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Neuropsychological, neurological and symptom correlates of impaired olfactory identification in schizophrenia
Schizophrenia Research 32 (1998) 23–30
Neuropsychological, neurological and symptom correlates of impaired olfactory identification in schizophrenia Terry J. Stedman a,b,*, Anne L. Clair c,d a Wolston Park Hospital, Wacol Q 4076, Australia b Department of Psychiatry, University of Queensland, St Lucia, Qld, Australia c Queensland Centre for Schizophrenia Research, Wolston Park Hospital, Wacol, Q 4076, Australia d School of Psychology, University of Queensland, St Lucia, Qld, Australia Received 28 January 1998; accepted 4 February 1998
Abstract Impaired olfactory identification has been reported in samples of schizophrenic patients. Little is known about the associations between these impairments and neuropsychological deficits, neurological deficits and olfaction-related symptoms. Forty-six subjects (37 men and 9 women) with schizophrenia were examined with the University of Pennsylvania Smell Identification Test ( UPSIT ), a selection of neuropsychological tests and standardised neurological and symptom evaluations. Eighty-five per cent of the subjects scored below the published norms’ 10th percentile on the UPSIT. Stepwise multiple regression found that WAIS-R Information score and Wisconsin Card Sort Test Failure to Maintain Set score ( WCST-FMS ) were the only significant predictors of the UPSIT percentile scores, accounting for 41% of the variance. Neurological signs did not contribute to the prediction of impaired olfactory identification. Although 26% of subjects reported olfactory hallucinations, there was no association between this symptom and olfactory impairment. The results suggest that general knowledge or general intelligence may have some influence on olfactory identification in subjects with schizophrenia; however, olfactory identification deficit could not be explained by gross impairments of sustained attention, memory or conceptual ability. © 1998 Elsevier Science B.V. All rights reserved. Keywords: Schizophrenia; Neuropsychology
Olfactory
identification;
Olfactory
1. Introduction The human olfactory system relies heavily on structures such as the entorhinal cortex, orbitofrontal cortex and lateral thalamic nuclei * Corresponding author. Present address: Wolston Park Hospital, Wacol Q 4076, Australia. Tel: +61 7 2718424; Fax: +61 7 2718567; e-mail [email protected] 0920-9964/98/$19.00 © 1998 Elsevier Science B.V. All rights reserved. PII: S0 9 20 - 9 96 4 ( 98 ) 00 0 2 1 -8
hallucinations;
Smell
Identification
Test;
( Freeman, 1991). As each of these brain regions has been implicated in the pathophysiology of schizophrenia, study of olfactory function provides an opportunity to explore some of the questions raised by these neuropathological findings. The availability of a practical test of indentification, the University of Pennsylvania Smell Identification Test ( UPSIT ), has greatly facilitated the study of this sense (Doty et al., 1984). To date, several
24
T.J. Stedman, A.L. Clair / Schizophrenia Research 32 (1998) 23–30
publications have used this test with subjects suffering from schizophrenia and all have suggested the presence of a deficit in olfactory identification (Hurwitz et al., 1988; Kopala et al., 1989, 1992, 1994; Warner et al., 1990; Serby et al., 1990; Seidman et al., 1992; Wu et al., 1993; Good et al., 1994; Houlihan et al., 1994; Malspina et al., 1994; Brewer et al., 1996). In comparison, schizophrenic subjects have been found to perform in the normal range on another sensory task of equal complexity—the Colour Identification Test—suggesting that olfactory agnosia is not part of a general difficulty with sensory identification ( Kopala et al., 1995). Olfactory impairment is not uncommon in neuropsychiatric conditions. Impairment of olfactory identification has also been noted as a feature of Alzheimer’s disease (Doty et al., 1987), Parkinson’s disease (Doty et al., 1988), Alcoholic Amnestic Syndrome (Mair et al., 1986) and orbitofrontal lobe lesions (Potter and Butters, 1980). It has not been shown to be present in small groups of depressed, bipolar and eating disordered patients who have served as psychiatrically ill controls for schizophrenic patients ( Warner et al., 1990; Hurwitz et al., 1988; Kopala et al., 1994). While one study of nine patients with major depressive disorder found olfactory identification scores similar to the schizophrenic group being studied (Serby et al., 1990), a larger study of 51 subjects with major depressive disorder found no significant difference between these subjects and matched normal controls (Amsterdam et al., 1987). Hurwitz et al. (1988) compared 18 schizophrenic subjects with a non-schizophrenic psychiatric control group receiving antipsychotic drugs and with normal controls. Schizophrenic subjects performed significantly more poorly than did either of the control groups. A suggestion of better performance in the three women in the schizophrenic group in the initial study was expanded upon in the next study from this group ( Kopala et al., 1989). This compared 41 schizophrenic patients and 43 normal control subjects and again demonstrated marked impairment in the schizophrenic group. When the results were examined for gender differences, one of 15
