Breaking News

Externalizing disorders affect boys

 The second outstanding sex difference in neuropsychiatry is that male-predominant disorders and female-preponderant diseases belong to distinct behavioral classes.  Most male-preponderant syndromes can be classified as belonging to the axis of  disorders of excessive turbulence (externalizing disorders) and/or of deficient language.  However,  most people consider that language handicaps are not psychiatric disorders,  and that is why we covered them in the section on neurological sex differences.  Most female preponderant disorders can be considered internalizing disorders.

The externalizing disorders which occur more frequently in boys and men are Tourette's disease, hyperactivity, conduct disorder, and the various dependencies such as substance abuse, gambling and sex addiction -which affect men many times more frequently than women. Details about male risk for externalizing disorders are provide in table 5.

Table 5

Externalizing disorders
  

Disorder
Male to female prevalence
References
Alcoholism
(14.1:1)
Yamamoto, 1993
Antisocial personality
(3.4:1)
Barry et al, 1997
Hyperactivity
(6.7:1)
O’Leary et al, 1985
Tourette’s disease
(9.3:1)
Burd et al, 1986
Compulsive gambling
(1.4:1)
Buchta, 1995
Paraphylia
(50:1)
Zaviacic, 1993
Drug abuse
(2.2:1)
Brown, 1988

One of the important reasons women are catching up to men in cigarette addiction,  or so they say when questioned,  is that cigarette smoking keeps weight down, an aspect which women claim to fancy more than men.

A vignette on a case with attention deficit disorder  and hyperactivity (ADHD)

S7 is a 9 year old boy, who, like S1, was recently seen in a local hospital neuropsychology service thus coming to my attention recently.   His father is a “compensated” hyperactive himself:  he manages a busy restaurant  -an occupation he enjoys and is good at despite his childhood hyperactivity and learning disabilities.   S7’s teachers knew in his first year that he was a hyperactive child:  he was distractible and agitated.   He is disobedient, impulsive, remorseless,  jealous, argumentative,  and gets along very poorly with other boys.  Cognitive evaluation revealed normal IQ,  but he was often unable to finish a task -revealing a major problem maintaining attentional focus.  His language was normal,  but his memory scores reached only borderline-normal levels.   Visuospatial functions were normal,  but he had a dysexecutive  syndrome (poor planning,  poor judgment, little flexibility).   He has difficulty with several school subjects and receives special education services.  This child’s parents had the good sense to get him involved in intensive sports activities which help him blow off some steam. The neuropsychologist recommended that Ritalin (methylphenidate) be prescribed in this particular case.  

Kleine-Levin syndrome affects nearly exclusively boys,  and is also an externalizing disorder.   It usually appears at adolescence and is transitory.  It comprises hyperphagia (extreme and compulsive over-eating),  aggressiveness or extreme acting out,  and hypersomnia (excessive sleep).  It is believed to follow from hormonal changes in the brain (probably the hypothalamus) occurring at puberty,  but this remains to be proven.  What then is meant by an externalizing disorder ?   Psychiatric disorders are termed externalizing disorders when most of the behavioral problem has to do with such things as acting out,  impulsivity,  destructiveness,  aggressiveness.   


A vignette on a case of Kleine-Levin syndrome

Christopher Gillberg reported case F,  with Kleine-Levin syndrome,  in a 1987 issue of the Journal of the American Academy of Child and Adolescent Psychiatry.      Until age 15, F was a happy, sociable and normal boy.    After a fever,  he became sullen and withdrawn and showed autistic traits.   He had a period of hypersomnolence (slept too much) and hyperphagia (ate too much).   Then he recovered.   However,  he had seven more such spells,  each time of decreasing intensity.  His EEG (electroencephalogram), CT scan (brain imaging) and blood tests were normal.   There was no consumption of drugs.   As often happens in this clinical syndrome,  the boy was misdiagnosed for a very long time.  He was first believed to have an encephalitis (infection of the brain).   It took two years and 25 consultations with pediatricians, child psychiatrists and psychologists before the correct diagnosis was finally made.    Because the prognosis (predicted outcome) for Kleine-Levin syndrome is very good,  early correct diagnosis would have spared the family a tremendous amount of anguish and expenditure.
N.B.   Kleine-Levin syndrome sometimes comprises symptoms of aggressiveness and hypersexuality,  but neither of these occurred in the present case.

