serotonin and gender-specific psychiatric disorders

( 1997 Martin Dumtz Ltd Intetnational Journal of Psychiatry in Clinml Practiw 1997 Volume 1 Pages 3-13 3

Serotonin and gender-specific psychiatric disorders

MEIR S T E I N E R ~ , ~ , PATRICIA LEPAGE' AND EDWARD J DUNN334

Departments of 'Psychiatry, 'Biomedical Sciences, 3Pathology and 4Laboratory Med- icine, S t Joseph's Hospital, McMasler Uni- versity, Hamilton, Ontario, Canada

Correspondence Address Prof Meir Steiner, Department of Psychiatry, St. Joseph's Hospital, 50 Charlton Avenue East, Hamilton, Ontario, Canada L8N 4A6 Tel +1 905 522 11.55 ext 360.5 Fax +1 90.5 521 6098

Received 13 December 1996; accepted for publication 4 January 1997

INTRODUCTION

The serotonergic system has been linked to the etiology of several, albeit disparate, psychiatric disorders. The accumulation of many lines of evidence support the view that there are gender differences in the serotonergic system in humans. It is further proposed that a gender dijferentiated serotonergic system acts as the nidus for the development of gender-specific psychiatric disorders. Depression, anxiety and eating disorders are largely seen in females, whereas alcoholism, aggressivity and suicide predominate in males. Evidence from both animal and human studies suggesting that the serotonergic system mediates between social- environmental experience and biological states is presented and reviewed. A reconceptualization of the serotonergic system as a gender-specific psychobiological interface is proposed. (Int J Psych Clin Prac 1997; 1: 3- 13)

Keywords

psychobiology psychiatric disorders serotonin gender

major challenge that continues to face psychiatry is A the bridging of biological and psychosocial theories in the aetiology of mental illness. Past efforts to conceptualize major theoretical orientations into a unified approach, particularly in the development of depression, have placed an emphasis not only on genetic vulnerability' and biological rhythms dysfunction' but also on the role of interpersonal relationships3, and socially mediated rhythms4. However, continued efforts to achieve a unifying theory will need to account for gender differences in the incidence and prevalence of the majority of psychiatric disorders. Adult women have higher rates of depression, anxiety, somatization and eating disorders, while alcoholism, antisocial personality and completed suicides predominate in adult men'. These sex differences in vulnerability to different psychiatric disorders are consistent across the lifespan' and cross-nationally'.

Serotonergic (5-HT) dysfunction has been implicated in the aetiology of each and every one of these psychiatric disorders8. 5-HT also plays a role in the modulation of a variety of physiological functions such as sleep, biological rhythms, pain, feeding, arousal, temperature regulation and neuroendocrine function'. In addition, fluctuations in measures of 5-HT appear to reflect age"', social context'', season'' and light changes13. Hence, efforts to integrate divergent models of pathophysiology must account for the

multiple lines of evidence that have delineated a role for 5- HT involvement as well as sex differences in several major categories of psychiatric illness". Pharmacologically, there is considerable evidence that most, if not all, antidepressant treatments, as well as lithium and electroconvulsive therapy, enhance 5-HT f ~ n c t i o n ' ~ - ' ~ . Specific serotonergic reuptake inhibitors (SSRIs) are being used to treat depressive illness'*, impulsive-aggressive obsessive-compulsive disorder (OCD)" and panic22, as well as eating disordersz3, a lcohol i~rn~~, premenstrual dysphoria25 and seasonal affective disorder (SAD)26.

The subject of 5-HT and psychiatric disorders is complicated by the delineation of several distinct 5-HT receptor types and the expansion of 5-HT 'specific' pharmacological agents available for use both clinically27 and experimentallyz8~2'. There are at least six major subtypes of serotonin receptors3' differentiated by their pharmacology3' as well as by their location in various brain systems32. The different 5-HT1 receptor subtypes are connected mostly with the limbic system and the basal ganglia, and the 5-HT2 receptors are mainly concentrated in the cerebral cortex, whereas 5-HT3 receptors are believed to be the link between the periphery and the central nervous system (CNS)33.

