To address the influence of estrogen and other hormones on behavior, Lyn Harper Mozley, Ph.D., assistant professor of psychology in psychiatry at the University of Pennsylvania, is examining olfaction in healthy women and in women with schizophrenia across the life span. She discussed her project at the 10th annual scientific symposium of the National Alliance for Research on Schizophrenia and Depression (NARSAD), held in New York. NARSAD is funding Mozley's work with a Young Investigator Award.
Mozley is involved with the Mental Health Clinical Research Center for schizophrenia within the university's department of psychiatry. "My mentors there, Ruben Gur [Ph.D.] and Raquel Gur [M.D., Ph.D.], have been interested in gender differences for some time," she said. "But this is really our first effort looking into women's health, and it's a very energetic and intensive effort."
Mozley said the evidence for a relationship between estrogen and psychosis comes from studies of gender differences in schizophrenia, as well as studies that examined clinical symptomatology associated with the menstrual cycle (Lindamer et al., 1997).
"Studies show that women tend to be diagnosed with schizophrenia about two to 10 years later than men," Mozley said. "Another gender difference is that after the age of 40 to 45, when there is reduced estrogen, women are more likely to be diagnosed with schizophrenia than are men. This observation led researchers to hypothesize that estrogen has some protective effect on premenopausal women, perhaps in the form of a raised vulnerability threshold for schizophrenia. And, later in life, at the time of menopause, there may be an increased risk of developing schizophrenia."
Mozley said Lindamer et al. looked at gender differences in age of onset. They loooked at almost 200 outpatients with schizophrenia, who ranged in ages from 35 to 97.
"When age of onset of schizophrenia was considered, results indicated that at less than 25 years of age, more men than women developed the illness, 51% compared to 37%," Mozley reported. "But after age 45, it was 37% in women compared to 16% in men."
The authors also noted that in another sample of older patients with schizophrenia, females had significantly more severe positive symptoms than males, added Mozley.
"In younger patients, it's been shown that women have a later age of onset and fewer negative symptoms [Kopala et al., 1995]," she said. "Women are more responsive to neuroleptic treatment, sometimes [require] lower doses of medication, have a less severe course of illness, and tend to have better social functioning than men."
With regards to the menstrual cycle, Mozley said it appears that clinical symptoms, such as thought disorder, are reduced when levels of estrogen are higher, and that symptoms are exacerbated with lower estradiol levels around the time of menstruation.
"This finding regarding the relationship between symptoms and menstrual status is consonant with the notion that estrogen acts as a neuroleptic, since positive symptoms have been associated with increased dopa-mine activity," Mozley said. "In addition, some authors have reported that women with schizophrenia tend to be admitted to the hospital during the low-estrogen phase of their menstrual cycles. Women with schizophrenia also tend to have more relapses postpartum and postmenopausally, and fewer relapses during pregnancy, when estrogen levels are higher. Furthermore, symptoms can also improve during pregnancy. This finding might be somewhat disorder-specific, in that the relapse rate for women with schizophrenia after childbirth is lower than [the relapse rate] for those with affective disorders."
Mozley next addressed the issue of olfaction and schizophrenia specific to gender.
"There are also sex differences in olfactory identification," she explained, citing Kopala et al. "Men with schizophrenia tend to have more impaired ability to identify odors than women [with schizophrenia do], even though their acuity, or their thresholds, are not impaired. Based on animal work, Kopala speculated that the functional specialization of the orbital frontal cortex, and perhaps the amygdala and hippocampus, might take place at different rates in males and females. These structures, in addition to a few others, are traversed by the olfactory pathway, so they're very much implicated in olfaction. These are regions that are also rich in dopamine pathways, as well as estrogen receptors."
As noted by the Kopala et al.study , Mozley continued, the assessment of olfaction in women with schizophrenia might be used as a means to identify subgroups of women with abnormalities in brain regions involved in olfaction.
"So we're really looking at olfaction as a probe to get at the potential role of estrogen in schizophrenia," she said.
