Late-Onset Schizophrenia Research: Current Findings and Future Benefits

By Arline Kaplan © 2000 (All Rights Reserved)

New research on middle-age-onset (late-onset) of schizophrenia suggests that it is a neurodevelopmental rather than neurodegenerative condition, yet it is a distinct subtype of schizophrenia, different from early-onset schizophrenia in several ways, said Dilip Jeste, M.D., recently honored as a "Distinguished Psychiatrist" by the American Psychiatric Association (APA).

Jeste, professor of psychiatry and neurosciences and chief of the Division of Geriatric Psychiatry at the University of California, San Diego and the VA San Diego Healthcare System, lectured on schizophrenia and the third age at the APA’s 153rd annual meeting in Chicago. The third age, he said, begins about age 45 or 50 or what sociologists view as middle age, with the fourth age beginning about 65 or 70 years of age.

"For the last dozen years or so, we have been doing studies at San Diego of middle-aged and elderly populations with schizophrenia and related disorders," said Jeste, who directs the Geriatric Psychiatry Intervention Research Center funded by the National Institute for Mental Health. "We use …DSM-III- R and DSM-IV criteria for schizophrenia based on the Structured Clinical Interview for DSM (SCID). When I talk about late-onset schizophrenia, I want to stress that this is not the age of onset of positive symptoms nor age of first hospitalization, but age of onset of prodromal symptoms."

"Now, why study schizophrenia in older people?" asked Jeste,. "One [reason] is the demographic imperative. The number of older people with schizophrenia is going to increase dramatically over the next 30 years. Second, the cost of mental health care in this population is very high. We published [an article] in the American Journal of Psychiatry where we looked at the cost of mental health care in San Diego for different psychiatric illnesses in different age groups, and we found that the highest cost of mental health care was for the oldest people with schizophrenia [Cuffel et al., 1996]….Third, there are increased risks of medication side effects in older people. For example, the risk of tardive dyskinesia is six times greater in older people with schizophrenia than it is in younger adults…And [fourth,] studying older people with schizophrenia has significant potential for improving our understanding and treatment of schizophrenia in general."

Most of the research efforts on schizophrenia as well as 90% of the papers published on it have focused on young adults. The number of studies on older people with schizophrenia "has been pretty small," Jeste said, adding that those few published studies have mostly been in institutionalized patients.

"In reality, …less than 10% of people in our population of schizophrenic patients are institutionalized," he said. "Interestingly, a substantial portion of the community-dwelling patients are living in board-and-care facilities. They are being cared for by private practitioners county mental health clinics or occasionally [by staff in] health maintenance organizations, but these are predominately nonacademically affiliated places. That may explain why there have been so few research studies of older people with schizophrenia."

The concept of late-onset schizophrenia is a controversial entity, Jeste acknowledged, with some researchers claiming that the symptomatology is different; that the psychosis is secondary to other disorders, such as strokes and tumors; and that it is a neurodegenerative rather than neurodevelopmental disorder.

Jeste and colleagues studied 259 patients with early-onset schizophrenia (mean age of onset was 24 years) and 68 patients with middle-age-onset (mean age of onset was 53). All of the patients are currently over the age of 40. The mean age is about age 60 at this time. The researchers compared the patients with schizophrenia to normal controls.

"Most importantly, we follow these patients," Jeste said. Some patients have been followed for up to 10 years. The follow-up evaluations include the SCID (Structured Clinical Interview for DSM-IV), various clinical psychiatric rating scales (e.g., Brief Psychiatric Rating Scale [BPRS], Scale for Assessment of Positive Symptoms [SAPS], Scale for the Assessment of Negative Symptoms [SANS]) and neuropsychological assessments. The goal is to insure the diagnosis does not change over time.

Jeste and his team found some similarities between patients with middle-age-onset of schizophrenia and early-onset schizophrenia in terms of sensory impairment (e.g., hearing and visual problems), minor physical anomalies, family history, childhood maladjustment, type of cognitive impairment, mortality from suicide and other causes, severity of positive symptoms, nonspecific brain imaging abnormalities and qualitative response to neuroleptics (Jeste et al., 1995, Jeste et al., 1997, Lohr et al., 1997)

"We found similar minor physical anomalies, such as low-set ears, hippocampal folds or cleft-palate," Jeste said. These are quite uncommon, but they seem to occur with equal frequency in middle-age-onset and early-onset schizophrenic patients and more commonly than in normal controls [Lohr et al.., 1997]. Why is this important? Minor physical anomalies are something one is born with, you don’t develop them in later life."