female schizophrenic and 15 of 26 male schizophrenic subjects were classified using the tables adjusted for age and gender as demonstrating abnormally poor olfactory identification. Kopala et al. (1992) subsequently compared 30 men and 10 women who were suffering from schizophrenia and had never received antipsychotic drugs. Thirty-one per cent of these men and 10% of these women were found to perform below the normal range for olfactory identification, apparently supporting their observation of a gender difference in olfactory identification. Recently this group (Good et al., 1994) has compared 15 pre-menopausal and 12 post-menopausal women with schizophrenia and found post-menopausal women performed at a level similar to the male groups in their previous studies. On this occasion the pre-menopausal women also performed more poorly than a female control group. Houlihan et al. (1994) failed to find a gender difference when they compared 25 male and 22 female subjects with schizophrenia. The possibility that medication may influence olfactory identification has been examined directly. Kopala et al. (1992) demonstrated impaired olfactory identification in a group of 40 patients who had never received neuroleptic medication and concluded that these deficits were present early in the course of illness and were not produced by drug treatment; Wu et al. (1993) examined 14 never-medicated schizophrenic patients and six who were drug free for longer than 3 weeks. Both groups demonstrated poor olfactory identification. Two studies using non-schizophrenic psychiatric controls receiving neuroleptic medications have failed to demonstrate impairments in the control groups ( Warner et al., 1990; Hurwitz et al., 1988). Of the remaining six studies that utilised the UPSIT, two considered whether medication was a potential confounding variable (Seidman et al., 1992; Houlihan et al., 1994). Both failed to find a significant effect. Overall, there is no evidence to suggest that impairment of olfactory identification is a consequence of drug treatment. Various groups have speculated on the anatomic implications of impaired olfactory functions. However, only three studies have addressed this directly (Seidman et al., 1992, 1997; Wu et al., 1993; Clark et al., 1991). Seidman et al. (1992,
T.J. Stedman, A.L. Clair / Schizophrenia Research 32 (1998) 23–30
1997) considered the UPSIT task and the Wisconsin Card Sort Test ( WCST ) to be orbitofrontal and dorsolateral frontal ‘probes’, respectively. Although they found the schizophrenia group to be impaired on both tasks, they found no correlation between olfactory impairment and performance on the WCST, WAIS-R Block Design or a sustained attention test, the Continuous Performance Task. They concluded that their results were not the result of a generalised impairment. Wu et al. (1993) administered the UPSIT, an olfactory match to sample task (a presumed olfactory memory test) and a comparable visual match to sample task. All three tests were performed significantly more poorly by the schizophrenic subjects than by normal controls. Correlation between test scores was high in the controls and low in the schizophrenic subjects. On the same day, subjects underwent Positron Emission Tomography while performing the Continuous Performance Task. UPSIT scores correlated significantly with activity of left middle and inferior frontal regions, while olfactory matching scores correlated significantly with activity of left temporal regions and visual matching scores correlated with the right caudate region. Clark et al. (1991) compared cerebral glucose metabolism in subjects with schizophrenia and olfactory agnosia with subjects with schizophrenia without olfactory agnosia, and found lower right basal ganglia and thalamic metabolism in subjects with schizophrenia and olfactory agnosia. This study aims to replicate the finding of impaired olfactory identification in schizophrenia, and to examine whether this is associated with impairments in attention, recognition memory, conceptual function and sensory integration. We also seek to investigate whether olfactory impairments are associated with clinical features of schizophrenia, such as olfactory hallucinations and anhedonia.
2. Methods 2.1. Subjects Thirty-seven men and nine women, with DSMIII-R diagnoses of schizophrenia ascertained by
25
consensus of two clinicians, consented to participate. All were of white European background and aged between 19 and 51 years (mean=36.39, SD= 8.05). Fifteen were non-smokers, the remainder smoked between 15 and 90 cigarettes per day (mean=26, SD=23; median=25). Males and females did not differ on age or number of cigarettes smoked. Subjects were excluded if they had a current upper respiratory tract infection, past nasal trauma or disease, or a history of significant head injury or current substance dependence. All were symptomatically stable on antipsychotic medication (chlorpromazine equivalents mean=694, SD=807); some were also taking anti-cholinergic medication. Their mean current WAIS-R FSIQ was 89, with a standard deviation of 13 points. They were inpatients in a research ward for the purpose of participation; however, a substantial number usually resided in the community. 2.2. Measures and procedures 2.2.1. University of Pennsylvania Smell Identification Test (Doty et al., 1984) This is a standardised ‘scratch and sniff ’ task presented in multiple-choice format. Raw scores have been reported to be influenced by age, gender, ethnic background and smoking habit. Percentile scores which adjust for age and gender were used (Doty et al., 1984). Unpublished Australian norms were also available to the authors (A. McKaySim, personal communication, 1993). Subjects were questioned about age of onset of illness, and any subjective change or loss in the senses of smell or taste since that time. Duration of illness was defined as time between age of onset and date of study assessment, with information regarding date of first admission used if uncertainty existed. Subjects were undergoing a larger study of the neuropsychology of schizophrenia. The neuropsychological variables were selected from a larger set available, prior to the commencement of the study. Intelligence, attention, memory and conceptual abilities may be required for successful performance of the olfactory identification task; the variables selected to measure these abilities are given below.