One of the most disturbing aspects frequently seen in externalizing disorders is aggressiveness.   Pathological aggressiveness is more often seen in the male sex.   Table 6 provides details of several disorders comprizing high levels of aggressiveness  which are clearly male prevalent.

Table 6

Male prevalent early onset syndromes comprising neurogenic aggressiveness

Neurogenic syndrome
Reference
Neophobic aggressive outbursts
Psychosis
Lewis et al, 1985
Rett syndrome*
Oliver et al, 1993
Autism
Smith, 1985
Sporadic aggressive explosions due to irritative brain disorders
Hypothalamic hamartoma
Berkovic et al, 1988
Episodic dyscontrol syndrome
Elliott, 1984
Epilepsy
Gillingham, 1988
Syndromes comprising chronic behavioral turbulence
Tourette’s disease
Comings et al, 1985
Character disorder
Miller, 1987
Hyperactivity disorder
Farrington, 1989
        *Rett’s syndrome is an X-linked condition which is fatal to the male sex prior to birth.

Internalizing disorders affect mostly women.  The internalizing disorders more prevalent in female children and women are depression,  phobia or extreme incapacitating fear of specific things  such as crowds or open spaces (agoraphobia),  spiders (arachnophobia),  enclosed spaces (claustrophobia),   anxiety disorders including panic disorder, hyperventilation syndrome, tension headache, as well as most of the neuroses (conversion disorder, hysteria, dissociative neurosis, etc.) and anorexia nervosa. Details concerning the female risk for internalizing disorders are presented in table 7.
Table 7

Internalizing disorders    

Disorder
Female to male prevalence
References
Anorexia nervosa
(10:1)
Rastam et al, 1989
Depression
(1.9:1)
Kivela et al, 1988
Phobia
(1.9:1)
Dick et al, 1994
Anxiety disorders
(2.3:1)
Angelopoulos, 1994
Neuroses (conversion, hysteria, dissociation, etc.)
(5.4:1)
Peiro et al, 1996
Elective mutism
(1.5:1)
Domènech, 1996
Post traumatic stress disorder
(1.5:1)
Garrisson et al, 1995

An interesting example of a female-prevalent internalizing disorder is somatization (also known as Briquet’s syndrome).  Somatization is a neurotic disorder consisting of numerous vague complaints of physical discomfort which cannot be medically substantiated.  One of the major psychiatric classification systems (DSM-III) used to require that women have 14 uncorroborated physical complaints, whereas only 12 were required of men -for the diagnosis to be posed.   The later versions of DSM modified this strange procedure,  removing the gender-specific criteria.  When the same criteria are applied to men and women for this type of disorder,  at least three times as many women are diagnosed as men.  These disorders are called internalizing disorders because most of the problem has to do with internal suffering,  dominated primarily either by feelings of sadness or of fear.   Even anorexia can be considered essentially a phobia ...  of fatness.  Because there are numerous signs of hormonal imbalance such as amenorhea (absence of menses), and lanugo (prolonged presence of baby hair),   and because this disorder typically appears at adolescence and is most often transitory, this latter disorder has been postulated to result from hormonal changes in the hypothalamus at puberty.   One author has even proposed that anorexia nervosa is the female analog of Kleine-Levin syndrome. We saw above that the only language disorder which affects girls more than boys is elective mutism,  an anxiety disorder.  We also know that boys are more at risk for virtually all sorts of epilepsy.   There is one exception however,  namely pseudo-epilepsy  -which affects girls more than boys.  This syndrome is more an anxiety disorder than anything else.   Pseudo-epilepsy,  self-induced convulsions,  occur most commonly in passive and emotionally dependent people who are very anxious.  Even though there is no overall sex prevalence for the obsessive-compulsive disorder,  boys and men are more often subject to aggressive compulsions,  and women to self-oriented compulsions such as cleaning, hand washing, and trichotillomania (hair twirling and pulling).    And remember that the early-onset, more severe forms, affect boys more often than girls. 

