Abstract

Olfactory identification deficits in schizophrenia patients are well documented. Less is known about the functioning of other olfactory domains and the possibility of lateralized dysfunctions. Thirty male schizophrenia patients and 30 male healthy controls underwent unirhinal assessment of various olfactory domains: detection threshold (dimethyl disulfide, phenyl ethanol), quality discrimination, and odor ratings (familiarity, pleasantness, edibility, intensity) of pure chemicals (Munich Olfaction Test), as well as familiarity and edibility judgments and identification of everyday odors. Aside from impaired identification, patients showed impaired familiarity and edibility judgments of everyday odors. With regard to odor ratings of pure chemicals, group differences were observed only in pleasantness ratings, with higher ratings in patients. Furthermore, patients had reduced sensitivity with dimethyl disulfide and reduced quality discrimination compared with controls. Further analyses showed that identification deficits were not attributable to reduced sensitivity but may be associated with impairments in quality discrimination. Olfactory dysfunctions were found across both nostrils. Results suggest specific dysfunctions in olfactory processing in schizophrenia patients, including early stages of the odor identification process.

Introduction

Given that neuroanatomical regions, particularly prefrontal and medial-temporal regions (see Eslinger et al. 1982; Pantelis and Brewer 1995; Shipley and Ennis 1996; Christensen and Bilder 2000), involved in olfactory processing have also been implicated in the pathophysiology of schizophrenia, interest in olfactory processing in this disorder has grown in recent years (Moberg et al. 1999; Rupp 2003). Assessing olfactory functions may provide information regarding the integrity of these brain areas. Clinical relevance of assessing olfactory dysfunction, furthermore, has been described in terms of the potential of a vulnerability marker that may be valuable for differential diagnosis (i.e., for differentiating between biologically distinct subtypes of this heterogeneous disorder). This seems supported by findings suggesting a possible genetic contribution to dysfunctional olfactory processing in schizophrenia, or psychosis, respectively (Kopala et al. 1991, 1998, 2001; Becker et al. 1993; Kwapil et al. 1996).

To date, the finding of reduced odor identification performance in patients with schizophrenia, mostly assessed with the University of Pennsylvania Smell Identification Test (UPSIT; Doty et al. 1984), is well documented (Hurwitz et al. 1988; Serby et al. 1990; Kopala et al. 1992, 1994, 1995; Wu et al. 1993; Houlihan et al. 1994; Malaspina et al. 1994; Brewer et al. 1996, 2001; Seidman et al. 1997; Moberg et al. 1997a, 1997b, 1999). Research suggests that identification deficits are not attributable to smoking (Kopala et al. 1992; Houlihan et al. 1994; Brewer et al. 1996), olfactory hallucinations (Kopala et al. 1992, 1994; Stedman and Clair 1998), or medication (Kopala et al. 1992; Wu et al. 1993; Brewer et al. 1996, 2001). Whether identification deficits are associated with negative symptoms is still controversial (Malaspina et al. 1994; Brewer et al. 1996, 2001; Good et al. 1998, 2002).

However, olfactory identification deficits are not specific to schizophrenia. They were seen in patients with affective and other forms of psychoses (Brewer et al. 2001), as well as in a wide variety of brain disorders and diseases (see Martzke et al. 1997; Doty 2001). Given the wide range of disorders accompanied by olfactory identification impairment, a single etiology seems unlikely, and the utility of this deficit as a marker for schizophrenia remains unclear.

Odor identification, as assessed in a multiple-choice test procedure (e.g., UPSIT), requires subjects to perceive, recognize, and select the name of the previously smelled odor from a list. The question of a cognitive basis for identification deficits in schizophrenia was first raised by Serby et al. (1990), who failed to find identification deficits in a yes/no identification task. Several other studies have since indicated a link between impairments in UPSIT performance and cognitive functions in schizophrenia (Brewer et al. 1996; Seidman et al. 1997; Purdon 1998; Stedman and Clair 1998; Good et al. 2002).