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2.2.2. Wechsler Adult Intelligence Scale-Revised (Wechsler, 1981) The Information and Vocabulary subtest agescaled scores were used as measures of general intelligence. These subtest scores have been shown to have acceptable psychometric properties in similar psychiatric populations (Piedmont et al., 1989) 2.2.3. Letter Cancellation Task Error scores from a task similar to those used by Diller et al. (1974) were used as an indication of sustained attention. 2.2.4. Auditory Verbal Learning Test (Rey, 1964) After a 5-min delay, recognition of 15 learned words was tested by asking the subject to identify the words from a 50-word list. 2.2.5. The Complex Figure (Rey, 1941) The 5-min reproduction scores were used as a test of visuographic memory. 2.2.6. Wisconsin Card Sorting Test (WCST) This test is a measure of concept formation, maintenance and shift. The standarised instructions and procedure of Heaton (1981) and the WCST Scoring Program Version 3.0 by Harris (1988) were employed and the scores ‘categories’, ‘perseverative errors’ and ‘failure to maintain set’ were used. 2.2.7. Trail Making Test (Reitan and Wolfson, 1985) The difference in number of corrected errors between Parts A and B were used a measure of simple conceptual alternation.
2.2.8. Present State Examination 9th edition (Wing et al., 1977) This is a 140-item instrument comprising a structured interview and observations of behaviour. The items ‘olfactory hallucinations’, ‘anhedonia’ and ‘depressed mood’ were selected, as impaired olfaction could be postulated to lead to decreased enjoyment of life. 2.2.9. The Neurological Evaluation Scale (Buchanan and Heinrichs, 1989) This was administered by a neurologist. It is a 26-item structured assessment of those neurological signs which are reported to have an increased incidence in schizophrenia. It provides a total score, item scores and scores for three functional areas (sensory integration, motor coordination and sequencing of complex motor acts) based on a conceptual consideration of neuroanatomy and frequently reported dysfunction in schizophrenia.
3. Results The group as a whole performed significantly below normal on olfactory identification. The details for men and women separately are shown in Table 1. The poor olfactory performance was not confined to males: only seven men (19%) and no women performed within the ‘normosmia’ range, i.e., at or above the 10th percentile for normal American subjects of the same age and gender, using Doty’s norms. The use of Australian norms showed 12 men (32%) and one woman (11%)
Table 1 Olfaction scores, smoking frequency and age of male and female schizophrenics Males (N=37)
Raw UPSIT score (max=40) UPSIT percentile Age Cigarettes/day
Females (N=9)
Mean (SD)
Range
Mean (SD)
Range
27 (7) 7 (14) 37 (8) 28 (24)
12–38 0–71 19–51 0–90
29 (4) 3 (6) 36 (8) 16 (21)
19–33 0–18 24–47 0–50
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T.J. Stedman, A.L. Clair / Schizophrenia Research 32 (1998) 23–30
scoring within the normal range. Seven men and one woman scored within the ‘anosmic’ range. Smokers (N=31) did not differ from non-smokers (N=15) on UPSIT raw or percentile scores. One-way analysis of covariance found that men and women did not differ on UPSIT percentile score with number of cigarettes per day as a covariate. Age of onset and duration of illness were not correlated with percentile scores. 3.1. Neurological and neuropsychological variables Examination of correlations revealed that the WAIS-R Information and Vocabulary subtests, WCST ‘failure to maintain set’, Rey Reproduction, total NES and the NES ‘Sensory Integration’ subscore were moderately correlated (r>0.3) with UPSIT percentile scores ( Table 2), while the correlations with the other variables were not. Bonferroni adjusted probabilities revealed that only the correlation between UPSIT percentile and WAIS-R Information reached statistical significance ( p<0.05). Since Total NES score and ‘sensory integration’ subscale (SI ) were very highly correlated (r= 0.837, p<0.001) and SI contributes to Total NES, multiple regression analysis was performed using SI as the more specific measure. Standard multiple regression between UPSIT
percentile as dependent variable and the moderately correlated set of cognitive variables and SI as independent variables was performed using SYSTAT MGLH following evaluation of assumptions. Table 2 displays the correlations between the variables, the unstandardised regression coefficients (B), the standardised regression coefficients ( b), and R, R2 and adjusted R2. R for regression was significantly different from zero, F = 5,32 5.083, p=0.002. Only two of the IVs contributed significantly to prediction of UPSIT percentile: WAIS-R Information and WCST Failure to Maintain Set. The variable set predicted 44% of the variability in UPSIT percentile scores. Stepwise multiple regression using the same variables found that WAIS-R Information and WCST Failure to Maintain Set alone accounted for 41% of the variance predicted (F =13.744, p<0.001). 2,40 3.2. Psychopathological variables Twelve subjects (26%)—10 men and two women—reported experiencing olfactory hallucinations in the preceding month. Bivariate correlations showed that UPSIT percentile was not associated with olfactory hallucinations, anhedonia, depressed mood or reported change in the sense of smell. It was noted incidentally that the presence of olfactory hallucinations was moder-
Table 2 Standard multiple regression of cognitive and neurological variables on olfactory identification percentile Variables
PSIT percentile (DV )
WAIS-R Info
WAIS-R Info WAIS-R Vocab WCST-FMS REY-Repro NES SI Mean SD
0.49 0.30 0.34 0.35 −0.31 6.48 12.82
0.71 −0.11 0.23 −0.49 9.68 2.78
WAIS-R Vocab
−0.13 0.22 −0.47 8.93 2.53
WCST FMS
0.13 −0.13 1.43 1.47
REY-Repro
−0.43 14.63 7.15
NES SI
1.92 2.22
B
b
2.78 −0.47 3.06 0.41 0.43 R2=0.44 Adjusted R2=0.36, R=0.66**
0.58* 0.09 0.33* 0.23 0.07
*p<0.05; **p<0.01. UPSIT, University of Pennsylvania Smell Identification Test; WAIS-R Info, Wechsler Adult Intelligence Scale-Revised Information score; WAIS-R Vocab, Wechsler Adult Intelligence Scale-Revised Vocabulary score; WCST-FMS, Wisconsin Card Sort Test Failure to Maintain Set score; Rey-Repro, Rey Complex Figure 5-min reproduction score; NES-SI, Neurological Evaluation Scale Sensory Integration score.
