VOL 22, NO. 3, 1996 Medical Comorbidity in 413

by Dilip V. Jeste, Abstract Mens sana in corpore sano. Downloaded from https://academic.oup.com/schizophreniabulletin/article/22/3/413/1829806 by guest on 24 September 2021 Julie Aklko Gladsjo, (Sound mind in a sound body.) Laurie A. Undamer, and The extent and consequences of [Juvenal, 2nd Century A.D.; cited Jonathan P. Lacro medical comorbidity in patients in New Encyclopedia Britannica, with schizophrenia are generally 1993, p. 667] underrecognized. Patients with comorbid conditions are usually excluded from research studies, although they probably represent The comorbidity of physical and the majority of individuals with mental illnesses has implications for the treatment, health care utilization schizophrenia. Elderly patients are and cost, quality of life, and under- especially likely to have comorbid standing of the pathophysiology of disorders. In this article, we review those disorders. A number of studies selected literature on medical have examined the relationship comorbidity in schizophrenia, between depression and physical ill- including physical illnesses, sub- nesses (see Schulberg et al. 1987). stance use, cognitive impairment, Medical comorbidity in schizophre- sensory deficits, and iatrogenic nia, however, has been studied to a comorbidity. Data from the Univer- much smaller extent. sity of California, San Diego Clini- cal Research Center on late-life psy- chosis are also presented. Older Anosognosia for Medical schizophrenia patients report fewer Comorbidity In Schizophrenia? comorbid physical illnesses than healthy comparison subjects, but Anosognosia is broadly defined as their illnesses tend to be more ignorance, real or feigned, of the severe. These results suggest that presence of (specifically of schizophrenia patients may receive paralysis) (Stedman 1990). We believe less than adequate health care. Sub- that, in a larger sense, there is an stance abuse is more common in insufficient awareness of (or patients with schizophrenia than in "anosognosia" for) medical comor- the general population and may bidity in schizophrenia on the part of exacerbate psychiatric symptoms in patients, caregivers, health care these patients. Although general- providers, and researchers. Medical ized cognitive impairment is associ- comorbidity has often been underrec- ated with schizophrenia, the main ognized and underdiagnosed in psy- contributors to in older chiatric patients, especially among patients are more likely to be those with schizophrenia (Koranyi comorbid neurological and other 1979; Sheline 1990). Some data sug- physical disorders, substance abuse, gest that schizophrenia patients may and medication side effects. Iatro- have a greater pain tolerance than genic comorbidity results primarily healthy subjects (Dworkin 1994). This from the use of neuroleptic (e.g., tar- deficit in schizophrenia patients' sen- dive dyskinesia) and anticholinergic sitivity to physical pain, combined (e.g., confusion) medications. Clini- cal and research recommendations Reprint requests should besent to Dr. are made for management of comor- D.V. Jeste, Geriatric Clinical bidity in schizophrenia. Research Center (116A), Veterans Affairs Schizophrenia Bulletin, 22(3): Medical Center, 3350 La Jolla Village Dr., 413-430,1996. San Diego, CA 92161. 414 SCHIZOPHRENIA BULLETIN

with poor insight, may result in a research that has sought to uncover found that 92 percent of the patients Downloaded from https://academic.oup.com/schizophreniabulletin/article/22/3/413/1829806 by guest on 24 September 2021 lower rate of schizophrenia patients associations between schizophrenia had at least one comorbid physical reporting physical problems to their and certain medical disorders, in disorder. was physicians. Neuroleptics—the most order to identify risk factors or possi- most prevalent (34%), followed by commonly used treatment for psy- ble etiological mechanisms for either neurological (22%), genitourinary chosis—may reduce pain sensitivity disorder. Even studies examining (17%), respiratory (17%), and gas- (Part et aJ. 1994) and have indeed physical comorbidity in schizophre- trointestinal (17%) disorders. been used to treat pain due to nia often have been narrowly focused Diagnosis of comorbid conditions and other chronic conditions. Thus, on a single medical condition, or they in schizophrenia patients has impor- many patients with chronic schizo- have been limited by methodological tant implications for their care and phrenia may not seek, and therefore problems that restrict the validity quality of life. Unrecognized physical may not receive, diagnosis and treat- and generalizability of the conclu- may exacerbate the symp- ment of physical illness. By focusing sions (Harris 1988). One major limita- toms of psychiatric illness by affect- solely on the presenting psychiatric tion has been the diagnosis of schizo- ing brain function or by affecting symptoms or by viewing physical phrenia itself. Across studies, differ- other organ systems. complaints as "psychosomatic" ent diagnostic systems have been In this article, we will review the symptoms, health-care professionals employed to diagnose schizophrenia, literature on the prevalence and risk also may tend to overlook coexisting making it difficult to compare results. factors or associations of five main medical conditions in their mentally Neuroleptic medication has adverse categories of comorbidity in schizo- effects, such as glucose intolerance ill patients. Koranyi (1979) studied phrenia: (1) physical illnesses; (2) detection of physical illnesses by and tardive dyskinesia (TD) (dis- substance abuse and dependence, physicians referring patients to a psy- cussed later); researchers must con- including alcohol use, smoking, illicit chiatric clinic and found that nonpsy- trol the effects of neuroleptic medica- drug use, caffeine consumption, and chiatric physicians missed one-third tion when they are investigating polydipsia; (3) cognitive impairment; and psychiatrists missed one-half of medical illnesses in individuals with their patients' comorbid medical con- schizophrenia. In addition to the (4) sensory deficits; and (5) iatrogenic ditions. In a study examining the methodological problems, numerous disorders. In each of these categories, prevalence of physical disease in psy- other confounds, such as the effects we will briefly summarize selected chiatric patients in the California of aging, institutionalization, and literature and will refer the reader to public health system, Koran et al. other health-related behaviors (e.g., more comprehensive reviews of these (1989) reported that only 47 percent smoking, lack of exercise), may have areas. We will also present data on of the patients' physical illnesses an impact on comorbidity findings in comorbidity from our cohort of older were recognized by the mental health schizophrenia. Despite these limita- schizophrenia patients. Finally, we staff. Among the undiagnosed med- tions, it is important to investigate will offer clinical and research recom- ical conditions, 16 percent of the medical comorbidity in schizophrenia. mendations. physical illnesses were considered Relatively few studies have exam- "causative" (i.e., entirely responsible Physical Comorbidity for the presenting psychiatric symp- ined concurrent medical and psychi- toms), whereas 45 percent were atric disorders in elderly mentally ill believed to have exacerbated a pre- patients. The likelihood of someone Literature Review. A number of existing psychiatric disorder. having a medical problem increases research reports have suggested that with age (Kovar 1977). The projection schizophrenia patients have a lower The tendency for researchers to that 130 million people in the United prevalence of some physical illnesses exclude from their studies subjects States will be over the age of 45 by and a higher prevalence of other with comorbid medical conditions in 2050 suggests that there will be a physical illnesses than people in the order to eliminate the possible con- large number of middle-aged and general population and, often, pa- founding effects of physical illnesses elderly persons with coexisting psy- tients with other psychiatric condi- is another factor that may contribute chiatric diagnoses and medical prob- tions. to the lack of awareness of the impact lems. Sheline (1990) examined the Rheumatoid arthritis. Several of physical illnesses on schizophrenia prevalence of physical illnesses in studies have reported a negative patients. The exception has been geriatric psychiatric inpatients and association between rheumatoid VOL22.NO. 3, 1996 415