The specific central pharmacology of these 5-HT receptor subtypes, the 'balance' with other neurotransmitters (in particular acetylcholine, noradrenaline and dopa- mine), and the functional role of 5-HT in multicellular

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EXTERNAUENVIRONMENTAL INTERNALENDOGENOUS

Season

Social Contea

Drugs & Alcohol

Nutrition

Gender Differentiated -

Biological Rhythms

Life Cycle Changes

Genetics

Temperament

Developmental --I-- Experiences

Figure 1 Schematic representation of a gender dijJerentiated S-HT system. The psychobiological interface system serves to mediate factors external to the 5-HT system, i.e. light and season, and is limited in its response by factors internal to the system, i.e. genetics and temperament. Varying degrees of interaction are possible; hence compensatory mechanism between internal and external factors.

interneuronal operations are still poorly ~ n d e r s t o o d ~ ~ , ~ ~ . Furthermore, this sophisticated serotonergic system, which uses different receptor subtypes to convey its messages throughout the mammalian brain, is constantly under the modulatory influence of gonadal and adrenal steroids. These steroids regulate both pre- and post-synaptic 5-HT processes and are CNS-region specific, as well as age-, sex- and time-~pecific~~.

Thus it seems that most, if not all, 5-HT-mediated processes are gender-specific and as such can be conceptualized as entry points or potential triggers of 5-HT dysregulation. External factors include environmental differences, psychosocial and life events, and experiential factors. Internal mediating factors may include neurobiochemical differences, genetically encoded developmental changes37 and endogenous rhythms38 as well as temperamental difference^^^. Inherent in this paradigm is the possibility of an overall net effect of multiple entry point involvement, as well as the role of individual differences and the recognition that vulnerability is relative. We share McGuire’s ethological view4’ that ‘the central problem to be explained in “psychiatric disorders” is compromised function and integration of physiological and behavioural mechanisms’.

Our goal in this paper is therefore to review and synthesize the evidence that: 1. the 5-HT system mediates information between the external and internal environment; and 2. this system is more vulnerable to dysregulation in females than in males. The suggestion that 5-HT acts as a psychobiological interface system with multiple entry points may be able to accommodate the epidemiological evidence of sex and gender differences in psychiatric disorders, as well as the complex interplay and reciprocity between psychological and sociological, internal and external factors in psychiatric illness.

PSYCHOSOCIAL AND ENVIRONMENTAL INFLUENCES

SEROTONERGIC FUNCTION IN ANIMAL MODELS Serotonergic function in primates is influenced by social interactions, and the nature of this influence varies with age, sex, and species. Dominant status in the male vervet monkey is associated with higher whole-blood serotonin (WBS) levels than in subordinate vervets, but when males are placed in all-female groups or their status is reduced to subordinate, the WES levels decline41. The importance of contextual reciprocity is further highlighted by the findings that WBS levels declined significantly in dominant males placed in conditions where they could see, but could not be seen by, the members of their group. The report that reduced serotonin increases the risk of being ostracized in vervet monkeys suggests that there exists a biological vulnerability to social isolation. The link between reduced serotonergic function and destructive aggression is sup- ported by studies which show that further drug-induced depletion of serotonin causes even more intense aggres- ~ i o n ~ ~ . Dominant status is associated with a greater metabolic effect of tryptophan loading, suggesting that dominant status confers a biochemical advantage in the metabolism of t r y p t ~ p h a n ~ ~ , ~ ~ , ~ ~ . These studies have also highlighted the distinction between dominance and aggression and have further established that serotonergic mechanisms promote dominance acquisition in adult male ~ e r v e t s ~ ~ . This biochemical advantage is apparently not limited to mammalian species: a differential sensitivity to dietary tryptophan has also been observed in dominant and subordinate male chickens45.