A vignette on a case of depression

D’Mello described Mrs A.,  a 32 year old depressive woman, in a 1983 issue of the Journal of Clinical Psychiatry.   Mrs A had been suffering from multiple depressive episodes over fifteen years.   She had been successfully treated with tricyclic antidepressant (serotonin agonist) medication.    She suffered from insomnia,  anorexia,  anergia (low energy),  and dysphoria (extreme sadness and dejection).    At age 32 she had a depressive episode which was treated with the tricyclic antidepressant protriptyline.     She soon developed dry mouth, constipation and eventually, severe epigastric distress (stomach ache) with marked abdominal distention.    It was determined that the severe epigastric distress was caused by aerophagia:  her anorexia,  dry mouth, excessive drinking of water,  constipation,  and additional effects of the tricyclic antidepressant medication had all concurred in producing swallowing of air and pocketing of this air in the abdomen.   Additional treatment was required to solve this particular problem.  


Female-prevalent disorders are stress related,  but the biological underpinnings are very complex.    It is very difficult to distinguish familial and interpersonal stress caused by a behaviorally disordered child from stress antedating and precipitating the behavioral disorder in that same child.  It is also difficult to tease out the effect of stress caused by the hereditary vector.  All the neuropsychiatric disorders,  male and female-prevalent, are to varying degrees heritable.  That means that one or both parents are relatively likely to suffer from some disorder within the hereditary spectrum,   thus stressing the child.   I never cease to be intrigued about how psychologists can claim to ever be dealing with «psychosocial stress» in a given individual,  giving no thought to the eventuality that something biological might be involved.  Nevertheless,  it has been observed that so-called psychosocial stress is a more significant and prevalent precipitator of female-prevalent chronic disorders.   Depression,  phobia, anxiety, somatization disorder, anorexia nervosa and elective mutism are all more prevalent in people (mainly of the female sex) undergoing interpersonal stress (dysfunctional families, bereavement,  financial crisis,   etc.).    The male-prevalent disorders are also stress-related,  but they seem to me to be less so (or are less linkable to ongoing stress in adulthood).   One of my reasons for believing this is that the female-prevalent disorders resemble the classical stress syndromes (post-traumatic stress syndrome for example),  whereas the male-prevalent syndromes do not.   For example,  psychopaths have nerves of steel, no sleep disorder,  no anxiety,  no sadness,  and do not suffer much emotionally.   Furthermore,  psychometric investigations of college students have generally found higher scores on scales of post traumatic stress disorder in women than in men.   One study investigating psychological effects of natural calamities found that women had higher scores on scales of post traumatic stress disorder.   In 1995, Sarah Ullman published results of a randomized community survey of 2,364 Los Angeles residents, in an investigation entitled “the Epidemiologic Catchment Area study”,   to examine the relationship of traumatic events to Diagnostic and Statistical Manual of Mental Disorders-III (DSM-III) criteria symptoms for post traumatic stress disorder (PTSD). Women manifested the syndrome more often than men.  In a study carrried out in 1989 in Japan (Tokyo) a well-known State-Trait Anxiety Inventory was administered to a representative community sample of 1,234 men and women whose ages ranged from 25 to 92 years. Women showed significantly higher anxiety than men.  Of course women’s stressors (rape, marital violence, poverty) are not the same as men’s (military combat, dangerous occupations, financial responsibilities),  but the results may reveal,  I think,  weaker resistance of mental health to stress in women.  
That women develop mental health problems with stress more than do men does not necessarily mean that women manifest a greater physiological stress response during stressful events themselves  -especially in parts of the body outside of the brain.  And in fact,  it appears that if there is any sex difference in the immediate physiology of stress,  it is the male sex which manifests a greater response.   Physiological components of the stress response include cortisol and adrenalin secretion by the adrenal gland,  as well as various indicators of autonomic nervous system arousal of the sympathetic branch (increased skin conductance associated with sweating, increased respiratory and heart rates, etc).  Cortisol is the main hormone involved in the stress response.  It is a steroid hormone like testosterone and estrogen,  but it is not a sex hormone. There is relatively greater conversion of cortisol to cortisone (a cortisol metabolite) in normal women than in matched men providing multiple blood samples (without any additional stress),  suggesting a more active physiological stress response in women  -even in the absence of a highly stressful event.   On the other hand,  several studies have found that men secrete more cortisol when faced with substantial stress than women do,  a finding which argues for greater stressability of men, not women, as could be superficially expected from our review of sex-typical prevalences of psychopathology above.  Adrenalin is the second most important hormone involved in the stress response.  There have been many investigations of adrenalin secretion during or soon after stress in male and female animals.  Males have generally been found to secrete more adrenalin than females when stressed.  In most of the relevant investigations, the heart rate response to stress does not seem to differ between males and females.  A few studies found a slightly greater heart rate response in women.  In animals (mice, rats, monkeys) and in humans,  stress reduces testosterone level,  especially in males.   None of the above argues for greater physiological (short term) stressability of females  -at least as can be judged from indicators found in the periphery of the brain (except perhaps for the heart rate indicator).  

