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Differences between males and females in rates of serotonin synthesis in human brain

Authors:
Sadahiko Nishizawa at Hamamatsu
Sadahiko Nishizawa
Chawki Benkelfat at McGill University
Chawki Benkelfat
Simon N Young at McGill University
Simon N Young
Marco Leyton at McGill University
Marco Leyton
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Rates of serotonin synthesis were measured in the human brain using positron emission tomography. The sensitivity of the method is indicated by the fact that measurements are possible even after a substantial lowering of synthesis induced by acute tryptophan depletion. Unlike serotonin levels in human brain, which vary greatly in different brain areas, rates of synthesis of the indolamine are rather uniform throughout the brain. The mean rate of synthesis in normal males was found to be 52% higher than in normal females; this marked difference may be a factor relevant to the lower incidence of major unipolar depression in males.
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... Another important mechanism is related to the differences in the functioning of the monoaminergic systems between the sexes. A deficiency in the serotonin precursor tryptophan leads to a temporary decline in serotonergic transmission in the female brain, resulting in significantly greater exacerbation of depressive symptoms in women compared to men suffering from this mental illness (44,45). Furthermore, various studies in patients and experimental animals have shown gender-specific differences in serotonin synthesis and metabolism, as well as in the activity of other monoaminergic systems such as dopamine and noradrenaline (44)(45)(46). ...
... A deficiency in the serotonin precursor tryptophan leads to a temporary decline in serotonergic transmission in the female brain, resulting in significantly greater exacerbation of depressive symptoms in women compared to men suffering from this mental illness (44,45). Furthermore, various studies in patients and experimental animals have shown gender-specific differences in serotonin synthesis and metabolism, as well as in the activity of other monoaminergic systems such as dopamine and noradrenaline (44)(45)(46). Differences in dopamine regulation were found, with women showing higher synaptic dopamine concentrations in the striatum compared to men. Additionally, age-related changes in serotonin and noradrenaline levels appear to be generally greater in women than in men (44,45). ...
... Differences in dopamine regulation were found, with women showing higher synaptic dopamine concentrations in the striatum compared to men. Additionally, age-related changes in serotonin and noradrenaline levels appear to be generally greater in women than in men (44,45). All of the abovementioned physiological phenomena and differences between women and men could partly explain the dissimilarities in the pathogenesis of depression and symptom presentation in both sexes. ...
Sexual dimorphism in the response to antidepressant therapy: Biological basis and clinical implications declaration of competing interests author contributions
Article
  • Jan 2024
Depression represents a complex mental health problem worldwide, affecting millions of people and causing significant societal and personal distress. A plethora of evidence has emerged indicating an important role of gender dimorphism in depression, with prevalence rates, symptomatology, and treatment responses differing between men and women. Women are generally more likely to suffer from depression, which is often attributed to hormonal influences, psychosocial stressors, and gender-specific coping mechanisms. In contrast, men may exhibit different depressive patterns, characterized by externalizing behaviors and higher suicide rates. Neurobiological studies highlight gender-specific differences in brain structure and function, as well as in neurotransmitter systems, which may impact treatment efficacy and response variability. While conventional pharmacotherapy remains pivotal, personalized approaches that integrate psychotherapeutic modalities such as cognitive-behavioral therapy and mindfulness-based interventions have increased in recent years. However, gender differences in treatment outcomes emphasize the need for differentiated, gender-sensitive clinical strategies. This review summarizes the current literature to highlight the complexity of depression and the importance of tailoring interventions to optimize clinical outcomes in diverse populations.
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... individuals (Oliva et al., 2011) and in clinical samples of patients with major depressive disorder (Jaworska et al., 2012), reporting steeper LDAEP in females relative to men. This sex difference may be viewed in connection with previous studies reporting lower serotonergic transmission in females compared to men (Nishizawa et al., 1997) which could be further linked to the observed sex differences in the prevalence of affective disorders ( Van de Velde et al., 2010). ...
