(2002)
F.M. van der Veen et al.
Acute tryptophan depletion reduces activation in the right hippocampus during encoding in an episodic memory task
Neuroimage
(2006)
E.A.T. Evers et al.
Acute tryptophan depletion improves performance and modulates the BOLD response during a Stroop task in healthy females
Neuroimage
(2006)
K.A. Smith et al.
Relapse of depression after rapid depletion of tryptophan
Lancet
(1997)
A.J.W. Van der Does et al.
Cognitive therapy does not prevent a response to tryptophan depletion in patients also treated with antidepressants
Biol Psychiatry
(2005)
M.A. Ellenbogen et al.
Mood response to acute tryptophan depletion in healthy volunteers: Sex differences and temporal stability
Neuropsychopharmacology
(1996)

L. Booij et al.

Predictors of mood response to acute tryptophan depletion: A reanalysis

Neuropsychopharmacology

(2002)

R.J. Cadoret et al.

Associations of the serotonin transporter promoter polymorphism with aggressivity, attention deficit, and conduct disorder in an adoptee population

Compr Psychiatry

(2003)

J. Covault 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)

P. Courtet et al.

Serotonin transporter gene may be involved in short-term risk of subsequent suicide attempts

Biol Psychiatry

(2004)

P. Gorwood et al.

Serotonin transporter gene polymorphisms, alcoholism, and suicidal behavior

Biol Psychiatry

(2000)

X.Z. Hu et al.

Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder

Am J Hum Genet

(2006)

N. Praschak-Rieder 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)

B.A. Cornblatt et al.

The continuous performance test, identical pairs version: IIContrasting attentional profiles in schizophrenic and depressed patients

Psychiatry Res

(1989)

L.H. Phillips et al.

Impulsivity and speed-accuracy strategies in intelligence test performance

Intelligence

(1995)

R.A. Richell et al.

Effect of acute tryptophan depletion on the response to controllable and uncontrollable noise stress

Biol Psychiatry

(2005)

A.J.W. Van der Does

The effects of tryptophan depletion on mood and psychiatric symptoms

J Affect Disord

(2001)

N. Praschak-Rieder et al.

Effects of tryptophan depletion on the serotonin transporter in healthy humans

Biol Psychiatry

(2005)

R.M. Salomon et al.

Lack of behavioral effects of monoamine depletion in healthy subjects

Biol Psychiatry

(1997)

J.M. Corwin et al.

Disorders of decision in affective disease: An effect of beta-adrenergic dysfunction?

Biol Psychiatry

(1990)

S.B. Park et al.

Tryptophan depletion in normal volunteers produces selective impairments in learning and memory

Neuropharmacology

(1994)

H.M. van Praag

Faulty cortisol/serotonin interplayPsychopathological and biological characterisation of a new, hypothetical depression subtype (SeCA depression)

Psychiatry Res

(1996)

Z. Rihmer et al.

‘Anxiety/aggression-driven depression’ and ‘male depressive syndrome’: Are they the same?

Psychiatry Res

(1998)

J. Crean et al.

Effect of tryptophan depletion on impulsive behavior in men with or without a family history of alcoholism

Behav Brain Res

(2002)

M.A. Oquendo 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)

A. Dumais 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)

M. Asberg

Neurotransmitters and suicidal behaviourThe evidence from cerebrospinal fluid studies

Ann N Y Acad Sci

(1997)

G.A. Ordway et al.

Neurocircuitry of mood disorders

M. Doland et al.

Relationship between 5-HT function and impulsivity and aggression in male offenders with personality disorders

Br J Psychiatry

(2001)

M. Virkkunen et al.

CSF biochemistries, glucose metabolism, and diurnal activity rhythms in alcoholic, violent offenders, fire setters, and healthy volunteers

Arch Gen Psychiatry

(1994)

L.L. Carpenter et al.

Tryptophan depletion during continuous CSF sampling in healthy human subjects

Neuropsychopharmacology

(1998)

W.A. Williams et al.

Effects of acute tryptophan depletion on plasma and cerebrospinal fluid tryptophan and 5-hydroxyindoleacetic acid in normal volunteers

J Neurochem

(1999)

S. Nishizawa et al.

Differences between males and females in rates of 5-HT synthesis in human brain

Proc Natl Acad Sci U S A

(1997)

A. Neumeister 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)

A. Neumeister 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)

A. Neumeister et al.

Neural and behavioral responses to tryptophan depletion in unmedicated patients with remitted major depressive disorder and controls

Arch Gen Psychiatry

(2004)

A. Neumeister

Tryptophan depletion, serotonin, and depression: Where do we stand?

Psychopharmacol Bull

(2003)

K.A. Smith et al.

Effect of tryptophan depletion on mood in male and female volunteers: A pilot study

Hum Psychopharmacol

(1997)

C. Benkelfat et al.

Mood-lowering effect of tryptophan depletion: Enhanced susceptibility in young men at risk for major affective disorders

Arch Gen Psychiatry

(1994)

S.N. Young et al.