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T.J. Stedman, A.L. Clair / Schizophrenia Research 32 (1998) 23–30
ately associated with depressed mood (r=0.46) and with reported change in sense of smell (r= 0.39).
4. Discussion This study provides further support for the observation that many people with schizophrenia have deficits in olfactory identification. At least 72% of the group studied performed below the 10th percentile for the Australian population. The raw scores and percentile scores obtained are similar to the lower end of the ranges reported previously, suggesting that this sample is comparable with those already studied. This study does not contain a sufficient number of female subjects to robustly test possible gender differences; however, since eight of nine female subjects fell within the range of impaired scores, it is unlikely that these impairments are confined to male subjects. A major finding is that 41% of the variance in scores of olfactory identification was predicted by the Information subtest of the WAIS-R and the WCST Failure to Maintain Set score. WAIS-R Information subtest performance relies on retrieval from a fund of general knowledge and it is plausible that recognition of a variety of smells requires similar ability; however, it seems unlikely that general intelligence would account for 41% of the variance in olfactory identification. The role of ‘failure to maintain set’ is difficult to explain, as the direction of the association is opposite to what might have been predicted (i.e., the more times the subject lost set in the WCST, the higher the olfactory identification score was likely to be). In a previous study, Clair et al. (1994) showed that WCST-FMS clearly loaded with memory variables when a principal components analysis was applied to neuropsychological test scores of these schizophrenic subjects. Seidman et al. (1992) have presented evidence that impairments of the WCST variables ‘categories’ and ‘perseveration’ are associated with dorsolateral prefrontal cortex and suggested that impaired FMS may imply orbitofrontal dysfunction. These researchers also found that performance on ‘cate-
gories’ and ‘perseveration’ variables did not predict performance on the olfactory identification task within the schizophrenia group. The strongest correlations between neuropsychological variables and raw UPSIT scores were also with the WCST subset ‘Loss of set’(a categoric equivalent to the FMS measure) and the direction of the association was also opposite to what might have been expected. Although puzzling, it is of interest that our results replicate a previously reported association. The present study suggests that olfactory identification is congruent to some extent with general knowledge or general intelligence. Together these results support the proposition that poor olfactory performance is not the result of impaired effort, unsustained attention or defective concept formation. Contrary to the finding of Moberg et al. (1997), olfactory identification ability was not correlated with duration of illness. This may be the result of a much narrower age range in the present study. A modest correlation between the presence of ‘neurological signs’ and impaired olfactory identification was found. Most of this resulted from the ‘sensory integration’ subscore which consists of the items: audiovisual integration, stereognosis, graphesthesia, extinction and left–right confusion. The presence of these neurological signs was also associated with poorer performance on the WAIS-R Information subscale. Sensory Integration, however, did not contribute significantly to predicting olfactory identification in the multiple regression analysis. Estimates of the prevalence of olfactory hallucinations have ranged from 11% to 36% for schizophrenic subjects (Mueser et al., 1989; Kopala et al., 1994). The present study found that 26% (12 of 46) described olfactory hallucinations within the last month. No correlation was found between olfactory impairment and the presence of olfactory hallucinations. This lack of association was also evident in the study by Kopala et al. (1994). Olfactory impairments in schizophrenia could soon be considered a robust finding of schizophrenia research and should not be ignored as an avenue for advancing our understanding of this complex disorder. As olfactory impairment has
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been shown to be present at the outset of schizophrenia, the prognostic importance of this impairment would also be useful information. Interesting research questions arise from recent advances in the understanding of olfaction. For example, many hundreds of distinct odorant receptors have been identified recently and it is believed that odours interact through one of two second messenger systems (Ronnett and Snyder, 1992). When this is further clarified, it may become possible to test the two systems separately and to narrow the possible source of the impairment. Studies of the genetics of olfactory recognition have suggested that adults who are insensitive to the pheromonal steroid, androstenone, could all detect the odour as children, suggesting that some changes in olfactory abilities take place with adolescence (Beauchamp et al., 1991). The parallels with hypotheses which focus on the brain changes of adolescence in the development of schizophrenia are clear. Elucidation of the mechanisms of olfactory impairments in schizophrenia may provide an interesting avenue to explore this disorder.
Acknowledgment Thanks to Dr Peter Mann, Consultant Neurologist, for carrying out the neurological assessments. This work was supported by the Rebecca L. Cooper Medical Research Foundation.