arthritis and schizophrenia. Rheuma- ship between rheumatoid arthritis cancer in schizophrenia are surpris- Downloaded from https://academic.oup.com/schizophreniabulletin/article/22/3/413/1829806 by guest on 24 September 2021 toid arthritis—a largely genetically and schizophrenia, but the reason for ing, given the high rates of smoking transmitted autoimmune disorder the decreased prevalence of rheuma- among schizophrenia patients (dis- that causes peripheral vascular and toid arthritis in schizophrenia is as cussed later). Some researchers have inflammatory changes in the joints— yet unknown (Vinogradov et al. hypothesized that neuroleptic med- affects approximately 1 to 3 percent 1991). ication may have an anticancer effect of the population (Sorensen 1990). Cancer. The relationship between (Mortensen 1992), but this theory More than 15 years before the intro- schizophrenia and cancer has been remains speculative. duction of neuroleptics, Nissen and studied extensively, but the findings Other illnesses. Other illnesses Spencer (1936) reported that they did have been inconsistent. In 1909, the appear to be more common in pa- not observe a single case of rheuma- Board of Control of State Hospitals tients with schizophrenia than in toid arthritis in 2,200 psychiatric suggested that hospitalized psychi- other psychiatric patients or in normal inpatients, with the predominant atric patients, especially those with comparison subjects. Several re- psychiatric disorder being schizo- schizophrenia, had some immunity searchers (Tsuang et al. 1983; Harris phrenia. Recently, Eaton et al. (1992) from cancer (cited in Baldwin 1979). 1988) have reported that compared to reviewed 14 epidemiologjcal studies Many other early studies concurred the general population, schizophrenia conducted between 1934 and 1985 with this finding; however, more patients may have an increased risk of and concluded that, despite various recent and more methodologically cardiovascular disorders, including methodological shortcomings, there rigorous research has found no sig- myocardial infarction and coronary was ample evidence supporting the nificant difference in the overall artery disease. Baldwin (1980) has negative association between these prevalence of in persons with reported, however, that this higher two disorders. In 12 of the 14 studies, schizophrenia as compared with per- prevalence is not specific to schizo- there was a reduced prevalence of sons in the general population. phrenia; increased risk of cardiovascu- rheumatoid arthritis, and this lower Tsuang et al. (1983) reviewed the lit- lar disorders was found in affective risk appeared to be specific to schizo- erature on cancer in schizophrenia disorder patients as well. A few pre- phrenia. In one study, frequencies of and concluded that previous reports liminary reports (Brambilla et al. 1976; rheumatoid arthritis in patients with of decreased cancer incidence were McKee et al. 1986) have suggested a schizophrenia, with "affective psy- flawed by an inappropriate use of positive association between non- chosis," and with "neurosis" were proportionate mortality-rate compar- insulin-dependent mellirus compared (Allebeck et al. 1985). In isons and other methodological prob- and schizophrenia. Because neurolep- this study, there were no significant lems. Results of some single-site tics are known to produce glucose differences in the prevalence of studies (e.g., Craig and Lin 1981; intolerance (Mukherjee et al. 1989a), it rheumatoid arthritis between Mortensen 1989) suggest that the is unclear whether the increased risk patients with "neurosis" and people incidence of some cancers, such as of non-insulin-dependent diabetes in the general population, but only and breast cancer, mellirus is related to schizophrenia or half of the expected number of cases may be increased, while the risk for whether it is secondary to neuroleptic of rheumatoid arthritis were found other cancers, particularly lung can- use. among the schizophrenia patients. cer, may be decreased. A recent study Several authors (Baldwin 1979; The rate of rheumatoid arthritis also that included Denmark, Japan, and Tsuang et al. 1983; Harris 1988) have was somewhat low in "affective psy- the United States (Gulbinat et al. comprehensively reviewed the asso- chosis"; however, this sample was 1992) and employed a large study ciation of schizophrenia and various not well defined and the difference sample showed that the overall risk other physical disorders, including from the general population was not of cancer was no different for schizo- infectious disease, Parkinson's dis- statistically significant. Researchers phrenia patients than for normal ease, ulcers, epilepsy, coeliac disease, have proposed various metabolic, individuals. Significant geographical and asthma. It appears that in schizo- neurochemical and neuroendocrine and gender differences in cancer inci- phrenia patients, some of these dis- (especially pertaining to prosta- dence were noted and were attrib- eases may be more common while glandins and corticosteroids), uted to probable environmental and others may be less common than in genetic, immunologic, and viral theo- hereditary differences. Findings that persons without schizophrenia. ries to explain the negative relation- suggest a reduced prevalence of lung However, the exact prevalence rates 416 SCHIZOPHRENIA BULLETIN

