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Evidence of Exacerbated Cognitive Deficits in Schizophrenia Patients With Comorbid Diabetes
Evidence of Exacerbated Cognitive Deficits in Schizophrenia Patients With Comorbid Diabetes DWIGHT DICKINSON, PH.D., JAMES M. GOLD, PH.D. FAITH B. DICKERSON, PH.D., M.P.H., DEBORAH MEDOFF, PH.D. LISA B. DIXON, M.D., M.P.H.
Type 2 diabetes is associated with both schizophrenia and cognitive performance. The authors compared cognitive performance in three groups: patients with schizophrenia and diabetes, patients with diabetes only, and patients with schizophrenia only. Results indicated that the schizophrenia/diabetes group was impaired cognitively relative to both other groups, especially in the domains of processing speed and visual/spatial ability. Also, these impairments were associated with diabetes severity markers. Because either illness creates cognitive vulnerability, comorbid occurrence is even more likely to undermine essential functional brain systems, leading to an increased rate and magnitude of cognitive decline with associated declines in community functioning. (Psychosomatics 2008; 49:123–131)
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eferences to the dire public health implications of obesity and diabetes mellitus in the United States have become commonplace. Yet, even against this backdrop, the elevated rates of metabolic dysregulation and disease among individuals with schizophrenia are alarming. Data from the Schizophrenia Patient Outcomes Research Team showed lifetime diagnoses of diabetes in 15% of schizophrenia patients surveyed in 1997 and current diabetes in 11%, even before the widespread use of second-generation antipsychotic medications.1 More recently, baseline data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) showed current diabetes in 13% of schizophrenia participants,2 50% greater than estimates of the general population rate.3 Remarkably, these figures probably understate the true dimensions of the problem. First, more than 40% of schizophrenia patients meet criteria for the metabolic syndrome (e.g., adiposity, glucose and lipid abnormalities, hypertension), which strongly predicts diabetes and cardiovascular disease.4–7 Second, evidence is accumulating that widely used second-generation antipsychotic medications (SGAs) worsen metabolic dysregulation.8–11 Third, the onset of diabetes occurs at sigPsychosomatics 49:2, March-April 2008
nificantly younger ages in schizophrenia than in comparison groups, with the sharpest disparity among individuals less than 49 years old.9,10,12 Thus, the already vulnerable and impaired schizophrenia population is at substantial risk in early middle age for another debilitating chronic illness. The well-known somatic consequences of diabetes (e.g., cardiovascular and kidney disease, stroke, blindness, amputation) are grave. However, schizophrenia patients may face additional risks of poor diabetes and overall health outcomes. Cognitive impairment in schizophrenia is well established and widely seen as a critical determinant of disability and reduced role-functioning.13 Less widely studied is the fact that cognition is also impaired in diabetes. Most studies show significant cognitive impairment in diabetes patients relative to non-diabetic control groups Received August 22, 2006; revised November 14, 2006; accepted November 28, 2006. From VISN 5 Mental Illness Research, Education, and Clinical Center, Baltimore, MD; the Dept. of Psychiatry, Univ. of Maryland, Baltimore, MD, and the Sheppard Pratt Health System, Baltimore, MD. Send correspondence and reprint requests to Dwight Dickinson, Ph.D., VISN 5 MIRECC, Suite 6A (BT/MIRECC), 10 North Greene St., Baltimore, MD 21201. e-mail: [email protected] 䉷 2008 The Academy of Psychosomatic Medicine
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Cognition in Schizophrenia and Diabetes across domains of verbal memory, processing speed, and problem-solving.14 These deficits are evident cross-sectionally.15,16 Moreover, longitudinal studies have documented accelerated cognitive decline in diabetes17–19 and increased long-term risk of vascular and Alzheimer’s dementias.20,21 In addition to diabetes diagnosis and duration, prediabetes glucose metabolism abnormalities and the metabolic syndrome also have been found to be associated with cognitive impairment.22–24 Although cognitive impairment in diabetes has been noted in diverse cognitive-performance domains, deficits on measures of information processing speed and efficiency are among the most consistent findings,17–19,22,25 to the point that “it is plausible to consider this as the ‘fundamental’ diabetes-associated cognitive deficit.”26 Importantly, this impairment is shown early in the course of illness. Speed decrements are evident in middle-aged adults with type 1 and type 2 diabetes15,16,27,28 and even in children with a relatively short duration of type 1 diabetes.29 Thus, diabetes and prediabetes symptoms are associated with significant risk of cognitive impairment. The earliest and most reliable cognitive impact appears to involve tasks requiring speeded mental processing. The cognitive impact of diabetes converges with known cognitive performance deficits in schizophrenia. Although schizophrenia deficits are broadly generalized, the most prominent impairment is in the same processing speed domain. Our recent metaanalysis showed that the schizophrenia deficit on the digit-symbol coding task—the prototype processing speed measure—was not only substantial (effect size [ES] ⬇ 1.5), it was significantly larger than deficits on measures from more often studied domains of verbal memory, executive functioning, and working memory.30,31 Furthermore, this speed deficit is also related to schizophrenia risk,32–34 premorbid cognitive status,35 and illness-related disability and outcome.36–40 Thus, it appears that diabetes may exert its largest cognitive effect precisely in the cognitive domain where schizophrenia patients have the least margin for additional impairment—in the realm of information processing speed and efficiency. Current analyses were conducted to test the hypothesis that exacerbated cognitive deficits, particularly processing speed deficits, are present in schizophrenia patients with diabetes relative to patients with either schizophrenia-only or diabetes-only. METHOD Background Work Data for current analyses were drawn from two bodies of work from our group. The first arises out of an NIMH124
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funded study of diabetes in schizophrenia (Dixon Diabetes Study; author LD is principal investigator). A total of 300 participants diagnosed with type 2 diabetes have been recruited into the study, including 101 persons with schizophrenia, 100 persons with severe mood disorder, and 99 persons without mental illness. Participants met the following inclusion criteria: age of 18 to 65 years, current medical record diagnosis of type 2 diabetes, English speaker, and ability to provide informed consent. Also, participants with severe mental illnesses had to have schizophrenia or schizoaffective disorder or a major mood disorder (bipolar disorder or major recurrent depression) recorded in their medical chart. This study describes and compares these three cohorts on a variety of diabetes-related measures. An extensive database on diabetes health behaviors, diabetes outcomes, physiologic measures, quality of diabetes care indicators, general health status, health services utilization, and medication data were assembled at baseline for the entire study cohort.41,42 All subjects in the Dixon Diabetes Study were administered a neuropsychological screening measure, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS43). The RBANS is a 25-minute, standardized cognitive screening instrument that assesses several performance domains and offers an efficient approach to screening for cognitive impairment. The RBANS adapts and consolidates a selection of well-known cognitive measures into a short battery. Subtests were selected and conormed to yield a total scaled score and five comparably scaled index scores: immediate memory, visual/spatial performance, attention, language, and delayed memory. For example, list-learning and story-memory tasks combine in an immediate-memory index. The attention index derives from adaptations of the information processing speed test, digit-symbol coding, and the working-memory task, digit span. The battery has good psychometric properties and alternative forms to allow repeated assessment. The second body of work involves a database of 575 schizophrenia RBANS evaluations (RBANS norms database). Two of the current authors (JMG, FBD) oversaw the RBANS assessments and development of this database. The database comprised two patient groups. Data from 305 patients were collected from four outpatient clinics and four inpatient units by the Maryland Psychiatric Research Center for a variety of research protocols. Data for 270 patients were collected at programs affiliated with the Sheppard Pratt Health System and Chestnut Lodge Hospital, also for different research protocols. All 575 patients met DSM–IV criteria for schizophrenia or schizoaffective Psychosomatics 49:2, March-April 2008
