Nondementia Nonpraecox Dementia Praecox?: Late-Onset Schizophrenia

Nondementia Nonpraecox Dementia Praecox? Late-Onset Schizophrenia Dilip v: Jeste, M.D., Laura L. Symonds, Ph.D. M. Jackuelyn Harris, M.D., Jane S. Paulsen, Ph.D. Barton w: Pal,ner, Ph.D., Robert K. Heaton, Ph.D. Schizopl,renia has traditionally been viewed as a PSJ'chotic disorder with onset in adolescence or early adulthood and a deteriorating COlll·se. Over the past decade, the tlzlthors have been studyil1,g patients lneeting DSM-/II-R as well as specified t·esearch critet·ia for late-onset schizopbrellia (onset after age 45) and several cOlnparisol1. groups with psycbiatric, neurologic, n eut·opsych o log ie, brain-inzaging, psychophysiological, and psyclJosocial assesSlnellts. Results to date suggest a nUlnber ofsi1nilarities and differel1.ces between late-onset schizophrenia and comparison gl·0UpS of other older patients witl} psychoses (inc/tIding earlier-onset schizophl·e1'lia). Later..onset schizophrenia is probably a neurobiologically distinct subtype of schizopbrenia. Differential involvelJ'lent of cOI·tico-striato-pallitlo-tbalalnic eil·Cllitr~y 1nay e:\plail'l dijfe1"ellees in age at onset. The authors

propose a new conceptual l1'lodel for level offU1lctioning at different stages aflife in late-onset schizophrenia. (Am] Geriatr Psychiatry 1997; 5:302-317)

u • • • liow correct Kraepelin was in calling the psychoses of old age 'the darkest field in psychiatry.t In fnet basic psychiatric understanding seems to lose its nleaning when one deals with lateaonset schizophrenia." -M. Bleuler l t

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chizophrenia has generated intense research during the 20th century. Yet surprisingly little attention has been paid, especially in the United States, to late-onset schizophrenia (LOS). In this article) we begin with a brief historical background, and then give a discllssion of the traditional

Received July 111 1996; revised November 18, 1996; accepted December 6 1 1996. From the Department of Psychiatry, University of Californiu, San Diego, and the San Diego VA Medical Center. Address correspondence to Dr. Jcstc t Director, Geriatric Psychiatry Clinical Rcsearch Center, San Diego VA Medical Centcr 116Al, 3350 L'lJolla Vilhlge Drive, San Diego, CA 92161. camail: [email protected]. 302

VOLUME 5 • NUM8ER 4 • FALL 1997

]este et al. conceptual models of schizopllrenia and tIle issues pertinent to determination of age at onset of schizophrenia. Next, we summarize the main findings from our ongoing clinical, neuropsycllo1ogical and magnetic resonance imaging (MIU) studies of LOS. Finally, we synthesize these results in an attempt to offer a new conceptual model, ending witll a short discussion of the suggestions for further work in this area. t

Historical Background Schizopllrenia is probably a very ancient disease and may be almost as old as civilization itself. 2 The scientific literature on schizophrenia is, however, of much more recent origin. Kraepelin 3 deserves most of the credit for formaliZing the concept of schizopllrenia, which lIe labeled de1nentia praecox. He divided psychiatric illnesses primarily into dementia praecox and manic-depressive illness. Dementia praecox was defined as an illness characterized by onset during "praecox" years (adolescence or early adulthood) and a progressive downllill course, wllereas manicdepressive illness was characterized by periodicity. Kraepelin's use of the term de1nentia was different from its present-day connotation. He referred mainly to personality deterioration, especially in the areas of emotion and volition. KraelJelin later found that some patients had onset of a predominately paranoid form of illness later in life. He diagnosed them as having pa1~phrel1ia. Krapelin also introduced the diagnostic entity of pat·al'loia to describe a chronic illness characterized by wellorganized delusions in the absence of hallucinations, formal thought disorder, or personality deterioration. He distinguished this disorder from paraphrenia, which, in addition to delusions, was characterized by hallucinations, and from paranoid dementia praecox, which was thought to have a deteriorating course of illness. 4 Follow-up investigations of Kra~pelin's paraphrenia THE AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY

