Psychosis in Late Life: How Does It Fit Into Current Diagnostic Criteria?

In this case presentation we describe a patient with a constellation of symptoms, both psychotic and affective, with onset after the age of 45. Psychotic symptoms arising in late life are of increasing clinical interest given our aging population. Furthermore, the conceptualization of these syndromes stimulates a number of intriguing research questions regarding current hypotheses of neural mechanisms implicated in the pathophysiology of psychotic disorders. For example, whether late-onset schizophrenia is a subtype clinically distinct from early-onset schizophrenia awaits clarification and may have implications for the development of treatment paradigms. In the arena of brain research, the questions of whether early and late-life psychosis reflect similar neurobiologic impairments and how these fit into neurodevelopmental models of schizophrenia also await further study.

The concept of late-life schizophrenia has been somewhat nebulous, as has its terminology. For example, the term “late-onset schizophrenia” has been used synonymously with “paraphrenia.” The earliest conceptualization of paraphrenia described by Kraepelin (1) did not have age boundaries but, rather, distinguished a group of patients with preservation of personality and affect, as distinct from dementia praecox. Later, the term “late paraphrenia” was coined by Roth (2), in describing essentially the same syndrome as earlier-onset paraphrenia, except with onset after the age of 60. Only recently has research begun to distinguish potential neurobiologic differences in these syndromes, yet the nosology remains controversial and inconsistent. The term “late-onset schizophrenia” has largely supplanted “paraphrenia,” although the concept is slightly different. Late-onset schizophrenia is typically defined as symptoms consistent with schizophrenia occurring after the age of 45. While it is often observed that the symptoms in late-onset schizophrenia may have a “paraphrenic” quality, the more typical “deficit”-type symptoms are also considered part of the syndrome. This entity was originally described by Manfred Bleuler (3) and was felt to represent essentially the same fundamental pathology as the early-onset type of schizophrenia.

The advent of increasingly sophisticated brain imaging techniques has stimulated a reappraisal of the role of neuropathologic changes with aging in the genesis of late-life psychosis. Further exploration of the epidemiologic, phenomenologic, and etiopathologic aspects of late-life psychoses should be undertaken to develop a better understanding of the pathophysiologic mechanisms involved. There is a growing awareness that late-life syndromes are heterogeneous and complex in nature, often characterized by a mixture of anxious, depressive, and cognitive symptoms. A critical reevaluation of current diagnostic systems in light of this awareness may be warranted, as exemplified by the case that follows.

CASE PRESENTATION

Ms. L was a youthful-appearing 76-year-old woman who visited a university geriatric internal medicine outpatient clinic to determine a physical source of several somatic complaints and to obtain treatment for symptoms of generalized anxiety. Her anxiety symptoms included a feeling of nervous tension, restlessness, and excessive worry and a long history of insomnia treated with a variety of benzodiazepines, such as temazepam, clonazepam, alprazolam, and triazolam over the preceding 20 years. During a review of systems at her initial encounter, she reported a history of diffuse abdominal pain, urinary hesitancy, and tactile sensations of burning and itching. Ms. L focused primarily on the abdominal pain, which she described as sharp and stabbing and as worsening with activity. At this visit the patient had brought an enlarged copy of her own previously obtained abdominal X-ray. On the film she identified a small dark spot, consistent with bowel gas, and stated that she believed it to be the source of her acute abdominal pain. The patient described this pain as occurring for the first time after an abortion at the age of 29, which was complicated by uterine perforation and sepsis. She indicated that she had been hospitalized for these complications and that while feeling “despondent” she had inserted a glass drinking straw into her uterus in a suicide attempt. She believed that a portion of the straw must have broken off and become the source of her pain. During this hospitalization she had also overhead the staff stating that “draining the abscess would kill her,” which contributed to her despondency and suicidality.