Dickinson et al. disorder and did not meet criteria for alcohol/drug dependence or mental retardation. The RBANS data have been used to map the psychometric properties of the instrument in this population. We have established that the RBANS is sensitive to the types and severity of cognitive impairment in schizophrenia and correlated with comprehensive cognitive batteries,44,45 stable across repeated assessments,44,46 and predictive of employment outcomes.44,47 Importantly for current purposes, the RBANS schizophrenia database has also been used to derive and publish schizophrenia normative data.48 Subjects RBANS and demographic data for the current study were drawn from three groups of subjects. The first group comprised the sample of patients with both schizophrenia and diabetes followed in the Dixon Diabetes Study. The second group was the “diabetes-only” comparison group from the same study who were free of any psychiatric diagnosis. From these two groups, data screening identified three schizophrenia/diabetes subjects and four diabetesonly subjects as diabetes duration outliers, each having had diabetes for more than 30 years. We conducted all analyses excluding these cases to avoid skewing results with influential observations. The third group consisted of the “schizophrenia-only” subjects included in the RBANS norms database. We should note that these patients were not screened for diabetes. Thus, although we expect that the preponderance of the 575 subjects were free of this diagnosis, the statistics cited earlier suggest that as many as 10% to 15% might have been affected. The validity of comparisons among these groups is enhanced by the fact that all data for the Dixon Diabetes and RBANS norms database were collected from clinics and inpatient units in the Baltimore metropolitan area, under the supervision of the same psychologists (FBD and JMG). Analyses There were three groups of analyses.1 The Dixon Diabetes Study did not include a non-diabetic schizophrenia sample that could have been used to test for an added cognitive burden of diabetes in schizophrenia. Therefore, the first group of analyses used the RBANS norms database to provide a preliminary test of this hypothesis. We conducted single-sample t-tests contrasting RBANS performance by the schizophrenia/diabetes sample with “population estimates” from the RBANS norms database. In connection with these analyses, we conducted separate tests of the Psychosomatics 49:2, March-April 2008
digit-symbol coding and digit-span subtests, which comprise the RBANS attention index, in order to distinguish processing speed and working memory domains.2 The second set of analyses contrasted RBANS performance in the schizophrenia/diabetes group with performance among the diabetes-only sample (both from the Dixon study) using independent-samples t-tests. Again, these analyses included separate tests of the digit-symbol coding and digitspan subtests.3 In our final set of analyses, partial-correlation analyses were used to examine the relationship of cognition to indexes of diabetes severity in the schizophrenia/diabetes patients and in the diabetes-only patients. Separately in the two groups, partial correlations examined the associations of duration of diabetes, age at diabetes onset, and glycosylated hemoglobin with RBANS total score and all index and subtest scores. Because of group differences, correlation analyses controlled for age and smoker status. RESULTS Sample Characteristics Demographic information for all groups and clinical data for the two diabetes groups are presented in Table 1. The diabetes-only group was older than the schizophrenia/ diabetes group by approximately 5 years, on average. By design, these groups were matched on education, gender, and race. Regarding diabetes-related clinical variables, the schizophrenia/diabetes patients were significantly younger than the diabetes-only patients on age at diabetes onset and were significantly more likely to be smokers. The samples did not differ significantly on body mass index or duration of diabetes. Both groups reported high rates of hypertension (⬇80%), which did not differ between groups.42 Alcohol use was very low and similar for the groups.42 Surprisingly, the glycosylated hemoglobin was lower in the schizophrenia/diabetes sample than in the diabetes-only comparison group. Hypotheses regarding this unexpected finding are considered in detail in the earlier article describing the main Dixon study findings,42 however, observed glycosylated hemoglobin levels were significantly above recommended levels for both groups. Relative to the schizophrenia/diabetes group, the normative study sample was younger, better educated, and more likely to be white and male. Means, standard deviations, mean comparisons, and effect sizes are presented in Table 2. The expectation in the healthy population is for RBANS scaled scores of 100 http://psy.psychiatryonline.org
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Cognition in Schizophrenia and Diabetes (standard deviation [SD]: 15) for the RBANS Total and all index scores.43 As indicated by the schizophrenia norms,48 people with the disorder show significant impairment on this battery, achieving RBANS Total scores of 70.5 (SD: 14.8) on average, two SDs below expectation. Poorest performance among patients is evident on memory and attention measures, with lesser impairment on visual/spatial tasks and relatively preserved performance on measures of language abilities. Data from the Dixon Diabetes Study suggest lesser, but nevertheless substantial, RBANS impairments among diabetes patients without psychiatric diagnoses. The deficits observed in this sample likely relate in part to the education matching of the diabetes-only patients to the schizophrenia/diabetes patients and may not generalize to all groups of diabetes patients. However, the current diabetes-only sample showed impairments approximating one SD across RBANS index scores, with relatively preserved language ability and relatively compromised visual/spatial ability.
RBANS Total score was significantly reduced in the schizophrenia/diabetes sample relative to schizophreniaonly normative group values,48 but the group effects were uneven across cognitive domains. Effects for processing speed (coding), visual/spatial performance, and memory were greater than the overall cognitive effect (as indicated by the RBANS Total score), and there were no group effects on language functioning or simple working memory (digit-span). The ES for the RBANS Total score was d ⳱ 0.26, and ESs were higher for the significant group differences on RBANS index and subtest scores, ranging up to d ⳱ 0.50 for visual/spatial performance. These ESs are small-to-medium, according to Cohen’s criteria (i.e., 0.20 for a small effect, 0.50 for a medium effect49). It is important to recognize, however, that in the schizophrenia-only sample, no effort was made to screen out subjects with diabetes, which may have reduced group differences and ESs in the foregoing comparisons. Cognitive Associations With Diabetes Severity Markers
Mean Comparisons In general, schizophrenia patients with diabetes performed significantly more poorly on RBANS variables than either diabetes-only or schizophrenia-only groups. The contrast between the schizophrenia/diabetes group and the diabetes-only group was relatively clear. Effect sizes approached one SD for all variables, with two exceptions. Between-group differences were small and nonsignificant for the visuospatial/constructional index and the digit-span task. However, contrasts between the schizophrenia/diabetes group and the schizophrenia-only group yielded more mixed results. Consistent with our main hypothesis, the
TABLE 1.
Partial-correlation analyses, focused on markers of diabetes severity, examined whether the association of diabetes course with cognition is different in a schizophrenia and diabetes sample than in a diabetes-only sample. Within the schizophrenia/diabetes group, RBANS Total score was modestly but significantly associated with self-reported duration of diabetes and age at onset of diabetes. Among the index scores, visual/spatial performance and attention were associated with diabetes severity markers, but the largest individual test effects were for coding and figure-copying tasks. Of note, these significant associations were not present in the nonpsychiatric, diabetes-
Demographic and Clinical Information
Sample size Age, years Education ⱕhigh school Sex, male Race, white Diabetes duration, years Age at diabetes diagnosis, years Glycosylated hemoglobin, % Body Mass Index Current smoker
Diabetes-Only (Diabetes Study)
Schizophrenia and Diabetes (Diabetes Study)
Schizophrenia-Only (Norms Database)
95 53 (9.0)*** 66% 52% 31% 6.6 (5.5) 46.1 (9.6)*** 8.6 (2.4)* 34.6 (6.5) 35%***
97 48.1 (8.9) 66% 58% 34% 7.8 (6.8) 39.7 (10.1) 7.8 (2.3) 32.8 (6.8) 60%
575 40.5 (9.7)‡ 57%‡ 68%‡ 69%‡ — — — — —
Values are mean (standard deviation) unless otherwise indicated. *p⬍0.05; ***p⬍0.001 for independent t-test comparing diabetes-only group with schizophrenia-and-diabetes group. ‡p⬍0.001 for single-sample t-test or chi-square test comparing schizophrenia norm values with schizophrenia-and-diabetes group values.