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Malspina, D., Wray, A.D., Friedman, J.H., Amador, X., Yale, S., Hasan, A., Gorman, J.M., Kaufmann, C.A., 1994. Odor discriminationdeficits in schizophrenia: association with eye movement disfunction. J. Neuropsychiatry Clin. Neurosci. 6, 273–278. Moberg, P.J., Doty, R.L., Turetsky, B.I., Arnold, S.E., Mahr, R.N., Gur, R.C., Bilker, W., Gur, R.E., 1997. Olfactory identification deficits in schizophrenia: correlation with duration of illness. Am. J. Psychiatry 154, 1016–1018. Mueser, K.T., Bellack, A.S., Brady, E.U., 1989. Hallucinations in schizophrenia. Acta Psychiatr. Scand. 82, 26–29. Piedmont, R.L., Sokolove, R.L., Fleming, M.Z., 1989. On WAIS-R difference scores in a psychiatric sample. Psychol. Assessment 1, 155–159. Potter, H., Butters, N., 1980. An assessment of olfactory deficits in patients with damage to prefrontal cortex. Neuropsychologia 18, 621–628. Reitan, R.M., Wolfson, D., 1985. The Halstead–Reitan Neuropsychological Test Battery. Neuropsychology Press, Tucson, AZ. Rey, A., 1941. L’examen psychologique dans le cas d’encephalopathie traumatique. Arch. Psychol. 28, 286–340. Rey, A., 1964. L’Examen Clinique en Psychologie. Presses Universitaires de France, Paris. Ronnett, G.V., Snyder, S.H., 1992. Molecular messengers of olfaction. Trends Neurosci. 12, 508–513.
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Neuropsychological, neurological and symptom correlates of impaired olfactory identification in schizophrenia Terry J. Stedman a,b,*, Anne L. Clair c,d a Wolston Park Hospital, Wacol Q 4076, Australia b Department of Psychiatry, University of Queensland, St Lucia, Qld, Australia c Queensland Centre for Schizophrenia Research, Wolston Park Hospital, Wacol, Q 4076, Australia d School of Psychology, University of Queensland, St Lucia, Qld, Australia Received 28 January 1998; accepted 4 February 1998
Abstract Impaired olfactory identification has been reported in samples of schizophrenic patients. Little is known about the associations between these impairments and neuropsychological deficits, neurological deficits and olfaction-related symptoms. Forty-six subjects (37 men and 9 women) with schizophrenia were examined with the University of Pennsylvania Smell Identification Test ( UPSIT ), a selection of neuropsychological tests and standardised neurological and symptom evaluations. Eighty-five per cent of the subjects scored below the published norms’ 10th percentile on the UPSIT. Stepwise multiple regression found that WAIS-R Information score and Wisconsin Card Sort Test Failure to Maintain Set score ( WCST-FMS ) were the only significant predictors of the UPSIT percentile scores, accounting for 41% of the variance. Neurological signs did not contribute to the prediction of impaired olfactory identification. Although 26% of subjects reported olfactory hallucinations, there was no association between this symptom and olfactory impairment. The results suggest that general knowledge or general intelligence may have some influence on olfactory identification in subjects with schizophrenia; however, olfactory identification deficit could not be explained by gross impairments of sustained attention, memory or conceptual ability. © 1998 Elsevier Science B.V. All rights reserved. Keywords: Schizophrenia; Neuropsychology
Olfactory
identification;
Olfactory
1. Introduction The human olfactory system relies heavily on structures such as the entorhinal cortex, orbitofrontal cortex and lateral thalamic nuclei * Corresponding author. Present address: Wolston Park Hospital, Wacol Q 4076, Australia. Tel: +61 7 2718424; Fax: +61 7 2718567; e-mail [email protected] 0920-9964/98/$19.00 © 1998 Elsevier Science B.V. All rights reserved. PII: S0 9 20 - 9 96 4 ( 98 ) 00 0 2 1 -8
hallucinations;
Smell
Identification
Test;
( Freeman, 1991). As each of these brain regions has been implicated in the pathophysiology of schizophrenia, study of olfactory function provides an opportunity to explore some of the questions raised by these neuropathological findings. The availability of a practical test of indentification, the University of Pennsylvania Smell Identification Test ( UPSIT ), has greatly facilitated the study of this sense (Doty et al., 1984). To date, several
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publications have used this test with subjects suffering from schizophrenia and all have suggested the presence of a deficit in olfactory identification (Hurwitz et al., 1988; Kopala et al., 1989, 1992, 1994; Warner et al., 1990; Serby et al., 1990; Seidman et al., 1992; Wu et al., 1993; Good et al., 1994; Houlihan et al., 1994; Malspina et al., 1994; Brewer et al., 1996). In comparison, schizophrenic subjects have been found to perform in the normal range on another sensory task of equal complexity—the Colour Identification Test—suggesting that olfactory agnosia is not part of a general difficulty with sensory identification ( Kopala et al., 1995). Olfactory impairment is not uncommon in neuropsychiatric conditions. Impairment of olfactory identification has also been noted as a feature of Alzheimer’s disease (Doty et al., 1987), Parkinson’s disease (Doty et al., 1988), Alcoholic Amnestic Syndrome (Mair et al., 1986) and orbitofrontal lobe lesions (Potter and Butters, 1980). It has not been shown to be present in small groups of depressed, bipolar and eating disordered patients who have served as psychiatrically ill controls for schizophrenic patients ( Warner et al., 1990; Hurwitz et al., 1988; Kopala et al., 1994). While one study of nine patients with major depressive disorder found olfactory identification scores similar to the schizophrenic group being studied (Serby et al., 1990), a larger study of 51 subjects with major depressive disorder found no significant difference between these subjects and matched normal controls (Amsterdam et al., 1987). Hurwitz et al. (1988) compared 18 schizophrenic subjects with a non-schizophrenic psychiatric control group receiving antipsychotic drugs and with normal controls. Schizophrenic subjects performed significantly more poorly than did either of the control groups. A suggestion of better performance in the three women in the schizophrenic group in the initial study was expanded upon in the next study from this group ( Kopala et al., 1989). This compared 41 schizophrenic patients and 43 normal control subjects and again demonstrated marked impairment in the schizophrenic group. When the results were examined for gender differences, one of 15