Mozley said her project is in many ways a replication of Kopala et al.'s pioneering study that examined the relationship between estrogen and olfaction in healthy women and in women with schizophrenia.
"One difference [between her study and ours] though, is that although she measured levels of estrogen, she didn't really control for where women were hormonally in their menstrual cycle," said Mozley.
In the Kopala et al. study, premenopausal women were tested at day 1 of their menstrual cycles and 14 days later. The postmenopausal women were tested on an arbitrary day 1, and again two weeks later.
"One of the difficulties with doing that sort of study in the premenopausal women is that even though you have two women with normal cycles, they might not be at the same place in their cycles, hormonally, at day 14," said Mozley. "So my study represents a modification in that I'm asking the premenopausal women to monitor their ovulation...I'm testing premenopausal women on the first day of their menstrual cycles and again 24 to 36 hours after ovulation. Postmenopausal women will be tested on day 1 and two weeks later. As you can see, it's really almost two studies in one, looking at olfaction in the menstrual cycle in healthy women, but then also comparing women with schizophrenia to healthy women."
Mozley explained that following the Kopala et al. study, her major hypotheses are that women with schizophrenia will be impaired in olfactory identification relative to healthy women, and that premenopausal women, regardless of diagnosis, will likely have better olfactory identification than the postmenopausal women, presumably because of a decrease in estrogen postmenopausally. Another hypothesis is that women with schizophrenia will have lower levels of circulating estradiol than controls.
Mozley said her study will ultimately include 30 women with schizophrenia and
30 healthy volunteers. Each group will include 15 premenopausal and 15 postmenopausal women. Blood will be drawn to assess hormonal levels. The primary olfaction measure is a scratch-and-sniff test that measures olfactory identification, the University of Pennsylvania Smell Identification Test (UPSIT).
"It's a standardized, forced-choice test in that you scratch the odor and give people four choices, such as [asking] 'does this smell most like pine, gasoline, menthol or licorice?'" Mozley said. "Odor detection thresholds are also measured, and an additional task, the Picture Identification Test, is given as a control for the non-olfactory, cognitive aspects of the UPSIT."
Mozley said that in addition to trying
to link estrogen levels to olfaction across
the menstrual cycle, she will also attempt
to evaluate neurotransmitter systems more directly.
"My husband, P. David Mozley [M.D., associate professor of nuclear medicine and psychiatry at the university], is studying the dopamine transporter system in healthy aging, as well as various disorders," she explained.
"We're also hoping to have these same subjects participate in his studies involving SPECT [single photon emission computerized tomography] imaging of dopamine transporter function on the same days. That will enable us to directly link dopamine to hormone levels and olfaction in the same women."
Addressing treatment implications, Mozley said: "At this point, there has really not been a lot of research done looking at augmenting neuroleptic treatment with estrogen. A few case studies have generally shown estrogen augmentation to be beneficial. A study which involved more patients [Kulkarni et al., 1996] found that, in combination with standardized neuroleptic treatment, estrogen was initially more helpful in reducing positive symptoms than medication alone. However, after two months, there was no difference in terms of positive symptomatology between the
two treatment groups."
In conclusion, Mozley noted that she, Raquel Gur and their colleagues are also planning longitudinal treatment studies.
"These are aimed at examining the effects of estrogen within the context of standardized medication protocols, as well as neuropsychological remediation and psychosocial skills training in women with schizophrenia," she said. "All this work is part of our efforts to include more interventional research."
Kopala LC, Good K, Honer WG (1995), Olfactory identification ability in pre- and postmenopausal women with schizophrenia. Biol Psychiatry 38(1):57-63.
Kulkarni J, de Castella A, Smith D et al. (1996), A clinical trial of the effects of estrogen in acutely psychotic women. Schizophr Res 20(3):247-252.
Lindamer LA, Lohr JB, Harris MJ, Jeste DV (1997), Gender, estrogen, and schizophrenia. Psycho-pharmacology Bull 33(2):221-228.