patients showed, however, that the course of their illness was largely similar to that of dementia praecox. 5 E. Bleuler was possibly the first scientist to use the term scbizoplJrenia. 6 He did not believe that either the age at onset or the course cllaracterized the disorder. It was his son, M. Bleuler, WilO studied latelife schizopllrenia, including LOS. 1 M. Bleuler believed tllat schizophrenia could begin later in life.' During the 1940s-1960s, a considerable amount of work was done on LOS in the United Kingdom. Roth and his colleagues used the term "paraphrenia,"8 althougl1 their definition of paraphrenia changed over time. 9 Some similarities were found (e.g., in delusions and hallucinations), but there were also some differences (e.g., paraphrenia patients were more likely to be women with sensory deficits but witllout a family history of schizo.. phrenia) between paraphrenia and schizophrenia. In the United States, LOS was essentially unstudied until very recently.9 10 Rabins et aLII published a paper in 1984 that described patients who seemed to have had onset of schizophrenia after age 44. Yet in this country there has been considerable resistance to accepting tIle concept of LOS. In the formal diagnostic classifications there was no mention of age at onset of schizophrenia until 1972. Feighner et a1. 12 published the research criteria in which the diagnosis of schizophrenia was restricted to persons widI onset of illness before the age of 40. DSM..I 13 and DSM-II 14 made no mention of age at onset of schizo.. phrenia. DSM-III 15 used 45 as the age cutoff and stated that schizophrenia could not be diagnosed if the onset was after age 45. Between 1980 and 1987, schizophrenia would not be diagnosed if the patients' onset of symptoms was after age 45; hence, these patients were given another diagno.. sis, such as upsychosis, not otherwise specified (NOS).'" There were no empirical clinical data, however, to justify why the upper age limit for schizophrenia should 1

303

Nondementia Nonpraecox Dementia Praecox? be 40, 45, or later. DSM-III-R16 did away with the age-at-onset cutoff and furtller specified LOS if the onset was after the age of 45. DSM.~17 similar to DSM·I and -II, made no mention of age at onset of schizophrenia. In our literature review, we found eight reports, mostly European inpatient studies, that determined age' at onset of schizopllrenia by'the age at first psychiatric hospitalization. 9 According to these studies, 77% of the patients had onset of schizophrenia before age 40, 13% had onset between the ages of 41 and 50, 7% had onset between 51 and 60, and 3% had onset after the age of 60. During the past 10 years, more research 113S been done on LOS in this country as well as in Europe. Murray and colleagues 18,19 reported that there was a second peak of age at onset of schizopllrenia after age 60 or 65. According to Murray et al.!S because LOS patients usually present after age 60 and have good premorbid functioning, it is "impJausible u that LOS could be neurodevelopmentaI in origin. LOS patients, instead, are proposed to be "a heterogeneous group," with"organic brain dysfunction as the final common pathway." 3

episodic illness, in his earliest formula.. tions, he later, in 1919, acknowledged that not all schizophrenic patients had progressive deterioration, that some stabilized, and others actually remitted symptomati.. cally. The modern theories of the etiopath.. ology of LOS (Figure 2) include the following: 1) it is a neurodegenerative condition; 18,19 2) it is a result of structural brain lesions t such as strokes and tumors;20.21 and 3) it is secondary to sensory deficits. 22 LOS patients, according to these theories, are almost normal until middle age or old age, at which time they have a psychotic breakdown and then deteriorate progressively. On the otller hand, early-onset schizopllrenia (EOS) is believed to be a neurodevelopmental disease. 23 - 25 The EOS patients are predisposed to schizophrenia, and they function at a suboptimal level from infancy.26-29 They continue to function at this suboptimal level until adolescence or early adulthood, at which time their performance level decreases markedly. There is a further deterioration over the next 5-10 years, after which time tIle level of functioning usually stabilizes,30 although some patients may worsen and a subgroup may have remission.'·31

Conceptual Models

Detennination of Age at Onset of Schizophrenia

The Kraepelinian concept of dementia praecox (Figure 1) is that some individuals are predisposed to develop the disease because of family historY or other reasons, and that at least some of these individuals "exhibit psychic abnormalities that precede tIle real onset of dementia....n; such abnormalities presumably "can be traced back into the first year of the patient's life" (p. 238).3 Despite a subnormal level of functioning, they continue to do reasonably well until adolescence or early adulthood, at which time their functioning decreases and then, progressively deterio.. rates. Although Kraepelin wrote about progressive deterioration, as contrasted with 304

Age at onset of schizophrenia is difficult to define, both as a conceptual issue and an operational one. If we believe that schizophrenia is a neurodevelopmental disease, the age at onset could probably be prenatal or at least early in childhood. Typically, however, by age at onset of illness, one would mean the age at first manifestation of tile disorder. This determination becomes problematic with schizophrenia, because "age at onset" may refer to the onset of prodromal symptoms, or positive symptoms, or first psyclliatric hospitaliza.. tion. Different investigators have referred to eacll of these three as age at onset of VOLUME 5 • NUMBER 4 • FALL 1997

]este et at.

