Schizophrenia in late life

Early-onset and late-onset schizophrenia 

Research on schizophrenia in late life—patients with late-onset schizophrenia (LOS) and patients with early-onset schizophrenia (EOS) who have survived into late-life—has challenged traditional notions of this disorder. Late-life schizophrenia has proved difficult to define and to categorize as a subtype of schizophrenia. In one of the earliest accounts, Kraepelin [1] referred to paraphrenia to define a syndrome characterized by late onset and by the development of delusions and hallucinations that were qualitatively different from that in early-onset cases. Roth [2] coined the term late paraphrenia to refer to patients with onset of illness after age 65. Subsequent research has shown that this term, paraphrenia, not only has been poorly defined, but also has little empirical basis. Paraphrenia originally was thought to represent a unique category of schizophrenia. There are few data to support an upper age limit for the diagnosis of schizophrenia. This paucity of data makes a separate category for schizophreina with onset in late life difficult to justify; this was acknowledged in DSM IV, in which previous age-onset distinctions for the diagnosis were deleted.

The central question is whether LOS is the same disorder as that acquired earlier in life or a schizophrenia-like syndrome that occurs late in life with a different pathophysiology. When patients with LOS are compared with patients with EOS or midlife-onset schizophrenia (MOS), several trends suggest that LOS is a different disorder. At the very least that there may be significant age-related differences in disease expression. LOS patients in general when compared to EOS patients

The typical schizophrenic with disease onset after age 60 (LOS) is different from an individual with EOS in the following ways. Phenomenologically there is a relative absence of formal thought disorder in LOS patients compared with EOS patients. Negative symptoms and overall disorganization tend to persist regardless of age of onset. Thought disorder, although it does occur in LOS, is much more common in EOS. Age-related medical comorbidity (eg, stroke, dementia) often is a part of the LOS syndrome and affects disease expression. This comorbidity may suggest a neurodegenerative cause for LOS. Medical comorbidity either may trigger the onset of disease or may be required for disease expression. There are also sex differences between these groups. EOS symptom onset is similar for both sexes—peaking early in the 20s. In the 30s, incident cases of schizophrenia are greater in men. Women experience a second peak in the late 40s and early 50s, however, generally around the time of menopause. The higher prevalence of women with LOS around the time of menopause led Bleauler to speculate that LOS might be due to “the influence of the climacterium” [4]. This observation led to studies of the potential impact of estrogen on treatment strategies.

Early-onset schizophrenia compared with midlife-onset schizophrenia 

Patients with EOS and MOS are similar in terms of genetic risk, presence and severity of positive symptoms, early psychosocial maladjustments, and presence of subtle abnormalities on structural imaging studies. By contrast, MOS patients typically have fewer negative symptoms, better neuropsychologic performance, and better response to antipsychotic medications [4].

Course of disease for schizophrenia in late life 

After the initial acute psychotic episode for EOS and MOS patients has remitted, the disorder often is remarkably stable with regard to persistence and severity of positive symptoms and neuropsychologic impairment [5], [6]. Not all chronic schizophrenics suffer the inevitable neurocognitive decline implied by the term dementia praecox. This term was coined by Morel in 1860 and subsequently attributed to Kraepelin to suggest that the end stage of chronic schizophrenia is a dementing illness. Knobler and colleagues [7] examined a population of chronically institutionalized schizophrenics and found that 60% of this severe, chronically institutionalized population satisfied the prediction of the dementia praecox label. Overall, data from population surveys including community-dwelling chronic schizophrenics suggest that only 20% to 25% of chronic schizophrenia patients experience dementia praecox [4], [8], [9], [10]. What clinicians know about dementia praecox schizophrenics, usually referred to as negative-symptom deficit or type II schizophrenia [11], [12], is that these patients usually have a more insidious course, have more negative symptoms, and tend to have more premorbid functional and psychosocial deficits [13].

These comparisons of EOS, MOS, and LOS have led investigators to speculate that EOS is often associated with an abnormal neurodevelopment that conveys cognitive and language impairments leading ineluctably to thought disorder when the disease is fully expressed. LOS patients have more adaptive skills when their illness strikes, and perhaps as a result formal thought disorder is not a prominent feature [14]. EOS and LOS are in some fundamental but as yet undefined way different—possibly as a result of the timing of the insult or the nature of the insult itself.

Treatment 

Studies of antipsychotics in older schizophrenics suggest that they are effective in treating psychosis, but their use is accompanied by a high frequency of side effects. There are not many well-conducted studies to guide the clinical use of antipsychotics in the elderly patient with schizophrenia relative to clinical trials in young and middle-aged patients. Relying on dosing strategies that emerge from studies of younger patients is ill-advised. The remainder of this article focuses on treatment of EOS and LOS patients older than age 65. This is a selective review and is not comprehensive of the entire literature. Some of the early literature investigating typical antipsychotics is reviewed, largely to support the issue of drug efficacy in managing positive symptoms. The focus is on the scant literature using atypical antipsychotics because they are now the mainstay of treatment.

Most studies of older schizophrenics include middle-aged patients younger than age 65. There are a few placebo-controlled studies; the most recent was published in 1965 [15]. Most clinical trials compared one antipsychotic compound with another. Small samples and inadequate control over doses, duration of treatment, and concomitant medication characterize these trials. Outcome measures often were based on clinical observation or inadequately validated rating scales.

Antipsychotics are effective in controlling agitation in psychotic elderly patients regardless of diagnostic subtype or age of onset. The degree of efficacy of these compounds for the treatment of the positive or negative symptoms of schizophrenia is not firmly established. The common assumption is that older schizophrenic patients, especially patients with LOS, are more treatment responsive and need fewer medications; these assumptions have not been convincingly established [16], [17]. None of the available studies of typical antipsychotics distinguished between LOS and EOS patients. A few studies of atypical neuroleptics differentiated between these categories. As noted by Palmer and colleagues [4], there is limited published research addressing the treatment of LOS, and the available studies depended on small sample sizes or case reports rather than well-controlled, double-blind trials. It is still not clear whether LOS patients respond to neuroleptic treatment differently from EOS patients. Based on the limited available information, LOS patients seem to show better symptomatic improvement with antipsychotic treatment compared with the outcome of neuroleptic treatment of EOS patients. The oldest, most chronically ill, and most severely symptomatic patients, who reside predominantly in institutions and who have been ill for most of their lives, are relatively treatment-resistant [18]. Antipsychotics are prescribed to these patients primarily to control agitation rather than to reduce core symptoms of schizophrenia.

Summary 

Antipsychotics, whether conventional or atypical, are the primary class of medications for the treatment of late-life psychosis. Although the efficacy of neuroleptics in controlling agitation and psychosis associated with late-life dementia has been established, evidence for their efficacy in treating core symptoms of late-life schizophrenia other than behavioral dyscontrol is just emerging. More controlled clinical trials are needed. The available data suggest that atypical neuroleptics are therapeutically efficacious, with a more favorable side-effect profile than conventional neuroleptics. This literature further suggests the importance of low therapeutic doses and careful attention to the emergence of side effects.

Future studies must distinguish between patients with true schizophrenic disorder and patients with psychosis secondary to dementia, affective illness, or organic impairment. Patients must be characterized further as having EOS versus LOS because these disorders may differ in symptom profile, course, and response to treatment. There is also a need in future studies to separate out the results of treatment of patients with EOS who have been severely ill for most of their lives from those whose course has been less devastating. Within these two groups, treatment response, effective dose ranges, and sensitivity to side effects can be scrutinized more carefully.