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Effect Size
0.26 0.27 0.50 0.08 0.27 ⳮ0.08 ⳮ0.03 0.39
p
0.01 0.007 ⬍0.001 0.47 0.011 0.41 0.734 ⬍0.001
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Effect size: Cohen’s d.
t [96]
ⳮ2.64 ⳮ2.74 ⳮ5.32 ⳮ0.72 ⳮ2.6 0.83 0.34 ⳮ3.67 0.96 0.95 0.25 0.80 0.85 0.77 0.20 0.91
p
⬍0.001 ⬍0.001 0.08 ⬍0.001 ⬍0.001 ⬍0.001 0.178 ⬍0.001
t [189]
66.7 (14.1) 67.1 (17.0) 70.0 (15.9) 83.4 (14.9) 68.6 (20.1) 74.7 (17.4) 9.6 (2.5) 28.3 (11.7)
ⳮ6.62 ⳮ6.63 ⳮ1.76 ⳮ5.5 ⳮ5.86 ⳮ5.04 ⳮ1.35 ⳮ6.29
Effect Size
DISCUSSION
70.5 (14.8) 71.8 (18.4) 78.6 (18.3) 84.5 (14.3) 73.9 (19.0) 73.2 (16.9) 9.5 (3.0) 32.7 (10.8)
SchizophreniaWith-Diabetes (Diabetes Study) Schizophrenia-Only (Norms Database) Diabetes-Only (Diabetes Study)
Mean RBANS Index Scaled Scores (SD)
Independent-Samples t-Tests of Schizophrenia-With-Diabetes group vs. Diabetes-Only Group
only group. Although not as clear as in the case of diabetes duration and age at onset, associations of cognitive performance with glycosylated hemoglobin, a marker of recent glycemic control, also were present in the schizophrenia/ diabetes group, but absent in the diabetes-only group.
80.4 (14.4) 83.8 (18.0) 74.1 (16.3) 94.4 (12.4) 84.7 (17.9) 87.9 (16.9) 10.1 (2.6) 39 (11.8) Total Score Immediate Memory Visual/Spatial Language Delayed Memory Attention Digit Span Coding
TABLE 2.
Means and Standard Deviations (SD) for Schizophrenia, Diabetes, Schizophrenia-With-Diabetes Groups and Mean Comparisons
One-Sample t-Tests of SchizophreniaWith-Diabetes Group vs. Schizophrenia Norms
Dickinson et al.
The present analyses were undertaken as an initial test of the hypothesis that diabetes exacerbates the already substantial cognitive impairment associated with schizophrenia. Two lines of analysis supported this hypothesis: First, RBANS performance was significantly impaired in schizophrenia patients with diabetes relative to a schizophrenia normative group and a diabetes-only comparison sample. Second, within the schizophrenia/diabetes sample, cognitive performance was negatively associated with certain markers of diabetes severity. This set of relationships was not evident among nonpsychiatric, diabetes-only patients, however. Our sample of diabetes patients with no current psychiatric conditions showed impairments across cognitive domain indices on the RBANS relative to population normative values, with the exception that language performance was preserved. However, the schizophrenia/diabetes patients showed substantial additional cognitive impairment relative to the diabetes-only group, approaching one SD across most cognitive domains assessed by the RBANS. Visual/spatial processing, which showed the greatest impairment among the diabetes-only patients, was the only index score that was not significantly different between groups. Analysis focused on the subtasks of the attention index (digit-span and coding), indicated that the group difference on this index was driven entirely by poorer processing speed performance (coding) among the schizophrenia/diabetes patients. This pattern of results was expected in light of the broad and well-documented cognitive deficits in schizophrenia30,50 and the lesser and more mixed findings in diabetes.14 Of greater importance, the comparison of RBANS performance by the schizophrenia/diabetes sample to the schizophrenia-only group also revealed significant incremental deficits. The RBANS is sensitive to the particular cognitive deficits observed in schizophrenia. As shown in the normative study,48 the typical schizophrenia impairment on this battery is two SDs below the expectation for the healthy population, and is one SD below schizophrenia performance on familiar measures of IQ (e.g., the WAIS51) and premorbid/crystallized verbal ability (e.g., the Wide http://psy.psychiatryonline.org
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Cognition in Schizophrenia and Diabetes Range Achievement Test, reading48). Significant diabetesrelated impairments on the RBANS must be considered against this backdrop. In the analyses here, modest differences were found between the schizophrenia and schizophrenia/diabetes group for the RBANS Total score. However, the pattern of exacerbated impairment was uneven, with more marked impairment in visual/spatial performance, processing speed, and memory. In the latter two domains, the findings signaled an additional diabetesassociated increment over impairments that are prominent and well-established in schizophrenia. By contrast, visual/ spatial performance in schizophrenia is preserved relative to these domains in schizophrenia-only patients, as seen in the RBANS normative data.48 We speculate that visual/spatial performance may be a cognitive domain in which the combination of schizophrenia and diabetes yields an especially harmful synergy. Two subtests comprise the visuospatial/constructional index of the RBANS: The first is a line-orientation task, based purely on visual/spatial analysis. The second is a complex figure-copying task, which taps constructional ability in addition to visual/spatial analysis. Performance on these very different tasks was equivalently impaired in the schizophrenia/diabetes group relative to the schizophrenia normative group (t ⳱ –6.33 and t ⳱ –4.65, respectively (df: 96), both p ⬍0.001). This finding counters
TABLE 3.
the argument that the visual/spatial performance impairment is due to peripheral motor functioning more than to visual/spatial abilities. Peripheral motor impairment might contribute to figure-copying deficits, but not to line-orientation performance, which requires only oral, and not motor responding. It is interesting to note that poor performance on both the RBANS Visuospatial/Constructional and Attention indexes has been shown in the early stages of subcortical dementias (e.g., Huntington’s disease) and distinguishes these conditions from the cortical dementias (e.g., Alzheimer’s disease52). Our analyses suggest that, among schizophrenia patients, diabetes may shift the RBANS performance profile in a fashion suggesting greater subcortical dysfunction than is seen in non-diabetic schizophrenia patients. Although the visual/spatial processing findings were unexpected, the literature provides ample reason to expect exaggerated processing speed deficits in schizophrenia patients also afflicted with diabetes. Processing speed impairment has emerged as the most prominent cognitive deficit in schizophrenia.30 It is likewise the most reliably impaired cognitive dimension in diabetes.17–19,22,25 The neurobiological underpinnings of processing speed impairment are uncertain. In schizophrenia, slowed processing has been associated with significantly reduced gray(but not white-) matter volumes in the bilateral prefrontal
Correlations of Diabetes-Severity Markers With Cognitive Performance by Group Schizophrenia-With-Diabetes Group Diabetes Duration
List Learning Story Memory Immediate Memory Index Figure Copy Line Orientation Visuospatial/Constructional Index Picture Naming Semantic Fluency Language Index Digit Span Coding Attentional Index List Recall List Recognition Story Recall Figure Recall Delayed Memory Index Total Scaled Score
Age at Diabetes Onset
Diabetes-Only Group
Glycosylated Hemoglobin
Diabetes Duration
Age at Diabetes Onset
Glycosylated Hemoglobin
ⳮ0.13 ⳮ0.20 ⳮ0.17 ⳮ0.31*** ⳮ0.21* ⳮ0.22*
0.15 0.22* 0.20 0.33*** 0.23* 0.21*
ⳮ0.21* ⳮ0.05 ⳮ0.12 ⳮ0.24* ⳮ0.19 ⳮ0.20
0.00 0.10 0.03 ⳮ0.13 0.06 ⳮ0.01
0.00 ⳮ0.10 ⳮ0.03 0.12 ⳮ0.07 0.00
ⳮ0.02 ⳮ0.13 ⳮ0.09 ⳮ0.18 ⳮ0.13 ⳮ0.12
ⳮ0.12 ⳮ0.12 ⳮ0.16 ⳮ0.11 ⳮ0.33*** ⳮ0.22* 0.04 ⳮ0.08 ⳮ0.06 ⳮ0.24* ⳮ0.09 ⳮ0.22*
0.15 0.13 0.19 0.07 0.35*** 0.20 ⳮ0.05 0.06 0.09 0.22* 0.06 0.21*
ⳮ0.17 ⳮ0.02 ⳮ0.07 ⳮ0.09 ⳮ0.22* ⳮ0.12 0.02 ⳮ0.04 0.01 ⳮ0.13 ⳮ0.04 ⳮ0.14
ⳮ0.02 ⳮ0.06 ⳮ0.08 0.11 ⳮ0.06 0.02 0.06 0.10 0.01 0.05 0.02 0.01
0.01 0.04 0.06 ⳮ0.11 0.06 ⳮ0.02 ⳮ0.06 ⳮ0.09 ⳮ0.01 ⳮ0.04 ⳮ0.02 ⳮ0.02
ⳮ0.06 ⳮ0.15 ⳮ0.15 ⳮ0.04 ⳮ0.13 ⳮ0.12 ⳮ0.12 ⳮ0.06 0.03 0.04 ⳮ0.02 ⳮ0.12
*p⬍0.05; ***p⬍0.001.