FIGURE 1. Kraepelinian concept of dementia praecox

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Age,.years schizophrenia,32 and each method has its own advantages and drawbacks. DSM-III-R and DSM_IV 16,17 use age at onset of prodromal symptoms as the age at onset of schizophrenia. A recent paper discussed the problems inherent in reliably determining the age at onset of schizophrenia by retrospective assessment. 32 Tile authors suggest that reliability can be increased by operationalizing the earliest signs of schizophrenia (e.g., considering prodromal symptoms only if they were continuous or recurrent) as well as by using a fairly detailed interview technique for assessing symptoms and course of disease.

Our Studies We have asked three main questions in our own studies: 33 1) Can schizophrenia manifest for the first time after age 45? If so, then 2) why do these patients develop schizophrenia?; and 3) what protects them THE AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY

from developing schizophrenia until late in life? For diagnosis, we used DSM-III-R 16 with SCID-~34 as well as additional inclusion/exclusion criteria. 35 These latter criteria were as follows: physical and psychiatric stability to undergo various as.. sessments; presence of medical records or a Significant Other to corroborate the patient's history; and exclusion of diagnosable dementia, seizure disorder, head injury with unconsciousness for more than '30 minutes, and substance abuse that could have produced psychosis. We excluded from the LOS group subjects with prodromal symptoms of schizophrenia (DSM..III.. R) or beginning of functional decline before age 45. Also excluded were patients who had treatment with neuroleptics, an.. tidepressants, or lithium for more than 1 month or any psychiatric hospitalization before age 45 and those with severely schizoid, schizotypal, or paranoid premorbid personality that had interfered with daily functioning during early adulthood. 305

Nondementia .Nonpraecox Dementia Praecox?

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Modern theories of early-onset schizophrenia (EOS) and late-onset schizophrenia (LOS)

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Age, years Chronically institutiona:lized patients were also excluded. Patients living in board-andcare facilities were, however, included in this study.35 All the research subjects gave written informed consent. Baseline workup included clinical and neuropsychological assessment. A brain MRI was. obtained in consenting and eligible (e.g., those without a pacemaker) subjects. The subjects were followed with clinical evaluations at 6-month intervals, with annual diagnostic reconfirmation and neuropsychological retesting. Several of the findings have been reported previously.35-38

Reliability of Determination of Age at Onset of Schizophrenia To assess the reliability ofestimating age at onset of schizophrenia, we determined the age at onset of prodromal symptoms at baseline and again at a 2-year followup in 53 patients with schizophrenia, 306

including both EOS. and LOS patients, all currently middle-aged or elderly. TIle assessments were done by different raters, and the raters at the second assessment had no access to information from the first raters. Thus it was, in a way, a combination of test-retest and interrater reliability. The intraclass correlation coefficient (ICC) between the first and the follow-up ratings was 0.96 (P < 0.001), which suggests that our determination of age at onset was reliable. We also compared the age at onset of schizophrenia by means of three different definitions of age at onset in a subsample of 13 middle-aged and elderly schizophrenia patients. The mean (with standard deviation [SD]) for the age at onset of prodromal symptoms was 24 ± 10; that for positive symptoms was 26 ± 9; and for first psyclliatric hospitalization, was 29 ± 11. Thus, the onset of prodromal symptoms preceded the onset of positive VOLUME 5 • NUMBER 4 • FALL 1997

]este etal. symptoms by an average of 2 years and first psychiatric hospitalization by 5 years. Study Sample We studied 45 patients WI10 met our strict criteria for LOS. Our comparison groups included 90 normal subjects over the age of 45, 151 older patients with EOS presently over the age of 45 (EOS-O), and 83 younger patients with EOS presently under age 45 (EOS-Y). Additional comparison groups have included patients with other late..life psychotic disorders, such as delusional disorder. Details of the clinical, neuropsychological, and brain inlaging evaluations have been described previously.35.37 The mean ages for the three nlain groups, EOS-Y, EOS-O, and LOS, were 30 ± 7, 57 ± 10, and 63 ± 8 years, respectively. The mean age at onset ofschizophrenia was 20 ± 6 years for the EOS-Y group, 26 ± 7 years for the EOS-O group, and 55 ± 8 years for the LOS group. The mean duration of illness was 10 ± 7 years for EOS-~ 31 ± 12 years for the EOS-O, and 9 ± 7 years for the LOS patients. There was a significant gender difference, with nlore women in the LOS group (49%) than in the EOS-Y (39%) and EOS-O (22%) groul)s. The majority of the patients over age 45 came from the VA Medical Center, where over 80% of the patients are men, so the fact that 49% of the LOS subjects were women is noteworthy. There was a significantly larger proportion of patients with paranoid subtype (76%) in the LOS, compared with tIle EOS-Y (25%) and E05-0 (51 %) groups. Clinical Studies The clinical symptoms on the various scales used (Brief Psychiatric Rating Scale [BPRS], Scale for the Assessment of Positive Symptoms [SAPS], and Scale for the Assessment of Negative Symptoms [SANs])3941 revealed that there was no group difference in terms of the severity of global