SEROTONIN AND SOCIAL EXPERIENCE Studies of changes in 5-HT metabolites also support the role of 5-HT as a system which reflects sociocultural interaction in adult primate groups. Yodyingyuad et a146 measured cerebrospinal fluid 5-hydroxy-indoleacetic acid (CSF 5-HIAA) levels in captive talapoin monkeys of both sexes during isosexual group formation. 5-HIAA increased in monkeys which became subordinate, and decreased in the highest ranking monkey in the acute phase of group formation. Males had significantly higher levels of 5-HIAA than females. Top-ranking males and females had lower levels of 5-HIAA than the lowest and intermediate ranking monkeys. Dominant talapoin males were found to have higher 5-HIAA levels on days when aggression was high, in contrast to subordinate animals where levels of 5-HIAA were highest regardless of aggressive behaviour. Elevated CSF 5-HIAA in talapoin monkeys seems to be part of a state-dependent consequence of occupying a position of low social a finding also replicated in Arctic ~ h a r r ~ ~ .

The influence of social experience on the 5-HT system in infant rhesus monkeys was originally studied by

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Set-otonin and gender-specijic disorders 5

Kraemer et a149 and more recently by Higley et a15'-j3, who examined the relationship between behavioural inhibition and cisternal CSF 5-HIAA in rhesus monkeys under two different types of early rearing: the infant - mother dyad and peer-reared groups. Female subjects showed higher concentrations of 5-HIAA than males at 6 months in the infant - mother dyad, as well as higher concentrations than both female and male infants reared in peer-only groups. The levels of 5-HIAA declined at 19 months in mother- reared subjects, although no such change was observed in the peer-reared groups. In a continuation study (up to 50 months) of the peer-reared monkeys, a positive correlation between levels of behavioural inhibition and CSF 5-HIAA concentrations was found only in males5', suggesting that early rearing experience may affect a maturational process that involves 5-HT function in a way which predisposes to the development of behavioural inhibition. Conversely, low CSF 5-HIAA concentrations were correlated with impulsive behaviour and unrestrained aggression in male nonhuman primates5'. These differences in 5-HT function between individuals and their relationship to behaviour seem to be stable over time5'.

In mixed-sex groups of rats, subordinate males show widespread changes in 5-HT systems, including high ratios of 5-HIAA to 5-HT, as well as changes in 5-HTIA receptor binding54. Subordination stress has been suggested as a relevant model for investigating the effects of chronic stress on behavioural changes, some of which are similar to many of the core symptoms of depression. Repeated stress activates the hypothalamic - pituitary - adrenal (HPA) axis more in female rats than in males, and readier activation of corticosterone release has been implicated in the defective adaptation of female rats in this paradigm, which is currently being used as an animal model for depression and may be a more appropriate model for studying sex differences in vulnerability to mood disorders in humans55.

SEROTONIN, PERSONALITY AND DEPRESSION Naturalistic data on social influences and the 5-HT system in humans is almost non-existent, but what is known provides us with interesting parallels to the non-human primates. Madsen and McGuire5' studied the relationship of Type A personality behavioural measures and WBS levels in male undergraduates and concluded that WBS differentiated a power-seeking orientation in humans similar to that of other primates. In a later study, M a d ~ e n ~ ~ demonstrated that individuals with high WBS showed distinctly different patterns of adrenocorticotrophic hormone (ACTH), cortisol and norepinephrine response under a competitive challenge paradigm, highlighting the need to understand the relationship between the central 5-HT system and how it modulates the stress response. In humans (in contrast to monkeys), the social-rank - WBS relationship is such that higher WBS marks higher rank only among aggressive individuals''. Similarly, aggressive children with attention-deficit hyperactivity disorder had a

significantly greater prolactin response to the fenfluramine challenge (reflecting a more sensitive 5-HT system) than a non-aggressive subgroupj8.

