Dr. I, a 48-year-old university professor, is brought to the ER by her husband because she has developed an irrational fear of being chased by Nazis. The fears have become increasingly bizarre, her husband reports. She believes her Nazi persecutors are bandaging their arms and using wheelchairs to pretend to be disabled. When out with her husband, Dr. I points to people in wheelchairs, convinced they are after her, will kill her, and are incensed because she left Germany—her country of birth. Her hus­band brought her to the ER when she started to hear her persecutors addressing her in German at night.

Psychoses of unknown cause usually begin in late ado­lescence or early adulthood. Less frequently the onset occurs in later adulthood (age ≥40). Late-onset psycho­sis is much more prevalent in women than in men for reasons that are imperfectly understood.

When you are evaluating a midlife woman with first onset of psychosis, don’t assume an illness of unknown cause (bipolar disorder or schizophrenia) until after you have done a comprehensive search for triggers of her psychotic symptoms. After age 40, women are more likely than men to develop psychosis because of gender-specific medical and psychological precipitants.

Predisposing factors for psychosis

Psychosis is an emergent quality of structural and chemical changes in the brain. As such, it can be ex­pected to surface during:

• brain reorganization or transition (adolescence, senescence, brain trauma, stroke, starvation, inflammation, or brain tumor)

• change in brain chemistry (flux in go­nadal, thyroid, or adrenal hormone levels; electrolyte imbalance; fever; exposure to chemical substances; immune response).

Psychological stress impacting the brain via stress hormones also can predispose a person to psychosis.

Because some individuals are more prone than others to develop psycho­sis during brain alteration, chemical and structural changes in the brain are as­sumed to interact with genetic propensi­ties to influence gene expression. Once a psychotic event has occurred, it is thought to sensitize the brain so that subsequent events emerge more readily.1

Schizophrenia—though not the only ill­ness in which psychosis plays a role—is a prototype for psychotic illness, and sev­eral reported sex differences in this dis­order are worth noting.2 The incidence of schizophrenia is approximately the same in both sexes, but women show a later age of onset—a paradox in that the brain de­velops at a faster pace in females and theo­retically should reach the threshold for the first appearance of schizophrenia earlier. Women also require lower doses of anti­psychotic medication to recover from an acute psychotic episode and to maintain remission, at least before menopause.3,4 Both of these differences can be explained as an effect of estrogen on a) gene expres­sion5 and b) liver enzymes that metabolize antipsychotics.6

The estrogen hypothesis. Women show a tendency toward premenstrual and post­partum exacerbation of symptoms when estrogen levels are relatively low. These clinical observations, confirmed by some but not all studies, have led to the hypoth­esis that estrogens are neuroprotective7 and also protect against psychosis.8

Estrogen withdrawal in specific brain cells may release a cascade of events that over time can increase the severity of psy­chotic and cognitive symptoms. The reason for suspecting such effects is based on what we know about estrogenic effects on neurotransmitter, cognitive, and stress-induction pathways, and—more fundamentally—on neuronal growth and atrophy.

According to the estrogen hypothesis, women are—to some degree—protected against schizophrenia by their relatively high gonadal estrogen production between puberty and and menopause. Women lose this protection with the onset of perimeno­pausal estrogen fluctuation and decline, accounting for their second peak of illness onset after age 45.



Epidemiologic studies showing a second peak of schizophrenia onset in women (but not men) around the age of menopause sup­port this hypothesis.9,10 Longitudinal out­comes for schizophrenia—which are better in women than in men during late adolescence or early adulthood11—gradually even out after the first 15 years of illness, suggest­ing that women’s advantage is lost at a time approximating menopause (Box 1).



The question, then, becomes: Is it only because of estrogen loss after age 40 that women become more prone to develop a psychotic illness? Other differences be­tween the sexes that may play roles include immune function, low iron stores, sleep suf­ficiency, thyroid function, exposure to toxic substances (including therapeutic drugs), societal pressures to be slim while aging (Table), and the experience of stress.12



CASE CONTINUED

Exhausted and confused

Dr. I is a well-groomed, handsome woman, but she hardly speaks when interviewed, looking frightened and somewhat bewildered. She has never had a mental health problem, nor has anyone in her family. She agrees to stay in the hospital but is not sure why. She has slept no more than 1 or 2 hours in the last several days.