Tryptophan depletion causes a rapid lowering of mood in normal males

Psychopharmacology (Berl)

(1985)

Cited by (114)

Pharmacogenetics of selective serotonin reuptake inhibitors (SSRI): A serotonin reuptake transporter (SERT)-based approach
2024, Neurochemistry International
Neuropsychiatric disorders are considered to be the most common cause of disability worldwide. Serotonin and its transporter is a prominent paradigm in mood disorders. Response to selective serotonin reuptake inhibitors (SSRI) is altered due to heterogeneity in the serotonin transporter gene, SLC6A4 (solute carrier family 6 member 4). The reported polymorphisms are found to be in different regions of the transporter gene: promoter region (5-HTTLPR and various single nucleotide polymorphisms within it), intron (STin2), and exon 9 (I425V). The long and short alleles of the 5-HTTLPR gene, which are prevalent among variations, may mediate differential effects. In long allelic variant carriers, an increased response to SSRI and timely recovery is due to increased availability of SERT. Whereas, SERT availability is significantly decreased in short allelic carriers, necessitating a reduction in SSRI dosage due to the increased risk of adverse drug reactions. Thus, pharmacogenetic investigations are required to understand the impact of functional variations on the efficacy and tolerability of SSRI. Identifying the carrier variants may aid in clear-decision making of the treatment regimen, aiding the approach of personalized medication.
A central serotonin regulating gene polymorphism (TPH2) determines vulnerability to acute tryptophan depletion-induced anxiety and ventromedial prefrontal threat reactivity in healthy young men
2023, European Neuropsychopharmacology
Serotonin (5-HT) has long been implicated in adaptive emotion regulation as well as the development and treatment of emotional dysregulations in mental disorders. Accumulating evidence suggests a genetic vulnerability may render some individuals at a greater risk for the detrimental effects of transient variations in 5-HT signaling. The present study aimed to investigate whether individual variations in the Tryptophan hydroxylase 2 (TPH2) genetics influence susceptibility for behavioral and neural threat reactivity dysregulations during transiently decreased 5-HT signaling. To this end, interactive effects between TPH2 (rs4570625) genotype and acute tryptophan depletion (ATD) on threat reactivity were examined in a within-subject placebo-controlled pharmacological fMRI trial (n = 51). A priori genotype stratification of extreme groups (GG vs. TT) allowed balanced sampling. While no main effects of ATD on neural reactivity to threat-related stimuli and mood state were observed in the entire sample, accounting for TPH2 genotype revealed an ATD-induced increase in subjective anxious arousal in the GG but not the TT carriers. The effects were mirrored on the neural level, such that ATD specifically reduced ventromedial prefrontal cortex reactivity towards threat-related stimuli in the GG carriers. Furthermore, the ATD-induced increase in subjective anxiety positively associated with the extent of ATD-induced changes in ventromedial prefrontal cortex activity in response to threat-related stimuli in GG carriers. Together the present findings suggest for the first time that individual variations in TPH2 genetics render individuals susceptible to the anxiogenic and neural effects of a transient decrease in 5-HT signaling.
Serotonin neurobiology in cocaine use disorder
2020, Handbook of Behavioral Neuroscience
Cocaine misuse can escalate, leading to compulsive drug-taking and drug-seeking which characterizes the development of cocaine use disorder (CUD), an acquired brain disorder with clinically significant impairment. Cocaine binds to the serotonin (5-hydroxytryptamine; 5-HT) transporter, inhibits reuptake, and increases extracellular 5-HT efflux within limbic-corticostriatal circuitry involved in CUD neurobiology. The role of 5-HT in the in vivo effects of cocaine depends upon the 5-HT receptors and downstream signaling webs triggered. Multiple 5-HT receptor mechanisms and perturbations in the balance of serotonergic control contribute to basal states of vulnerability to CUD processes as well as the altered neurobiological states that drive the transition toward CUD and promote relapse. This review emphasizes the role of 5-HT and its receptor proteins and the implications of current findings to the future of therapeutics to enhance recovery and extend abstinence from CUD.
The role of serotonin in performance monitoring and cognitive control
2020, Handbook of Behavioral Neuroscience
Performance monitoring provides means to flexibly adjust behavior to changing demands. This requires an evaluation of performance and feedback, and its integration into behavioral control. As a central neuromodulator, serotonin has been implicated in many aspects of this feedback loop from error monitoring to inhibitory processes and decision-making. Studies in humans rarely found that serotonergic manipulations change error detection. In contrast, serotonin does appear to modulate how action errors relate to subsequent behavioral inhibition. This is especially true when initiation of new actions, rather than action cancellation, is investigated, suggesting that serotonin influences decision formation rather than action execution. In line with this, serotonergic involvement in shielding motivated behavior from alternative paths of actions has been demonstrated in animal studies. Therefore, a role for serotonin in performance monitoring may be to confer the value and especially the costs of future actions.
The androgen model of suicide completion
2019, Progress in Neurobiology
Citation Excerpt :
Violence, impulsivity, and aggression are associated with suicidal behaviors, and it is assumed that the serotonergic system is involved in this relationship (Apter et al., 1993; Mann, 2003; Zalsman, 2012). Thus, studies relating testosterone, serotonin signaling, and aggression to each other (Birger et al., 2003; Kranz et al., 2015; Kuepper et al., 2010; Walderhaug et al., 2007) also indicate that androgens may directly affect suicidal ideation, suicide attempts, and suicide completion. As already introduced in Section 6.1.1, there is some evidence suggesting a potentiating interaction between the prenatal androgen load (2D:4D ratio as a proxy) and adult androgen levels (related to challenging situations (Manning et al., 2014)), which may also be relevant for suicide completion.
Suicide is a devastating public health issue that imposes severe psychological, social, and economic burdens not only for the individuals but also for their relatives, friends, clinicians, and the general public. Among the different suicidal behaviors, suicide completion is the worst and the most relevant outcome. The knowledge of biological etiopathological mechanisms involved in suicide completion is limited. Hitherto, no objective markers, either alone or in combination, can reliably predict who will complete a suicide. However, such parameters are strongly needed to establish and optimize prediction and prevention.
We introduce here a novel ideation-to-completion framework in suicide research and discuss the problems of studies aiming at identifying and validating clinically useful markers. The male gender is a specific risk factor for suicide, which suggests that androgen effects are implicated in the transition from suicidal ideation to suicide completion. We present multiple lines of direct and indirect evidence showing that both an increased prenatal androgen load (with subsequent permanent neuroadaptations) and increased adult androgen activity are involved in suicide completion. We also review data arguing that modifiable maternal behavioral traits during pregnancy contribute to the offspring’s prenatal androgen load and increase the risk for suicide completion later in life.
We conclude that in utero androgen exposure and adult androgen levels facilitate suicide completion in an synergistic manner. The androgen model of suicide completion provides the basis for the development of novel predictive and preventive strategies in the future.
Dating violence victimization and substance use: The role of a serotonin transporter gene polymorphism (5HTTLPR)
2018, Drug and Alcohol Dependence
While there is developing research on how genes moderate the effect of stressful life events on substance use, the limited research has yet to focus on specific stressors. As adolescent dating violence victimization has been linked to various substance use behaviors, the current research seeks to further examine the longitudinal outcomes of adolescent dating violence victimization and the role that genes play in moderating these effects. Specifically, using data from the National Longitudinal Study of Adolescent to Adult Health (Add Health), a series of logistic and negative binomial regressions are run to analyze the direct and interactive effects of adolescent dating violence victimization and a polymorphism (5HTTLPR) in the promoter region of the serotonin transporter gene on both alcohol use problems and marijuana use. The results find that 5HTTLPR interacts with adolescent dating violence victimization to increase odds of marijuana use for the sample. However, the interaction between 5HTTLPR and adolescent dating violence has differential effects for males and females, suggesting sex differences regarding the susceptibility properties of 5HTTLPR. Implications of these findings are discussed.

