The earlier the onset, the more boys are at risk

 One outstanding sex difference in neuropsychiatry is that diseases with early onset are more prevalent in the male child.   Some of these diseases or disorders are more prevalent in males no matter whether their onset is relatively early or relatively late in childhood:  autism (consisting essentially of emotional and verbal shutdown), hyperactivity (extreme agitation without psychosis), Tourette's disease (bizarre tics including obscene utterances),   character disorder (immorality and destructiveness).   Likewise,  nearly all developmental language disorders affect boys more than girls, and do so earlier in boys.   These include  language delay,  developmental aphasia (severe and relatively permanent failure to acquire language functions), stuttering, dyslexia (reading impairment), and hyperlexia (excellent recital or reading out loud,  but without understanding of what is being read).  There is one interesting exception to this rule in the domain of language disorders, namely elective mutism.  For reasons which I shall explain later,  girls are more at risk for this disorder.      In a more subtle vein,  those neuropsychiatric disorders which affect either sex approximately equally over the entire life span,  are more prevalent in male children in their early onset forms:  obsessive-compulsive disorder (uncontrollable thoughts or acts), schizophrenia (delusions and hallucinations), mania (agitation, euphoria or extreme happiness, grandiosity).  Several psychiatric disorders which afflict the female sex more prevalently tend to become manifest at puberty or adolescence.  These include depression (extreme sadness with insomnia, loss of appetite, constipation), anorexia nervosa (extreme repulsion for personal fatness with resultant self-starving), phobia (unreasonable fear of specific objects), anxiety (fear without an identifiable object).  Elective mutism, a female-preponderant disorder,  can also be considered a form of internalizing disorder:  it is essentially a social phobia,  or anxiousness expressing itself as a partial shutdown of social interaction limited to language.  The elective mutist typically refuses to speak to anybody with the occasional exception of a sister or one or both parents.  Jane Campion, the director of the film “The Piano” presents a wonderfully effective portrait of an elective mutist woman.  Finally,  some diseases such as schizophrenia or tardive dyskinesia (abnormal movements) tend to occur around menopause in women,  whereas their onset is more often in childhood in males.

There is an additional twist to this story:   early onset variants of behavioral disorders usually express themselves more severely than do the late (adult) onset variants.  Consequently,  the male sex is not only more at risk for a longer pathological trajectory,  but also for a more debilitating condition.   Details of these phenomena are presented in table 4.

Table 4

Examples of neuropsychiatric disorders whose early onset forms are more severe than the adult onset forms

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Disorder	Reference
Female prevalent disorders regardless of onset
Anorexia nervosa	Walford et al, 1991
Panic disorder	Maier et al, 1989
Generalized anxiety disorder	Scheibe et al, 1992
Bulimia	Witcher et al, 1992
Phobia	Holt et al, 1992
Male prevalent disorders regardless of onset
Tourette’s disease	Hyde et al, 1993*
Autism	Garreau et al, 1984*   Short et al, 1988*
Psychopathy	Offord et al, 1983*
Alcoholism	Lee et al, 1985*
Disorders which are male-prevalent only in the early onset forms
Manic-depressive disease	Dwyer et al, 1987 Thompson et al, 1992*
Obssessive-compulsive disorder	Flor-Henry, 1990*   Hanna, 1995*
Schizophrenia	Szymanski et al, 1995*  Seeman, 1982*
Depression	Golden et al, 1985;  Gasquet,  1994*

* These authors demonstrate that the early onset  and more severe forms are more prevalent in the male sex.

There are several lines of explanation of this wide-reaching pattern of sex differences:  the human male could manifest early-onset forms of neuropsychiatric disease because 1) he is more susceptible to brain damage related to difficult prenatal or obstetric events relating to maternal health during pregnancy and complications during childbirth; 2) there could be an adverse influence of maternal immunity on the male fetus;  3) the balance of his steroid hormones could affect his early brain development in an unfavorable direction.

The early onset forms of schizophrenia (hebephrenia, catatonia, etc.) are more chronic (long lasting bouts of incapacitation) and are more devastating (requiring institutionalization) than the late onset forms.   The latter (often the paranoid form) are typically less chronic (intermittent,  recurrent) and are less devastating (less frequently requiring prolonged institutionalization).  The childhood-onset forms of schizophrenia are twice more frequent in the male sex.  On the other hand, schizophrenia occurring at or just after the age of menopause is twice as frequent in women.  There is only one type of drug class which has unequivocally been proven to alleviate the problems of schizophrenics (delusions, hallucinations, agitation).  These are neuroleptics (also known as major tranquilizers).    All neuroleptics are effective against these specific symptoms exactly in proportion to their ability to reduce the brain activity of one neurotransmitter,  dopamine.    Estrogen has an antidopaminergic brain effect.  It is an indirect dopamine antagonist.   Testosterone, on the other hand,  is an indirect dopamine agonist.  It favors the synthesis of dopamine.  Menopause comprises a gigantic drop in estrogen,  many times more significant than the low point in the fertile woman's menstrual cycle.  In men, the blood concentration of testosterone undergoes a constant decline in adulthood through to senescence. The girl is protected against schizophrenia by her estrogen until menopause at which time she becomes more susceptible than the age-equivalent man,   whose testosterone has descended low enough to remove the risk factor which threatened him as a child.  