psychopathology and of positive symptoms. On the severity of negative symptoms, however, tl1ere was a significant difference; LOS patients had less severe negative symptoms than the EOS-Y and EOS-O groups. A striking difference was present in terms of the daily neuroleptic dose being prescribed by the patients' individual clinicians. The LOS patients had significantly lower mean daily neuroleptic dose expressed in chlorpromazine-equivalent than EOS-O subjects; this finding could be related to the difference in tile severity of negative symptoms. Negative symptoms do not respond well to typical neurolep.. tics, leading to an increase in the dose for a l)atient witll EOS-O who continues to have negative symlJtonls. An alternative possibility is that the neuroleptics them.. selves might be producing "secondary negative symptoms," so that tile higher the dose, the more the akinesia, psychomotor retardation, and so 00, which mimic negative symptoms. We must stress) 1lowever, that this was not a controlled-dosage study, and, therefore, the dose-related finding 'should be viewed cautiously. On the Gittelman-Klein scale,42 there were similar levels of childllood maladjustment in the EOS-O and LOS patients in relationship to normal..comparison (NC) subjects. During adolescence and early adulthood, though, it was only the EOS-O group that continued to have significant premorbid maladjustment) with the LOS patients being intermediate between EOS-O and NC subjects. Thus, the LOS subjects had a significant amount of maladjustment during childhood, but they seemed, to do better than the EOS-O patients during adolescence and early adulthood until tiley had a psychotic break in middle- or older-age. Significantly more LOS patients (60%) were married at one time than EOS-Y (1%) and EOS-O (39%) patients. On the atller hand, the proportions of ever-married LOS and EOS-O patients who were still married at evaluation were statistically similar (34% and 24%, respec-

THEAMEmCANJOURNALOFGEmATroCPSYCH~TRY

307

Nondementia Nonpraecox Dementia Praecox? tively). The LOS and EGS patients also had similar family history of SCllizophrenia, with approximately 10%-15% having a first-degree relative with SCllizophrenia. We found that the LOS, EOS-O, and NC groups were comparable on uncorrected (constitutional) but not on corrected (e.g., with eyeglasses or hearing aids) visual and hearing deficits. 43 Thus, when tested without eyeglasses or hearing aids, the three groups had similar visual acuity and hearing capacity. With such correcting devices (if any) that tile subjects were using, how.. ever, the LOS and EOS·O groups had greater sensory deficits than the NC subjects. It appeared that there was a problem with correction of sensory deficits in the older schizophrenia group as a whole. In other words, the sensory deficits per se did not seem to predispose to LOS, but rather, the sensory deficits remained largely uncorrected in older patients with schizophrenia. Alternatively, the causes for sensory deficits might be such that in this group the deficits were not correctable. We examined the annual rate of mortality over an average period of 4 years and found that in both the LOS and EOS-O groups, the mortality was 2-3 times greater than in the comparison groups: patients with other late-onset psychoses, NC subjects, and the United States population between the ages of 55 and 65. 44 This finding is consistent with the literature on schizophrenia, suggesting higher mort,l1ity from both non-natural (e.g., suicide) and natural (e.g., myocardial infarction) causes in subjects with this disorder. 45 •46

Neuropsychological Studies We assessed cognitive l)erformance with an expanded version of the HalsteadReitan test battery.3 6 Overall, LOS was similar to EOS in terms of the pattern of neuropsycllological im!)airnlent. 35.36 The neurOl)sychological deficit scores (corrected for age, gender, and education) were similar among the three 308