View all citing articles on Scopus

View full text

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

Background

Methods

Results

Conclusions

Section snippets

Participants

Effects of ATD on Tryptophan Levels

Effects of ATD on Mood

Discussion

Addict Behav

Biol Psychiatry

Biol Psychiatry

Biol Psychiatry

Pharmacol Biochem Behav

Neuroimage

Neuroimage

Lancet

Biol Psychiatry

Neuropsychopharmacology

Neuropsychopharmacology

Compr Psychiatry

Biol Psychiatry

Biol Psychiatry

Biol Psychiatry

Am J Hum Genet

Biol Psychiatry

Psychiatry Res

Intelligence

Biol Psychiatry

J Affect Disord

Biol Psychiatry

Biol Psychiatry

Biol Psychiatry

Neuropharmacology

Psychiatry Res

Psychiatry Res

Behav Brain Res

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

Risk factors for suicide completion in major depression: A case-control study of impulsive and aggressive behaviors in men

Am J Psychiatry

Neurotransmitters and suicidal behaviourThe evidence from cerebrospinal fluid studies

Ann N Y Acad Sci

Neurocircuitry of mood disorders

Relationship between 5-HT function and impulsivity and aggression in male offenders with personality disorders

Br J Psychiatry

CSF biochemistries, glucose metabolism, and diurnal activity rhythms in alcoholic, violent offenders, fire setters, and healthy volunteers

Arch Gen Psychiatry

Tryptophan depletion during continuous CSF sampling in healthy human subjects

Neuropsychopharmacology

Effects of acute tryptophan depletion on plasma and cerebrospinal fluid tryptophan and 5-hydroxyindoleacetic acid in normal volunteers

J Neurochem

Differences between males and females in rates of 5-HT synthesis in human brain

Proc Natl Acad Sci U S A

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

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

Neural and behavioral responses to tryptophan depletion in unmedicated patients with remitted major depressive disorder and controls

Arch Gen Psychiatry

Tryptophan depletion, serotonin, and depression: Where do we stand?

Psychopharmacol Bull

Effect of tryptophan depletion on mood in male and female volunteers: A pilot study

Hum Psychopharmacol

Mood-lowering effect of tryptophan depletion: Enhanced susceptibility in young men at risk for major affective disorders

Arch Gen Psychiatry

Tryptophan depletion causes a rapid lowering of mood in normal males

Psychopharmacology (Berl)

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