Further history revealed extensive somatic preoccupations. Ms. L produced a 5-by-7-inch photograph of a dental X-ray and reported that during an endodontic procedure 10 years earlier she had been the inadvertent recipient of a radio transmitter implanted in her tooth to enable others to “follow me and keep track of me, like they do birds and animals.” She stated that the transmitter device made a beeping noise when she entered certain buildings. She also indicated that she was being followed in her car by teenage boys who would “throw dirt which gets into my mouth and eyes.” She had previously contacted the local police regarding these events. Last, during this initial medical evaluation she endorsed numerous depressive symptoms, including initial insomnia, poor concentration, low mood, and loss of interest, but indicated that these were chronic and did not have a discrete episodic occurrence.

Ms. L had an interesting constellation of psychotic and affective symptoms and multiple somatic complaints with a probable insidious course and an unclear point of origin in time. It is important to remain aware in the care of the elderly that the source of psychiatric symptoms may be a medical condition of recent onset that has created a subacute or acute delirium or precipitated a depressive syndrome. Before a primary psychiatric diagnosis can be documented, a thorough evaluation to exclude a psychiatric syndrome secondary to a medical illness must be completed. Therefore, it is essential to obtain a comprehensive medical history and perform any necessary medical tests to completely evaluate any physical complaints.

Review of Systems

The symptoms noted included shortness of breath, palpitations, sweating and chills, lump in her throat, and decreased concentration. A medical history was obtained. Ms. L’s illnesses included 1) non-insulin-dependent diabetes mellitus of several years’ duration controlled by diet, 2) bilateral macular degeneration, 3) peptic ulcer disease, and 4) hypertension. Her previous operations included 1) hysterectomy and left oophorectomy, 2) vagotomy secondary to peptic ulcer disease, and 3) dilation and curettage of intrauterine pregnancy complicated by postoperative infection. Further medical history was notable for two previous motor vehicle accidents within the past few years without sequelae or loss of consciousness. Brain images obtained with computed tomography (CT) after the motor vehicle accidents were unremarkable except for somewhat prominent ventricles. Physical examination revealed no gross abnormalities with the exception of abnormalities on fundoscopic examination consistent with macular degeneration. Her sensorium was intact, but her Mini-Mental State score was 27 out of 30, with two errors on serial seven subtraction and one error in short-term recall. The results of a basic metabolic panel, hemogram, and urinalysis were within normal limits. After this initial evaluation, further assessment by the general surgery, gynecology, and urology services and a pain management clinic were requested to complete the diagnostic process.

The general surgery service obtained an abdominal CT scan to evaluate the persistent abdominal pain. The CT scan revealed diverticulosis of the sigmoid colon and atherosclerotic disease with a calcified density in the left pelvis, most likely vessel calcification. Gynecologic evaluation was notable for a benign Gardner’s cyst and vaginal atrophy. Hormone replacement therapy was recommended by the gynecology service. The results of a cystoscopy were within normal limits, but because of the patient’s sensation of not emptying her bladder, treatment with terazosin was recommended. The pain management clinic reported the patient to have chronic ilioinguinal pain of unclear etiology and recommended treatment with low-dose amitriptyline to target both the patient’s chronic sleep disorder and chronic pain complaints.

Ms. L presented an interesting diagnostic challenge. At this point, most acute medical illnesses had been excluded. Her long-term psychiatric presentation was characterized by affective symptoms and was heavily emotionally laden, particularly in regard to the abortion and subsequent persistent abdominal pain. In addition to depressive symptoms, she had persistent psychotic symptoms, including somatic delusions and probable auditory hallucinations. In such cases it is difficult to distinguish among chronic affective psychosis versus schizophrenia spectrum illness versus an “organic” syndrome such as dementia with psychotic features. Diagnostic clarification can be obtained by gathering further information regarding lifelong social and occupational functioning, ideally with input from an outside informant.