However,  there is evidence of brain differences between the sexes in the response of neurotransmitters to stress,  and even that these sex differences are mediated by sex hormones.   A very interesting investigation was carried out on this subject in 1993 by a team of Japanese researchers. Sex-dependent changes in dopamine (DA) and serotonin (5HT) metabolisms under restraint stress were investigated in correlation with sex hormones. Male and female rats were divided into normal groups (in which female rats were further divided into proestrus, estrus, metestrus and diestrus subgroups), and castrated, estradiol-given, progesterone-given, and testosterone-given groups. Each group was subjected to the same restraint stress (the animal is immobilized, a subjection which is well known to be highly stressful), and DA, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5HT and 5-hydroxyindoleacetic acid (5HIAA) in the cerebral cortex, thalamus and brainstem were measured by the HPLC-ECD method.  DOPAC and HVA are dopamine metabolites,  and 5HIAA is a serotonin metabolite.  In the normal female group, DA and 5HT and their metabolites showed remarkable increase under the stress during proestrus and estrus phases. These phenomena were not observed in the castrated female group, suggesting that estradiol and progesterone are related to stress reactions of DA and 5HT metabolisms. In male rats, however, no distinct difference in the stress reactions of monoamine metabolisms was noted between the normal and castrated groups. In comparison of the hormone-given groups with the castrated groups, the increase in DA and DOPAC in the brainstem for both sex and the increase in 5HIAA in the brainstem for females, were notable.  In the progesterone-given group, DOPAC, HVA and 5HIAA were increased in female cerebral cortex, but not in male cortex. DA metabolism showed no great difference between the testosterone-given and the castrated groups for both sexes, but 5HIAA was increased in female cerebral cortex and brainstem. These findings suggest that stress reactions of DA and 5HT metabolisms in the brain differ according to sex, and that estradiol and progesterone accelerate the stress reactions of DA and 5HT metabolisms.    Another investigation on similar mechanisms in rats led the authors to the following conclusion and speculation:  « ...corticosterone facilitates adaptation to single restraint but impairs adaptation to repeated restraint  [in rats]. As failure to adapt to repeated stress is an animal model of depression, results as a whole suggest that increased corticoid levels and decreased 5HT functional activity may have a role in the development of the illness and its greater incidence in women ».    Ingenious experimentation has even begun to map the brain’s physiological response during stress as a function of an animal’s gender.   In one such study carried out on rats, restraint and formalin injections into a forelimb were used as stressors and 2-[14C]-deoxyglucose (2DG) autoradiography was used to evaluate regional brain glucose metabolism, an index of neural activity.  Analysis of blood samples collected during the 2DG procedure confirmed that stress elevates plasma glucose levels signficantly more in females than in males. Moreover, females showed higher brain glucose utilization in all regions examined, including sex hormone-responsive regions such as the medial amygdala, medial preoptic nucleus, the ventromedial nucleus of the hypothalamus, and arcuate nucleus, as well as the CA1 layer and dentate region of the hippocampus, the posterior parietal (sensorimotor) cortex, medial and lateral habenula, and splenium of the corpus callosum. The sex differences were apparent regardless of whether animals were injected with saline (a less painful injection) or formalin. Interestingly, the medial preoptic area, which shows robust neuroanatomical sex differences, demonstrated greater activation in response to formalin than to saline only in females. In some brain regions of both males and females, glucose utilization was higher on the side of the brain contralateral to the saline or formalin injection site. These findings suggest that there are widespread, gender-related differences in neuronal as well as endocrine activation in response to highly stressful conditions.    In monkeys,  severe early postnatal psychosocial stress caused by rearing in isolation chronically disturbs male behavior more profoundly and more frequently than female behavior.   