female schizophrenic and 15 of 26 male schizophrenic subjects were classified using the tables adjusted for age and gender as demonstrating abnormally poor olfactory identification. Kopala et al. (1992) subsequently compared 30 men and 10 women who were suffering from schizophrenia and had never received antipsychotic drugs. Thirty-one per cent of these men and 10% of these women were found to perform below the normal range for olfactory identification, apparently supporting their observation of a gender difference in olfactory identification. Recently this group (Good et al., 1994) has compared 15 pre-menopausal and 12 post-menopausal women with schizophrenia and found post-menopausal women performed at a level similar to the male groups in their previous studies. On this occasion the pre-menopausal women also performed more poorly than a female control group. Houlihan et al. (1994) failed to find a gender difference when they compared 25 male and 22 female subjects with schizophrenia. The possibility that medication may influence olfactory identification has been examined directly. Kopala et al. (1992) demonstrated impaired olfactory identification in a group of 40 patients who had never received neuroleptic medication and concluded that these deficits were present early in the course of illness and were not produced by drug treatment; Wu et al. (1993) examined 14 never-medicated schizophrenic patients and six who were drug free for longer than 3 weeks. Both groups demonstrated poor olfactory identification. Two studies using non-schizophrenic psychiatric controls receiving neuroleptic medications have failed to demonstrate impairments in the control groups ( Warner et al., 1990; Hurwitz et al., 1988). Of the remaining six studies that utilised the UPSIT, two considered whether medication was a potential confounding variable (Seidman et al., 1992; Houlihan et al., 1994). Both failed to find a significant effect. Overall, there is no evidence to suggest that impairment of olfactory identification is a consequence of drug treatment. Various groups have speculated on the anatomic implications of impaired olfactory functions. However, only three studies have addressed this directly (Seidman et al., 1992, 1997; Wu et al., 1993; Clark et al., 1991). Seidman et al. (1992,
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1997) considered the UPSIT task and the Wisconsin Card Sort Test ( WCST ) to be orbitofrontal and dorsolateral frontal ‘probes’, respectively. Although they found the schizophrenia group to be impaired on both tasks, they found no correlation between olfactory impairment and performance on the WCST, WAIS-R Block Design or a sustained attention test, the Continuous Performance Task. They concluded that their results were not the result of a generalised impairment. Wu et al. (1993) administered the UPSIT, an olfactory match to sample task (a presumed olfactory memory test) and a comparable visual match to sample task. All three tests were performed significantly more poorly by the schizophrenic subjects than by normal controls. Correlation between test scores was high in the controls and low in the schizophrenic subjects. On the same day, subjects underwent Positron Emission Tomography while performing the Continuous Performance Task. UPSIT scores correlated significantly with activity of left middle and inferior frontal regions, while olfactory matching scores correlated significantly with activity of left temporal regions and visual matching scores correlated with the right caudate region. Clark et al. (1991) compared cerebral glucose metabolism in subjects with schizophrenia and olfactory agnosia with subjects with schizophrenia without olfactory agnosia, and found lower right basal ganglia and thalamic metabolism in subjects with schizophrenia and olfactory agnosia. This study aims to replicate the finding of impaired olfactory identification in schizophrenia, and to examine whether this is associated with impairments in attention, recognition memory, conceptual function and sensory integration. We also seek to investigate whether olfactory impairments are associated with clinical features of schizophrenia, such as olfactory hallucinations and anhedonia.
2. Methods 2.1. Subjects Thirty-seven men and nine women, with DSMIII-R diagnoses of schizophrenia ascertained by
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consensus of two clinicians, consented to participate. All were of white European background and aged between 19 and 51 years (mean=36.39, SD= 8.05). Fifteen were non-smokers, the remainder smoked between 15 and 90 cigarettes per day (mean=26, SD=23; median=25). Males and females did not differ on age or number of cigarettes smoked. Subjects were excluded if they had a current upper respiratory tract infection, past nasal trauma or disease, or a history of significant head injury or current substance dependence. All were symptomatically stable on antipsychotic medication (chlorpromazine equivalents mean=694, SD=807); some were also taking anti-cholinergic medication. Their mean current WAIS-R FSIQ was 89, with a standard deviation of 13 points. They were inpatients in a research ward for the purpose of participation; however, a substantial number usually resided in the community. 2.2. Measures and procedures 2.2.1. University of Pennsylvania Smell Identification Test (Doty et al., 1984) This is a standardised ‘scratch and sniff ’ task presented in multiple-choice format. Raw scores have been reported to be influenced by age, gender, ethnic background and smoking habit. Percentile scores which adjust for age and gender were used (Doty et al., 1984). Unpublished Australian norms were also available to the authors (A. McKaySim, personal communication, 1993). Subjects were questioned about age of onset of illness, and any subjective change or loss in the senses of smell or taste since that time. Duration of illness was defined as time between age of onset and date of study assessment, with information regarding date of first admission used if uncertainty existed. Subjects were undergoing a larger study of the neuropsychology of schizophrenia. The neuropsychological variables were selected from a larger set available, prior to the commencement of the study. Intelligence, attention, memory and conceptual abilities may be required for successful performance of the olfactory identification task; the variables selected to measure these abilities are given below.