Social and Family History

Ms. L indicated that she was the second of seven children, raised by both parents in a family of very limited financial means. She was the only sibling able to attend college and obtained a certificate in elementary education. She taught school for 1 year and worked as a substitute teacher at various times. She also taught piano in her home for a number of years. She stopped teaching school after her marriage and raised four children. Her marriage of 50 years had ended in divorce 9 years previously. Physical and emotional abuse became a pattern in the marriage; Ms. L had sustained a detached retina and broken teeth secondary to trauma. Since the divorce Ms. L had been living near one of her daughters, who was employed as a nurse. Ms. L enjoyed baby-sitting her grandchildren and had a number of hobbies, although she did not socialize with others besides family members. Ms. L and her daughter indicated that the most substantial change in her ability to function socially occurred during her mid-50s, when she became more despondent, discontinued teaching piano, and became increasingly socially withdrawn.

Her family psychiatric history was significant for probable major depressive disorder in a younger sister and in two paternal aunts. Ms. L reported that one cousin may have been hospitalized for psychotic symptoms.

This additional information clarified that Ms. L had had some mild disturbances over the majority of her adult life, which became significantly worse and probably syndromal when she was in her 50s. Her level of social achievement was greater than one would expect for early-onset schizophrenia; i.e., she completed high school and some college, married, and raised children. However, it is possible that she was experiencing psychotic symptoms at the time of the complicated abortion and could have been suffering from chronic psychosis from that point onward, or she may have experienced a discrete episode of psychosis in the context of a mood disturbance. It is also possible that her psychotic symptoms originated in her mid-50s and affected her recollection of earlier events, such that they had a paranoid overlay. As the daughter was the only available informant, further details regarding the episode following the abortion were not available. Even if some psychotic symptoms were present early in life, it is possible that the severity of these symptoms increased sufficiently that her course is consistent with late-onset schizophrenia, although the persistent and prominent affective complaints detract from the likelihood of a primary psychotic disorder. However, the course of late-onset schizophrenia is often characterized by nonspecific premorbid psychiatric disturbances, such as schizoid or schizotypal-like symptoms earlier in life. Also, previous episodes of affective symptoms would not preclude the diagnosis of late-onset schizophrenia, as these patients may suffer affective symptoms both premorbidly and in the context of late-life psychosis.

Other diagnostic considerations include the possibility of a partially treated major depressive disorder. While Ms. L did not report an episodic quality to her symptoms, elderly patients may experience longer symptomatic depressions than younger patients, and the elderly may be more functionally impaired by persistent subsyndromal depressive illness (4). Last, it is not possible to exclude a nonspecific prodromal syndrome in the context of an impending dementia syndrome. After completion of the medical and surgical evaluations of Ms. L, a more extensive psychiatric and neuropsychological evaluation was pursued to more fully characterize her syndrome.

Psychiatric Evaluation

The psychiatric evaluation was notable for symptoms of depressed mood and tearfulness of indeterminate duration, as well as fatigability, feelings of worthlessness, and helplessness. Ms. L did not report a diurnal variation in symptoms. The other vegetative symptom reported was a long history of sleep disturbance, characterized by initial and middle insomnia. She did not report a weight or appetite change. However, concurrent with the onset of the insomnia, she had begun to express the belief that people came into her house at night and moved or took things. She also voiced vague persecutory beliefs that her husband and others wished to harm her. There was no evidence of overt disorganization, auditory hallucinations, ideas of reference, thought broadcasting, thought insertion, or thought withdrawal cross-sectionally during the examination. She did have multiple somatic complaints of a delusional quality and endorsed 30 physical complaint items on the Briquet’s Syndrome Checklist. She had a score of 27 out of 30 on the Mini-Mental State examination of cognition. At this time the patient was felt to meet sufficient criteria for a diagnosis of major depressive disorder, although somatization disorder was considered as well. It was suggested that her amitriptyline dose be increased from the low dose of 40 mg/day to 100–150 mg/day. Neuropsychological testing revealed cognitive functioning within normal limits with the exception of mildly impaired performance in verbal recall.