as well as possible mechanisms for viously reported (Lacro and Jeste (average severity per category); num- Downloaded from https://academic.oup.com/schizophreniabulletin/article/22/3/413/1829806 by guest on 24 September 2021 the apparent differences in preva- 1994) on the number of physical ill- ber of illnesses with level 3 severity lence between individuals with ver- nesses and number of medications (severe/constant significant disabil- sus those without schizophrenia are associated with middle-aged and ity/uncontrollable chronic prob- unknown. It is possible that con- elderly patients with schizophrenia lems); number of illnesses with level founding factors such as health (n = 78), Alzheimer's disease (AD; 4 severity (extremely severe/immedi- habits or psychotropic medications, n = 62), and major depression (n = ate treatment required/end organ rather than schizophrenia per se, 41). The data were obtained by inter- failure or severe impairment in func- may account for at least some of the viewing patients and available care- tion); and total score. Because we reported variations in physical givers and by reviewing the medical wished to compare physical comor- comorbidity. For the most part, it charts. The patients with schizophre- bidity only, we omitted the category appears that patients with schizo- nia reported fewer physical illnesses rating presence and severity of psy- phrenia may not differ significantly (mean = 1.0) than did AD and de- chiatric illness. from the population at large in terms pressed patients (means = 1.4 and We first examined the mean num- of the total number of coexisting 2.4, respectively, p < 0.0001). The ber of illnesses reported on Axis III of physical illnesses. prevalence of degenerative joint dis- the DSM-1II-R (American Psychiatric Mortality. Reports suggest that ease, , coronary artery Association 1987), based on the com- mortality in persons with schizophre- disease, and congestive heart failure bined information from subject and nia is 2 to 4 times higher than that in was significantly lower in schizo- caregiver interviews, medical the general population (Koranyi phrenia patients than in patients with records, and the physician's history 1979; Tsuang et al. 1983; Allebeck AD or major depression. There were and physical examination. The num- 1989). The average lifespan of the no significant group differences in ber of illnesses for the patients with schizophrenia patient is approxi- the prevalence of diabetes mellitus, schizophrenia (mean = 1.3) was mately 10 years shorter than that of a chronic obstructive pulmonary dis- lower than that for the normal com- normal person. This discrepancy ease, gastrointestinal disease, thyroid parison subjects (mean = 2.1, p < between individuals with schizo- disease, or neurological illnesses. 0.03). Although the two groups were phrenia and normal individuals is Schizophrenia patients also received comparable in terms of mean educa- due in part to an elevated risk for sui- significantly fewer nonpsychotropic tion level (13 years) and gender dis- cide in schizophrenia patients. medications than did the other two tribution (> 60% male), the compari- Approximately 10 percent of schizo- groups. son subjects were significantly older phrenia patients commit suicide In an attempt to assess comorbid- than the schizophrenia patients (67.6 (Caldwell and Gottesman 1990). ity in a more quantitative fashion, we and 56.0 years, respectively; p < Schizophrenia patients are 8 times recently examined physical comor- 0.0001). Despite the age discrepancy more likely to die from traumatic bidity in a sample of outpatients with between the two groups, the mean injuries and 14 times more likely to schizophrenia (n = 53) and healthy number of CIRS-G categories have an undetermined cause of death comparison subjects {n = 38), all over endorsed was similar for the normal registered in their autopsy reports the age of 45 years, who were partici- and schizophrenia subjects (2.2 cate- than are normal individuals (Alle- pating in our Clinical Research Cen- gories). The severity index, total beck 1989). The latter finding sug- ter, using the Cumulative Illness Rat- score, and number of illnesses with gests that among patients with schiz- ing Scale for Geriatrics (CIRS-G; level 3 severity also did not differ ophrenia, physical diseases are likely Miller et al. 1992; Parmelee et al. between the patient and comparison to be missed as the cause of death. 1995). The CIRS-G yields quantita- groups. None of the subjects in either Mortensen and Juel (1990) noted that tive measures of physicians' ratings group had illnesses of level 4 sever- at least some proportion of mortality of physical illness severity in 14 ity. In other words, it appeared that in schizophrenia may be directly as- organ systems (e.g., upper gastroin- the schizophrenia patients'endorsed sociated with side effects of neuro- testinal, respiratory). Each item is a greater number of illnesses when leptic medication. rated on a scale of 0 to 4 (0 is absent, they were assessed in a structured 4 is most severe). The CIRS-G has manner using the CIRS-G than they five summary variables: number of did when assessed with unstruc- University of California at San categories endorsed; severity index tured, subjective reporting. The total Diego (UCSD) Studies. We pre- VOL22.NO. 3, 1996 417

number of illnesses reported for the more likely it is that both the patient nia (LOS). LOS was defined as schiz- Downloaded from https://academic.oup.com/schizophreniabulletin/article/22/3/413/1829806 by guest on 24 September 2021 schizophrenia patients was similar to and the health care staff may under- ophrenia manifesting after the age of that reported for the normal subjects estimate or ignore co-occurring med- 45 (American Psychiatric Association who were, on an average, 12 years ical illnesses. Using a triage model, 1987). Twenty-two outpatients with older. It is possible that caregivers treating a patient's comorbid physi- LOS were followed for an average of and health care professionals may be cal conditions may be seen as rela- 5 years (range of 2-9 years). The unaware of the physical illnesses of tively less important in the context of mean age at illness onset was 57 their schizophrenia patients unless a florid psychosis. It is also possible years, the mean duration of illness at the illnesses are more severe. Among that comorbid physical illness may study entry was 4 years, and the the schizophrenia subjects, the exacerbate certain psychotic symp- baseline mean MMSE score was CIRS-G total score did not correlate toms. The positive relationship 27/30. We initially hypothesized that with education, duration of illness, observed between depressive symp- some of the schizophrenia subjects severity of negative symptoms based toms and CIRS-G total score could would develop dementia during the on the Scale for the Assessment of also be bidirectional. Schizophrenia course of the study at a rate greater Negative Symptoms (SANS; Andrea- patients with more severe depressive than that in the age-comparable gen- sen and Olsen 1982), or degree of symptoms may experience reduced eral population. At 5-year followup, cognitive impairment on the Mini- motivation or feelings of hopeless- none of the subjects had become Mental State Examination (MMSE; ness and, consequently, be less likely demented or institutionalized. Five Folstein et al. 1975) and the Mattis to seek care for their medical ill- LOS subjects had died, however, Dementia Rating Scale (Mattis 1976). nesses. Alternately, patients with a with two suicides, two deaths from Surprisingly, in the schizophrenia comorbid medical condition may cancer, and one death from cardiac subjects, age was not correlated with have depressive symptoms sec- arrest. This mortality rate was more any measure of physical comorbidity, ondary to their illness. than twice what would be expected although in normal subjects, age cor- for the general population over this related significantly with CIRS-G One limitation of the present study time period (U.S. Department of indices (p < 0.01). This could be re- was the age difference between the Health and Human Services 1994). lated to a wider age range and to the schizophrenia subjects and the nor- This suggests that LOS patients have older mean age of the normal sub- mal comparison group. The normal an increased mortality rate, as has jects compared with those with schiz- comparison group was, on average, been reported for schizophrenia in ophrenia. Significant positive correla- 12 years older than the patient group. general. tions were noted for the CIRS-G total In general, as people age, they tend score with age at onset of schizophre- to have an increasing number of ill- Specific Management Considera- nia (Spearman's r = 0.34, p < 0.02), nesses, and these illnesses tend to be tions. Schizophrenia patients, care- severity of positive symptoms on the more severe. The older age of the givers, and clinicians frequently may normal subjects would tend to bias Scale for the Assessment of Positive be unaware of the patients' comorbid the results in favor of finding more Symptoms (r = 0.29, p < 0.05) (SAPS; physical illnesses. It may be helpful severe illnesses in the normal group. Andreasen and Olsen 1982), depres- to use a standardized instrument, Thus, despite the age difference, sive symptoms using the Hamilton such as the CIRS-G, to systematically schizophrenia patients endorsed a Depression Rating Scale (Hamilton assess physical comorbidity in schiz- 1967) (r = 0.37, p < 0.01), and overall comparable number of illnesses as did the comparison subjects who ophrenia patients, especially among assessed with the the older individuals. By recognizing Brief Psychiatric Rating Scale (BPRS; were significantly older. The present study demonstrates the need for sys- physical illnesses sooner, patients Overall and Gorham 1962,1988) (r = may benefit from early treatment, 0.40, p < 0.006). tematic assessment of physical ill- nesses in patients with schizophre- thereby preventing at least some of the later complications. Thus, the CIRS-G total score corre- nia. We plan to use the CIRS-G to lated positively with three measures examine comorbid physical illnesses of psychopathology severity in schiz- in larger groups matched for age. Substance Abuse and Dependence ophrenia patients. One possible inter- In a related study at UCSD Oeste et pretation is that the more severe posi- al. 19956), we followed a cohort of Literature Review. Patients with tive symptoms that a patient has, the patients with late-onset schizophre- schizophrenia are much more likely 418 SCHIZOPHRENIA BULLETIN