The impact of psychosocial factors on the 5-HT system has also been studied in depressed patients. Deakin and c011eagues~~ found that elevated basal cortisol concentrations in depressives with chronic psychosocial difficulties were strongly and inversely predictive of a blunted prolactin response following L-tryptophan infusions, indicative of an impairment in 5-HT systems. It has also been noted that unipolar depressed patients with environment-sensitive recurrence of episodes had lower CSF 5-HIAA than those with autonomous episodes6". A neurobiological mechanism by which psychosocial stress may initiate an affective illness that becomes self-sustaining has been suggested. It is postulated that stress sensitization and episode sensitization occur and become encoded at the level of gene expression, altering neurotransmitters, receptors and neuropeptides in such a way that the anatomical and biochemical substrate of affective disorders is in a dynamic interchange with the environment6'.

Season and light are also conceptualized as external or environmental factors that mediate changes in the 5-HT system", affecting binding, transport and metabolism in the multiple entry point model. A seasonal variation in measures of 5-HT function has been reported in animals and humans for melatonin, a metabolite of serotonin63, free and total tryptophanh4, platelet serotonin and 3H- paroxetine binding in platelets" (see also review by Wirz-

Consistent with these observations is the reported light-induced seasonal variation in the incidence rate of affective illness6' and suicides69, as well as some evidence of changes in the therapeutic effects of antidepressants throughout the year64. Phototherapy has been proposed as treatment for SAD7' and for premenstrual dysphoric disorder (PMDD)7'. The reported light-induced augmentation of 'H-imipramine binding in both patients and healthy volunteers72 supports the evidence for changes in the 5-HT system as a function of light treatment, thus illustrating the potential role of 5-HT as a psychobiological interface system. Furthermore, Kasper et a173 have shown that seasonality of mood disorders is more common in females during their reproductive years, and the sex difference in prevalence of SAD seems to disappear after the menopause.

The neuroendocrine pharmacology of the 5-HT system has been recently reviewed". Glucocorticoids and 5-HT modulate behaviour and the HPA axis responses75. Hence, 5-HT is a potential neurotransmitter underlylng the hypercortisolism of psychiatric illness76. Furthermore, 5- HT as an interface model could explain individual differences along the HPA axis in that it would subsume the role of sensitization-zeitgeber phenomena and compensatory mechanisms and therefore, the net effect of internal and external mediating factors77. In a recent review of the evidence, it was suggested that stressful life events may trigger depression by a genomic action of corticoster-

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oids7'. Sex-linked differences in cortisol, ACTH and prolactin release following administration of 5-hydroxytryptophan have also been documented, lending further support to gender-specific stress-related differences in the serotonergic system79.

NEUROBIOLOGICAL DIFFERENCES BETWEEN MALES AND FEMALES

ANIMAL STUDIES Numerous animal studies have found sex differences in the central 5-HT system. In general, these findings support the suggestion of a greater storage capacity, higher enzymatic capacity and precursor availability, indicative of increased synthesis and turnover of 5-HT in female and vervet rnonkey~'~. These data suggest that females have the anatomical and physiological concomitants for greater 5- HT modulation of behaviour.

Female rats are more sensitive than males to pharmacological interventions that increase central 5-HT avail- abilitys5 and are more likely to exhibit the 'serotonin behavioural syndrome' when challenged with 5-HT,, agonistsa2,83 ,8687 . When rats were subjected to a restraint stress, a model of learned helplessness, males and females also differed in their adaptive capacities, and the failure of female rats to adapt to repeated stress was associated with dysregulated 5-HT synthesis55.

The role of the 5-HT system in the display of aggressive behaviours has been extensively studied and The differential pattern of aggressive behaviour between the sexes suggests either that females have a mechanism for greater inhibitory control, or that males have a stronger aggressive drive.