At this point, Ms. L’s symptoms could be conceptualized as an affective disorder with persistent delusional symptoms. Her somatic preoccupations were certainly characteristic of depression in the elderly, but the severity of her depressive symptoms was less than one would expect for a psychotic depression, and there was no episodic quality or prominent vegetative symptoms with the exception of the sleep disturbance. This scenario typifies the sort of difficulty inherent in the diagnosis of late-life syndromes. Criterion-based systems, which are based on large-scale observations of younger adults, are less clearly applicable to the duration of illness and specific symptom clusters seen in elderly patients. Most difficult to interpret are the often-refractory depressive syndromes that may be prodromes to the onset of Alzheimer’s disease or other dementias (5). In the absence of more definitive criteria to guide treatment decisions, often such syndromes are treated symptomatically. Medications are typically selected according to the particular symptom cluster that is accounting for the greatest degree of distress in a given individual, and frequently combinations of psychotropic agents are used.

Course

After the preceding evaluation Ms. L did not return for psychiatric follow-up visits, but she was evaluated several times in the pelvic pain clinic for chronic abdominal and pelvic pain of probable musculoskeletal etiology. In addition to amitriptyline and hormone replacement therapy, she was placed on a regimen of nonsteroidal anti-inflammatory medication for probable musculoskeletal pain. Within 6 weeks of the increased dose of amitriptyline, her pain complaints were resolved. She reported that her mood was significantly improved, but she continued to display tearfulness at her clinic visits and continued to complain of difficulty falling asleep. She confided feelings of being “stalked” by her husband’s friends and believed that individuals were entering her home and rearranging her furniture to cause her further stress and anxiety. She also claimed that often when she passed a group of boys she smelled a smoke-like smell from them, which she believed indicated that they would beat her. She had repeatedly contacted the police about this. During this period, her chronic abdominal pain remained in remission, although she continued to report variations of vague somatic complaints. For example, her hormone replacement therapy was discontinued because of complaints of breast tenderness. The only other somatic complaint during this interval was persistent vaginal discharge, which Ms. L associated with “draining an abscess, which had been there for over 10 years.”

Ms. L had no further contact with the psychiatry clinic but continued to receive amitriptyline for approximately 3 years, until she sustained a right femoral neck fracture and was hospitalized for a right total hip arthroplasty. After the arthroplasty she was referred to the psychiatry clinic because of persistent anxiety and complaints of “being watched all the time.” Ms. L indicated that she could hear neighbors in her apartment complex following her around from room to room. She also began to complain of a “fine dust” that had settled in her apartment, which she found distressing. She perceived this dust to be toxic and stated that it might have been placed in her home by her ex-husband. At that time she continued treatment with amitriptyline, with the addition of haloperidol, 4 mg/day. Subsequent visits to the psychiatry clinic revealed perseveration regarding concerns of being followed. Short-term memory deficits became more apparent during this period. Inability to manage her own prescribed medications necessitated closer monitoring by the patient’s daughter. She scored 26 out of 30 on the Mini-Mental State during this period.

Six months later Ms. L was seen on an emergency basis in the psychiatry clinic, with increasing delusions that her upstairs neighbors were following her from room to room and that a “fine dust” had settled in her apartment, necessitating sweeping several times a day. She perceived that the dust made her eyes and skin itch, and she called the police to have the air tested. Her sleep was stable, and she reported adequate energy to enjoy sewing, cooking, and watching television. She worried about being robbed, so she hid certain items in her apartment but then could not find them herself. When unable to find these things, she became convinced that someone had entered her apartment. She continued to receive amitriptyline, 100 mg/day, without an increase in dose because of concern of the anticholinergic potential. Risperidone, 1 mg at bedtime, was also initiated.

Over the next few months the patient’s sleep continued to be stable and her mood improved significantly. She voiced enjoyment of reading, watching sports events, and cooking; however, her thoughts that her upstairs neighbor was “putting something in the air” troubled her, and she continued to miss certain items and thought that others were taking them. During this period neuropsychological testing revealed intellectual function somewhat lower than would be expected given her academic attainment. Except for impaired performance on a verbal memory delayed-recall task, however, the patient’s learning and auditory and verbal memory functions were not significantly worse than those of normal elderly comparison subjects.