With regard to olfactory processing, odor identification requires accurate odor detection (sensitivity) and quality discrimination. Moberg et al. (1999), in their meta-analyses on olfactory functions in schizophrenia, observed substantial olfactory deficits across all domains, including identification, memory, detection threshold, and discrimination. Unfortunately, none of these studies assessed the basic olfactory functions within a sample. The interpretation of data pertaining to more “secondary” or “higher order” olfactory processing (e.g., identification) is possible only within the context of available data about the integrity of the “primary” sensory systems (e.g., intact sensitivity) (Martzke et al. 1997), a premise routinely applied in other fields of neurobehavioral assessment. It may be worthwhile to note that the characterization as primary and secondary olfactory measures only maintains an appreciation for the latter's (higher order) dependence upon the former (Martzke et al. 1997). This does not rule out an influence of central processes in all olfactory measures. Identification (higher order) in general requires accurate sensitivity and odor discrimination (both lower order), and discrimination requires accurate sensitivity but not necessarily identification or naming of an odor. Thus, a finding of reduced sensitivity potentially limits the significance of reported deficits in, for instance, identification (Martzke et al. 1997). Furthermore, in the meta-analyses of Moberg et al. (1999) the number of studies that used detection threshold and discrimination was extremely limited (four and two studies, respectively). Meanwhile, no further study has assessed misperception via discrimination, also described as a linking process between threshold and identification (de Wijk and Cain 1994), in schizophrenia. The findings concerning threshold are also controversial. Results range from hypersensitivity (Bradley 1984; Sirota et al. 1999) to intact sensitivity (Geddes et al. 1991; Kopala et al. 1992; Good et al. 1998; Striebel et al. 1999; Kohler et al. 2001) and hyposensitivity (Gross-Isseroff et al. 1987; Serby et al. 1990; Sirota et al. 1999).

Because the olfactory system is unique among the senses in that second order neurons send information directly, with primarily ipsilateral projections, unirhinal assessment of olfactory functions provides an interesting opportunity to probe for asymmetric neuropathology. The few studies that have investigated higher order identification have found poor performance across nostrils (Good et al. 1998; Kohler et al. 2001). Only analyses of post hoc defined subgroups (Good et al. 1998) revealed that unirhinally impaired patients were more likely to have a left (left < right) rather than a right (right < left) nostril disadvantage in identification (Good et al. 2002). A match-to-sample task also failed to demonstrate atypical asymmetry (Dunn and Weller 1989). Contrary to these findings, Purdon and Flor-Henry (2000) found an asymmetrical left nostril impairment in sensitivity in unmedicated patients.

In summary, the present study was undertaken to extend prior research by exploring various olfactory domains unirhinally in a within-subjects experimental design. Following a multivariate approach to behavioral measurement in olfaction, we included tasks tapping basic olfactory domains such as sensitivity (detection threshold) and quality discrimination, odor identification, and ratings about odors such as familiarity, edibility, pleasantness, and intensity (Eslinger et al. 1982; Royet et al. 1999; Zald and Pardo 2000). We hypothesized that male schizophrenia patients would demonstrate deficits in olfactory domains aside from impaired higher order identification. The second aim was to assess whether the same patients would show abnormal patterns of laterality in these olfactory functions.

Methods

Subjects

Thirty male patients meeting DSM–IV criteria (American Psychiatric Association 1994) for schizophrenia and 30 male healthy controls with no history of central nervous system disease and a negative family history (among first degree relatives) of mental disorder participated in the study. The two groups were comparable in age and smoking status. Demographic and clinical characteristics of the sample are illustrated in table 1.