schizophrenia groups and different from (intermediate between) scores in the NC subjects and Alzheimer's disease (AD) patients. There was a characteristic dissociation in terms of learning and retaining information. TIle schizophrenia patients had mild..to-moderate impairment on learn.. ing but showed normal retention of infor.. mation, whereas the patients with AD were markedly impaired on both. Although the overall pattern of 1lormal neu· ropsychological functioning for LOS and EOS groups was similar, there were some differences between LOS and EGS-O; these were in terms of learning47 and abstraction/flexibility of thinking, with the LOS group being less impaired on these measures. More specifically, wIlen we conducted a thorougll analysis of tIle learning and memory profiles in schizophrenia, we found that age at onset was llseful in understanding some of the cognitive heterogeneity often reported. Our findings showed that schizophrenia patients classified as having a normal learning and memory pattern had an older age at onset than patients witil abnormal learning and memory profiles. Also, age at onset of schizophrenia was positively associated with total recall across learning trials and negatively associated with evidence of retrieval problems. In another study, we characterized the integrity of semantic memory in both LOS and EOS patients and fOllnd a striking dissimilarity:f8 The organization of semantic memory was almost normal in the LOS patients, whereas it was significantly impaired in tIle EOS..O patients. We have followed these patients over a period of 2 years or longer, and there has been no deterioration in neuropsychological functioning. 49 Hence, our results so far suggest that LOS is primarily a nondementing disorder. MRI Studies We found no significant differences among the age-comparable LOS, EOS-O, VOLUME 5 • NUMBER 4 • FALL 1997

]este et al. and NC groups in terms of clinically relevant structural brain abnormalities, SUCll as strokes, tumors, cysts, or other lesions tllat .are obvious to a clinical neuroradiologist reporting on the MIU. 50 Otller groups of investigators have found a higller, incidence of structural brain abnormalities, such as strokes and tumors, in LOS patients. 21 ,51 We believe that if there is a patient with a relevantly located stroke or brain tumor who develops new~onset psychosis, the diagnosis Sllould be pSyCllosis, NOS or psychosis secondary to a general medical condition, rather than LOS with stroke or tumor. Patients with a history or physical examination indicative of a stroke or brain tunl0r had been excluded from our LOS group before an MRI was obtained. We performed a computerized quantitative analysis of gray matter, white matter, and fluid volumes in different regions of the brain in a subset of the subjects. 52 ,53 Comparing the three groups, LOS, EOS-O, and Ne, similar in age (all over 45)) gender, and education, the only significant differences in MRI measures were in ventricular and thalamic volumes.. 37 There were no significant differences between LOS and EOSo groups in terms of nonspecific structural brain abnormalities: ventricular enlargement) and white-matter hyperintensities. The ventricles were significantly larger in LOS patients, compared with NC subjects) with E08-0 patients being intermediate. The LOS patients had a significantly larger thalamus than EOS-O patients, with NC subjects being intermediate. (The difference in ventricular volume between EOSo and NC subjects or in thalamic volume between either schizophrenia group and NC subjects was not significant, probably because of small sample sizes for MID analyses.) The functions of the thalamus include filtering stimuli, sensory gating, and focusing attention,54 all of which are impaired in schizophrenia. TIle thalamus is actually composed of several separate nuclei that are considered THE AMERICAN JOURNAL OF GEIUATIUC PSYCHIATRY

to be either sensory or associational in nature. 55 Tile sensory nuclei are the major way station for information on its way to the cerebral cortex. In contrast, the association thalamic nuclei, including the dorsomedial, anterior, and pulVinar nuclei) receive their major input from the cerebral cortex; they also send most of their cifer.. euts tllere. The association nuclei therefore provide a route whereby information from one cortical area can be tllodified and passed on to other cortical areas.. 56 As such, the major filtering, gating, and attentional functions of the thalamus may be primarily dependent on the association, or nhigher.. order" nuclei. 57 Several studies have found a reduced neuronal number or density in the dorsomedial nucleus of the thalamus in EOS,58-61 although Bogerts and colleagues, who studied only the left hemisphere of the brain 62 ,63 did not find such a difference. 64 Andreasen and colleagues65 ,66 found a reduced thalamic volume in MRI, primarily on the right, and Buchsbaum et a1.67 relJorted a reduced metabolic rate in positron emission tomograplly (pEn, primarily in the right-posterior and left-ante.. rior portions of tIle thalamus in neuroleptic-naive patients with schizophrenia. All of these investigations were restricted to EOS patients and did not include any LOS patients.. Hence, our finding of a smaller thalamus in EOS is consistent with the literature, whereas that of a larger thaIanlUS in LOS is new.

Synthesis The similarities between LOS and EOS (see Table 1) include severity of positive symptoms, chronicity of course, and qualitative response to neuroleptics (i.e., the positive symptoms improve with typical neuroleptics, and the negative symptoms do not improve as much, and when patients stop taking neuroleptics they tend to have a relapse). There is a similar in.. crease in mortality in LOS and EOS groups, similar prevalence of uncorrected or 309

Nondementia Nonpraecox Demel'ltia Praecox? TABLE 1.