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Dickinson et al. cortex, whole temporal lobe, and superior temporal gyrus in schizophrenia patients relative to control subjects.53 The effects of diabetes are likely to be more systemic. Type 2 diabetes is characterized by impaired insulin secretion and changes in the sensitivity of insulin receptors, leading to a progressive loss of glycemic control.11 Among other complications are impairments in nerve-signaling involving the limbs (peripheral neuropathy) and viscera (autonomic neuropathy). Corresponding effects in the CNS, sometimes termed “central neuropathy,” may result from diffuse cerebral microvascular abnormalities, white-matter damage, and axonal injury, which undermine the rapid neural transmission and integration on which processing speed and other cognitive tasks depend.18,26,27 Analyses of the associations of diabetes course markers (i.e., diabetes duration, age at onset, and glycosylated hemoglobin) offered some support for a central neuropathy hypothesis. Within the schizophrenia/diabetes sample, these markers were significantly associated primarily with the same domains of cognitive performance that distinguished this sample from the schizophrenia-only normative group. That is, among those with both diabetes and schizophrenia, longer duration of diabetes, earlier age at onset, and worse glycemic control were associated with worse cognitive performance. It is somewhat surprising that these relationships were entirely absent in the diabetes-only comparison sample. It may be that the association of diabetes course markers with cognitive performance typically is evident only in later stages of diabetes, but that the markers signal earlier and more robustly in an already cognitively-impaired group, such as the schizophrenia sample studied here. An important limitation of the current work is that critical comparisons were made between a schizophrenia/ diabetes group ascertained in the context of an NIMH diabetes study and a schizophrenia-only group assembled to examine the psychometric properties of the RBANS. These samples were not matched on variables of age, education, race, or gender. A number of considerations allay this concern to a degree. As noted, all patient groups were recruited from the same psychiatric settings in the Baltimore metropolitan area during approximately the same time period and assessed under the direction of the same investigators. Moreover, the largest mismatch between the schizophrenia/ diabetes group and the schizophrenia-only group was on age, but RBANS scoring incorporates an age-correction for total and index scores, and Wilk and colleagues found limited age effects on RBANS performance in schizophrenia.48 Another point is that, in the schizophrenia-only normative group, no effort was made to screen out subjects Psychosomatics 49:2, March-April 2008
with diabetes. Thus, the 575-person sample that was analyzed to derive normative values likely included at least 10%–15% schizophrenia patients with diabetes, reducing group differences and effect sizes in the foregoing comparisons. Notwithstanding these considerations, the mismatch on demographic variables means that these findings must be considered preliminary. Further investigations are planned to determine the extent to which the findings hold up in more precisely-designed comparisons. Rates of diabetes pose problems of national scope. These problems are magnified in schizophrenia by higher diabetes and prediabetes prevalence rates, iatrogenic effects of first-line antipsychotic treatments, and early onset of illness. Compounding these problems, the cognitive effects of diabetes are likely to have a disproportionate impact in schizophrenia patients. Because either illness alone creates cognitive vulnerability, the two illnesses together are even more likely to undermine essential functional brain systems, leading to an increased rate and magnitude of cognitive decline. These converging cognitive deficits have adverse practical implications. Medical management of schizophrenia and diabetes each requires a lifetime commitment on the part of patients to treatment adherence and behavioral self-regulation. The broad cognitive impairment associated with schizophrenia, exacerbated by diabetes-related cognitive deficits, is likely to limit patients’ ability to maintain this level of engagement and discipline. Such patient vulnerabilities are unlikely to be offset by health care as currently delivered to these patients. Although there is evidence that many providers are aware of heightened diabetes risk in schizophrenia,54 schizophrenia patients receive fewer recommended diabetes services and treatments than comparison groups, are less educated about their illness, show elevated markers of diabetes severity, have poorer physical health and functional outcomes, and experience resulting reductions in quality of life.1,41,42,55–58 At the same time, however, diabetes has proven more tractable from a healthcare standpoint than schizophrenia. Diabetes risk and severity are modifiable through education, lifestyle changes, and treatment. The analyses presented in this article suggest that, in schizophrenia, diabetes prevention and treatment might prove especially beneficial, yielding better cognitive outcomes, along with improved general health. These issues merit future investigation. This work was supported by MH 58717 (LD), and by a Research Career Development Award, Rehabilitation Research and Development Service, Department of Veterans Affairs (DD) http://psy.psychiatryonline.org
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19. Yaffe K, Blackwell Scientific Team, Kanaya AM, et al: Diabetes, impaired fasting glucose, and development of cognitive impairment in older women. Neurology 2004; 63:658–663 20. Arvanitakis Z, Wilson RS, Bienias JL, et al: Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Arch Neurol 2004; 61:661–666 21. Ott A, Stolk RP, van Harskamp F, Pols HA, et al: Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology 1999; 53:1937–1942 22. Abbatecola AM, Paolisso G, Lamponi M, et al: Insulin resistance and executive dysfunction in older persons. J Am Geriatr Soc 2004; 52:1713–1718 23. Vanhanen M, Koivisto K, Kuusisto J, et al: Cognitive function in an elderly population with persistent impaired glucose tolerance. Diabetes Care 1998; 21:398–402 24. Yaffe K, Kanaya A, Lindquist K, et al: The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA 2004; 292:2237–2242 25. Ryan CM, Williams TM, Orchard TJ, et al: Psychomotor slowing is associated with distal symmetrical polyneuropathy in adults with diabetes mellitus. Diabetes 1992; 41:107–113 26. Ryan CM: Diabetes, aging, and cognitive decline. Neurobiol Aging 2005; 26(suppl 1):21–25 27. Knopman D, Boland LL, Mosley T, et al: Cardiovascular risk factors and cognitive decline in middle-aged adults. Neurology 2001; 56:42–48 28. Ryan CM, Geckle MO, Orchard TJ: Cognitive efficiency declines over time in adults with type 1 diabetes: effects of micro- and macrovascular complications. Diabetologia 2003; 46:940–948 29. Hershey T, Bhargava N, Sadler M, et al: Conventional versus intensive diabetes therapy in children with type 1 diabetes: effects on memory and motor speed. Diabetes Care 1999; 22:1318–1324 30. Dickinson D, Ramsey ME, Gold JM: Overlooking the obvious: a meta-analytic comparison of digit symbol coding tasks and other cognitive measures in schizophrenia. Arch Gen Psychiatry 2007; 64:532–542 31. Henry JD, Crawford JR: A meta-analytic review of verbal fluency deficits in schizophrenia relative to other neurocognitive deficits. Cogn Neuropsychiatry 2005; 10:1–33 32. Byrne M, Clafferty BA, Cosway R, et al: Neuropsychology, genetic liability, and psychotic symptoms in those at high risk for schizophrenia. J Abnorm Psychol 2003; 112:38–48 33. Hoff AL, Svetina C, Maurizio AM, et al: Familial cognitive deficits in schizophrenia. Am J Med Genet B Neuropsychiatr Genet 2005; 133:43–49 34. Laurent A, Biloa-Tang M, Bougerol T, et al: Executive/attentional performance and measures of schizotypy in patients with schizophrenia and in their nonpsychotic first-degree relatives. Schizophr Res 2000; 46(2,3):269–283 35. Niendam TA, Bearden CE, Rosso IM, et al: A prospective study of childhood neurocognitive functioning in schizophrenic patients and their siblings. Am J Psychiatry 2003; 160:2060–2062 36. Bellack AS, Gold JM, Buchanan RW: Cognitive rehabilitation for schizophrenia: problems, prospects, and strategies. Schizophr Bull 1999; 25:257–274 37. Brekke JS, Raine A, Ansel M, et al: Neuropsychological and psychophysiological correlates of psychosocial functioning in schizophrenia. Schizophr Bull 1997; 23:19–28 38. Dickerson F, Boronow JJ, Ringel N, et al: Neurocognitive deficits and social functioning in outpatients with schizophrenia. Schizophr Res 1996; 21:75–83