To obtain a more structured environment, Ms. L moved into a retirement village. Her adjustment seemed to go well initially, but within a few weeks she developed an episode of confusion requiring acute hospitalization. It was learned that she had not been eating regularly and had not taken her medication for an unknown period of time. In the emergency room she was combative, loud, and agitated and had unintelligible speech. The results of an electrocardiogram and laboratory evaluations were negative except for a mildly elevated white blood cell count. Head CT revealed prominent ventricles but no other evidence of structural abnormalities. Urinalysis results were consistent with a urinary tract infection. A psychiatric consultant recommended tapering and discontinuation of amitriptyline because of anticholinergic effects and reinstitution of risperidone. Ms. L’s mental status gradually improved, and she became alert, although she continued to display occasional paranoid ideation. She was discharged from the hospital after a course of the antibiotic levofloxacin, 250 mg/day, for the urinary infection, and she was also receiving trazodone, 25 mg/day; risperidone, 0.5 mg/day; glyburide, 15 mg/day; metformin, 500 mg/day; and benazepril, 10 mg/day.

Ms. L returned to the retirement village. At her next psychiatry visit she reported concern about a “fine dust” that had settled all around her apartment. She described the dust as “like a feather,” tickling her nose and awakening her at night, so she purchased an air cleaner to try to rid her apartment of this dust. The risperidone dose was increased to 1.5 mg/day. At her next visit she brought to the clinic an envelope containing grayish dust that she wished to be examined. She also expressed worry that her ex-husband was “saying bad things” and asked whether her clinician had heard of any negative remarks about her. She began to confide that she sometimes heard sounds in the attic above her apartment and began worrying that someone was entering her apartment and removing or rearranging her belongings. Eventually nortriptyline was initiated in place of the trazodone, as the patient insisted she had felt much better previously, while taking the tricyclic antidepressants. The risperidone dose was also gradually increased to 3 mg/day. Ms. L’s sleep and mood improved, although she continued to report the presence of dust in her apartment. In subsequent sessions there was a notable decrease in delusional talk and less preoccupation with delusional ideas. Instead the patient was focused on her shyness and her wish to become more involved in activities at the retirement village. She continued to have mild psychotic symptoms but overall functioned well at the retirement village.

DISCUSSION

This is the case of an elderly patient with onset of psychotic and depressive symptoms in late life, as well as mild cognitive impairment. If the clinician considers the psychotic symptoms to be primary, the patient meets the DSM-IV and ICD-10 criteria for schizophrenia. There is a long history of debate, since the first descriptions of schizophrenia, about whether the psychopathologic process is the same among those with onsets in childhood, adolescence, adulthood, and late life. Kraepelin (1) originally stated that only a small percentage of patients with schizophrenia were likely to develop their first symptoms in the fourth, fifth, or sixth decade of life, and he described their clinical features as essentially the same as those seen in juvenile forms of schizophrenia. This conceptualization was later supported by Eugen Bleuler (6), who also stated that typical schizophrenic symptoms could start in late life, but Kraepelin had additionally recognized a “paraphrenic” subgroup with an affectively intact, primarily delusional, less deteriorating course. As mentioned in the introduction, Manfred Bleuler (3) in 1943 coined the term “late-onset schizophrenia” to describe a form of schizophrenia with an onset between the ages of 40 and 60. He further described unique characteristics that often distinguished the late-onset group, such as less affective flattening and less formal thought disorder than seen in patients with early-onset illness. These observations are reminiscent of Kraepelin’s “paraphrenic” conceptualization of a delusional syndrome in the absence of other deterioration or disorganization.

The degree of overlap and lack of clear boundaries between the terms “late-onset schizophrenia” and “paraphrenia” make this literature prone to confusion and limit comparability of research findings. Late paraphrenia is primarily a British concept that includes “patients . . . with a well-organized system of paranoid delusions with or without hallucinations existing in a well-preserved personality and affective response” (2). In recent years it has become more widely accepted that late-onset schizophrenia is a “true” schizophrenia that begins between ages 40 and 60, whereas the term “late paraphrenia” includes delusional disorders starting after age 60 (7).

