Late-Onset Schizophrenia and Very-Late-Onset Schizophrenia-Like Psychosis: An International Consensus

Studies of late-onset schizophrenia began with Manfred Bleuler (1), who personally examined 126 patients whose illness began after the age of 40 years. These late-onset cases constituted 15% of the schizophrenia patients he examined; 4% of the patients had an onset after 60. About 50% of the patients with late-onset schizophrenia had symptoms that were indistinguishable from those seen in schizophrenic patients with the more typical younger age at onset. Bleuler’s age cutoff of 40 years influenced the German literature (2). Subsequent reports in the English literature used either 55 or 60 years of age as the dividing line (3, 4) and adopted the term “late paraphrenia” to both distinguish the illness from chronic schizophrenia and emphasize its clinical similarities with the condition described by Kraepelin (5). This was an unfortunate choice, however, since Kraepelin had never regarded late age at onset as a feature of paraphrenia. Moreover, the concept of paraphrenia—experiencing hallucinations and delusions without deterioration or disturbance of affective response, thus distinguishing the disorder from dementia praecox—had been discredited (6). Driven by the early emergence in Europe of geriatric psychiatry as a distinct subspecialty, as well as the apparent syndromic coherence of late paraphrenia, including female preponderance (4, 7, 8), abnormal premorbid personality and social functioning (4, 9, 10), and deafness (4, 7, 11–13), the late paraphrenia concept was readily adopted and included in ICD-9.

In the United States, the inclusion within DSM-III-R of a separate category for patients whose illness emerged after age 45 was largely in reaction to the unsatisfactory upper limit for age at onset that had hitherto prevailed for a diagnosis of schizophrenia (14, 15). With what represented unprecedented transatlantic agreement (in late-onset schizophrenia terms), neither ICD-10 nor DSM-IV contained separate codeable diagnoses for late-onset schizophrenia. The current “official” view would seem to be that all cases that satisfy diagnostic criteria for schizophrenia, regardless of onset age, fall into the same illness category. Ghosts of the earlier diagnoses remain, however. DSM-IV mentions that cases of schizophrenia with onset after age 45, while similar to early-onset cases, are associated with a higher ratio of women, better occupational and marital histories, more paranoid delusions and hallucinations, and less disorganization and negative symptoms. The presence of sensory deficits is also mentioned among those with the “oldest age at onset” (over 60).

Although one of his diagnostic criteria for late-onset schizophrenia had been a symptom profile similar to that of earlier-onset schizophrenia, Bleuler (1) did report some differences. Just over 50% had “paraphrenia-like, depressive-anxious catatonic or confused agitated” symptoms. The rest had symptoms similar to those of earlier-onset patients, but with less affective flattening and a more favorable prognosis. Subsequent researchers have also been struck by similarities between the symptoms of early- and late-onset schizophrenia (15, 16–28). Late-onset patients, however, are more likely than their earlier-onset counterparts to complain of visual, tactile, and olfactory hallucinations (18, 20, 21); persecutory delusions (21, 29); partition delusions (7, 21, 30); and third-person, running commentary, and accusatory or abusive auditory hallucinations (29, 31); they are less likely to display formal thought disorder (21, 29), affective flattening, or blunting (21, 25, 29). When onset of psychosis is after age 60, formal thought disorder and negative symptoms are very rare (8, 32).

Some diagnostic criteria for schizophrenia exclude late-onset cases, and since many incidence and prevalence studies of psychotic disorders did not include patients older than 60 (27, 28, 33, 34), data for this group are scarce. The point prevalence of paranoid ideation in the general elderly population has been estimated to be 4%–6% (35–37), but most of these patients will have dementia. The proportion of schizophrenia patients whose illness first emerged after the age of 40 has been estimated to be 23.5% (22), and the 1-year prevalence rate of schizophrenia in individuals between ages 45 and 64 is 0.6% (38). For individuals over 65 years of age, community prevalence estimates for schizophrenia range from 0.1% to 0.5% (39–42). From a register of contacts with psychiatric services (41), incidence rates of 12.6 per 100,000 population per year have been reported for cases of DSM-III-R-defined schizophrenia with first onset after 44 years. First admission data for patients over the age of 60 suggest that the annual incidence of schizophrenia-like psychosis increases by 11% with each 5-year increase in age (43).

Later onset of schizophrenia among women and overrepresentation of women among late-onset cases are robust findings (7, 8, 15, 32, 42, 44–49) that are not readily explicable in terms of sex differences in care-seeking and societal role expectations (50, 51) or in delay between symptom emergence and service contact (52). It is conceivable that aging-associated psychosocial factors such as retirement, financial difficulties, bereavement, deaths of peers, or physical disability may contribute to the precipitation of the symptoms of schizophrenia in later life. The role of these factors has not, however, been studied systematically in late-onset patients.

Most of the reported family studies that involved patients with late-onset schizophrenia suffer from methodological shortcomings (53), but there is good evidence that the relatives of very-late-onset patients have a lower morbid risk for schizophrenia than the relatives of early-onset schizophrenia patients (21, 54). Although the classical descriptions of very-late-onset patients stressed the high prevalence of sensory deficits, particularly longstanding conductive deafness (4, 9, 12, 13), these seem to be less strongly associated with onset after 40 years and may reflect paranoid patients’ reluctance to seek corrective measures or their inability to get correction of these deficits because of problems with the health care system for mentally ill older adults (26). Premorbid educational, occupational, and psychosocial functioning is less impaired in late-onset than early-onset schizophrenia (25, 55), although many late-onset patients are reported to have had premorbid schizoid or paranoid personality traits that fell short of currently accepted diagnostic criteria for personality disorders (4, 9, 10, 21, 25).