The brain’s response to the physiological components of the stress response (e.g., cortisol secretion)  may also in itself be sexually dimorphic.  Indeed,  it seems that estrogen  has a protective function against cortisol in the brain,  particularly in the oxidative destruction of neurons wrought by stress-induced brain cortisol.  One study found that oxidative stress-induced cell death caused by the neurotoxins amyloid beta protein, hydrogen peroxide and glutamate in the clonal mouse hippocampal cell line HT22 is inhibited by the antioxidant effect of 17-beta estradiol. Other steroid hormones, such as progesterone, aldosterone, corticosterone and the steroid precursor cholesterol, did not protect the cells. The neuronal protection afforded by 17-beta estradiol was estrogen receptor-independent. These data demonstrate a potent neuroprotective activity of the antioxidant 17-beta estradiol, which may have implications for the prevention and treatment of Alzheimer's disease.

The interaction between age of onset and the effect of stress.    Though adult males seem to present a more vigorous peripheral bodily reaction to stress,  suggesting that they are more stressable,  adult females seem to present a characteristic delayed response to stress occurring in the brain from puberty through adulthood.    It has now been documented that prolonged central nervous system effects of stress include degeneration of hippocampal and other neurons,  via the effects of cortisol.   The human female brain could be sensitive to the deleterious effects of cortisol in a manner different from what occurs  in the male brain:  the female brain’s response being perhaps somehow delayed and perhaps destabilizing more selectively the serotonin brain network.   In human males,  perhaps the effects of cortisol on the brain are more immediate and destabilize more selectively the brain dopamine network...   Therein lies a speculative explanation of why women would develop more stress-related psychopathologies.   Psychopathology severe enough to be recognized as an official mental disorder does not develop in the short term,  but usually over several years.   It would be absurd to think that a psychopathological syndrome could result directly form morbid peripheral physiology without some central nervous system abnormality intervening.   However,  the above account may be a little too simplistic to fully account for the relevant facts.   Effects of stress on the brain seem to depend on the age of the animal.   Offspring of rats stressed during pregnancy manifest brain changes in several of the sex dimorphic nuclei and in the cortex.   In particular,  the preoptic nucleus of the hypothalamus is substantially reduced in size once the prenatally stressed offspring reaches adulthood. Furthermore, the asymmetry in cortical thickness (favoring the right side) normally observed in male rats,  is not observed when that rat’s mother has been stressed during pregnancy. Finally,  the spinal bulbocavernal nucleus also does not develop to full size in prenatally stressed rats.  These effects are observed only in males.  When one thinks of it,  this is not so surprising:  masculinization of the male fetus brain is androgen dependent,  and a stressed mother is androgen deficient, so the fetus’s brain could be left unmasculinized in that  manner. However, there are numerous other indirect findings suggesting that prenatally stressed male rats have weakened development of brain areas that are not sexually dimorphic.   So  it could also be that stress contributes to the masculine propensity to show early onset psychopathological disorders,  and the feminine propensity to show stress-related psychopathological disorders in adulthood.  A gigantic epidemiological study carried out by the American National Institute of Mental Health in 1967 supports this point of view.   One broad category of psychopathology surveyed in hospitals  and clinics throughout the country was labeled «neurotic disorders ...that are highly reactive to situational stress».   Between the ages of 5 and nine years the female to male prevalence ratio was .51.  Between 10 and 14 years of age,  it was 1.06,  and between 15 and 19 years of age it was 1.77.

A vignette of a case of elective mutism

Atoynatan described in a 1986 publication the case of a girl named Ruth.   At age three,  shortly after her family moved and her mother’s miscarriage,  Ruth gradually stopped talking to boys and men  -whom she claimed to be afraid of.   The only man she would occasionally talk to was her father.   She had been friendly to men prior to this.    Ruth had been and remained disobedient, capricious, defiant and idiosyncratic.    Ruth’s mother had been treated roughly as a child,  making her shy and very reserved it was thought.  She had several psychopathological traits (anxiety attacks, phobias,  illusions,  nightmares,  unjustified symptoms of stress).     It is at the time these symptoms took the form of depression that Ruth developed her selective mutism.   Then the mother’s psychological and emotional state improved during a prolonged regimen of psychotherapy.  In parallel to these improvements,  Ruth also gradually started talking normally to boys and men.