Epidemiologic studies suggest that between 15% and 32% of patients with schizophrenia could be considered to have late onset of illness. Specific risk factors that have been described include female gender, visual and auditory sensory impairment, and premorbid schizoid personality traits. It has also been reported that patients with late-onset schizophrenia frequently have a less robust family history of schizophrenia and show a favorable response to neuroleptics (8). Likewise, clinical descriptions demonstrate that although there are important similarities with early-onset schizophrenia, late-onset schizophrenia is more likely to have an affective component, visual, olfactory, and tactile hallucinations, and a predominance of paranoid symptoms (i.e., persecutory and organized delusions) (9, 10). It has also been stated that patients with late-onset schizophrenia are less likely to have cognitive deterioration, formal thought disorder (i.e., looseness of association and inappropriateness of affect), and negative symptoms (11–13). Two major issues arise from these observations. First, is it possible for the morbid process in schizophrenia to begin in late life? Second, could these late-onset cases be clinically differentiated from early-onset forms; i.e., is the late-onset disorder a distinct subtype of schizophrenia?

It is of interest that Ms. L exhibited some of the clinical features associated with late-onset schizophrenia. Ms. L was a married woman with paranoid personality traits who had good premorbid and psychosocial functioning. Typically, patients with late-onset schizophrenia are employed until middle age, and they have a marriage rate similar to that of the normal population. In contrast, patients with early-onset schizophrenia usually have occupational difficulties and have a significantly lower rate of marriage (10). Before the onset of schizophrenic symptoms, Ms. L had a history of affective symptoms. After the onset of her psychotic symptoms, Ms. L did not report episodic symptoms consistent with a discrete period of major depression or mania, but she did have persistent nonspecific anxious and depressive symptoms. It is possible that she had a “minor depression” or dysthymic disorder, although this is difficult to reconcile with her chronic psychosis. Overall, the course of the mood disorder appeared independent of her psychotic symptoms. Her psychotic symptoms consisted of prominent paranoia with bizarre delusions and olfactory hallucinations, with an absence of negative symptoms. She did have somatic preoccupations, which may be perceived as depressive symptoms or as somatic delusions within the psychotic disorder spectrum.

One may also make a case for the diagnosis of delusional disorder, but the bizarre nature of her delusions and the presence of olfactory hallucinations with secondary delusional interpretations are not entirely consistent with delusional disorder. That is, patients with schizophrenia typically develop secondary bizarre delusional interpretations to explain their olfactory hallucinations, whereas in delusional and depressive patients, olfactory hallucinations are perceived as originating from the patients’ own bodies and are associated with body self-awareness (14, 15). Ms. L also lacked a well-circumscribed delusional system and had questionably intact cognition. Thus, while this patient experienced persistent psychotic symptoms for a number of years, she had a variable presentation, substantial depression and anxiety, and better functioning than a primary psychotic disorder would suggest. As a result, she received clinical diagnoses of both dysthymia and delusional disorder but did not fit neatly into any single diagnostic category. This may in part reflect a general tendency among clinicians to avoid making a diagnosis of schizophrenia for people with a late onset of symptoms and reflect the complexity and controversial nature of this diagnosis for the older adult.

Neuropsychological evaluation of the patient did not reveal cognitive deterioration at the beginning of the psychotic symptoms. In contrast to the cognitive impairment observed among patients with early-onset schizophrenia, Paulsen et al. (16) found that patients with the late-onset disorder have a normal semantic network and relatively unimpaired episodic memory. Consistent with these findings, the cognitive evaluation of Ms. L did not demonstrate substantial cognitive deterioration over the previous several years. Her very mild cognitive decline over time does not suggest a progressive dementia syndrome associated with the psychotic symptoms; however, an early prodromal form of dementia cannot be excluded.