Late-onset schizophrenia: similarities with early-onset schizophrenia

1. Severity of positive symptoms 2. Chronic course 3. Sensory impairment 4. Family history of schizophrenia 5. Early childhood maladjustment 6. Increased mortality 7. Qualitative response to ncuroleptics 8. Overall pattern of neuropsychological impairment 9. Nonspecific magnetic resonance imaging (MRI) abnormalitics

TABLE 2.

Late-onset schizophrenia: differences from early-onset schizophrenia

1. More common in \vornen 2. Rarity of disorganized subtype 3. Less severe negativc synlptoms 4. Bettcr premorbid functioning in adolescence and carly adulthood 5. Less severe impairment in learning and possibly, in abstraction/flexibility of thinking 6. Less disturbed semantic ncnvork 7. Need for lower doses of ncurolcptics 8. Larger thalamus on magnctic resonance imaging (MRI)

constitutional sensory impairments, and cOlnparably increased family 1Iistory of schilophrenia. 35 The groups have similar levels of early childhood maladjustment, overall patterns of neuropsycllological impairment, and nonspecific MRI abnormalities. These similarities suggest that what we call LOS is indeed schizolJhrenia; it is neither a mood disorder nor a progressive dementia suell as AD. Furthermore, a predisposition to schizophrenia as well as the primary underlying brain lesions are probably common in the·LOS and EOS groups. In other words, the LOS patients may have, at a very early stage of their lives, a predisposition to schizophrenia similar to that of the EOS patients. There are also a number of differences between LOS and EOS (see Table 2), for example, in terms of subtype: LOS is 310

predominantly paranoid, with the disorganized subtype being very rare. LOS is more common in women. Furthermore, LOS patients have less-severe negative symptoms, less-severe impairment in learning and abstraction and fleXibility of thinking, and a more intact semantic network. Also, the LOS group exhibits better premorbid functioning in adolescence and early adultllood. The LOS patients seem to need (based on the dosages prescribed) lower doses of neuroleptics and have a larger thalamus on MIU. The differences between the LOS and EOS groups suggest that altilougll tllere is a similar predisposition and probably similar brain lesions, the severity might be less in LOS patients. A second possibility is that another difference, such as a larger thalamus might be a protective factor, although it is also conceivable that a larger thalamus is abnormal and contrib.. utes to the illness (predisposes to LOS). According to the popular model (see Figure 2), the premorbid level of function.. iog in patients with EOS is below the normal level (consistent with the neurodevelopmental theorie.s); this level of func.. tioning continues through adolescence, at which time there is some deterioration, and then functioning stabilizes. LOS patients are presumed to have nearly normal premorbid functioning. Our proposed model (Figure 3) is different from the conventional one in that the LOS patients also start out at a subnor~allevel, possibly not quite as low as EOS patients, but lower than the normal subjects, consistent with our belief that LOS, too, is a neurodevel.. 0lJmental disorder. TIle LOS patients then remain stable through adolescence and early adulthood, before having a decrease in the level of functioning during oliddleor old-age, suggesting at least an early degenerative component. Feinberg20,23 proposed that abnormal pnlning of neural elenlents in the brains of schizophrenia patients may explain many of the clinical features of schizophrenia, including frequent onset in adolescence and VOLUME 5 • NUMBER 4 • FALL 1997

]este et at. FIGURE 3.

Proposed model of early-onset schizophrenia (EOS) and late-onset schizophrenia (LOS)

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an apparent disruption in formal, logical thinking. Keshavan et al. G8 further elabo.. rated this hypothesis to take into account tIle accumulation of additional knowledge of normal brain development over the previous decade. Both of these authors have drawn attention to the possible relevance to schizophrenia of the normal pattern of development of the central nervous system. Normal postnatal development in.. valves programmed structural and morphological rearrangement of neuronal dendrites and synapses. Specifically, work in botil hUlnan and nonhuman primate postmortem tissues has shown that soon after birth there is a massive increase in the numbers and density of synapses in the cortex, including prefrontal cortex, a subsequent leveling off in childhood, followed by a period of a marked reduction THE AMEIUCAN JOURNAL OF GEIUATIUC PSYCHIATRY

in synaptic density during adolescence.69,7o Such a dramatic pnlning of the neural elements responsible for communication among neurons is thought to playa role in the progressive cognitive development of the adolescent and young adult. For example, Feinberg23 refers to his own observations in Piaget's laboratory, some 30 years earlier, that younger children could often propose, but not implement, sophisticated and conceptually correct problemsolving strategies. He observed that the problem-solving difficulty appeared to stem from "an inability to pursue an idea to its conclusion because of multiple com.. peting ideas" (p. 325).23 Schizophrenia patients also often display marked difficulties in screening out potentially distracting stimuli and maintaining a focus on one idea or task. Feinberg20 reasoned that if such a widespread 311