to abuse a wide variety of substances lect data on substance use. some areas of the brain (Giorguieff- Downloaded from https://academic.oup.com/schizophreniabulletin/article/22/3/413/1829806 by guest on 24 September 2021 than are healthy comparison subjects. Comorbid substance abuse and Chesselet et al. 1979). Animal re- There is considerable evidence that dependence have significant effects searchers have shown that nicotine schizophrenia patients have higher on the course of illness, on physical increases the release of dopamine in than average rates of alcohol and health, on hospitalization, and on the nucleus accumbens (Imperato et illicit drug use, cigarette smoking, quality of life (Mueser et al. 1992). al. 1986). Some investigators have and polydipsia (excessive water For example, recent research examin- suggested that smoking may actually drinking). Our experience suggests ing alcohol use in schizophrenia be therapeutic for patients, as the in- that schizophrenia patients may have demonstrated that higher alcohol use creased release of dopamine may higher than average rates of caffeine was associated with more severe psy- alleviate negative symptoms (Glass- consumption as well. In the Epidemi- chiatric symptoms, more disturbed man 1993). Adler et al. (1993) re- ological Catchment Area study, the behavior, and more severe orofacial ported that cigarette smoking could lifetime prevalence of alcohol abuse dyskinesia Puke et al. 1994). Use of transiently normalize the impairment or dependence in persons meeting illicit drugs such as marijuana of auditory sensory gating in schizo- DSM-III-R criteria for schizophrenia (Negrete et al. 1986) and cocaine phrenia patients. A related study was 3.3 times higher than that in the (Brady et al. 1990) was also associ- examined nonsmoking relatives of general population, with 33 percent ated with more severe psychiatric schizophrenia patients who shared of the subjects with schizophrenia symptoms and worse prognoses. the auditory gating defect reported in being affected (Regier et al. 1990). Several researchers (Drake et al. 1989; schizophrenia. In a double-blind, The odds of having a lifetime illicit Mueser et al. 1992) have reported placebo-controlled procedure, use of drug-abuse disorder are 6 times poorer medication compliance, nicotine gum transiently normalized higher for individuals with schizo- higher rates of rehospitalization, and this sensory gating deficit (Adler et phrenia (27.5%) than for individuals poorer adjustment and treatment al. 1992). without a . Preva- response in schizophrenia patients Some epidemiological studies have lence of smoking has been reported with comorbid drug and alcohol found an inverse relationship be- to be 50 to 90 percent (Masterson and abuse or dependence than in those tween cigarette smoking and the O'Shea 1984; Hughes et al. 1986), and patients without such abuse or prevalence of idiopathic Parkinson's polydipsia may affect up to 20 per- dependence. Increased likelihood of disease (Baron 1986). Smoking may cent of chronically institutionalized violent behavior (Cuffel et al. 1994) also decrease neuroleptic-induced schizophrenia patients (de Leon et al. and greater use of emergency serv- parkinsonism; in one study, the num- 1994). It is possible that some deaths ices (Day and Graham 1991) are also ber of cigarettes smoked daily corre- of undetermined causes may be due associated with substance abuse in lated inversely with ratings of neu- to undiagnosed polydipsia that re- schizophrenia. Most available roleptic-induced parkinsonism in sulted in water intoxication (Kushnir research confirms the clinical dictum schizophrenia patients (Goff et al. et al. 1990). that substance abuse exacerbates psy- 1992). Some researchers have re- chiatric symptoms. Substance use. Estimates of the ported a positive association between prevalence of substance-abuse disor- Smoking. Studies examining nicotine use and increased preva- ders in schizophrenia have varied rates of cigarette smoking have found lence of TD (Yassa et al. 1987), somewhat because of differences in higher rates in schizophrenia patients although this finding has not been sample demographic characteristics, than in normal subjects (even when replicated by others (Menza et al. study methodology, and assessment demographic variables and socioeco- 1991). techniques. Cuffel (in press) re- nomic status were controlled for) and Polydipsia. This is an unusual viewed prevalence studies of drug in patients with other psychiatric dis- and poorly understood condition and alcohol abuse in schizophrenia orders as well (e.g., Hughes et al. that is seen most frequently in male and found that the prevalence esti- 1986). Smoking increases neuroleptic Caucasian inpatients with schizo- mates of substance abuse were corre- metabolism and consequently may phrenia (Jos et al. 1986). It is associ- lated with the year in which the data be associated with the use of higher ated with an early age at onset of were collected. This finding was neuroleptic doses (Goff et al. 1992). It schizophrenia, heavy tobacco use, attributed to the use of increasingly has been speculated that nicotine poor response to neuroleptic medica- more sophisticated measures to col- increases the release of dopamine in tion, and increased prevalance of TD VOL.22, NO. 3, 1996 419