In his extensive review, S o ~ b r i e ~ ~ suggests that inhibition, passivity and waiting could be the main neuropsychological concomitants of 5-HT control of behaviour. Serotonin appears to have a facilitating role in the sexual, reproductive and maternal behaviours of the female rat93-96. Notably, deficits in maternal behaviours such as an inability to initiate suckling and failure to retrieve pups, as well as cannibalism, have been observed in postpartum rats following lesions of 5-HT n e ~ r o n e s ~ ~ , and filicide has been reported in female rats following an experimental treatment which causes a long-lasting reduction in 5-HT levels95. The fact that the destruction of serotonergic neurones can have harmful consequences for the mammalian offspring illustrates the need for a system which balances inhibitory controls with responsiveness to environmental demands, such as those imposed by caretaking functions in these species.

STUDIES IN HUMANS The relationship of the hormonal environment, 5-HT and behavioural response in 'less complex' animals enables us

to appreciate that human females are also subject to phasic and reciprocal changes throughout the life ~ y c l e l ~ , ~ ~ . Despite the obvious difficulties in interspecies comparisons, it seems likely that a system with such a crucial role in animals also plays a significant role in the behaviour of humans. The phylogenetic differences between the sexes along the 5-HT cascade may be an indicator of the differential gender predisposition to depressive illness and aggressive behaviour in humans.

Thus, gender differences in measures of 5-HT function in humans have been reported but are not abundant. A trend, though, for increased synthesis and turnover of 5-HT in females seems to indicate that in humans, as in other animals, the female capacity for 5-HT modulation of behaviour is greater. CSF levels of 5-HIAA were found to be higher in women than men, in both depressed patients and patients with chronic Changes in appetite frequently accompany depressive illness, more so in women than menloo, and are the cardinal feature of the eating disorders. It is well established that the synthesis of brain 5-HT is a function of the carb0hydrate:protein ratios that effectively increase or decrease the availability of tryptophan"'. Nutritional intake of 5-HT precursors such as tryptophan, therefore, present an obvious route by which a biochemical intervention may induce behavioural changes. Delgado et alloZ reported a depressive relapse in patients fed a tryptophan-free amino acid mixture which remitted with a return to regular food intake. Women have been found to have a greater reduction in levels of plasma tryptophan compared to men following a 3-week period of dietinglo3 and to have a more pronounced prolactin response to L-tryptophan loading (i.e. 5-HT 'supersensitiv- ity') than dieting menlo4. This occurred despite the fact that the percentage weight loss was similar in both males and females. It is notable that bulimic subjects whose plasma tryptophan increased during bingeing and vomiting also increased their plasma prolactin, suggesting that bingeing is a maladaptive effort to increase one's own 5-HT pre- c u r s o r ~ ~ ~ ~ . The implications of these results for gender- specific eating disorders have yet to be studied.

The role of diet and appetite changes, as well as cyclical disturbances related to season, menstruation and sleep in SADlo6, PMDDlo7 and 'hysteroid dysphoria', has recently been reviewed. Based on both clinical and biochemical findings, these predominantly female disorders can be redefined as variants of atypical depressive disorder"'. The association between mood and changes in appetite, specifically carbohydrate craving, suggests that these disorders are different manifestations of the same under- lying serotonergic pathophysiology and raises the question of the role of the different receptor subtypes and of developmentaVontogenetic issues in psychiatric disor- derslW.

Anxiety, aggression and suicide have been linked to diminished 5-HT metabolism but it is unclear whether they are independently related to 5-HT dysfunction or whether they are all linked together along a conti-

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Sct oronin mid gendet--specific disorders 7

n u u m l l o J 11 . Coccaro"' has specifically addressed the relationship of 5-HT to suicidal and impulsive aggressive behaviours, and hypothesizes that 5-HT post-synaptic receptor function in the limbic hypothalamic system underlies the pathophysiology of impulsive aggressive disorders, both inwardly and outwardly directed. Not surprising, however, is the fact that the studies reviewed by Coccaro were conducted in healthy male individuals and male psychiatric patients.