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2.2.2. Wechsler Adult Intelligence Scale-Revised (Wechsler, 1981) The Information and Vocabulary subtest agescaled scores were used as measures of general intelligence. These subtest scores have been shown to have acceptable psychometric properties in similar psychiatric populations (Piedmont et al., 1989) 2.2.3. Letter Cancellation Task Error scores from a task similar to those used by Diller et al. (1974) were used as an indication of sustained attention. 2.2.4. Auditory Verbal Learning Test (Rey, 1964) After a 5-min delay, recognition of 15 learned words was tested by asking the subject to identify the words from a 50-word list. 2.2.5. The Complex Figure (Rey, 1941) The 5-min reproduction scores were used as a test of visuographic memory. 2.2.6. Wisconsin Card Sorting Test (WCST) This test is a measure of concept formation, maintenance and shift. The standarised instructions and procedure of Heaton (1981) and the WCST Scoring Program Version 3.0 by Harris (1988) were employed and the scores ‘categories’, ‘perseverative errors’ and ‘failure to maintain set’ were used. 2.2.7. Trail Making Test (Reitan and Wolfson, 1985) The difference in number of corrected errors between Parts A and B were used a measure of simple conceptual alternation.
2.2.8. Present State Examination 9th edition (Wing et al., 1977) This is a 140-item instrument comprising a structured interview and observations of behaviour. The items ‘olfactory hallucinations’, ‘anhedonia’ and ‘depressed mood’ were selected, as impaired olfaction could be postulated to lead to decreased enjoyment of life. 2.2.9. The Neurological Evaluation Scale (Buchanan and Heinrichs, 1989) This was administered by a neurologist. It is a 26-item structured assessment of those neurological signs which are reported to have an increased incidence in schizophrenia. It provides a total score, item scores and scores for three functional areas (sensory integration, motor coordination and sequencing of complex motor acts) based on a conceptual consideration of neuroanatomy and frequently reported dysfunction in schizophrenia.
3. Results The group as a whole performed significantly below normal on olfactory identification. The details for men and women separately are shown in Table 1. The poor olfactory performance was not confined to males: only seven men (19%) and no women performed within the ‘normosmia’ range, i.e., at or above the 10th percentile for normal American subjects of the same age and gender, using Doty’s norms. The use of Australian norms showed 12 men (32%) and one woman (11%)
Table 1 Olfaction scores, smoking frequency and age of male and female schizophrenics Males (N=37)
Raw UPSIT score (max=40) UPSIT percentile Age Cigarettes/day
Females (N=9)
Mean (SD)
Range
Mean (SD)
Range
27 (7) 7 (14) 37 (8) 28 (24)
12–38 0–71 19–51 0–90
29 (4) 3 (6) 36 (8) 16 (21)
19–33 0–18 24–47 0–50
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scoring within the normal range. Seven men and one woman scored within the ‘anosmic’ range. Smokers (N=31) did not differ from non-smokers (N=15) on UPSIT raw or percentile scores. One-way analysis of covariance found that men and women did not differ on UPSIT percentile score with number of cigarettes per day as a covariate. Age of onset and duration of illness were not correlated with percentile scores. 3.1. Neurological and neuropsychological variables Examination of correlations revealed that the WAIS-R Information and Vocabulary subtests, WCST ‘failure to maintain set’, Rey Reproduction, total NES and the NES ‘Sensory Integration’ subscore were moderately correlated (r>0.3) with UPSIT percentile scores ( Table 2), while the correlations with the other variables were not. Bonferroni adjusted probabilities revealed that only the correlation between UPSIT percentile and WAIS-R Information reached statistical significance ( p<0.05). Since Total NES score and ‘sensory integration’ subscale (SI ) were very highly correlated (r= 0.837, p<0.001) and SI contributes to Total NES, multiple regression analysis was performed using SI as the more specific measure. Standard multiple regression between UPSIT
percentile as dependent variable and the moderately correlated set of cognitive variables and SI as independent variables was performed using SYSTAT MGLH following evaluation of assumptions. Table 2 displays the correlations between the variables, the unstandardised regression coefficients (B), the standardised regression coefficients ( b), and R, R2 and adjusted R2. R for regression was significantly different from zero, F = 5,32 5.083, p=0.002. Only two of the IVs contributed significantly to prediction of UPSIT percentile: WAIS-R Information and WCST Failure to Maintain Set. The variable set predicted 44% of the variability in UPSIT percentile scores. Stepwise multiple regression using the same variables found that WAIS-R Information and WCST Failure to Maintain Set alone accounted for 41% of the variance predicted (F =13.744, p<0.001). 2,40 3.2. Psychopathological variables Twelve subjects (26%)—10 men and two women—reported experiencing olfactory hallucinations in the preceding month. Bivariate correlations showed that UPSIT percentile was not associated with olfactory hallucinations, anhedonia, depressed mood or reported change in the sense of smell. It was noted incidentally that the presence of olfactory hallucinations was moder-
Table 2 Standard multiple regression of cognitive and neurological variables on olfactory identification percentile Variables
PSIT percentile (DV )
WAIS-R Info
WAIS-R Info WAIS-R Vocab WCST-FMS REY-Repro NES SI Mean SD
0.49 0.30 0.34 0.35 −0.31 6.48 12.82
0.71 −0.11 0.23 −0.49 9.68 2.78
WAIS-R Vocab
−0.13 0.22 −0.47 8.93 2.53
WCST FMS
0.13 −0.13 1.43 1.47
REY-Repro
−0.43 14.63 7.15
NES SI
1.92 2.22
B
b
2.78 −0.47 3.06 0.41 0.43 R2=0.44 Adjusted R2=0.36, R=0.66**
0.58* 0.09 0.33* 0.23 0.07
*p<0.05; **p<0.01. UPSIT, University of Pennsylvania Smell Identification Test; WAIS-R Info, Wechsler Adult Intelligence Scale-Revised Information score; WAIS-R Vocab, Wechsler Adult Intelligence Scale-Revised Vocabulary score; WCST-FMS, Wisconsin Card Sort Test Failure to Maintain Set score; Rey-Repro, Rey Complex Figure 5-min reproduction score; NES-SI, Neurological Evaluation Scale Sensory Integration score.