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Dickinson et al. 39. Dickinson D, Coursey RD: Independence and overlap among neurocognitive correlates of community functioning in schizophrenia. Schizophr Res 2002; 56(1,2):161–170 40. Gladsjo JA, McAdams LA, Palmer BW, et al: A six-factor model of cognition in schizophrenia and related psychotic disorders: relationships with clinical symptoms and functional capacity. Schizophr Bull 2004; 30:739–754 41. Dickerson FB, Goldberg RW, Brown CH, et al: Diabetes knowledge among persons with serious mental illness and type 2 diabetes. Psychosomatics 2005; 46:418–424 42. Dixon LB, Kreyenbuhl JA, Dickerson FB, et al: A comparison of type 2 diabetes outcomes among persons with and without severe mental illnesses. Psychiatr Serv 2004; 55:892–900 43. Randolph C: Repeatable Battery for the Assessment of Neuropsychological Status. San Antonio, TX, The Psychological Corporation, 1998 44. Gold JM, Queern C, Iannone VN, et al: Repeatable Battery for the Assessment of Neuropsychological Status as a screening test in schizophrenia, I: sensitivity, reliability, and validity. Am J Psychiatry 1999; 156:1944–1950 45. Hobart MP, Goldberg R, Bartko JJ, et al: Repeatable Battery for the Assessment of Neuropsychological Status as a screening test in schizophrenia, II: convergent/discriminant validity and diagnostic group comparisons Am J Psychiatry 1999; 156:1951–1957 46. Wilk CM, Gold JM, Bartko JJ, et al: Test–retest stability of the Repeatable Battery for the Assessment of Neuropsychological Status in schizophrenia. Am J Psychiatry 2002; 159:838–844 47. Gold JM, Goldberg RW, McNary SW, et al: Dixon LB, Lehman AF: Cognitive correlates of job tenure among patients with severe mental illness. Am J Psychiatry 2002; 159:1395–1402 48. Wilk CM, Gold JM, Humber K, et al: Brief cognitive assessment in schizophrenia: normative data from the Repeatable Battery for
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the Assessment of Neuropsychological Status. Schizophr Res 2004; 70(2,3):175–186 49. Cohen JD: Statistical Power for the Behavioral Sciences. Hillsdale, NJ, Lawrence Erlbaum Associates, 1988 50. Heinrichs RW, Zakzanis KK: Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. Neuropsychology 1998; 12:426–445 51. The Psychological Corporation: The WAIS-III/WMS-III Technical Manual. San Antonio, TX, The Psychological Corporation, 1997 52. Randolph C, Tierney MC, Mohr E, et al: The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS): preliminary clinical validity. J Clin Exp Neuropsychol 1998; 20:310– 319 53. Sanfilipo M, Lafargue T, Rusinek H, et al: Cognitive performance in schizophrenia: relationship to regional brain volumes and psychiatric symptoms. Psychiatry Res 2002; 116(1,2):1–23 54. Newcomer JW, Nasrallah HA, Loebel AD: Atypical Antipsychotic Therapy and Metabolic Issues National Survey: practice patterns and knowledge of psychiatrists. J Clin Psychopharmacol 2004; 24(suppl 1):S1–S6 55. Dickerson FB, Brown CH, Daumit GL, et al: Health status of individuals with serious mental illness. Schizophr Bull 2006; 32:584–589 56. Dickerson FB, Brown CH, Kreyenbuhl JA, et al: Obesity among individuals with serious mental illness. Acta Psychiatr Scand 2006; 113:306–313 57. Dixon L, Goldberg R, Lehman A, et al: The impact of health status on work, symptoms, and functional outcomes in severe mental illness. J Nerv Ment Dis 2001; 189:17–23 58. Kreyenbuhl J, Dickerson FB, Medoff DR, et al: Extent and management of cardiovascular risk factors in patients with type 2 diabetes and serious mental illness. J Nerv Ment Dis 2006; 194:404– 410
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Type 2 diabetes is associated with both schizophrenia and cognitive performance. The authors compared cognitive performance in three groups: patients with schizophrenia and diabetes, patients with diabetes only, and patients with schizophrenia only. Results indicated that the schizophrenia/diabetes group was impaired cognitively relative to both other groups, especially in the domains of processing speed and visual/spatial ability. Also, these impairments were associated with diabetes severity markers. Because either illness creates cognitive vulnerability, comorbid occurrence is even more likely to undermine essential functional brain systems, leading to an increased rate and magnitude of cognitive decline with associated declines in community functioning. (Psychosomatics 2008; 49:123–131)
R
eferences to the dire public health implications of obesity and diabetes mellitus in the United States have become commonplace. Yet, even against this backdrop, the elevated rates of metabolic dysregulation and disease among individuals with schizophrenia are alarming. Data from the Schizophrenia Patient Outcomes Research Team showed lifetime diagnoses of diabetes in 15% of schizophrenia patients surveyed in 1997 and current diabetes in 11%, even before the widespread use of second-generation antipsychotic medications.1 More recently, baseline data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) showed current diabetes in 13% of schizophrenia participants,2 50% greater than estimates of the general population rate.3 Remarkably, these figures probably understate the true dimensions of the problem. First, more than 40% of schizophrenia patients meet criteria for the metabolic syndrome (e.g., adiposity, glucose and lipid abnormalities, hypertension), which strongly predicts diabetes and cardiovascular disease.4–7 Second, evidence is accumulating that widely used second-generation antipsychotic medications (SGAs) worsen metabolic dysregulation.8–11 Third, the onset of diabetes occurs at sigPsychosomatics 49:2, March-April 2008
nificantly younger ages in schizophrenia than in comparison groups, with the sharpest disparity among individuals less than 49 years old.9,10,12 Thus, the already vulnerable and impaired schizophrenia population is at substantial risk in early middle age for another debilitating chronic illness. The well-known somatic consequences of diabetes (e.g., cardiovascular and kidney disease, stroke, blindness, amputation) are grave. However, schizophrenia patients may face additional risks of poor diabetes and overall health outcomes. Cognitive impairment in schizophrenia is well established and widely seen as a critical determinant of disability and reduced role-functioning.13 Less widely studied is the fact that cognition is also impaired in diabetes. Most studies show significant cognitive impairment in diabetes patients relative to non-diabetic control groups Received August 22, 2006; revised November 14, 2006; accepted November 28, 2006. From VISN 5 Mental Illness Research, Education, and Clinical Center, Baltimore, MD; the Dept. of Psychiatry, Univ. of Maryland, Baltimore, MD, and the Sheppard Pratt Health System, Baltimore, MD. Send correspondence and reprint requests to Dwight Dickinson, Ph.D., VISN 5 MIRECC, Suite 6A (BT/MIRECC), 10 North Greene St., Baltimore, MD 21201. e-mail: [email protected] 䉷 2008 The Academy of Psychosomatic Medicine
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Cognition in Schizophrenia and Diabetes across domains of verbal memory, processing speed, and problem-solving.14 These deficits are evident cross-sectionally.15,16 Moreover, longitudinal studies have documented accelerated cognitive decline in diabetes17–19 and increased long-term risk of vascular and Alzheimer’s dementias.20,21 In addition to diabetes diagnosis and duration, prediabetes glucose metabolism abnormalities and the metabolic syndrome also have been found to be associated with cognitive impairment.22–24 Although cognitive impairment in diabetes has been noted in diverse cognitive-performance domains, deficits on measures of information processing speed and efficiency are among the most consistent findings,17–19,22,25 to the point that “it is plausible to consider this as the ‘fundamental’ diabetes-associated cognitive deficit.”26 Importantly, this impairment is shown early in the course of illness. Speed decrements are evident in middle-aged adults with type 1 and type 2 diabetes15,16,27,28 and even in children with a relatively short duration of type 1 diabetes.29 Thus, diabetes and prediabetes symptoms are associated with significant risk of cognitive impairment. The earliest and most reliable cognitive impact appears to involve tasks requiring speeded mental processing. The cognitive impact of diabetes converges with known cognitive performance deficits in schizophrenia. Although schizophrenia deficits are broadly generalized, the most prominent impairment is in the same processing speed domain. Our recent metaanalysis showed that the schizophrenia deficit on the digit-symbol coding task—the prototype processing speed measure—was not only substantial (effect size [ES] ⬇ 1.5), it was significantly larger than deficits on measures from more often studied domains of verbal memory, executive functioning, and working memory.30,31 Furthermore, this speed deficit is also related to schizophrenia risk,32–34 premorbid cognitive status,35 and illness-related disability and outcome.36–40 Thus, it appears that diabetes may exert its largest cognitive effect precisely in the cognitive domain where schizophrenia patients have the least margin for additional impairment—in the realm of information processing speed and efficiency. Current analyses were conducted to test the hypothesis that exacerbated cognitive deficits, particularly processing speed deficits, are present in schizophrenia patients with diabetes relative to patients with either schizophrenia-only or diabetes-only. METHOD Background Work Data for current analyses were drawn from two bodies of work from our group. The first arises out of an NIMH124