As seen in early-onset cases, computed tomography (56–60) and magnetic resonance imaging (MRI) (61–65) studies have reported nonspecific structural changes (e.g., higher ventricle-to-brain ratio and third ventricle volume) in patients with late-onset schizophrenia than in appropriate age-matched comparison subjects. Focal structural abnormalities such as volume reductions of the left temporal lobe (66) or superior temporal gyrus (61) again mirror changes reported in younger patients. Thalamic volume in one series of late-onset patients, although not significantly different from unaffected subjects, has been reported to be larger than that seen in early-onset patients (64). Focal cerebrovascular abnormalities—in the form of actual infarcts (67, 68) or areas of high signal intensity seen on T₂-weighted MRI (67, 69–74)—have been reported in very-late-onset patients. However, studies that carefully screened to eliminate organic cerebral disorder (62, 64, 75, 76) have not revealed an excess of such abnormalities when compared with comparison subjects. In functional imaging studies, regions of hypoperfusion in frontal and temporal areas (72), left posterior frontal and bilateral inferior temporal (77), and bilateral frontal and temporal lobes (78) have been reported. Neuroreceptor studies that used positron emission tomography (PET) and single photon emission computed tomography (SPECT) have shown both an increase (61) and no increase (79) in D₂ receptor density in late-onset patients in relation to that of comparison subjects. In an event-related potential study, late-onset schizophrenia patients had a significantly later peak latency of the N400 congruity effect than did normal subjects (80), a finding similar to that reported in younger patients with schizophrenia (81).

Studies of neuropsychological function in early-onset schizophrenia patients who have grown old have reported both deterioration (82, 83) and stability or improvement (84, 85). Such patients do not have an excess of those neuropathological abnormalities found in neurodegenerative disorders (86, 87). Although a precise characterization of the cognitive abnormality that accompanies schizophrenia is still awaited, young patients seem to be impaired on most cognitive tasks (88–91). Late-onset schizophrenia patients (like earlier-onset patients) perform significantly less well than comparison subjects on measures of executive functions, learning, motor skills, and verbal ability, but they are relatively less impaired on the Wisconsin Card Sorting Test and the learning score from the California Verbal Learning Test (25). In patients whose illness emerges after the age of 60, a similar pattern of impairment is seen, with widespread functional deficits (57, 71, 92) that are quantitatively and qualitatively different, since the patients’ learning capacity is preserved, from those seen in patients with dementia.

Few controlled trials of the use of typical antipsychotic medications in these patients have been reported. In open studies, 48%–61% (9, 15, 21, 93–96) of patients show full remission of psychotic symptoms with treatment, although poor compliance may render treatment in the community less successful (97). In four North American clinical centers, 192 mg of chlorpromazine equivalents was the mean daily dose prescribed to late-onset patients (22), which is about 40% of the amount given to young patients at the same centers and about 150% of the dose given in the United Kingdom to patients with illness onset after the age of 60 (97). The newer atypical antipsychotics appear to be well tolerated, since they have less potential for producing extrapyramidal side effects and tardive dyskinesias (98–101). The atypical antipsychotics do have some side effects of their own and also do not produce complete remission of all the symptoms of schizophrenia in most patients. Psychosocial and behavioral approaches, which include cognitive behavior therapy and social skills training, are important adjuncts to pharmacological therapy for patients with schizophrenia, although their role in the management of patients with late-onset schizophrenia remains to be investigated.

Schizophrenia-like psychoses, which cannot be attributed either to an affective disorder or focal or progressive structural brain abnormality, can arise at any time in the life cycle between childhood and old age. The expression of such psychotic symptoms shows greatest variation when onset age is at both extremes of life. Since the etiologies and the distinctive pathophysiologies of schizophrenia are at present unknown, variations in epidemiology, symptomatology, pathophysiology, and treatment response with age at onset can help to provide important clues to causative risk factors.

The available data suggest that categorization by specific age at onset ranges is relatively arbitrary. Although consensus was achieved, members of the group could not reach unanimity on either the presence of age cutoffs or where they should be set. There was general agreement that cutoffs have clinical utility and act to stimulate research effort. Epidemiological evidence is strongest for a cutoff at age 60 to define the very-late-onset group. Some clinical studies support another cutoff at age 40, although epidemiological data suggest that this age point may be too high for the middle-age onset group (102).

After much discussion, a consensus was reached that cases in which onset occurs between age 40 and 60 be called late-onset schizophrenia and that cases in which onset occurs after the age of 60 should be called very-late-onset schizophrenia-like psychosis. The purpose of this nomenclature is to clarify the position of these patients and to stimulate more research, rather than to put a closure on this issue.

Regardless of age at onset, psychiatric and medical examinations and available investigative procedures should always be obtained to exclude identifiable etiologies. If available, brain imaging should be obtained in cases of late-onset schizophrenia and very-late-onset schizophrenia-like psychosis. The presence of sensory impairments and social isolation should be ascertained and appropriate remedial action taken if found. The place of nonpharmacological treatments has not been adequately investigated but access to these therapies should not be prejudiced by age. Psychological management may reduce distress associated with psychotic symptoms and facilitate a therapeutic relationship, within which commencement and compliance with medication can occur.

Antipsychotic drugs are a mainstay of therapy. Drug treatment should be started at very low doses and increases in dose should be made slowly. Typical late-onset patients will respond to dose amounts that are about one-quarter to one-half those given to early-onset patients. Very-late-onset cases may respond to dose amounts as low as one-tenth of those used in young adults. Use of depot medication at very low doses may be successful in ensuring compliance. With the exception of clozapine, whose use is problematic in older patients, the atypical antipsychotic agents are clearly advantageous in the treatment of late-onset patients because of the reduced likelihood of extrapyramidal symptoms and tardive dyskinesias for which elderly patients are at higher risk.