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ately associated with depressed mood (r=0.46) and with reported change in sense of smell (r= 0.39).
4. Discussion This study provides further support for the observation that many people with schizophrenia have deficits in olfactory identification. At least 72% of the group studied performed below the 10th percentile for the Australian population. The raw scores and percentile scores obtained are similar to the lower end of the ranges reported previously, suggesting that this sample is comparable with those already studied. This study does not contain a sufficient number of female subjects to robustly test possible gender differences; however, since eight of nine female subjects fell within the range of impaired scores, it is unlikely that these impairments are confined to male subjects. A major finding is that 41% of the variance in scores of olfactory identification was predicted by the Information subtest of the WAIS-R and the WCST Failure to Maintain Set score. WAIS-R Information subtest performance relies on retrieval from a fund of general knowledge and it is plausible that recognition of a variety of smells requires similar ability; however, it seems unlikely that general intelligence would account for 41% of the variance in olfactory identification. The role of ‘failure to maintain set’ is difficult to explain, as the direction of the association is opposite to what might have been predicted (i.e., the more times the subject lost set in the WCST, the higher the olfactory identification score was likely to be). In a previous study, Clair et al. (1994) showed that WCST-FMS clearly loaded with memory variables when a principal components analysis was applied to neuropsychological test scores of these schizophrenic subjects. Seidman et al. (1992) have presented evidence that impairments of the WCST variables ‘categories’ and ‘perseveration’ are associated with dorsolateral prefrontal cortex and suggested that impaired FMS may imply orbitofrontal dysfunction. These researchers also found that performance on ‘cate-
gories’ and ‘perseveration’ variables did not predict performance on the olfactory identification task within the schizophrenia group. The strongest correlations between neuropsychological variables and raw UPSIT scores were also with the WCST subset ‘Loss of set’(a categoric equivalent to the FMS measure) and the direction of the association was also opposite to what might have been expected. Although puzzling, it is of interest that our results replicate a previously reported association. The present study suggests that olfactory identification is congruent to some extent with general knowledge or general intelligence. Together these results support the proposition that poor olfactory performance is not the result of impaired effort, unsustained attention or defective concept formation. Contrary to the finding of Moberg et al. (1997), olfactory identification ability was not correlated with duration of illness. This may be the result of a much narrower age range in the present study. A modest correlation between the presence of ‘neurological signs’ and impaired olfactory identification was found. Most of this resulted from the ‘sensory integration’ subscore which consists of the items: audiovisual integration, stereognosis, graphesthesia, extinction and left–right confusion. The presence of these neurological signs was also associated with poorer performance on the WAIS-R Information subscale. Sensory Integration, however, did not contribute significantly to predicting olfactory identification in the multiple regression analysis. Estimates of the prevalence of olfactory hallucinations have ranged from 11% to 36% for schizophrenic subjects (Mueser et al., 1989; Kopala et al., 1994). The present study found that 26% (12 of 46) described olfactory hallucinations within the last month. No correlation was found between olfactory impairment and the presence of olfactory hallucinations. This lack of association was also evident in the study by Kopala et al. (1994). Olfactory impairments in schizophrenia could soon be considered a robust finding of schizophrenia research and should not be ignored as an avenue for advancing our understanding of this complex disorder. As olfactory impairment has
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been shown to be present at the outset of schizophrenia, the prognostic importance of this impairment would also be useful information. Interesting research questions arise from recent advances in the understanding of olfaction. For example, many hundreds of distinct odorant receptors have been identified recently and it is believed that odours interact through one of two second messenger systems (Ronnett and Snyder, 1992). When this is further clarified, it may become possible to test the two systems separately and to narrow the possible source of the impairment. Studies of the genetics of olfactory recognition have suggested that adults who are insensitive to the pheromonal steroid, androstenone, could all detect the odour as children, suggesting that some changes in olfactory abilities take place with adolescence (Beauchamp et al., 1991). The parallels with hypotheses which focus on the brain changes of adolescence in the development of schizophrenia are clear. Elucidation of the mechanisms of olfactory impairments in schizophrenia may provide an interesting avenue to explore this disorder.
Acknowledgment Thanks to Dr Peter Mann, Consultant Neurologist, for carrying out the neurological assessments. This work was supported by the Rebecca L. Cooper Medical Research Foundation.
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