2 (Kirch et al. 1985; de Leon et al. 1994). ill patients lacked the social skills tively; x = 26.25, dj = 2, p < 0.0001; Downloaded from https://academic.oup.com/schizophreniabulletin/article/22/3/413/1829806 by guest on 24 September 2021 Polydipsia may lead to water intoxi- necessary to participate in heavy figure 1). Current smoking in patients cation, hyponatremia, and death. drug use. with schizophrenia was related to There is some suggestion that pa- younger current age (p < 0.01), earlier tients who develop polydipsia may UCSD Studies. A UCSD study onset of illness (p < 0.01), and higher also exhibit other substance-use dis- daily neuroleptic dose (p < 0.001). orders. examining cognitive abilities in A number of explanations have younger schizophrenia patients (Zisook et al. 1992) found that patients Specific Management Considera- been proposed for the observed high tions. Substance abuse and depend- rates of substance abuse in the schiz- who abused drugs or alcohol per- formed better on neuropsychologjcal ence in schizophrenia are frequently ophrenia population. Self-medication associated with medication noncom- has been the most frequently offered testing than did nonabusers. One pos- sible explanation consistent with the pliance, psychosocial problems, med- hypothesis for increased rates of ical and iatrogenic complications, smoking as well as for alcohol and results of the above-mentioned stud- psychotic exacerbation, and worse illicit drug abuse. Use of a particular ies is that acquiring and using drugs overall prognosis. As with nonpsy- substance appears to be related more and/or alcohol require some amount to the availability of that substance of cognitive (and social) abilities. chiatric individuals, patients with than to a selective matching of sub- In our sample of older schizophre- schizophrenia may minimize or be stance effects with specific symptoms nia patients (mean age = 60 years), inaccurate in reporting their sub- (Schneier and Siris 1987; Cuffel, in the prevalence of DSM-III-R lifetime stance use. It is therefore important press). There is also evidence that alcohol abuse or dependence was 31 to routinely screen for substance-use individuals often tend to use multi- percent, compared with 8 percent in disorders when working with schizo- ple substances, such as alcohol, illicit normal comparison subjects (x2 = phrenia patients. Substance-use drugs, and cigarettes; according to 15.36, df=l,p< 0.0001). Among the screening tests, such as the Michigan the Epidemiologic Catchment Area schizophrenia patients, those with a Alcohol Screening Test (Selzer 1971), data, 21 percent of all individuals comorbid diagnosis of alcohol abuse CAGE (Mayfield et al. 1974), Drug with alcohol abuse or dependence or dependence performed signifi- Abuse Screening Test (Skinner 1982), had another lifetime substance-use cantly better on attention measures and urine toxicology tests may be disorder (Regier et al. 1990). The {p < 0.01) and overall cognitive func- helpful in identifying individuals with effects of combined substance use tioning (p < 0.05). The groups with comorbid substance-use disorders. may serve to further exacerbate those without alcohol abuse or Many substance-abusing individu- symptoms of psychosis and cognitive dependence did not differ in terms of als use multiple substances. Rela- impairment. age, gender, age at onset or duration tively little research has been done to of schizophrenia, education, BPRS Investigations into the risk factors address the consequences of multi- total, SAPS or SANS total, and daily associated with substance abuse have ple-substance abuse in schizophrenia, neuroleptic or anticholinergjc dose. revealed some surprising results. It but it seems likely that substance In another study, comorbid alcohol appears that better premorbid func- interactions may further compromise abuse or dependence was found to tioning is associated with an in- health status, cognitive functioning, creased risk of comorbid drug and be associated with an increased inci- and psychiatric symptoms (Koczap- alcohol use among schizophrenia dence of TD (Jeste et al. 1995b). It has ski et al. 1990). Substance use may patients (Mueser et al. 1990; Dixon et been hypothesized that the central al. 1991). Mueser et al. (1990) have nervous system changes associated also be associated with an increased suggested that drug-abusing patients with heavy alcohol use may result in risk of side effects, such as akathisia may have milder clinical symptoms, a "premature aging" of the brain, Puke et al. 1994) and TD (Binder et which are reflected in better social thereby increasing the risk for TD. al. 1987; Jeste et al. 1995a). It is impor- tant to consider that substance abuse skills and an ability to take part in The prevalence of current cigarette is also associated with a heightened the social interactions related to ac- smoking was nearly 6 times higher risk of suicide in the general popula- quiring and using drugs. Earlier among our older schizophrenia tion. Schizophrenia patients with studies in this area (Cohen and Klein patients than among the normal com- 1970) also noted that more severely parison subjects (40% and 7%, respec- comorbid substance abuse may be 420 SCHIZOPHRENIA BULLETIN

Figure 1. Prevalence of smoking and alcohol abuse/dependence in 71 normal comparison subjects Downloaded from https://academic.oup.com/schizophreniabulletin/article/22/3/413/1829806 by guest on 24 September 2021 and 158 patients with schizophrenia

45%

31%

Current Smoking Never Smoked Alcohol Abuse/ Dependence

Normal Comparison Schizophrenia Patients Subjects (N = 71) (N = 158)

AH subjects were over 45 years of age p < 0.001 (x* test). even more likely to act on suicidal Harourunian 1995; and Goldberg et described dementia praecox, it was ideas (Cohen et al. 1990). Hence, al. 1995). Cognitive deficits are assumed that schizophrenia was appropriate assessment and manage- thought to be an integral feature associated with a downward course ment of polysubstance-use disorders reflecting brain dysfunction in schiz- and eventual dementia, although in schizophrenia are critical. ophrenia. Against the background of Kraepelin defined dementia as a generalized cognitive impairment, "destruction of the psychic personal- some researchers have noted particu- ity" and a loss of volition over think- Cognitive Impairment lar deficits in abstraction and prob- ing, feeling, and behavior. Kraepelin lem solving (Bomstein et al. 1990; himself later questioned the use of Literature Review. A large body of Braff et al. 1991; Beatty et al. 1994) the term "dementia," as he observed existing research demonstrates that and selective impairment in memory that the disorder did not always schizophrenia is associated with and learning (Saykin et al. 1991). It is result in permanent deterioration. moderate generalized cognitive less clear what proportion of patients Past research addressing the preva- impairment (reviewed by Heaton with schizophrenia develop demen- lence of dementia in late-life schizo- and Drexler 1987; Davidson and tia. When Kraepelin (1919/1971) phrenia has yielded conflicting re- VOL 22, NO. 3,1996 421