Linnoila and Virkk~nen"~ proposed a model for the pathogenesis of impulsivity. They have postulated a 'low serotonin syndrome' in impulsive male violent offenders, who have low CSF 5-HIAA concentrations as well as a predisposition to mild hypoglycaemia, a history of early- onset alcohol and substance abuse, increased risk of suicide, a family history of alcoholism, and disturbances in circadian rhythms1I4. They have further suggested that these features may represent a male-specific serotonergic dysregulation at the level of the suprachiasmatic nucleus (SCN) .

Dysregulation of the 5-HT system is in itself of paramount importance in the pathogenesis of alcohol abuse and dependen~e"~."" and it is believed that a low 5- HT tone underlies alcohol-seeking beha~iour"~. Alcohol- ism is more common in men than women, and coexists with several mental conditions, especially anxiety and affective disorders. Alcohol relieves anxiety and promotes sleep and is probably used as 'self-medication' in some of these comorbid conditions.

One of the most practical 5-HT-specific clinical probes available is the administration of oral fenfluramine HCl (FEN-challenge) which stimulates the release of prolactin and is currently regarded as a promising index of central serotonergic activity18. Mann et all1* recently reported that CSF 5-HIAA levels are positively correlated with maximal prolactin release following the administration of FEN- challenge in suicidal patients. Low 5-HIAA levels are a consistent finding in suicidal and impulsive-aggressive individual^"^ 120. A blunted prolactin response to fenfluramine has been described in depression121, in depressed patients with personality disorders'" and in antisocial personality disorder"'.

A blunted prolactin response following the meta- chlorophenylpiperazine HC1 (rn-CPP) challenge (a 5-HT receptor agonist), but not following the FEN-challenge test, has been reported in patients with OCD'23, and more so in female OCD patients, both at baseline and following m- CPP124. Brewerton et all2' reported similar findings in bulimic patients, using pi-CPP. Ryan et all2' found hypersecretion of prolactin following the infusion of L- tryptophan, a serotonergic precursor, in prepubertal girls with major depression, as did Maes et a179 in adult females with melancholia. Neither found augmented prolactin responses in comparable groups of depressed males. Normative data using the FEN-challenge test in healthy adults suggested significant effects of age and gender. McBride et all2' demonstrated that subjects over 30 years

of age have a decreased prolactin response compared with younger subjects and that women have a more robust prolactin response than men. Notably, the net prolactin responses in female subjects were up to double those of men in the same younger age group, suggesting enhanced serotonergic tone, although this may also reflect variability in the secretory capacity of the pituitary lactotroph.

Thus, differences in prolactin response to these various probes may not represent specific psychiatric disorders but rather the summation of many factors, including gender, age, developmental stage, seasonality, and rhythmicity, as well as the balance of serotonergic receptor subtypes. Despite the accumulation of a considerable amount of data it remains disparate, reflecting the complexity of the 5-HT system and the demand for a more coordinated research approach.

An ethological approach to testing and understanding the significance of these data would predict the need for greater control of impulsive aggression in females to ensure successful reproduction and rearing of offspring. The role of serotonergic dysfunction in infanticide and child abuse has yet to be explored. If, as Soubrie'l suggests, inhibition, passivity and waiting are the main neuropsychological concomitants of 5-HT-mediated behaviour, then the findings of McBride et have special significance when viewed in the context of the life cycle, i.e. successful reproduction and rearing of offspring.