Two senior psychiatrists independently diagnosed all patients. Three were outpatients and the remaining 27 were inpatients treated at the Department of Psychiatry, Innsbruck Medical University. Controls were mainly recruited within the medical center and screened with a semistructured interview. Most of them were male nurses or other hospital staff. Exclusion criteria were (1) history of a psychiatric disorder (other than schizophrenia for the patient group), (2) history of a neurological disorder or head injury with loss of consciousness, (3) history of electroconvulsive therapy, (4) substance dependence or (recent) substance abuse (Rupp et al. 2003), (5) medical conditions that could alter cerebral functioning, and (6) other conditions known to affect olfactory functioning (e.g., upper respiratory tract infection). Psychiatrists (H.O., C.W.), who were blind to patients' olfactory status, rated symptom severity using the Positive and Negative Syndrome Scale (PANSS; Kay et al. 1987). All subjects had an otorhinolaryngological (ENT) examination, including inspection of the outer nose, the nasal cavity, and the transnasal airflow. ENT findings were graded on a five-point scale (1 = no pathological finding, 2 = septum deviation, 3 = concha hyperplasia, 4 = moderate acute or chronic mucositis, and 5 = complete obstruction of the nasal cavity by acute or chronic paranasal sinuses, acute or chronic rhinitis, trauma, or tumor). Subjects rated 5 were not entered into the study. Handedness preference was assessed using the Edinburgh Handedness Inventory (EHI; Oldfield 1971). Subjects with a laterality quotient > 0.70 were classified as dextral. After complete description of the study to the subjects, written informed consent was obtained prior to participation. None of the subjects had previously undergone an olfactory assessment.

Olfactory Testing

Olfactory measures

Using a slightly modified version of the Munich Olfaction Test (MOT) (cf. Kruggel 1989, 1993; Diekmann et al. 1994; Hudson et al. 1994), we assessed the following olfactory domains: detection threshold (sensitivity), (quality) discrimination, and ratings of familiarity, pleasantness, and edibility. Modifications of the MOT consisted of an extra dilution step (detection threshold) and an additional intensity rating. Test and retest reliability for the threshold and discrimination have been described (threshold 0.92, discrimination 0.96; Kruggel 1989). Except for the detection threshold task (sodium tetraborate), the substances were diluted with diethyl phthalate and presented in concentrations sufficiently above threshold to be easily detected by normosmics.

All odors were presented in 250 mL polyethylene squeeze bottles with a flip-up spout equipped with an exchangeable handmade Teflon nosepiece that fit snugly into the subject's nostril, allowing testing of each nostril separately (Eskenazi et al. 1986; Laska and Hudson 1991; Cain et al. 1992; Martinez et al. 1993; Laska and Teubner 1999; Mohr et al. 2001).

The detection threshold task (sensitivity) consisted of a geometric dilution set of phenyl ethanol (pleasant; 1 g/L) and dimethyl disulfide (unpleasant; 0.2 g/L), successively diluted by factor 5. Thresholds were measured using an ascending triple-forced choice procedure, starting with the lowest concentration (no. 1). With variations (two vs. three alternatives; ascending vs. descending procedures), this kind of method of limits is widely used to establish thresholds in basic research (e.g., Laska and Hudson 1991; Laska and Teubner 1999; Lehrner et al. 1999), clinical research (e.g., Eskenazi et al. 1983, 1986; Cain et al. 1988; Jones-Gotman and Zatorre 1988; Zatorre and Jones-Gotman 1991; Martinez et al. 1993; Lehrner et al. 1997; Mohr et al. 2001), and research in schizophrenia (e.g., Serby et al. 1990; Striebel et al. 1999; Purdon and Flor-Henry 2000). In brief, three bottles were presented in random order, two containing the pure diluent and the third the odor at a certain dilution. Threshold was defined as the weakest concentration of solution for which the subject was able to select the odor-containing bottle correctly on two consecutive trials. If a subject failed on step no.7, they got the triplet with the stock solution bottles (no. 8; 5 g/L).

In the quality discrimination task, eight triplets of bottles were presented in random order, with two containing the same odor and the third a different one (citronellyl1 nitrile vs. methylpyrrolidine, phenyl ethanol vs. dimethyl disulfide, pyridine vs. butanol, t-butylcyclohexyl acetate vs. cyclopentadecanone, 2-methyl-4-phenyl-2-butanol vs. dihydrorose oxide, eugenol vs. anethole, octyl acetate vs. decyl acetate, allylcapronat vs. amylpropionate). Subjects had to determine which of the three bottles smelled different (Eskenazi et al. 1983; Martinez et al. 1993; Hummel et al. 1997; Laska and Teubner 1999; Mohr et al. 2001).