suits. Most cross-sectional (Heaton et observed in older schizophrenia with AD (n = 42) and normal com- Downloaded from https://academic.oup.com/schizophreniabulletin/article/22/3/413/1829806 by guest on 24 September 2021 al. 1994; Hyde et al. 1994) and longi- patients may be at least partly sec- parison subjects (n = 38) on a com- tudinal (Bleuler 1968; Ciompi 1980) ondary to depression, medication prehensive neuropsychological test studies investigating cognitive side effects, alcohol and drug use, battery. There were no significant dif- decline in schizophrenia suggest that comorbid medical problems, sensory ferences among the schizophrenia schizophrenia is associated with a deficits, or prolonged institutional- groups in the level or pattern of neu- stable cognitive deficit rather than ization. Untreated depression in ropsychological functioning, but the dementia, although some studies schizophrenia patients may manifest schizophrenia patients differed sig- have found evidence indicating a as the so-called "pseudodementia" nificantly from both the normal com- progressive deterioration during the similar to that seen in other elderly parison subjects and the AD patients. initial course of the disease (Bilder et patients (Jeste et al. 1990). AntichoUn- The schizophrenia patients per- al. 1992). ergic medications, which are given to formed worse than the normal sub- Two recent studies focusing on treat the extrapyramidal side effects jects and demonstrated mild to mod- chronically institutionalized patients of neuroleptics, may have detrimen- erate impairment in all the cognitive from State hospitals in New York re- tal effects on the integrity of memory ability areas except for memory, ported somewhat different findings and cognitive functions (Spohn and which was within normal limits. regarding the risk of AD in schizo- Strauss 1989; Paulsen et al. 1995). Consistent with previous studies phrenia. Davidson and Haroutunian Both institutionalized and independ- (Heaton and Drexler 1987; Saykin et (1995) reported that 60 percent of ently living elderly patients often al. 1991; Goldberg and Weinberger schizophrenia patients who were receive multiple medications, and 1994), our patients with schizophre- chronically institutionalized were these medications may have syner- nia were mildly to moderately im- demented, with MMSE scores near gistic and sedative effects that may paired in learning, abstraction, motor zero. Despite the severity of their mimic dementia. Comorbid sub- skills, attention, verbal ability, psy- dementia, the pattern of deficits in stance abuse in schizophrenia chomotor speed, and sensory abili- impaired schizophrenia patients patients may predispose them to ties. Neuropsychological impairment could be distinguished from that dementia. Neurological and other in schizophrenia was unrelated to seen in AD patients. Neuropathologi- physical disorders, such as diabetes current age, age at onset of schizo- cal examinations of the subjects' mellitus and cardiovascular and cere- phrenia, or duration of illness. These brains did not reveal cellular changes brovascular disorders, may also findings provide further support for characteristic of AD. In contrast, Pro- result in brain damage and associ- the notion that the cognitive impair- hovnik et al. (1993) studied a similar ated dementia. Sensory deficits are ment associated with schizophrenia cohort of subjects and found that 28 discussed later. Finally, prolonged is essentially nonprogressive. Unlike percent of the chronically institution- institutionalization may contribute to people with AD, the schizophrenia alized patients with schizophrenia real or apparent cognitive deteriora- patients, including the comparably had AD-like neuropathology at tion. Any of these factors superim- aged patients with LOS, did not have autopsy. posed on schizophrenia may lead one rapid forgetting of newly learned to misattribute progressive cognitive information. In their review of more than 100 declines to chronic schizophrenia In a study comparing the clinical studies focusing on the effects of perse. aging in schizophrenia, Heaton and and neuropsychological characteris- Drexler (1987) concluded that the tics of LOS and EOS (Jeste et al. cognitive deficit associated with UCSD Studies. We previously re- 19956), we evaluated 25 patients with schizophrenia was not significantly ported on the influence of age and LOS (i.e., patients with schizophrenia related to aging. With the exception chronicity of schizophrenia on neu- onset after age 45), 39 patients with of a subset of patients, cognitive per- ropsychological deficits in patients EOS, and 35 healthy comparison sub- formance in most schizophrenia with schizophrenia (Heaton et al. jects. We found that the LOS patients were similar to the EOS patients but patients appears to be relatively sta- 1994). We compared the performance different from the normal subjects on ble and is not associated with pro- of three groups of schizophrenia out- most variables assessed, including gressive deterioration despite chronic patients (early-onset young [EOS-Y; illness or long-term treatment. It is the overall pattern of neuropsycho- n = 85], early-onset old [EOS-O; n = likely that the apparent dementia logical impairment, although the 35], and LOS [n = 22]) with patients 422 SCHIZOPHRENIA BULLETIN

degree of cognitive impairment was language impairment commonly schizophrenia patients and should Downloaded from https://academic.oup.com/schizophreniabulletin/article/22/3/413/1829806 by guest on 24 September 2021 slightly milder in the LOS than in the observed in schizophrenia. Using have important implications for ther- EOS patients. But at the time of as- multidimensional scaling and apeutic interactions. For example, sessment, the LOS patients were tak- Pathfinder analysis (Dearholt and when providing a patient with ing lower daily doses of neuroleptic Schvaneveldt 1990) on responses to instructions on taking medication, it medication than were the EOS sub- an animal fluency task, the semantic may be important to present the jects. Many previous studies have networks of 56 schizophrenia information repeatedly in more than reported some normalization of neu- patients and 28 normal subjects were one modality (e.g., oral and written ropsychological deficits with neu- compared. Consistent with previous instructions), to provide cues or roleptic treatment (reviewed in findings, the schizophrenia patients reminders to help the patient remem- Spohn and Strauss 1989). When neu- showed significantly less fluency ber, or to associate taking medication roleptic dosage was controlled for, than did healthy subjects. Detailed with some other part of the patient's however, the results of the neuropsy- semantic network analysis found that normal routine. Behavior perceived chological deficits still did not differ. the performance varied with the age as noncompliance or resistance to Another UCSD study examined at onset and the.subtype of schizo- treatment may actually reflect the the characteristics of the learning and phrenia. Patients with an earlier age patient's encoding and retrieval memory impairment seen in schizo- at onset of illness and those with problems. Thus, incorporating phrenia (Paulsen et al. 1995). Schizo- nonparanoid subtypes had more dis- research information into clinical phrenia patients (n = 175) performed organized semantic networks, sug- interactions may improve treatment worse than healthy comparison sub- gesting an association between some response. jects (n = 229) on all measures of of the cardinal symptoms of schizo- learning, free recall, and recognition phrenia (e.g., thought disorder) and memory. Greater impairment was impaired neuropsychological per- Sensory Deficits associated with earlier age at onset of formance. schizophrenia, more severe negative Literature Review. Houston and Royce (1954) proposed that sensory symptoms as assessed by the SANS, Specific Management Considera- and higher daily anticholinergic deficits, especially deafness, may pre- tions. It is important to consider dispose individuals to develop schiz- dosages. The pattern of the schizo- that performance on tests of cogni- phrenia patients' learning and mem- ophrenia and other paranoid psy- tive functioning may appear to be choses in late life. It was suggested ory performance was consistent with spuriously lower in patients who are a mild encoding deficit and a promi- that as a person began to have hear- severely delusional or hallucinating ing impairment, he or she might have nent retrieval deficit. Use of a dis- or markedly apathetic than in pa- criminant function analysis that dif- difficulty understanding speech and tients who are not actively psychotic. might tend to misinterpret what oth- ferentiated subjects with cortical If dementia is observed in an elderly dementia, subcortical dementia, and ers were saying. This perceptual psychotic patient, a comprehensive problem might lead to mispercep- normal learning and memory pat- medical workup is indicated to rule terns categorized 50 percent of the tions that others were talking about out untreated depression, medication the individual (ideas of reference), schizophrenia patients as having a side effects, substance or alcohol subcortical profile, 35 percent as hav- eventually progressing to delusions abuse, neurological or other physical of persecution. Several other investi- ing a normal profile, and 15 percent comorbidity, sensory impairment, or as having a cortical profile. This find- gators (e.g., Kay and Roth 1955,1961) institutionalization as possible con- have supported the association be- ing reflected the heterogeneity seen tributors to the cognitive impair- in the clinical presentation of schizo- tween "late-life paraphrenia" and ment. Treatment of the appropriate sensory deficits. phrenia. It also provided support for conditions may result in some im- In 1993, we reviewed 27 published the notion that schizophrenia may be provement in cognitive functioning. studies examining the possible asso- associated with primarily subcortical Research on the cognitive impair- ciation between sensory (visual or pathology. ment associated with schizophrenia hearing) impairment and late-life has consistently demonstrated A recently completed UCSD study psychosis with paranoid features deficits in learning. This deficit is (Paulsen et al., in press) sought to (FVager and Jeste 1993). Although the clinically relevant to working with investigate the mechanisms of the validity and generalizability of this VOL.22, NO. 3, 1996 423