The nosologic status of these primary late-onset psychotic states, i.e., those that are not due to an organic or affective disorder, has been controversial in the systems for classification of mental illnesses. In DSM-III, schizophrenia could be diagnosed only if onset occurred before age 45; therefore, chronic psychosis starting after the age of 45 was classified as an atypical psychosis. DSM-III-R added the category of late-onset schizophrenia to define illness occurring after the age of 45. DSM-IV does not use any age limit for the diagnosis of schizophrenia, and it does not specify late-onset schizophrenia as a separate subcategory. ICD-10 effectively splits the heterogeneous group of nonaffective psychosis with onset in late life into schizophrenia and delusional disorder. While one could argue for delusional disorder in the case of Ms. L, the absence of a clear and discrete delusion and the bizarre nature of some of the beliefs make this diagnosis less likely.

Aside from a purely nosologic interest, case reports such as this have given rise to some important questions regarding current theories postulated to explain neural mechanisms implicated in the pathophysiology of psychosis in late life. Can pathoetiologic models of schizophrenia explain the onset of symptoms in late life? Or, in contrast, could these late-onset cases represent a different pathophysiologic entity? Or are there distinct affective syndromes in late life that involve chronic psychosis and may present as prodromes to a degenerative dementia syndrome?

It has been postulated that psychosis in late life is associated with a variety of neurologic abnormalities, e.g., white matter diseases or vascular lesions (17–19). It is of note that Ms. L had risk factors for vascular disease, such as hypertension and adult-onset diabetes mellitus, which suggests that subclinical degenerative processes due to a vascular pathology may have been occurring as well, although this was not noted on her CT scan. If that hypothesis proves to be correct, cases of late-life psychosis should be considered as having an etiology independent from that for early-onset schizophrenia. Structural neuroimaging studies (20, 21) have had inconsistent results, showing a lack of gross abnormalities in patients with late-onset schizophrenia. Structural brain imaging studies have also shown that some patients with late-onset schizophrenia have cerebral abnormalities that resemble those associated with early-onset illness: large ventricular space (21, 22), small anterior superior temporal gyrus (23), and high D₂ receptor density (24). In contrast, some structural differences have been demonstrated, such as greater thalamic volume in late-onset than in early-onset schizophrenia (21, 23).

Convincing etiological theories regarding late-life psychosis and its overlap with depressive and dementia syndromes await elucidation. Pearlson and Petty (25) established that late-onset schizophrenia is a well-defined syndrome with a heterogeneous patho­etiology. It may be that effects of development and degeneration are combined in the pathogenesis of late-onset schizophrenia, so that a neurodevelopmental abnormality that is compensated for in early adulthood becomes unmasked by the loss of brain capacity with aging or environmental cerebral insults (26).

For over a century there has been debate as to whether schizophrenia is a neurodegenerative versus neurodevelopmental process in light of the delay in appearance of the illness into young adulthood. Another layer of complexity is added when the aging brain is considered in the process. Perhaps one way to conceptualize the process is to view the schizophrenic brain as neurodevelopmentally vulnerable to the disease state, although not necessarily symptomatically so under optimal conditions. When an additional stressor is added, however, sufficient disruptions may ensue and precipitate and propagate the disease process. In some individuals a measure of biological change or endocrine fluctuations in adolescence may suffice, and in others a more severe insult, such as vascular disease or postmenopausal changes, may produce the pathophysiologic disruptions responsible for the constellation of symptoms we presently call schizophrenia. In yet other conditions, a combination of degenerative processes with an underlying depressive syndrome may also result in a constellation of symptoms that present as a late-life psychotic disorder. There is clearly an enormous need to clarify these mechanisms in order to streamline treatment recommendations for the already complex and vulnerable elderly population.

Received April 30, 1998; revision received Oct. 22, 1998; accepted Nov. 2, 1998. From the Department of Psychiatry, College of Medicine, University of Iowa Hospitals and Clinics; and the Instituto de Salud “Carlos III,” Madrid. Address reprint requests to Dr. Schultz, Department of Psychiatry, Mental Health Clinical Research Center, University of Iowa, 2911 JPP, 200 Hawkins Dr., Iowa City, IA 52242; [email protected] (e-mail)