For the ratings of familiarity, pleasantness, edibility, and intensity, subjects were successively presented with eight odors (methyl cinnamate, methylpyrrolidine, cyclopentadecanone, (-)-carvone, pyridine, 5α-androst-16-en–3-one, isoamyl acetate, eugenol) and asked to rate them using linear rating scales from −5 (extremely negative) to 5 (extremely positive) (e.g., Ayabe-Kanamura et al. 1998; Distel et al. 1999; Herz et al. 1999).

To assess olfactory identification, we employed commonly known everyday odors—real-world items. The reasons for this are manifold. First, identification deficits are well documented in schizophrenia employing the UPSIT, which has no adequate German version; because some of the odors and descriptors used in the test are nearly unknown in our culture, the test cannot be used without adaptation. Second, everyday odors, possibly achieving maximum ecological validity, are widely used in both basic and clinical research of identification (e.g., Larsson and Bäckman 1997; Lehrner et al. 1997, 1999; Ayabe-Kanamura et al. 1998; Cain et al. 1998; Distel et al. 1999; Lehrner and Deecke 2000). Furthermore, the use of everyday odors enables assessment of categorical identification of real-world items (e.g., edibility judgments) (Larsson 1997; Ayabe-Kanamura et al. 1998; Distel et al. 1999; Olsson and Fridén 2001). Categorical identification does not necessarily require the knowledge of odor names or precise identification (Schab 1991; Larsson 1997; Olsson and Fridén 2001). Finally, assessing odor identification by using squeeze bottles allows the subject to smell and select the response (name) simultaneously.

Identification was assessed using a multiple-forced-choice task format. Selection of odors (and descriptors) mainly derived from research by Lehrner et al. (1997, 1999, 2000). In brief, subjects were required to identify the odor from sets of four alternative descriptors: chocolate (garlic, gasoline, cleaner), mustard (fish, tomato, mayonnaise), pencil shavings (marzipan, salami, detergent), coffee (tea, hazelnut, potato chips), cigarette butt (rubber, cigar, tobacco pipe), cinnamon (melon, blueberry, vanilla), peppermint (liquorice, beer, tar), and peanut (rye bread, wine, lemon).

Judgments for familiarity and edibility of everyday odors were assessed prior to identification (yes/no/don't know).

Identification and judgments of everyday odors were scored as accurate = 1 and incorrect = 0 (including a “don't know” answer). To minimize visual, acoustic, or proprioceptive cues in these tasks, everyday odors were secured in disposable teapot filter bags, and these were suspended inside the bottles (Ayabe-Kanamura et al. 1998).

Procedure

At the beginning of each test session, subjects were allowed time to familiarize themselves with the bottles and with the sampling technique. Olfactory measurements were performed separately for the left and right nostrils. The testing sequence was randomized by a predetermined order related to day and time of testing (10 a.m., 1 p.m., and 4 p.m.) and counterbalanced between groups: half of each group started with the right nostril (R–L) and half of each group with the left nostril (L–R). Individual testing lasted 1½ to 2 hours, including a break of about 10 minutes after the completion of the first nostril testing. Subjects were not given feedback on their performance. All subjects were told not to use perfumes or perfumed cosmetics on the day of olfactory testing. They were also instructed to eat nothing, to drink only water, and to refrain from smoking at least ½ hour before commencement of testing. Testing took place in a quiet, odorless, and well-ventilated room. Using a semistructured interview at the end of a test session (Kruggel 1993), we interviewed subjects about olfactory experiences, hallucinations, and changes they had experienced, either before or since illness onset.