literature are limited by methodolog- the normal subjects. This suggested mine whether the patient has any Downloaded from https://academic.oup.com/schizophreniabulletin/article/22/3/413/1829806 by guest on 24 September 2021 ical flaws such as vague diagnostic that older psychiatric patients were major sensory deficits. Objective test- criteria, inadequate assessment of at a disadvantage in getting appro- ing may compensate for the patient's hearing and vision, and lack of priate correction of their hearing and reduced awareness of any such def- appropriate comparison groups, the visual deficits. Our results question icits. Hearing and visual deficits are majority of these studies seem to the notion that sensory deficits pre- generally correctable, at least in part. indicate an association between hear- dispose older persons to developing Uncorrected sensory deficits may re- ing deficits and late-onset psychosis. LOS or other paranoid psychosis; sult in overestimation of symptoms The causality, however, was not instead, they suggest that suboptimal and deficits and may reduce the determined. (or correctability) of sensory deficits quality of life for the patients. Using a crossover design, Kreeger may be related to problems associ- et al. (1995), recently investigated the ated with severe psychopathology. impact of hearing deficits on mental It appears that older schizophrenia latrogenic Comorbidlty status ratings in geriatric psychiatric patients may be at a particular disad- patients. The investigators found that vantage in getting appropriate correc- Literature Review. Medications hearing-impaired patients displayed tion for their sensory deficits. Anec- used for the treatment of schizophre- less psychopathology and improved dotally, we have discussed the prob- nia may result in adverse effects such MMSE performance when they were lem of adequate treatment of our as akathisia, parkinsonism, neurolep- assessed while wearing a functional patients with ear, nose, and throat tic malignant , TD, other (compared with a nonfunctional) surgeons. These physicians report dif- tardive , and even sudden hearing aid. ficulty with assessing sensory func- death. Other iatrogenic effects may tioning in psychotic patients. For include glucose intolerance and car- UCSD Studies. We (Prager and example, doctors may have trouble diovascular disease. Jeste 1993) conducted a case-control determining if a patient's complaints TD. TD represents the most com- study of 87 subjects over age 45, of hearing noises represent tinnitus or mon persistent iatrogenic movement including 16 patients with LOS, 25 an auditory . In every- disorder in patients with schizophre- with EOS, 20 mood disorder patients, day practice, schizophrenia patients nia. The reported prevalence of TD and 26 healthy comparison subjects. may also experience other barriers to ranges widely due to methodological Using standardized audiometry and adequate assessment and treatment, variations as well as differences in visual acuity measures, raters who such as a lack of medical insurance study populations and criteria for were blind to psychiatric diagnosis and trouble communicating their TD. In their review and reanalysis of needs clearly to their physicians. assessed both corrected and uncor- data from 76 published studies, Yassa rected sensory deficits (i.e., sensory and Jeste (1992) found a reported TD deficits of the subjects were assessed Specific Management Considera- prevalence of 3 to 62 percent among with and without corrective mea- tions. Sensory impairments are neuroleptic-treated patients, with a sures such as hearing aids or eye- common in the elderly. Hearing mean of 24.2 percent. Some re- glasses, if any, that the subjects were impairment is the second most com- searchers (Kane et al. 1988) have using). Subjects also completed a self- mon medical problem in the geriatric pointed out that the reported preva- report questionnaire about hearing in population, with approximately 25 lence of TD may be artificially low- which they were asked about subjec- percent of the individuals between ered due to the masking of symp- tive problems with social conversa- the ages of 65 and 74 and 50 percent toms by neuroleptics. tion and other situations. There were of those over age 75 being so affected There has been some evidence that no significant differences among the (Mhoon 1990). In terms of visual aging (Kane et al. 1992), female gen- groups in terms of uncorrected (con- impairment, 75 percent of persons der (Yassa and Jeste 1992), substance stitutional) hearing or visual abilities, over age 60 have cataracts, with abuse (Dixon et al. 1992), brain dam- but all the psychiatric groups had about 15 percent experiencing a sig- age or dysfunction (Manschreck et al. significantly more problems with cor- nificant visual loss (Rich 1990). When 1990), and comorbid diabetes melli- rected social hearing and vision (i.e., assessing a patient's cognitive func- rus (Ganzini et al. 1991) may increase with any hearing aids or eyeglasses tioning and psychiatric symptoma- a person's risk of developing TD. that the subjects were using) than did tology, it is important to first deter- Other studies have reported data 424 SCHIZOPHRENIA BULLETIN