Is the right hemisphere more fragile in females and the left hemisphere more fragile in males ?   A few neuropsychiatrists have put forward the speculation to the effect that the main cause of gender differences in neuropsychiatry are due to a sex difference in asymmetric fragility of the hemispheres,  but I believe most specialists remain unconvinced.   Metabolic imaging of the brain,  neuropsychological testing and electroencephalographic investigations have shown that depression and anorexia nervosa are associated slightly more with right than left hemisphere abnormality.  On the other hand,  investigation of depression secondary to a localized brain lesion has concluded that the left frontal lobe is the most critical brain area. There is not much convincing evidence available, as far as I was able to determine, suggesting any asymmetry of hemispheric disturbance in other female-prevalent disorders such as phobia or anxiety. One interesting study investigated the asymmetry of galvanic skin response (GSR),  a measure influenced by sweat,  which is in turn controlled by a primitive part of the nervous system called the autonomic nervous system.  It is known that the autonomic nervous system is not controlled in the same way by the two cerebral hemispheres.  At any rate,  the study found a relative left-hemispheric GSR dominance in panic patients and a relative right-hemispheric GSR dominance in generalized anxiety patients.  This hint of a greater involvement of the right hemisphere in pathological anxiety has recently been bolstered by a study of 309 patients who had a stroke (a cerebrovascular accident in one hemisphere) and subsequently developed a pure clinical anxiety disorder.  A large proportion of the cases had a right hemisphere stroke.  One study investigated a sample of 42 females and 10 males (mean age 34.3 years) with conversion symptoms (neurologically implausible body symptoms such as forearm paralysis believed to be of psychological origin).  The conversion symptoms occurred on the subjects' left side in 63%. The probability of this distribution occurring by chance is .07 (2-tailed test). For the females, the distribution was even more skewed; the symptoms occurred on the left in 30 cases, or 71%.    The majority of similar investigations have reported trends in the same direction.

There is no disagreement about the fact that developmental language disorders are much more associated with (and also caused by) left hemisphere than right hemisphere disturbance.  However,  boys are more at risk for just about every developmental disorder,  not just the language disorders.  There is little if any evidence to the effect that character disorder, or even its most extreme form, psychopathy,  is a left hemisphere disorder.  There is electroencephalographic, neuropsychological, and even brain imaging evidence to the effect that hyperactivity is more a right than a left hemisphere disorder,  and yet boys are more often affected.


Student’s tribune:  Mania and agitation versus depression and lethargy  result from right and left lesions respectively
My student,  Caroline Larocque has recently completed a research project on psychomotor agitation or mania and psychomotor lethargy or depression caused by unilateral brain lesions. She found that the lesion is much more often located in the right hemisphere for agitation and mania in adults,  but not for acquired childhood hyperactivity.  She also found that psychomotor lethargy and/or depression are more often caused by left hemisphere lesions,  even in children.  However,  these effects were strongly significant in girls and women,  but barely so in boys and men,  suggesting again that neuropsychiatry does not support a simple notion of hemispheric fragility being segregated by gender. 

One common effect of a unilateral lesion is contralateral hemineglect.  A right hemisphere lesion will typically cause a patient to neglect visual, auditory or somesthetic (tactile) stimuli located on his or her left body side. Congenital dyslexia and hyperactivity are both highly male-prevalent brain disorders. Recent findings of left hemineglect in congenital hyperactivity  argue against a general postulate of left hemisphere fragility in boys,  on the contrary.  


Student’s tribune:  Developmental hyperactivity and dyslexia result from right and left hemisphere dysfunctions respectively
My student Marie-Anne Archambeault recently completed her thesis on performance deficits on each side of the body in unilaterally brain damaged children, in developmentally dyslexic children and in developmentally hyperactive children.   She found that children,  as adults,  show neglect and motor weakness on the body half opposed to the brain lesion.   There is a simple explanation for that:   in the normal brain the right or left body half is controlled by the brain hemisphere opposite to it,  both sensorially and motorically.   What was more interesting was that dyslexics and hyperactives showed the same lateralized weakness and hemineglect as the brain damaged children.    The dyslexics neglected significantly on the right body side suggesting a left hemisphere dysfunction and the hyperactives neglected significantly on the left body side suggesting a right hemisphere dysfunction.

Finally,  there is a very slight trend in the evidence suggesting that Tourette's disease, a male prevalent disorder,  may involve more pathology of the right hemisphere.  It is important to take note of the fact that many findings of psychiatric effects resulting from unilateral brain lesions have not,  at least at present, given any indication of a sex difference.  For example,  orgasm seems to be harder to achieve in both sexes after right hemisphere lesions than after left hemisphere lesions.  In short,  it seems  incorrect to make a general statement about a uniform sex difference in asymmetry of fragility of the hemispheres of the brain.  Rather,  it seems that sex differences in neuropsychiatric disorders relate to a variety of hemispheric disorder asymmetries -sometimes located in different areas within the hemispheres,  as well as to disorders without asymmetric hemispheric disturbance. 