The researchers also explored how the middle-age-onset patients functioned before developing schizophrenia.

"We find that in early childhood, the patients with middle-age-onset schizophrenia had maladjustment, especially in terms of socialization compared to normal controls, and the maladjustment was similar to that of early-onset patients," Jeste said. "However, for some reason, the middle-age-onset patients start doing better from adolescence onwards. Typically, they complete high school and often one or two years of college. The majority of patients were married at one time, in contrast to early-onset patients, most of whom do not get married ever…They have been modestly productive as homemakers, or they have done multiple short-term jobs. So their performance has not been quite comparable to normal subjects, and yet it is considerably better than that of early-onset patients. In premorbid personality, they are often shy or somewhat suspicious. They have schizoid or paranoid traits, however, these are not personality disorders.…They function reasonably adequately until they have onset of symptoms in middle age or later life."

The similarities in minor physical anomalies, family history and childhood maladjustment, Jeste said, suggest that patients with middle-age-onset schizophrenia have early indicators of development of schizophrenia.

"In other words, it looks like middle-age-onset schizophrenia is also a neurodevelopmental disease," he said.

While some experts contend that patients with late-onset schizophrenia are less likely to display formal thought disorder, Jeste said his team did find the presence of thought disorder (Palmer et al., 2001).

On each of the subscales in SAPS: hallucinations, delusions, bizarre behavior and thought disorder, "the two schizophrenia groups were similar to each other and had significantly more symptoms than the normal controls," Jeste said. "So, formal thought disorder is as prevalent in middle-age-onset patients as it is in early-onset patients."

Considering the Differences

Despite the similarities, significant differences exist between middle-age-onset and early-onset patients in terms of gender, negative symptoms, type of schizophrenia, severity of learning impairment and neuroleptic dose.

Since the time of Kraepelin, Jeste said, researchers have been aware that there is a gender difference in the age of onset of schizophrenia. Castle (1999) found that more men than women have schizophrenia up until the age of 40. Between 40 and 65 years of age, twice as many women as men have schizophrenia. Beginning at age 65, many more women have schizophrenia-like psychosis than men do.

Looking at negative symptoms, Jeste said that both schizophrenia groups had more psychopathology than the normal controls as measured by the subscales on the SANS. However, the middle-age-onset group had less severe negative symptoms than did the early-onset patients (Palmer et al., 2001).

"They do have significant affective blunting and significant negative symptoms, compared to normal subjects, but the symptoms are less severe than in the early-onset patients," he said.

For the neuropsychological assessment, Jeste and his team used an expanded Halstead-Reitan Battery. In four areas—verbal, attention, psychomotor and memory retention—there were no differences between the early-onset and middle-age-onset groups, and both the schizophrenia groups were significantly more impaired than normal controls. However, in three areas—learning, motor and abstraction—there was a significant difference between the two schizophrenia groups: the middle-age-onset group being less impaired than the early-onset group (Jeste et al., 1997). However, once again, both schizophrenia groups were more impaired than normal controls.

On magnetic resonance imaging scans, Jeste said they found a difference in the size of the thalamus.

"Many investigators have reported smaller thalamus in early-onset patients, so what is new here is that the middle-age-onset patients seem to have larger thalami [Corey-Bloom et al., 1995]. A caveat is that the sample sizes are quite small," he said. "The thalamus has been shown to have some important role in higher function, possibly in schizophrenia, so it may have some relevance to later age of onset."

On the issue of whether middle-age-onset schizophrenia may be the beginnings of dementia, Jeste and colleagues (Palmer et al., unpublished data) used the Mattis Dementia Rating Scale to compare patients with middle-age-onset schizophrenia with those patients who had early Alzheimer’s disease.