Statistical Analyses

Data were analyzed using SPSS (version 11.0.1). Group comparisons with respect to demographic and clinical characteristics were evaluated by t tests or Fisher's exact test. To test our hypotheses and to assess the main effects of group (schizophrenia vs. controls) and the statistical interaction between group and tested side (left vs. right) on olfactory measures, data were analyzed using multiple analysis of variance (MANOVA). To limit the number of dependent variables considered in a single MANOVA, the total set of ten olfactory measures was divided into two subsets: olfactory performance (detection threshold, discrimination, identification, and edibility and familiarity judgments of everyday odors) and olfactory ratings (MOT; familiarity, pleasantness, edibility, and intensity), each of which was analyzed in a separate MANOVA (within-subjects factors side and olfactory measure, between-subjects factor group). If the main effect of group or the group-by-side interaction was found to be statistically significant, subsequent univariate analyses (repeated-measures analyses of variance [ANOVAs] with side as the within-subjects factor and group as the between-subjects factor) were performed. To facilitate the comparison of group effects across the individual olfactory measures, effect sizes were calculated as the difference between the mean scores in the patient group and the control group divided by the standard deviation of the measure in the control group.

To test for possible effects of age and smoking, MANOVAs as above with the additional covariates age and smoking were carried out; subsequent univariate analyses were performed if at least one of the covariates or its interaction with group showed a significant effect in the MANOVA. To check for group differences in performance over test sessions (first vs. second test session), MANOVAs as above (within-subjects factors session and olfactory measure, between-subjects factor group) were performed. Finally, we studied whether deficits in secondary (higher order) main olfactory domains (e.g., identification, discrimination) are merely a consequence of primary (lower order) olfactory deficits (e.g., threshold) or whether these deficits exist independently. This was performed by repeated-measures analyses of covariance (ANCOVAs) using the higher order olfactory measure of interest as the dependent variable and including the score of the lower order measure as a covariate (within-subjects factor side, between-subjects factor group).

Within patients, separate MANOVAs (within-subjects factors side and olfactory measure) with psychopathology ratings (PANSS positive, negative, and total) as covariates were performed. To compare patients with and without olfactory hallucinations (or deviant olfactory experiences), separate MANOVAs with the same within-subjects factors as above and olfactory hallucinations (or deviant olfactory experiences) as the between-subjects factor were performed.

Results

Subject Characteristics

Table 1 presents the demographic and clinical characteristics of all subjects. Patients and controls did not differ in terms of age and smoking characteristics. Controls had significantly higher levels of education, but all subjects had completed at least 8 years of grade school. There was no significant difference between groups in handedness preference (EHI), and no differences were observed with regard to the ENT examination (chi-square test; Fisher's exact test for comparison of groups divided into with and without [1] a pathological finding [2–4]).

At the time of assessment, half of the patient group suffered from olfactory hallucinations (n = 4) or deviant olfactory experiences (n = 11). Only 2 patients reported them to be pleasant, with 11 patients reporting unpleasant experiences. The rest (50%) definitively denied having olfactory hallucinations or deviant olfactory experiences. In terms of olfactory perception history, 5 patients associated a self-reported enhanced olfactory perception with the beginning of their illness, and 4 described a reduction, which most associated with medication intake (n = 3).

Olfactory Performance

The MANOVAs showed a significant effect of group on olfactory performance (detection threshold: phenyl ethanol, dimethyl disulfide; discrimination, identification, and edibility and familiarity judgments of everyday odors) (table 2). Subsequent repeated-measures ANOVAs revealed a significant effect of group in all olfactory measures except the detection threshold with phenyl ethanol. Patients showed a significantly higher threshold (lower sensitivity) with dimethyl disulfide and significantly lower mean scores in discrimination, identification, and correct edibility and familiarity judgments of everyday odors. The effect sizes for the group differences in these measures were moderately high, ranging from 0.65 (identification) to 1.08 (discrimination). No significant main effect of side, or group-by-side interaction, was observed.