suggesting that African-Americans dozapine and risperidone (in lower tions and side effects. For example, Downloaded from https://academic.oup.com/schizophreniabulletin/article/22/3/413/1829806 by guest on 24 September 2021 (Glazer et al. 1994) and patients with doses) appear to have a lower risk for among the elderly it would be impor- mood disorders (Mukherjee et al. extrapyramidal side effects, probably tant to assess the risk for falls due to 1986; Casey and Keepers 1988) have a lower risk of TD (Kane et al. 1993), postural hypotension. an increased risk of developing TD. and possibly less cognitive impair- Kane et al. (1988) followed 850 young ment (Jeste et al., in press). On the schizophrenia patients (mean age = other hand, clozapine is associated Discussion 29 years) over 6 years. They found with other iarrogenic problems, in- that the incidence of TD increased cluding agranulocytosis, seizures, Research Implications. Clearly, bet- with the duration of neuroleptic and anticholinergic toxicity; risperi- ter controlled studies on medical treatment. Cumulative incidence of done is associated with postural comorbidity in schizophrenia are TD in this population was 5,10, and hypotension. needed. Traditionally, research on 15 percent after 1, 2, and 3 years, schizophrenia has excluded subjects UCSD Studies. We (Jeste et al. respectively, and increased to 26 per- with comorbid conditions. Because a 1995a) followed a group of patients cent by the end of the 6th year. majority of the patients with schizo- over age 45 (n = 266, mean age = 65 phrenia are affected by at least one Other side effects. DSM-IV years) who had a median duration of type of comorbid condition, this (American Psychiatric Association 21 days of lifetime neuroleptic expo- exclusion has compromised the gen- 1994a) includes a section on medica- sure at baseline. Twenty-five percent eralizability and ecological validity of tion-induced movement disorders. of the subjects were neuroleptic- research. Rather than continuing to All but one of the disorders listed are naive at baseline, while 45 percent view physical illnesses, substance secondary to neuroleptic use. These had fewer than 90 days of lifetime abuse, and sensory deficits as disorders may masquerade as other neuroleptic exposure. All the patients comorbid medical conditions. They "nuisance variables," these aspects were treated with relatively low may be upsetting to patients and should be studied in research proto- doses of neuroleptics, usually of may lead to noncompliance (Ameri- cols so that the interaction of schizo- haloperidol or thioridazine, and were can Psychiatric Association 1994b). phrenia and comorbid illnesses can followed with clinical and instru- be better understood, with the ulti- A number of preliminary reports mental assessments by "blind" raters mate goal being more effective treat- have suggested an association be- for up to 3 years. Cumulative inci- tween impaired glucose tolerance ment of the patients. dence of TD was 26, 52, and 60 per- and schizophrenia (Brambilla et al. cent after 1, 2, and 3 years, respec- Another research goal should be to 1976; Mukherjee et al. 1989b), espe- tively. The incidence of TD was com- study the interactions of more than cially in patients with TD. It is still parable in schizophrenia and non- one type of comorbid condition on not clear whether schizophrenia and schizophrenia subjects. Risk factors the clinical course and treatment of impaired glucose tolerance or famil- schizophrenia. For example, alcohol ial Type II diabetes mellitus are re- for the development of TD included cumulative amounts of neuroleptics abuse is a risk factor for certain phys- lated via some genetic association or ical illnesses, for cognitive impair- whether impaired glucose tolerance (especially the high-potency ones) used, history of alcohol abuse or ment, and for TD, and all these are represents a side effect of neuroleptic likely to complicate clinical manage- use (McKee et al. 1986). dependence, and presence of a subtle movement disorder at baseline. ment. Further research on medical Older patients appear to be at a conditions that seem to covary higher risk for the development of specifically with schizophrenia in many side effects. Older age is associ- Specific Management Considera- either their presence or absence (e.g., ated with alterations in pharmacoki- tions. To minimize the risk for de- polydipsia and rheumatoid arthritis, netic and pharmacodynamic re- velopment of TD and other iarro- respectively) may help shed light on sponses, with an increased sensitivity genic complications in schizophrenia at least some aspects of the patho- to medication. Concurrent medical patients, high doses of neuroleptics physiology of schizophrenia. illnesses and may fur- should be avoided. Neuroleptic dose ther alter drug metabolism and, con- should be maintained at the lowest sequently, the side effect profile. effective level. It is important to mon- Clinical Implications. To optimize Atypical antipsychotics such as itor for possible medication interac- treatment of patients with schizo- VOL.22, NO. 3, 1996 425

phrenia, it is important to recognize medication regimens is associated DSM-UI-R: Diagnostic and Statistical Downloaded from https://academic.oup.com/schizophreniabulletin/article/22/3/413/1829806 by guest on 24 September 2021 comorbid physical conditions. Dis- with poor outcome, including in- Manual of Mental Disorders. 3rd ed., semination of findings to health-care creased risk of relapse, rehospitaliza- revised. Washington, DC: The Associ- professionals can raise awareness tion, and suicide (Weiden et al. 1995). ation, 1987. and help compensate for patients' Cognitive deficits and iatrogenic side American Psychiatric Association. deficits in reporting comorbid condi- effects play a role in decreasing com- DSM-IV: Diagnostic and Statistical tions. Information about risk factors pliance. Patients may not be able to Manual of Mental Disorders. 4th ed. can help direct assessment. Use of manage complicated medication regi- Washington, DC: The Association, more systematic evaluations and use mens, or they may simply forget to 1994a. of multiple sources of information take their . Many iatrogenic side effects are distressing to the American Psychiatric Association. (e.g., caregivers, laboratory tests) Medication-induced movement dis- would improve assessment of comor- patients and increase their resistance to taking medication. Increasing clin- orders. In: Diagnostic and Statistical bid conditions. Finally, knowledge of Manual of Mental Disorders: DSM-IV. comorbidity can aid in the clinical ician awareness of comorbid condi- tions that may have an impact on 4th ed. Washington, DC: The Associa- management of patients. For exam- tion, 1994b. pp. 678-680. ple, there is considerable evidence patient compliance can lead to closer that schizophrenia patients are monitoring of patient characteristics Andreasen, N.C., and Olsen, S. 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Past substance abuse and clinical Department of Veterans Affairs. Research Center, Veterans Affairs Downloaded from https://academic.oup.com/schizophreniabulletin/article/22/3/413/1829806 by guest on 24 September 2021 course of schizophrenia. American Medical Center, San Diego, CA. Julie Journal of Psychiatry, 149:552-553,1992. Akiko Gladsjo, Ph.D., and Laurie A. Lindamer, Ph.D., are Postdoctoral The Authors Fellows; Jonathan P. Lacro, Pharm.D., Acknowledgments is Assistant Clinical Professor of Psy- This work was supported in part by Dilip V. Jeste, M.D., is Professor of chiatry, University of California, San USPHS grants MH-49671, MH-43693, Psychiatry and Neurosciences, Uni- Diego, and Clinical and Research and MH-49671 from the National versity of California, San Diego, and Pharmacist, San Diego Veterans Af- Institute of Mental Health and by the Director, Geriatric Psychiatry Clinical fairs Medical Center, San Diego, CA.

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