"Over a two-year period, there was no significant change in the cognitive impairment in people with late-onset schizophrenia, however, there was a significant deterioration in cognition in the early Alzheimer’s patient. It goes on to show that what we are calling middle-age-onset schizophrenia is not dementia."

Proposed New Nomenclature

Jeste expressed the hope that the DSM-V will include a better classification of schizophrenia developing in later life.

"We should call it late-onset schizophrenia spectrum disorders. There should be a category called middle-age-onset schizophrenia…it is a distinct subtype of schizophrenia different from the early-onset variety in a number of ways including gender distribution, negative symptoms, etc.," Jeste said. "Then, there is very-late-onset schizophrenia-like psychosis.…[and] very-late-onset schizophrenia-like psychosis is a heterogeneous group of disorders. It includes a number of patients who may go on to develop dementia. Many of these have psychosis secondary to general medical conditions. Some of them have delusional disorder, and a tiny proportion may even have schizophrenia [Howard et al., 2000]."

Jeste also called for a shift in focus in schizophrenia research to include neurohormones, such as estrogen.

"There have been studies, mainly from Europe, that suggest there are fluctuations in symptoms of schizophrenia associated with different phases of menstrual cycle. In women who have schizophrenia, the symptoms seem to improve during phases of menstrual cycle when estrogen level is going up. In contrast, when estrogen level is going down, symptoms may get worse [Seeman, 1997, 2000]."

Jeste said his team studied 24 postmenopausal women with schizophrenia who had received estrogen for at least one year, and 28 women who had never received any hormone replacement therapy (Lindamer et al., 2000).

"We found that consistently, the group that had received hormone replacement therapy had less severe negative symptoms than the group that had never received hormones, and that was true on the Brief Psychiatric Rating Scale-Subscale of Negative Systems, Positive and Negative Syndrome Scale-Negative Symptoms, and Scale for the Assessment of Negative Symptoms," he said. "We are just beginning a long-term, prospective study in which we are assigning in a double-blind fashion postmenopausal women with schizophrenia to estrogen versus placebo. Of course, all of these women receive the standard antipsychotic treatment, and we augment with estrogen in one group, but not in the other. We want to see if there is any positive effect of estrogen in this population."

In assessing current treatments, Jeste said that the atypical antipsychotics are considerably better than the older conventional neuroleptics, especially in terms of the movement disorders, however, they are still not perfect.

"We need antipsychotics that are more effective and safer…we need selective estrogen receptor modulators that will have the neuroprotective effects without the cancerogenic effects on breast or uterus. We need better cognitive enhancers for people with schizophrenia," he said. "At the same time, in the immediate future, it is unlikely that we will have medication that will cure schizophrenia. Which means there will be a place, a very important place, for psychosocial management. We currently are doing some studies of cognitive behavioral therapy, social skills training, case management and caregiver support—those aspects of management are going to be as critical as pharmacological management, at least in the near future."

Meanwhile, the research continues. Because no single site can study a large number of older people with schizophrenia, Jeste said, a consortium is being formed to conduct multisite studies.

"The next step is to standardize assessment across the sites, and then most importantly to do some intervention studies," he said. "This is an open consortium, and I hope a number of people will be interested in participating in such a study."

Optimistic about the impact of this kind of collaborative effort, Jeste said that if we study late-onset schizophrenia and the factors associated with the delayed onset of schizophrenia, we may find clues as to how to delay the onset of schizophrenia by 10 years in those who are predisposed to it. "If we can postpone the onset of schizophrenia from age 20 to age 30," he said, "we will have contributed in a major way to improved functioning."

References
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Cuffel BJ, Jeste DV, Halpain M et al. (1996), Treatment costs and use of community mental health services for schizophrenia by age cohorts. Am J Psychiatry 153(7):870-876.

Howard R, Rabins PV, Seeman MV et al. (2000), Late-onset schizophrenia and very-late-onset schizophrenia-like psychosis: an international consensus. Am J Psychiatry 152:172-178.

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Palmer BW, McClure FS, and Jeste DV (2001), Schizophrenia in late life: findings challenge traditional concepts. Harv Rev Psychiatry 9(2):51-58.

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Seeman MV (1997), Psychopathology in women and men: focus on female hormones. Am J Psychiatry 154(12):1641-1647.