A significant effect of age on olfactory performance was observed in the MANOVA; subsequent repeated-measures ANOVAs revealed an effect of age on discrimination, indicating a decrease with increasing age (de Wijk and Cain 1994; Hummel et al. 1997). No significant effect on olfactory performance was observed for the covariate smoking or for its interaction with group. The same held true by controlling for effects of education. MANOVAs controlling for effects of session showed a significant effect of session on olfactory performance (F = 6.799, df = 6, 53, p < 0.001); subsequent repeated-measures ANOVAs revealed a significant effect of session on identification (F = 8.006, df = 1, 58, p = 0.006) and correct judgments of edibility (F = 8.778, df = 1, 58, p = 0.004) and familiarity (F = 18.265, df = 1, 58, p < 0.001) of everyday odors, indicating an improvement from the first to the second nostril testing. However, as there was no significant interaction between session and group, the significant effect of group on these measures was not affected by this finding.

Repeated-measures ANCOVAs adding the olfactory measure to control for as a covariate demonstrated that the differences in discrimination and identification between groups remained significant even after controlling for detection thresholds (discrimination with phenyl ethanol: F = 13.650, df = 1, 57, p < 0.001; with dimethyl disulfide: F = 10.646, df = 1, 57, p = 0.002; identification with phenyl ethanol: F = 5.099, df = 1, 57, p = 0.028; with dimethyl disulfide: F = 7.301, df = 1, 57, p = 0.009). However, the significant group difference in identification disappeared after controlling for differences in quality discrimination (F = 1.718, df = 1, 57, p > 0.1).

Olfactory Ratings (MOT)

The separate MANOVAs with the olfactory ratings (MOT; familiarity, pleasantness, edibility, and intensity) also showed a significant effect of group (table 2). Subsequent repeated-measures ANOVAs revealed a significant effect of group for only the pleasantness ratings. Patients showed significantly higher pleasantness ratings than controls. No significant main effect of side, or group-by-side interaction, was observed.

No significant effect was found for age or smoking as covariates or for their interaction with group. MANOVAs controlling for effects of session showed a trend toward an effect of session on olfactory ratings (F = 2.533, df = 4, 55, p = 0.050); subsequent repeated-measures ANOVAs revealed a significant effect of session on familiarity (F = 6.525, df = 1, 58, p = 0.013) and edibility ratings (F = 7.991, df = 1, 58, p = 0.006), indicating an increase in these ratings from the first to the second nostril testing. However, again no significant session-by-group interaction was observed.

Relation to Psychiatric Symptoms

MANOVAs (olfactory performance, olfactory ratings) with PANSS scores (positive, negative, and total) as covariates revealed no significant effect. Additional MANOVAs (olfactory performance, olfactory ratings) comparing patients with (n = 15) and without (n = 15) olfactory hallucinations or deviant olfactory experiences revealed no significant main effect of group or group-by-side interaction.

Discussion

To our knowledge, this is the first study investigating various olfactory domains unirhinally within a sample of male schizophrenia patients and healthy controls. The main findings of this study are (1) male patients with schizophrenia showed impaired identification of everyday odors, (2) these everyday odors were less familiar to patients, and (3) they judged everyday odors less correctly concerning edibility; (4) furthermore, the same patients showed reduced sensitivity with dimethyl disulfide and (5) impaired quality discrimination; (6) olfactory ratings of pure chemicals revealed higher pleasantness ratings in patients compared with controls; moreover, (7) no abnormal laterality in olfactory measures was found in patients. All observed olfactory dysfunctions were present bilaterally.

Results indicate that observed olfactory dysfunctions cannot be explained by the influence of smoking, olfactory hallucinations, or test sessions. No association was found between olfactory performance and psychiatric symptoms. With regard to medication, although a potential contribution from long-term antipsychotic treatment cannot be excluded (Moberg et al. 1997b), previous research has failed to indicate medication effects (Kopala et al. 1992; Wu et al. 1993; Moberg et al. 1999; Brewer et al. 2001). In addition, a potential detrimental effect of medication on sensitivity (Sirota et al. 1999) would have most likely reduced sensitivity for both odors, dimethyl disulfide and phenyl ethanol. Purdon and Flor-Henry (2000) have observed that an asymmetrical left nostril impairment in detection thresholds in patients dissipated with medication treatment. Therefore, our findings in a medicated sample, which do not provide evidence for any asymmetrical olfactory deficit, have to be interpreted with this fact in mind. In any case, the fact that we observed olfactory dysfunctions across both nostrils suggests dysfunctional processing of olfactory brain regions in both hemispheres, at least in medicated patients with schizophrenia.