Nondementia Nonpraecox Dementia Praecox? programmed elimination of synapses oc.. curred during normal adolescence, then an . error in the same process might lead to at least some of the observed schizophrenia psychopathology. Keshavan et a1. 68 sum.. marized neuropathological and neuroimaging studies to suggest further that both excessive' pruning in some brain regions (such as the prefrontal cortex) and a failure of normal pnlning in other regions (such as the lenticular nucleus) could combine to produce symptoms of schizophrenia. One could speculate that LOS patients may have defective pnlning in the thalamus rather than the lenticular nucleus, Wl1ich would explain the larger thalamus in the LOS patients. Alternatively, a larger thalamus might have been present from birth, or the volume of the thalamus might have increased later in life because of chronicity of illness or treatment. The latter pOSSibility is unlikely because we did not find any correlation between thalamic vol.. ume and duration of illness or current neuroleptic dosage. We defined LOS as schizophrenia with onset after the age of 45, but we do not know if age at onset of schizophrenia is properly considered a continuous variable or a categorical one, and, if it is a categorical variable, what the age cutoff should be. In AD, when age at onset is earlier (Le., less than 65), the syndrome is much more likely to be familial, and the chances of observing a defect in the chromosome are very high. In this example, the age at onset suggests a subtype of AD with a distinct etiology. In contrast, several adult-onset diseases demonstrate a linear relationship with the clinical features of disease. For instance, age at onset is negatively associated with severity of illness and/or rate of disease progression in Huntington's disease, Kennedy's disease, spinocerebellar atrophy-I, and Inyotonic dystrophy.71-73 At this point, it is difficult to determine what the exact age cutoff for defining LOS should be. Larger sample sizes will be necessary for this purpose. Nonetheless, the available 312

data suggest that LOS is probably a neurobiologically distinct subtype of schizophrenia. An important related area of scientific inquiry pertains to other late-onset psychoses, such as delusional disorder. In one study, we compared 14 middle-aged and elderly patients who had delusional disorder with 50 patients who had schizophrenia with illness onset after age 40 on clinical and neuropsychological characteristics. 4 The delusional disorder group had a less frequent history of past hospitalization but more severe overall psychopathologic symptoms. The level of neuropsychological impairment seemed somewhat lower in the delusional disorder group, but differences were nonsignificant because ofsmall sample size. Diagnoses remained stable during up to 8 years of followooup (average: 4 years). These preliminary findings provi~e partial support to the clinical categooo rization of delusional disorder as a disorder distinct from schizophrenia. 4

Future Directions In recent years there has been considerable interest in cortico-striato-pallido-thaoo lamie (CSP'I) circuitry.74 75 These neuronal circuits are thought to consist. of at least five parallel loops, which begin in specified regions of the frontal cortex, and project in sequence to the striatum, pallidum/ substantia nigra, thalamus, and back to the same frontal cortex region. This portion of the circuit consists of the "closed" part of the loop in the original formulation of the CSPT circuitry mode1. 7.• ,7S Also, each of the CSPT circuits receives inputs from functionally related areas of the cortex, constituting an "open" portion of the loop. Recently it has been proposed that the CSPT circuits may not be as closed as they were originally thought to be. 76 In general, however, the two models agree on the elements and basic circuitry of the loops. Of the five different CSPT circuits, one is motor, one is oculomotor, and three subserve t

VOLUME 5 • NUMBER 4 • FALL 1997

]este et al. more cognitive functions. The "cognitive" circuits start and end in three different regions of frontal cortex: dorsolateral-pre.. frontal, orbitofrontal, and anterior cingulate. Each of these three cortical areas, and the circuits of which they are a part, ap.. pear to serve different functions. 77,78 The evidence to support this theory is based on patients with neurological lesions as well as on ablation behavior and electrophysiological recording experiments in nonhu.. man primates (for example, Milner,79 Goldman-Rakic,80 and FusterH ). Lesions in the dorsolateral-prefrontal circuit are believed to result in impairment of the ex.. eClltive functions, whereas lesions in the orbitofrontal CSPT circuit appear to result in personality changes such as disinhibition, and lesions in the anterior cingulate circuit produce changes in emotional, and especially motivational, processes. Cummings77 and Mega and Cummings78 have described these syndromes as dorsolateralprefrontal syndrome, orbitofrontal syndrome, and anterior cingulate syndrome, respectively. If this theory is correct, it may give us a clue for understanding some of the similarities and differences between LOS and EOS (Table 3). LOS and EGS patients are similar in terms of the severity of positive symptoms. It is conceivable that the positive symptoms such as hallucinations and delusions are, in a way, functionally related to the disinhibitory personality changes seen in patients who sustain lesions of the orbitofrontal cortex. As such, positive symptoms may be a result of a disruption of the orbitofrontal circuitry. We could TABLE 3.