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funded study of diabetes in schizophrenia (Dixon Diabetes Study; author LD is principal investigator). A total of 300 participants diagnosed with type 2 diabetes have been recruited into the study, including 101 persons with schizophrenia, 100 persons with severe mood disorder, and 99 persons without mental illness. Participants met the following inclusion criteria: age of 18 to 65 years, current medical record diagnosis of type 2 diabetes, English speaker, and ability to provide informed consent. Also, participants with severe mental illnesses had to have schizophrenia or schizoaffective disorder or a major mood disorder (bipolar disorder or major recurrent depression) recorded in their medical chart. This study describes and compares these three cohorts on a variety of diabetes-related measures. An extensive database on diabetes health behaviors, diabetes outcomes, physiologic measures, quality of diabetes care indicators, general health status, health services utilization, and medication data were assembled at baseline for the entire study cohort.41,42 All subjects in the Dixon Diabetes Study were administered a neuropsychological screening measure, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS43). The RBANS is a 25-minute, standardized cognitive screening instrument that assesses several performance domains and offers an efficient approach to screening for cognitive impairment. The RBANS adapts and consolidates a selection of well-known cognitive measures into a short battery. Subtests were selected and conormed to yield a total scaled score and five comparably scaled index scores: immediate memory, visual/spatial performance, attention, language, and delayed memory. For example, list-learning and story-memory tasks combine in an immediate-memory index. The attention index derives from adaptations of the information processing speed test, digit-symbol coding, and the working-memory task, digit span. The battery has good psychometric properties and alternative forms to allow repeated assessment. The second body of work involves a database of 575 schizophrenia RBANS evaluations (RBANS norms database). Two of the current authors (JMG, FBD) oversaw the RBANS assessments and development of this database. The database comprised two patient groups. Data from 305 patients were collected from four outpatient clinics and four inpatient units by the Maryland Psychiatric Research Center for a variety of research protocols. Data for 270 patients were collected at programs affiliated with the Sheppard Pratt Health System and Chestnut Lodge Hospital, also for different research protocols. All 575 patients met DSM–IV criteria for schizophrenia or schizoaffective Psychosomatics 49:2, March-April 2008
Dickinson et al. disorder and did not meet criteria for alcohol/drug dependence or mental retardation. The RBANS data have been used to map the psychometric properties of the instrument in this population. We have established that the RBANS is sensitive to the types and severity of cognitive impairment in schizophrenia and correlated with comprehensive cognitive batteries,44,45 stable across repeated assessments,44,46 and predictive of employment outcomes.44,47 Importantly for current purposes, the RBANS schizophrenia database has also been used to derive and publish schizophrenia normative data.48 Subjects RBANS and demographic data for the current study were drawn from three groups of subjects. The first group comprised the sample of patients with both schizophrenia and diabetes followed in the Dixon Diabetes Study. The second group was the “diabetes-only” comparison group from the same study who were free of any psychiatric diagnosis. From these two groups, data screening identified three schizophrenia/diabetes subjects and four diabetesonly subjects as diabetes duration outliers, each having had diabetes for more than 30 years. We conducted all analyses excluding these cases to avoid skewing results with influential observations. The third group consisted of the “schizophrenia-only” subjects included in the RBANS norms database. We should note that these patients were not screened for diabetes. Thus, although we expect that the preponderance of the 575 subjects were free of this diagnosis, the statistics cited earlier suggest that as many as 10% to 15% might have been affected. The validity of comparisons among these groups is enhanced by the fact that all data for the Dixon Diabetes and RBANS norms database were collected from clinics and inpatient units in the Baltimore metropolitan area, under the supervision of the same psychologists (FBD and JMG). Analyses There were three groups of analyses.1 The Dixon Diabetes Study did not include a non-diabetic schizophrenia sample that could have been used to test for an added cognitive burden of diabetes in schizophrenia. Therefore, the first group of analyses used the RBANS norms database to provide a preliminary test of this hypothesis. We conducted single-sample t-tests contrasting RBANS performance by the schizophrenia/diabetes sample with “population estimates” from the RBANS norms database. In connection with these analyses, we conducted separate tests of the Psychosomatics 49:2, March-April 2008
digit-symbol coding and digit-span subtests, which comprise the RBANS attention index, in order to distinguish processing speed and working memory domains.2 The second set of analyses contrasted RBANS performance in the schizophrenia/diabetes group with performance among the diabetes-only sample (both from the Dixon study) using independent-samples t-tests. Again, these analyses included separate tests of the digit-symbol coding and digitspan subtests.3 In our final set of analyses, partial-correlation analyses were used to examine the relationship of cognition to indexes of diabetes severity in the schizophrenia/diabetes patients and in the diabetes-only patients. Separately in the two groups, partial correlations examined the associations of duration of diabetes, age at diabetes onset, and glycosylated hemoglobin with RBANS total score and all index and subtest scores. Because of group differences, correlation analyses controlled for age and smoker status. RESULTS Sample Characteristics Demographic information for all groups and clinical data for the two diabetes groups are presented in Table 1. The diabetes-only group was older than the schizophrenia/ diabetes group by approximately 5 years, on average. By design, these groups were matched on education, gender, and race. Regarding diabetes-related clinical variables, the schizophrenia/diabetes patients were significantly younger than the diabetes-only patients on age at diabetes onset and were significantly more likely to be smokers. The samples did not differ significantly on body mass index or duration of diabetes. Both groups reported high rates of hypertension (⬇80%), which did not differ between groups.42 Alcohol use was very low and similar for the groups.42 Surprisingly, the glycosylated hemoglobin was lower in the schizophrenia/diabetes sample than in the diabetes-only comparison group. Hypotheses regarding this unexpected finding are considered in detail in the earlier article describing the main Dixon study findings,42 however, observed glycosylated hemoglobin levels were significantly above recommended levels for both groups. Relative to the schizophrenia/diabetes group, the normative study sample was younger, better educated, and more likely to be white and male. Means, standard deviations, mean comparisons, and effect sizes are presented in Table 2. The expectation in the healthy population is for RBANS scaled scores of 100 http://psy.psychiatryonline.org
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Cognition in Schizophrenia and Diabetes (standard deviation [SD]: 15) for the RBANS Total and all index scores.43 As indicated by the schizophrenia norms,48 people with the disorder show significant impairment on this battery, achieving RBANS Total scores of 70.5 (SD: 14.8) on average, two SDs below expectation. Poorest performance among patients is evident on memory and attention measures, with lesser impairment on visual/spatial tasks and relatively preserved performance on measures of language abilities. Data from the Dixon Diabetes Study suggest lesser, but nevertheless substantial, RBANS impairments among diabetes patients without psychiatric diagnoses. The deficits observed in this sample likely relate in part to the education matching of the diabetes-only patients to the schizophrenia/diabetes patients and may not generalize to all groups of diabetes patients. However, the current diabetes-only sample showed impairments approximating one SD across RBANS index scores, with relatively preserved language ability and relatively compromised visual/spatial ability.