There is increasing evidence that serotonergic dysfunction is important in the aetiology of PMDD13,25,109.'28. PMDD shares many of the phenomenological features of depression and anxiety states, eating disorders and impulsive-aggressive disorder^^^^^'^"^^^^ . Perimenstrual behaviour changes, including increased feeding, isolativeness and aggressivity, have been observed in female baboons and vervet monkey^'^^,'^' and suggest an evolutionary con- tinuity with human females along the serotonergic cascade. It is further suggested not only that PMDD should serve as a model of serotonergic dysfunction'" but that the onset of menstruation should be viewed as an added factor in the multiple entry point system which may trigger 5-HT dysregulation in vulnerable females'33.

Several biochemical parameters that influence or reflect changes in the 5-HT system over the course of the menstrual cycle have been reportedI3'. Platelet monoamine oxidase (MAO) activity is known to fluctuate in relation to the menstrual cycle, peaking at the time of ovulation and reaching a nadir in the early luteal p h a ~ e ' ~ ~ . ' ~ ~ , changes which may affect serotonin a~ailabil i ty '~~. Wirz-Justice and Chappi~s-Arndt '~~ reported a correlation between chlorimipramine-induced inhibition of platelet 5-HT uptake and the menstrual cycle. A significant elevation in platelet 5-HT uptake during the early luteal phase13', as compared to the significantly lower uptake demonstrated in the late luteal phase'", suggests an increase in 5-HT binding with increased oestrogenic influences. Lower platelet 3H-imipramine binding in women with PMDD also supports the hypothesis that changes in central 5-HT function may contribute to premenstrual ~ y m p t o m a t o l o g y ~ ~ ~ ~ ' ~ ~ . Not

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only has the administration of oestrogens been implicated in mood changes'43, but it has also been proposed as a treatment for d e p r e s ~ i o n ' ~ ~ . ~ ~ ~ . Most recently, bright artificial light71, S S R I S ~ ~ ~ and L- t rypt~phan '~~ have been reported in the treatment of PMDD, suggesting that PMDD and SAD share at least some pathophysiology. A parsimo- nious explanation for these findings would hold that each is an example of 5-HT dysregulation-a physiological end- point-in a system with multiple entry points and implied compensatory mechanisms. Support for this view is presented in the case report by Sothern et all4' of a woman in whom statistically significant rhythms, both menstrual and seasonal, were found in body temperature fluctuations associated with 11 manic episodes in 11 years. The authors suggest that a temporal schedule for psychophannacological treatment, designed from individual longitudinal records, that adjusts both for season and phase of the menstrual cycle, with increased doses just prior to the anticipated times of highest risk for an episode, may be appropriate for some women with affective disorders.

CONCLUSION The reconceptualization of 5-HT as gender-differentiated and as a psychobiological interface system that mediates internal and external change has considerable heuristic value. It attempts to make meaningful the disparate data regarding the role of 5-HT in psychiatric illness, as well as to provide direction for future study. The preclinical evidence reviewed here, based on physiological, pharmacological, and behavioural studies, clearly indicates gender specificity of 5-HT regulation in animals. Results from the most recent studies in female rats suggest a convergent CNS pathway through which steroids and neurotransmitters can control sexual behavi~ur '~~ . The selectivity of receptor subtypes involved in regulating sexual behaviour in the female rat has been identified for both the d~paminergic'~' and the ser~tonergic~~' systems. If, as Mani et suggest, a dual mechanism for activating steroid hormonal receptors exists, it may represent the link between neurotransmission and steroid receptor-dependent gene transcription. Such a mechanism may further explain gender-specific neuroendocrine behavioural and emotional responses.

In human studies the evidence so far is only tentative. Research efforts, therefore, need to span the science of 5- HT receptor subtypes, serotonergic metabolites and associated sex differences and bridge between animal and clinical studies. The fact that mammalians have a host of 5- HT receptor subtypes is believed to be an adaptive advantage. The 5-HT system is also unique in that it is highly localized (most cell bodies are found within the raphe nuclei) but the fibres fan out to virtually all parts of the brain. Considering the extent of these projections, it is not surprising that the serotonergic cascade is implicated in so many functions and integrated behaviours. Beyond

direct neurotransmission ('wiring transmission'), it is now believed that 5-HT may relay chemical signals by diffusion through the extracellular fluid ('volume t ransmi~s ion ' )~~~ and possibly modulate other neurotransmitter^'^^.