Loudness dependence of the auditory evoked potential: temporal stability, associations to sociodemographic variables, and functional significance—implications for clinical research
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Introduction The loudness dependence of the auditory evoked potential (LDAEP) has been suggested as a biomarker for central serotonergic function, and as such a proxy for serotonin related psychiatric symptomatology and intervention outcome, particularly in depression. This study aims to explore LDAEP characteristics in a large healthy population by assessing its test–retest reliability and examining associations with sociodemographic variables, psychological distress, and performance-based cognitive function. Methods Our sample included 100 healthy adults whose LDAEP was measured and correlated with age, sex, self-reported psychological distress, and cognitive performance. Results Participants examined twice (n = 38) showed high test-retest reliability with intraclass correlations (ICCs) between 0.67 and 0.89 over a 2-to-3-month interval. Furthermore, the magnitude of the LDAEP was significantly higher in women than men, and female hormonal contraceptive users exhibited higher LDAEP than non-users. In females, age was inversely correlated with LDAEP. However, no significant associations were found between LDAEP and measures of psychological distress, including depressive symptoms, nor with cognitive test performance. Discussion These results underline LDAEP's reliability as a biomarker over time, but also highlight age, sex and hormonal contraceptive use as significant factors influencing the LDAEP. Future research in clinical population should take these results into account, with an emphasis on providing the necessary sample sizes for relevant sub-group analyses.
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... /\nd a111ong humans, C. N serotonin producrion is (on av<.:ragc:) 52% grc:ttcr am ng male. than fc malcs (Nishizawa et al., 1997). ln adtl ícion, for some adult males, physical abuse dming childhOl d act.1v�tccs ...
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  • Sep 2004
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The Biological Benefits of Failure on Learning and Tools to Manage the Fallout
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Full-text available
  • Apr 2025
  • EDUC PSYCHOL REV
Failure can be an effective tool for learning, but it comes with negative consequences. Educators and learners should practice strategies that leverage the benefits of failure while managing its negative consequences on learners’ motivation and persistence. Towards that goal, this paper examines the biological effects of failure on learning to (1) explain how failure primes the brain for learning and (2) propose behavioral strategies for coping with the negative consequences, focusing on postsecondary students. This conceptual literature review article draws upon neuroscience literature to explain biological mechanisms related to failure and education literature to explore connections to learning theory and environments. The paper is organized into two major sections: (1) the benefits of failure and (2) tools to deal with its negative effects. Within each section, the paper describes related neurochemicals and behavioral strategies to affect them that could be explored in educational settings. By understanding these biological effects, we can better design learning environments and support students through failure. Each section of the paper also describes non-invasive research tools that could be used to study the effects of interventions that aim to improve students’ experience of failure in education.
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Sex differences in the relationship between exercise habits and loneliness among older adults: a cross‐sectional study
Article
  • Mar 2025
  • PSYCHOGERIATRICS
Background Although loneliness has been associated with reduced physical activity, the association between exercise habits and loneliness remains unclear. Methods This study examined whether exercise habits are associated with loneliness among older adults by sex. This study included 10 152 individuals. The University of California Los Angeles Loneliness Scale was used to measure loneliness, with a score of 44 or more defined as loneliness. Information on exercise habits during the year was obtained using a questionnaire on whether participants performed 14 types of exercise. Binomial logistic regression analysis was conducted, with loneliness as the dependent variable and exercise habits as the independent variable. Results Overall, 3591 people (35.4%) were lonely, with more males (43.9%) experiencing loneliness than females (28.3%) ( P < 0.05). Binomial logistic regression analysis stratified by sex showed that the following exercise types were associated with loneliness among males (odds ratio (95% confidence interval): golf, 0.77 (0.67–0.89); gymnastics, 0.86 (0.75–0.99); exercise circle, 0.77 (0.65–0.91); and team games, 0.76 (0.63–0.90), P < 0.05). In contrast, no association was found between exercise habits and loneliness among females ( P > 0.05). Conclusions Loneliness was reduced among males through certain exercise practices. Group exercise interventions may effectively prevent loneliness among males, who are more likely to feel lonely than females.
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Dose-related Effects of Calcium to Enhance the Effects of L-tryptophan on Gut Hormones and Energy Intake in Obesity
Article
  • Jan 2025
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The Structured Clinical Interview for DSM-III-R (SCID): I: History, Rationale, and Description
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  • Aug 1992
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• The history, rationale, and development of the Structured Clinical Interview for DSM-III-R (SCID) is described. The SCID is a semistuctured interview for making the major Axis I DSM-III-R diagnoses. It is administered by a clinician and includes an introductory overview followed by nine modules, seven of which represent the major axis I diagnostic classes. Because of its modular construction, it can be adapted for use in studies in which particular diagnoses are not of interest. Using a decision tree approach, the SCID guides the clinician in testing diagnostic hypotheses as the interview is conducted. The output of the SCID is a record of the presence or absence of each of the disorders being considered, for current episode (past month) and for lifetime occurrence.