RBANS Total score was significantly reduced in the schizophrenia/diabetes sample relative to schizophreniaonly normative group values,48 but the group effects were uneven across cognitive domains. Effects for processing speed (coding), visual/spatial performance, and memory were greater than the overall cognitive effect (as indicated by the RBANS Total score), and there were no group effects on language functioning or simple working memory (digit-span). The ES for the RBANS Total score was d ⳱ 0.26, and ESs were higher for the significant group differences on RBANS index and subtest scores, ranging up to d ⳱ 0.50 for visual/spatial performance. These ESs are small-to-medium, according to Cohen’s criteria (i.e., 0.20 for a small effect, 0.50 for a medium effect49). It is important to recognize, however, that in the schizophrenia-only sample, no effort was made to screen out subjects with diabetes, which may have reduced group differences and ESs in the foregoing comparisons. Cognitive Associations With Diabetes Severity Markers
Mean Comparisons In general, schizophrenia patients with diabetes performed significantly more poorly on RBANS variables than either diabetes-only or schizophrenia-only groups. The contrast between the schizophrenia/diabetes group and the diabetes-only group was relatively clear. Effect sizes approached one SD for all variables, with two exceptions. Between-group differences were small and nonsignificant for the visuospatial/constructional index and the digit-span task. However, contrasts between the schizophrenia/diabetes group and the schizophrenia-only group yielded more mixed results. Consistent with our main hypothesis, the
TABLE 1.
Partial-correlation analyses, focused on markers of diabetes severity, examined whether the association of diabetes course with cognition is different in a schizophrenia and diabetes sample than in a diabetes-only sample. Within the schizophrenia/diabetes group, RBANS Total score was modestly but significantly associated with self-reported duration of diabetes and age at onset of diabetes. Among the index scores, visual/spatial performance and attention were associated with diabetes severity markers, but the largest individual test effects were for coding and figure-copying tasks. Of note, these significant associations were not present in the nonpsychiatric, diabetes-
Demographic and Clinical Information
Sample size Age, years Education ⱕhigh school Sex, male Race, white Diabetes duration, years Age at diabetes diagnosis, years Glycosylated hemoglobin, % Body Mass Index Current smoker
Diabetes-Only (Diabetes Study)
Schizophrenia and Diabetes (Diabetes Study)
Schizophrenia-Only (Norms Database)
95 53 (9.0)*** 66% 52% 31% 6.6 (5.5) 46.1 (9.6)*** 8.6 (2.4)* 34.6 (6.5) 35%***
97 48.1 (8.9) 66% 58% 34% 7.8 (6.8) 39.7 (10.1) 7.8 (2.3) 32.8 (6.8) 60%
575 40.5 (9.7)‡ 57%‡ 68%‡ 69%‡ — — — — —
Values are mean (standard deviation) unless otherwise indicated. *p⬍0.05; ***p⬍0.001 for independent t-test comparing diabetes-only group with schizophrenia-and-diabetes group. ‡p⬍0.001 for single-sample t-test or chi-square test comparing schizophrenia norm values with schizophrenia-and-diabetes group values.
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Effect Size
0.26 0.27 0.50 0.08 0.27 ⳮ0.08 ⳮ0.03 0.39
p
0.01 0.007 ⬍0.001 0.47 0.011 0.41 0.734 ⬍0.001
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Effect size: Cohen’s d.
t [96]
ⳮ2.64 ⳮ2.74 ⳮ5.32 ⳮ0.72 ⳮ2.6 0.83 0.34 ⳮ3.67 0.96 0.95 0.25 0.80 0.85 0.77 0.20 0.91
p
⬍0.001 ⬍0.001 0.08 ⬍0.001 ⬍0.001 ⬍0.001 0.178 ⬍0.001
t [189]
66.7 (14.1) 67.1 (17.0) 70.0 (15.9) 83.4 (14.9) 68.6 (20.1) 74.7 (17.4) 9.6 (2.5) 28.3 (11.7)
ⳮ6.62 ⳮ6.63 ⳮ1.76 ⳮ5.5 ⳮ5.86 ⳮ5.04 ⳮ1.35 ⳮ6.29
Effect Size
DISCUSSION
70.5 (14.8) 71.8 (18.4) 78.6 (18.3) 84.5 (14.3) 73.9 (19.0) 73.2 (16.9) 9.5 (3.0) 32.7 (10.8)
SchizophreniaWith-Diabetes (Diabetes Study) Schizophrenia-Only (Norms Database) Diabetes-Only (Diabetes Study)
Mean RBANS Index Scaled Scores (SD)
Independent-Samples t-Tests of Schizophrenia-With-Diabetes group vs. Diabetes-Only Group
only group. Although not as clear as in the case of diabetes duration and age at onset, associations of cognitive performance with glycosylated hemoglobin, a marker of recent glycemic control, also were present in the schizophrenia/ diabetes group, but absent in the diabetes-only group.
80.4 (14.4) 83.8 (18.0) 74.1 (16.3) 94.4 (12.4) 84.7 (17.9) 87.9 (16.9) 10.1 (2.6) 39 (11.8) Total Score Immediate Memory Visual/Spatial Language Delayed Memory Attention Digit Span Coding
TABLE 2.
Means and Standard Deviations (SD) for Schizophrenia, Diabetes, Schizophrenia-With-Diabetes Groups and Mean Comparisons
One-Sample t-Tests of SchizophreniaWith-Diabetes Group vs. Schizophrenia Norms
Dickinson et al.
The present analyses were undertaken as an initial test of the hypothesis that diabetes exacerbates the already substantial cognitive impairment associated with schizophrenia. Two lines of analysis supported this hypothesis: First, RBANS performance was significantly impaired in schizophrenia patients with diabetes relative to a schizophrenia normative group and a diabetes-only comparison sample. Second, within the schizophrenia/diabetes sample, cognitive performance was negatively associated with certain markers of diabetes severity. This set of relationships was not evident among nonpsychiatric, diabetes-only patients, however. Our sample of diabetes patients with no current psychiatric conditions showed impairments across cognitive domain indices on the RBANS relative to population normative values, with the exception that language performance was preserved. However, the schizophrenia/diabetes patients showed substantial additional cognitive impairment relative to the diabetes-only group, approaching one SD across most cognitive domains assessed by the RBANS. Visual/spatial processing, which showed the greatest impairment among the diabetes-only patients, was the only index score that was not significantly different between groups. Analysis focused on the subtasks of the attention index (digit-span and coding), indicated that the group difference on this index was driven entirely by poorer processing speed performance (coding) among the schizophrenia/diabetes patients. This pattern of results was expected in light of the broad and well-documented cognitive deficits in schizophrenia30,50 and the lesser and more mixed findings in diabetes.14 Of greater importance, the comparison of RBANS performance by the schizophrenia/diabetes sample to the schizophrenia-only group also revealed significant incremental deficits. The RBANS is sensitive to the particular cognitive deficits observed in schizophrenia. As shown in the normative study,48 the typical schizophrenia impairment on this battery is two SDs below the expectation for the healthy population, and is one SD below schizophrenia performance on familiar measures of IQ (e.g., the WAIS51) and premorbid/crystallized verbal ability (e.g., the Wide http://psy.psychiatryonline.org
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Cognition in Schizophrenia and Diabetes Range Achievement Test, reading48). Significant diabetesrelated impairments on the RBANS must be considered against this backdrop. In the analyses here, modest differences were found between the schizophrenia and schizophrenia/diabetes group for the RBANS Total score. However, the pattern of exacerbated impairment was uneven, with more marked impairment in visual/spatial performance, processing speed, and memory. In the latter two domains, the findings signaled an additional diabetesassociated increment over impairments that are prominent and well-established in schizophrenia. By contrast, visual/ spatial performance in schizophrenia is preserved relative to these domains in schizophrenia-only patients, as seen in the RBANS normative data.48 We speculate that visual/spatial performance may be a cognitive domain in which the combination of schizophrenia and diabetes yields an especially harmful synergy. Two subtests comprise the visuospatial/constructional index of the RBANS: The first is a line-orientation task, based purely on visual/spatial analysis. The second is a complex figure-copying task, which taps constructional ability in addition to visual/spatial analysis. Performance on these very different tasks was equivalently impaired in the schizophrenia/diabetes group relative to the schizophrenia normative group (t ⳱ –6.33 and t ⳱ –4.65, respectively (df: 96), both p ⬍0.001). This finding counters
TABLE 3.