This reasoning could apply to another  male preponderant psychiatric disorder,  though perhaps less clearly.  Indeed,  the most effective medication for the specific symptoms of Tourette's disease, a male prevalent disorder, is neuroleptic medication.   As for hyperactivity and character disorder,  another neurotransmitter of the brain could be involved,  noradrenalin.   Noradrenalin has a molecular structure identical to the hormone secreted by the adrenal gland called adrenaline.  It is commonly known that adrenaline excites people when it is secreted in large doses into the blood stream.   The effects of noradrenalin in the brain are more complex,  more subtle,  and less understood.   The drugs most effective against the specific symptoms of hyperactivity and turbulent forms of character disorder are composites molecularly close to amphetamine (a central nervous system stimulant) as well as to noradrenalin,    such as methylphenidate (Ritalin).   Logically, in light of the effectiveness of methylphenidate, one ought not be surprised to find some sort of insufficiency of brain noradrenalin in hyperactive or conduct-disordered boys,   and this has indeed been observed in several investigations.   In accordance with this,   one experimentally induced brain lesion which produces hyperactivity in rats happens to be situated in a posterior part of the brain surface (cortex) called the parietal lobe,  but only when it is the right side of the brain which is lesioned,  not the left.  And it is the right sided lesion of this brain area which produces a huge drop in brain noradrenalin, not the left.  One ought perhaps not be surprised then that right sided cortical lesions result much more frequently in psychomotor agitation or mania (psychomotor agitation with delusions of grandeur or persecution and elated mood) in humans,  than do left sided lesions.

A vignette on a case with Tourette’s disease

S1 is a case seen in a hospital neuropsychology service which came to my attention recently.  This 11 year old boy of Haitian extraction was first seen because of learning disability in a Quebec school.   He had been to five schools previously and was already in a special education class in a public school.   In school and at home he was disobedient,  disruptive, pig headed,  socially inept and isolated,  suspicious, anxious and very nervous but not depressed.   He was believed to have an attention deficit by his teachers.   He reached the clinical criteria for hyperactivity and conduct disorder,  but his essential problem was immediately identified by the neuropsychologist:  he manifested multiple changing tics,  eye blinking,  shoulder shrugs,  sniffing, barking, swearing,  trichotillomania (hair twirling),  and he would slap his own head persistently when frustrated.  These are typical manifestations of Tourette’s disease,  and the other behavioral disturbances noted above are common co-morbidities.   Cognitive evaluation revealed preserved attention,  borderline IQ and memory,  normal visuospatial ability,  but very poor executive abilities.  Executive abilities are a constellation of abilities associated with frontal lobe function which include planning,  judgment,  mental flexibility,  and the like.   Recommendations were made to transfer him to a school specialized in behavior disorders,  and to provide him with ongoing neurological care and a very structured environment with regard to surveillance,  rules,  emotional security,  leisure activities,  and so on.

Why would many female-preponderant psychiatric disorders often have an onset at puberty or adolescence ?   One idea has been that the onset of these disorders, though determined primarily by hereditary factors and by environmental stress (family conflict or emotional disturbance due to life events),  is helped along by high levels of estrogen,  which in turn favor the build-up and metabolism of the neurotransmitter serotonin in the brain.   Studies of animals and humans have shown that serotonin influences appetite and sleep more than most other neurotransmitters.  Drugs effective against depression, such as Prozac, influence the metabolism of serotonin more than of any other known neurotransmitter.   Estrogen is an indirect serotonin agonist.   The problem with this model is that it predicts that depression ought to be caused by excess serotonin,  and should be treatable with serotonin antagonists.  Well,  it just so happens that things are the other way around!  Antidepressant medication increases serotonin concentrations and activity in the brain.   What seems more likely to me is that estrogen puts serotonin neuron networks into high gear and at the same time destabilizes and disturbs them,  and antidepressant medication such as Prozac somehow stabilizes serotonin metabolism.  I review this notion three sections down.