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Mood-Lowering Effect of Tryptophan Depletion
Article
  • Sep 1994
  • ARCH GEN PSYCHIAT
Methods: A double-blind placebo-controlled cross-over study in which plasma tryptophan was manipulated by administration of a tryptophan-deficient amino acid mixture. In the placebo condition, all subjects received a nutritionally balanced amino acid mixture that contained tryptophan. To further standardize baseline amino acids, each subject was provided with a low-protein diet the day before amino acid challenges. Subjects were euthymic, healthy men aged 18 to 30 years with either a multigenerational family history of affective illness or no family history of psychiatric illness in the present or in the two previous generations. Each subject was screened with a structured clinical interview to rule out a personal history of psychiatric illness.Results: Plasma tryptophan was reduced by 89% 5 hours after the administration of the tryptophan-deficient amino acid mixture. Six of 20 subjects with a family history of affective illness and none of 19 subjects without a family history of psychiatric illness showed a lowering of mood of 10 or more points on the Profile of Mood States depression scale (P=.012, Fisher's Exact Test) 5 hours after tryptophan depletion. No significant mood changes were observed following the control treatment (balanced amino acid mixture) in either group.Conclusions: Our data support the hypothesis that subjects with no prior depressive episodes but with a multigenerational family history of major affective disorder show a greater reduction in mood after tryptophan depletion. They are also consistent with theories that implicate deficient serotonergic function as one possible etiological factor in major depressive disorders.
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Serotonin Function and the Mechanism of Antidepressant Action
Article
  • May 1990
  • ARCH GEN PSYCHIAT
• Brain serotonin content is dependent on plasma levels of the essential amino acid tryptophan. We investigated the behavioral effects of rapid tryptophan depletion in patients in antidepressant-induced remission. Twenty-one patients who were depressed by DSM-III-R criteria received a 24-hour, 160-mg/d, lowtryptophan diet followed the next morning by a 16—amino acid drink, in a double-blind, placebo-controlled (acute tryptophan depletion and control testing), crossover fashion. Total and free tryptophan levels decreased 87% and 91%, respectively, during acute tryptophan depletion. Fourteen of the 21 remitted depressed patients receiving antidepressants experienced a depressive relapse after the tryptophan-free amino acid drink, with gradual (24 to 48 hours) return to the remitted state on return to regular food intake. Control testing produced no significant behavioral effects. Free plasma tryptophan level was negatively correlated with depression score during acute tryptophan depletion. The therapeutic effects of some antidepressant drugs may be dependent on serotonin availability.
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??gren H, Mefford IN, Rudorfer MV, Linnoila M, Potter WZ. Interacting neurotransmitter systems. A non-experimental approach to the 5HIAA-HVA correlation in human CSF. J Psychiatr Res 20: 175-193
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The repeatedly observed strong positive correlation between 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) in human cerebrospinal fluid (CSF) prompted an investigation to see if conclusions concerning possible interactions between brain serotonin and dopamine turnover could be reached from human CSF concentrations of these acid metabolites. CSF data from patients with depressive disorders diagnosed according to the RDC from Sweden (n=140) and from the National Institute of Mental Health (n=35) were used to test structural hypotheses by two statistical approaches—LISREL analysis and logistic regression. Results from both men and women were unequivocal: 5HIAA “controls” HVA, interpretable as a regulatory action of serotonin turnover on dopamine turnover. In women, only 5HIAA was affected by age, height and body size (higher in elderly, short and stout women); no similar relationships were seen in males. The concept of a serotonergic regulation of dopamine turnover was tested on brain punch analyses of serotonin and dopamine and their metabolites in two sets of dogs in a large number of brain areas. Results confirm a facilatory effect of serotonin on indices of dopamine turnover in many brain regions, especially brain stem and hypothalamus. The animal data validate the data analytic approach in humans.
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The use of analog rating scales in rating feelings
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Regional distribution of monoamines and their metabolites in human brain
Article
  • May 1978
Noradrenaline (NA), dopamine (DA), 5-hydroxytryptamine (5-HT), 3-methoxyphenylethylene glycol (MHPG), homovanillic acid (HVA), 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindolylacetic acid (5-HIAA) were measured in twenty areas of post-mortem brain from ten psychiatrically and neurologically normal patients. There was a marked difference, which did not appear to be related to sex, medication, cause of death or time between death and dissection, in amine and metabolite concentrations between brains. In the cortex, 5-HT, MHPG, HVA, DOPAC and 5-HIAA were approximately even in their distribution; NA and DA could not be detected. In sub-cortical areas there were clear differences in the distribution of the three amines accompanied by less marked differences in the distribution of their respective metabolites.
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