the argument that the visual/spatial performance impairment is due to peripheral motor functioning more than to visual/spatial abilities. Peripheral motor impairment might contribute to figure-copying deficits, but not to line-orientation performance, which requires only oral, and not motor responding. It is interesting to note that poor performance on both the RBANS Visuospatial/Constructional and Attention indexes has been shown in the early stages of subcortical dementias (e.g., Huntington’s disease) and distinguishes these conditions from the cortical dementias (e.g., Alzheimer’s disease52). Our analyses suggest that, among schizophrenia patients, diabetes may shift the RBANS performance profile in a fashion suggesting greater subcortical dysfunction than is seen in non-diabetic schizophrenia patients. Although the visual/spatial processing findings were unexpected, the literature provides ample reason to expect exaggerated processing speed deficits in schizophrenia patients also afflicted with diabetes. Processing speed impairment has emerged as the most prominent cognitive deficit in schizophrenia.30 It is likewise the most reliably impaired cognitive dimension in diabetes.17–19,22,25 The neurobiological underpinnings of processing speed impairment are uncertain. In schizophrenia, slowed processing has been associated with significantly reduced gray(but not white-) matter volumes in the bilateral prefrontal
Correlations of Diabetes-Severity Markers With Cognitive Performance by Group Schizophrenia-With-Diabetes Group Diabetes Duration
List Learning Story Memory Immediate Memory Index Figure Copy Line Orientation Visuospatial/Constructional Index Picture Naming Semantic Fluency Language Index Digit Span Coding Attentional Index List Recall List Recognition Story Recall Figure Recall Delayed Memory Index Total Scaled Score
Age at Diabetes Onset
Diabetes-Only Group
Glycosylated Hemoglobin
Diabetes Duration
Age at Diabetes Onset
Glycosylated Hemoglobin
ⳮ0.13 ⳮ0.20 ⳮ0.17 ⳮ0.31*** ⳮ0.21* ⳮ0.22*
0.15 0.22* 0.20 0.33*** 0.23* 0.21*
ⳮ0.21* ⳮ0.05 ⳮ0.12 ⳮ0.24* ⳮ0.19 ⳮ0.20
0.00 0.10 0.03 ⳮ0.13 0.06 ⳮ0.01
0.00 ⳮ0.10 ⳮ0.03 0.12 ⳮ0.07 0.00
ⳮ0.02 ⳮ0.13 ⳮ0.09 ⳮ0.18 ⳮ0.13 ⳮ0.12
ⳮ0.12 ⳮ0.12 ⳮ0.16 ⳮ0.11 ⳮ0.33*** ⳮ0.22* 0.04 ⳮ0.08 ⳮ0.06 ⳮ0.24* ⳮ0.09 ⳮ0.22*
0.15 0.13 0.19 0.07 0.35*** 0.20 ⳮ0.05 0.06 0.09 0.22* 0.06 0.21*
ⳮ0.17 ⳮ0.02 ⳮ0.07 ⳮ0.09 ⳮ0.22* ⳮ0.12 0.02 ⳮ0.04 0.01 ⳮ0.13 ⳮ0.04 ⳮ0.14
ⳮ0.02 ⳮ0.06 ⳮ0.08 0.11 ⳮ0.06 0.02 0.06 0.10 0.01 0.05 0.02 0.01
0.01 0.04 0.06 ⳮ0.11 0.06 ⳮ0.02 ⳮ0.06 ⳮ0.09 ⳮ0.01 ⳮ0.04 ⳮ0.02 ⳮ0.02
ⳮ0.06 ⳮ0.15 ⳮ0.15 ⳮ0.04 ⳮ0.13 ⳮ0.12 ⳮ0.12 ⳮ0.06 0.03 0.04 ⳮ0.02 ⳮ0.12
*p⬍0.05; ***p⬍0.001.
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Dickinson et al. cortex, whole temporal lobe, and superior temporal gyrus in schizophrenia patients relative to control subjects.53 The effects of diabetes are likely to be more systemic. Type 2 diabetes is characterized by impaired insulin secretion and changes in the sensitivity of insulin receptors, leading to a progressive loss of glycemic control.11 Among other complications are impairments in nerve-signaling involving the limbs (peripheral neuropathy) and viscera (autonomic neuropathy). Corresponding effects in the CNS, sometimes termed “central neuropathy,” may result from diffuse cerebral microvascular abnormalities, white-matter damage, and axonal injury, which undermine the rapid neural transmission and integration on which processing speed and other cognitive tasks depend.18,26,27 Analyses of the associations of diabetes course markers (i.e., diabetes duration, age at onset, and glycosylated hemoglobin) offered some support for a central neuropathy hypothesis. Within the schizophrenia/diabetes sample, these markers were significantly associated primarily with the same domains of cognitive performance that distinguished this sample from the schizophrenia-only normative group. That is, among those with both diabetes and schizophrenia, longer duration of diabetes, earlier age at onset, and worse glycemic control were associated with worse cognitive performance. It is somewhat surprising that these relationships were entirely absent in the diabetes-only comparison sample. It may be that the association of diabetes course markers with cognitive performance typically is evident only in later stages of diabetes, but that the markers signal earlier and more robustly in an already cognitively-impaired group, such as the schizophrenia sample studied here. An important limitation of the current work is that critical comparisons were made between a schizophrenia/ diabetes group ascertained in the context of an NIMH diabetes study and a schizophrenia-only group assembled to examine the psychometric properties of the RBANS. These samples were not matched on variables of age, education, race, or gender. A number of considerations allay this concern to a degree. As noted, all patient groups were recruited from the same psychiatric settings in the Baltimore metropolitan area during approximately the same time period and assessed under the direction of the same investigators. Moreover, the largest mismatch between the schizophrenia/ diabetes group and the schizophrenia-only group was on age, but RBANS scoring incorporates an age-correction for total and index scores, and Wilk and colleagues found limited age effects on RBANS performance in schizophrenia.48 Another point is that, in the schizophrenia-only normative group, no effort was made to screen out subjects Psychosomatics 49:2, March-April 2008
with diabetes. Thus, the 575-person sample that was analyzed to derive normative values likely included at least 10%–15% schizophrenia patients with diabetes, reducing group differences and effect sizes in the foregoing comparisons. Notwithstanding these considerations, the mismatch on demographic variables means that these findings must be considered preliminary. Further investigations are planned to determine the extent to which the findings hold up in more precisely-designed comparisons. Rates of diabetes pose problems of national scope. These problems are magnified in schizophrenia by higher diabetes and prediabetes prevalence rates, iatrogenic effects of first-line antipsychotic treatments, and early onset of illness. Compounding these problems, the cognitive effects of diabetes are likely to have a disproportionate impact in schizophrenia patients. Because either illness alone creates cognitive vulnerability, the two illnesses together are even more likely to undermine essential functional brain systems, leading to an increased rate and magnitude of cognitive decline. These converging cognitive deficits have adverse practical implications. Medical management of schizophrenia and diabetes each requires a lifetime commitment on the part of patients to treatment adherence and behavioral self-regulation. The broad cognitive impairment associated with schizophrenia, exacerbated by diabetes-related cognitive deficits, is likely to limit patients’ ability to maintain this level of engagement and discipline. Such patient vulnerabilities are unlikely to be offset by health care as currently delivered to these patients. Although there is evidence that many providers are aware of heightened diabetes risk in schizophrenia,54 schizophrenia patients receive fewer recommended diabetes services and treatments than comparison groups, are less educated about their illness, show elevated markers of diabetes severity, have poorer physical health and functional outcomes, and experience resulting reductions in quality of life.1,41,42,55–58 At the same time, however, diabetes has proven more tractable from a healthcare standpoint than schizophrenia. Diabetes risk and severity are modifiable through education, lifestyle changes, and treatment. The analyses presented in this article suggest that, in schizophrenia, diabetes prevention and treatment might prove especially beneficial, yielding better cognitive outcomes, along with improved general health. These issues merit future investigation. This work was supported by MH 58717 (LD), and by a Research Career Development Award, Rehabilitation Research and Development Service, Department of Veterans Affairs (DD) http://psy.psychiatryonline.org
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