Do human females have a fragile serotonin network and human males a fragile dopamine/noradrenalin network ?   Only a few neuropsychiatrists have dared go out on a limb and propose that the fundamental reason for sex differences in psychiatric disease prevalence is a fragility of specific brain neurotransmitters.   Pierre Flor-Henry, for example,  has stated that women have a fragile serotonergic brain network and men have a fragile dopamine/noradrenalin network.   The model certainly explains female prevalence in insomnia, migraine, depression, panic disorder, anorexia nervosa, bulimia, lower pain thresholds (including recognized syndromes such as maxillary joint pain syndrome),  and higher prevalence of obesity.  All these disorders are treated with serotonin reuptake inhibitors  -though I would not want to argue that this treatment is always extremely effective. Serotonin reuptake inhibitors even seem to be just as effective in treating most anxiety disorders and phobias as are the so called anxiolytics (anti-anxiety drugs) which belong to the class of drugs called benzodiazepines (GABA agonists).  Post-mortem investigation of clinically depressed patients has identified specific forebrain anomalies in the serotonin neuron network. In unmedicated depressed patients studied post mortem, several studies found a significant cortical increase in serotonin (5HT-sub-2) receptor binding over control values.  Antidepressant-treated patients dying while depressed had 5HT-sub-2 receptor densities not significantly different from control values. Patients who died euthymic (i.e., recovered) showed a marked reduction in 5HT-sub-2 receptor binding when compared with controls.  However, in another study a drop in 5HT-sub-2 receptor binding was observed in the limbic structure called the hippocampus.  A recent positron emission tomography (metabolic brain imaging) study looked specifically at the serotonin network in living depressives by injecting into the blood stream with the standard radioisotope a serotonin ligand (a molecule that has an affinity for serotonin receptors).  A forebrain deficiency in the serotonin network was found.   There exist inhibitory self-recurrent serotonin loops making the whole issue very complex,   but altogether,  the research shows without a doubt that serotonin neuron networks are critical in depression.    One piece of evidence presents a more direct argument for human female fragility of serotonin brain dynamics. The increase in plasma prolactin (a primarily female hormone) which follows intravenous administration of L-tryptophan (LTP) (a metabolic precursor of serotonin,  i.e., a molecule used by neurons to synthesize,  create, serotonin) was used to assess changes in brain 5-hydroxytryptamine (i.e.,  the neurotransmitter serotonin,  also known as 5HT) function in normal male and female subjects, following a three week period of dieting. In women, but not men, there was a marked increase in the prolactin response to LTP, suggesting that dieting had caused alterations in brain 5HT-mediated responses. In contrast, dieting did not alter the prolactin response to thyrotropin releasing hormone in either men or women, indicating that the changes in response to LTP could not be attributed to an increase in pituitary reserve of prolactin.  These same authors (Goodwin and colleagues) also published another report on sex differences in effects of dieting on dynamic relations between other hormones and brain serotonin. The authors concluded that dieting alters brain 5HT function in women but not in men,  and that biological factors as well as greater psychosocial pressures to diet may contribute to the high prevalence of eating disorders and depression amongst women.  This study has been recently replicated and the same findings were reported.