The risk that dysfunction of the 5-HT system will have significant pathological consequences is therefore high. At present, the 5-HTlA receptor subtype seems to be a consistent thread through the phenomenological pattern of depressive syndromes. The 5-HTlA or a 5-HTlA-like receptor subtype is believed to be involved in regulating the endogenous circadian rhythms of the SCN, which are modulated by 5-HT1543155 and by me la t~n in '~~ . In rats, not only is the 5-HTlA receptor subtype important in the control of biological rhythms, but it is itself modulated by gonadal In humans, though, the majority of studies of chronobiology and psychiatric disorders have examined circadian and/or circannual rhythms but have virtually ignored the effects of the superimposed gender- specific rhythms related to the female reproductive cycle. At the same time, epidemiological studies continue to indicate that women may be more prone to dysregulation of biological rhythms and thereby at greater risk of mood disorders during their reproductive year^'^','^^.

The complexity of gender-specific biological rhythms may also be extremely relevant to treatment. The enzymes responsible for the oxidative metabolism of many psychotropic medications, and, in particular, tricyclic antidepressants as well as SSRIs, include the cytochromes P450 2D6 and the P450 3A family160-'62. Not only are these the same enzymes that are involved in metabolizing many other medications, but, more importantly, they also metabolize gonadal steroids", and the expression of these enzymes is subject to genetic p~lymorphisrn'~~. Sex-specific cytochrome P450 has also been identified as the cause for gender- and species-related differences in drug Rhythms in efficacy as well as side-effects of psychotropic drugs may be due to rhythms in the brain's susceptibility, which reflects shifting relationships between the drug, the receptor subtype it affects and the surrounding neuroendocrine envir~nrnent'~~.

Although gender differences in the pharmacokinetics and pharmacodynamics of psychotropics have long been recognized'66, and recommendations have been made regarding the inclusion of women in psychopharmaco- logical trials'67, women, especially in their reproductive years, continue to be under-represented in clinical trials.

Linkage markers specifying genetic location, the isolation of 5-HT receptor subtype genes and the evaluation of putative pathophysiological markers are just a few examples of valuable new research tools in this area168-170 . Of equal importance would be further investigation of whether 5-HT as a psychobiological interface system is accountable for the well-known endocrinological concomitants of depression and alcoholism-examples of psychiatric illnesses well differentiated by sex. This might explain the epidemiological findings of sex differences in psychiatric illness and comorbidity of 5-HT-related disease^'^'-'^^. Comorbidity

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Serotonin and gender-specijic disorders 9

may reflect the summation of multiple routes of entry by which dysregulation of 5-HT occurs (e.g. SAD and bulimia). The inherent compensatory aspects of this model would suggest that the impact of life events, particularly of relationships, could be either a protective factor or a vulnerability factor. It could also explain the phenomenon of ‘incubation’ (the process by which life events influence the onset of psychiatric disorders after an appreciable delay), which seems to be restricted to women with depressive disorder^"^. It could explain the lack of specificity of 5-HT parameters, as well as the influence of seasonal factors in depression and suicide. Most importantly, it bridges the gap between a life events model and a biological causation model, helping to explain the cumu- lative effects of recent loss and alcoholism in males who commit suicide and the vulnerability to depression in females who do not commit suicide. Furthermore, the 5-HT system reconceptualized in this way contains a blueprint for future research efforts. In particular, it suggests the need to collect naturalistic data-primarily on temperament and life events as vulnerability factors in later life. Most importantly,

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ACKNOWLEDGEMENTS The authors would like to thank Marianne Jaszek for her editorial assistance and final preparation of the manuscript.

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