argue, therefore, the orbitofrontal CSPT circuit is involved to a similar extent in bodl LOS and EOS patients. The involvement of some element of the orbitofrontal circuit may be a "core lesion," that is, common to all types ofschizophrenia. We also find that the LOS patients have significantly fewer negative symptoms. This feature of schizophrenia may be most intimately related to the motivational processes of the CSPT circuit originating in the anterior cingulate cortex. We suggest that this circuit may be associated with early-onset, poorerprognosis t deficit schizophrenia, rather than later-onset, better-prognosis, paranoid SCllizophrenia.The involvement of tIle third t dorsolateral-prefrontal cortex circuit in LOS may be somewhere intermedi.. ate. Tllis circuit is concerned with executive functions, which are impaired in most schizophrenia patients. So far we have found only a nonsignificant trend for the LOS patients to have better executive functions on neuropsycllological testing tllan the EOS patients. One could argue that executive functions have a somewhat intermediate impairment in LOS. Although Mega and Cummings78 suggest that learning is also dependent on dorsolateral-prefrontal functions, we l1ave not specified it as such in Table 3 because recent findings suggest that the learning and memory impairments in schizophrenia are heterogeneous and possibly referable to varying etiological mechanisms. We found that ap.. proximately 50% of 175 schizophrenia patients had a learning and memory profile similar to that in patients with Huntington's disease, 35% had a profile similar to

Putative differential involvement of CSPT circuitry in subtypes of schizophrenia

Cortical Component of CSPT Circuit

Putative Result of Dysfunction

Orbitofrontal Dorsolateral-Prefrontal Anterior Cingulate

Positive symptoms Impaired executive functions Negative symptoms

Schizophrenia Subtype EOS

EOS EOS

or LOS

> LOS

Note: CSPT = corticQ-striato-pallido-thalamic; LOS ::::: late-onset schizophrenia; EOS schizophrenia.

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Outcome Better Intermediate Worse

= early-onset

313

Nondementia Nonpraecox Dementia Praecox? that in NC subjects, and 15% had a profile similar to that in AD patients. 47 Altll0Ugh the organization and categorization of the to-be-Iearned material is likely dependent on dorsolateral-prefrontal functions, the initiation of search-and-retrieval mechanisms may rely on the anterior cingulate cortex, whereas the disinhibition of competing stimuli is vulnerable to lesions of the orbitofrontal cortex. Thus, future research is needed to better understand the specific contribution of CSPT circuitry dysfunction to discrete aspects oflearning and memory dysfunction in schizophrenia. Although speculative, our proposed model can lead to several testable hypoth.. eses. For example, we might expect LOS patients to be less impaired than EOS patients in other cognitive tasks presumed to be related to the anterior cingulate area, such as the Stroop Interference Test,82-84 and concomitantly; for the anterior cingulate area to demonstrate different patterns of activation in functional neuroimaging in LOS vs. EOS.

Conclusions We believe that, although SUCll occur.. rence is uncommon, schizophrenia can manifest for the first time after age 45. Later-onset SCllizophrenia is probably a neurobiologically distinct subtype of schizophrenia. Differential involvement of the cortico..striato-pallido-thalamic (CSPT)

circuitry may. help explain, in part, differences in the age at onset of schizophrenia.

Future Work It should be apparent that much more work needs to be done in this area. Larger sample sizes should be followed over long periods of time. Genetic, psyCllO" physiological, functional brain imaging, psychosocial, neurochemical, and psychopharmacological studies are warranted, as are post-mortem investigations. Such research should be focused on testing specific hypotheses. Complementary basic science studies are also needed to understand the' interactions between aging and schizophrenia. Decades of neglect of LOS and related psychoses by researchers can only be offset by intensive investigations during tIle immediate future. The payoff is likely to be considerable in terms of advancing our knowle~get not only of LOS, but also of schizol)hrenia and aging in general. This article l-eceived the 1996A1nericanAssociation for Geriat1-ic Psychiatry (AAGP) Seniot· Investigator Azvat-d (Dr. jeste). TJJe work was stljJported, ilt part, by National Institute of J.l1ental Health grallts MH49671, MH45131, and MH43693; b)J the Depa1·tl1zent of Vetel¥lns

Affairs; and bJ! tbe National Alliance for Researcb on ScbizoplJrenia and Depression (NARSAD) and Scottish Rite Schizophrenia Reseal·ch Progra1n, N.MJ., US.A.

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