Flor-Henry's model certainly also fits with the known male prevalence of hyperactivity  -which is treated with amphetamine agonists (ex: Ritalin)  -themselves molecularly related to noradrenalin,  and Tourette's disease,  stuttering, and juvenile schizophrenia,  all of which are best treated with dopamine (D2-receptor) antagonists.   One of the fundamental roles of the dopamine neurotransmitter is the modulation of pleasure.   For example,  patients with Parkinson’s disease are known to be anhedonic (pleasureless).  The pleasure they used to derive from  food, sex, cultural activities dwindles very significantly.   These patients have pathologically low levels of brain dopamine in one of the main dopamine neuron networks,  called the nigrostrial network.   We have seen (in chapter 2) that the male mammal usually has slightly higher brain dopamine concentrations than the female mammal (though this has not been consistently found),  this certainly being the case for humans.   A few years ago,  evidence was reported of presence of an abnormal gene on chromosome 11 controlling aspects of one dopamine receptor molecule (D2) in alcoholics,  Tourette patients and  psychopaths.  Since these are all male-prevalent disorders,  the hypothesis of a sort of fragility of the dopaminergic network in boys and men began to take credence in the scientific literature.  Replications of this specific finding were,  however,  not very conclusive.     Very recently,  several research teams, in Israel and in the United States,  found that an abnormal variant of another dopamine-controlling gene is over-represented in heroin addicts, gamblers, and even in people with spinal cord injuries.   Of course,  these disorders are all male-prevalent.  Specifically,  it was the D4DR gene,  involved in the metabolism of the D4 dopamine receptor, which was found in mutant form.    Several of these researchers are suggesting that this gene,  via abnormal dopamine metabolism,  favors risk taking behavior.  

It is noteworthy that Ritalin and amphetamine are known to alleviate psychopathic excess (a highly male-prevalent psychiatric disorder).   However,  since there is little internal distress or suffering in psychopaths,  psychiatrists are reticent to prescribe such a drug regimen.  Furthermore,  there is little reason why non-incarcerated psychopaths would comply with such a regimen.    The idea of  fragility of the central nervous system noradrenergic axis in men is  still controversial.  One investigation looked at beta-adrenergic receptor binding in frontal cortices obtained at autopsy from 21 suicide victims (mean age 36.4 years) who died predominantly by violent, nonpharmacologic means and from 21 control subjects who were matched for age, gender, postmortem delay, and degree of violence associated with death.  There was a significant 28% increase in the number of serotonin-sub-2 binding sites and a 73% increase in beta-adrenergic antagonist binding in the frontal cortices of suicide victims compared with controls.   Of course there were many more men than women in this sample because violent non-pharmacological suicide is more typical of men.  Animal models relevant to a « neurotransmitter fragility » concept of sex differences in psychiatry are,  in principle,  of paramount importance.    In one investigation male and female rats were treated with different high doses of adrenaline for five days. Their food and water intakes and body weights were recorded. A considerable sex-difference was found on the 5th day in body weights and plasma glucose concentrations. Males had higher plasma glucose and lost more weight than females. Females ate and drank more than males throughout the experiment. The adrenaline-sensitivity of females decreased by the third day but it did not change in males. These data suggest that females are able to activate mechanisms that compensate the effects of high adrenaline levels while males are not, or their compensatory mechanisms are less efficient.

Now my evaluation of this "pharmacological" model of gender differences in prevalence of psychiatric disease is the following.   It seems to contain a great deal of truth,  but it does not explain all of the important sex differences in psychiatric disease.    For example, women are more at risk for tardive dyskinesia, a disease probably involving a dopamine dysfunction...    On the other hand,  this "pharmacological"  model of gender differences in prevalence of psychiatric disease  presents one important advantage.  It reconciles several apparently contradictory generalities in neurobiological gender research.  On the one hand,  normal women are known to have higher concentrations of serotonin,  and normal males may have higher concentrations of dopamine.  But on the other hand,  female-prevalent disorders seem to be associated with insufficient serotonin and insufficient serotonergic activity (enzymatic activity for example),  and male prevalent disorders are often associated with an excess of dopamine or of dopaminergic activity.   One would have predicted the pathological male pattern from the normal male pattern,  but one would not,  it seems to me,  have predicted the pathological female pattern from the normal female pattern.   Recall that women seem to have higher concentrations of brain serotonin, overall,  than men.   However,  perhaps the key to understanding the role of these neurotransmitters in psychiatric disease is not so much in terms of their concentrations or activity levels,  but indeed in terms of the fragility of the neuronal network which makes use of a specific neurotransmitter.  I suspect that though the human female's normal serotonergic baseline is higher than the human male's,  she cannot tolerate to descend as low as the male without developing psychiatric symptoms.  One piece of evidence in support of this is the following.  Post-mortem comparison of serotonin concentrations directly measured in suicide victim's brains found that the women who had committed suicide still had higher serotonin concentrations than normal men.    Another argument in support of this interpretation is that extreme psychosocial stress has been shown to first increase the serotonin level in the human brain (measured from cerebrospinal fluid),  but prolongation of extreme stress ends up depleting  brain serotonin

No comments