Our study replicates previous findings of impaired identification in schizophrenia patients (Hurwitz et al. 1988; Serby et al. 1990; Kopala et al. 1992, 1994, 1995; Wu et al. 1993; Houlihan et al. 1994; Malaspina et al. 1994; Brewer et al. 1996, 2001; Seidman et al. 1997; Moberg et al. 1997a, 1997b, 1999) and extends them, in so far as our results indicate that patients have reduced ability to identify everyday odors. Furthermore, as odor identification has been viewed as a continuum of informational specificity, ranging from nonverbal feelings of familiarity to specific object names (Schab 1991; Larsson 1997), impaired familiarity and edibility judgments in our patients suggest impaired semantic knowledge of everyday odors. Aside from implications for subjects' real-life experiences, these findings demonstrate that schizophrenia patients show dysfunctions in olfactory processing that do not necessarily require the knowledge of odor names or precise identification.

The hypothesis of dysfunctions in early stages of olfactory processing in schizophrenia patients is further supported by our findings of reduced sensitivity (dimethyl disulfide) and quality discrimination, which are in keeping with Moberg et al.'s (1999) meta-analysis. For the first time, the present study demonstrates sensitivity, discrimination, and identification deficits within the same patient sample. Identification and discrimination impairments cannot be explained by reduced sensitivity. Our results indicate that deficits in (verbal) identification may reflect impaired (nonverbal) quality discrimination. Although not completely devoid of cognitive demands, odor discrimination has been proposed to be a useful measure of alterations in olfactory functioning, if cognitive limitations are an issue (de Wijk and Cain 1994). We submit that verbal or semantic factors, previously observed to influence even discrimination performance (Savic and Berglund 2000), cannot explain our finding of reduced discrimination in patients. A semantic influence in olfaction refers to a subject's general knowledge of an odor and is usually expressed by odor identification and familiarity ratings (Schab 1991; Schab and Cain 1991; Larsson 1997; Savic and Berglund 2000). Because our (nonverbal) discrimination task used pure chemicals, which in general were not very familiar to either group, and furthermore, because patients and controls did not differ in familiarity and edibility ratings of these odors, it seems unlikely that semantic or verbal factors played a major role for discrimination deficits. Moreover, the finding of comparable performance in the detection threshold task with phenyl ethanol, using the same task format, also argues against the fact that the observed discrimination deficits in patients were due to cognitive impairment related to task complexity. As we found no effect of test session in these tasks, attentional problems due to test duration are also an unlikely explanation of our findings. Thus, we suggest that schizophrenia patients suffer from an impairment of odor quality discrimination that could be related to misperception. Errors in identification seem to arise from such discrimination deficits, recently also observed in young male patients with schizophrenia (Rupp et al. 2000).

Our results argue against a generalized olfactory impairment. Dysfunctions seem specific to different types of olfactory processing. With regard to odor ratings, which some have suggested represent steps in the odor name identification process (Royet et al. 1999, 2001), we and others (Hudry et al. 2002; Moberg et al. 2003) found no impairments in intensity ratings. Of interest, in contrast to the everyday odors, pure chemicals were not perceived differently by patients and controls with regard to familiarity and edibility ratings, and patients showed higher pleasantness ratings. A possible explanation may be related to the familiarity of the odors used. Recently, Hudry et al. (2002) found lower pleasantness and disturbed edibility ratings of odors that also showed lower familiarity in schizophrenia patients compared with healthy controls. The level of familiarity may be regarded as a continuum covering the subject's implicit level of odor knowledge, with a high familiarity rating presumably reflecting more specific knowledge about an odor (e.g., about edibility) (Larsson 1997). Thus, it can be assumed that group differences in odor familiarity ratings should also have their expression in ratings such as edibility, as we have found for everyday odors. Aside from odor properties, another interesting aspect of odor pleasantness derives from a recent observation by Crespo-Facorro et al. (2001), who suggested that there may be an association between psychotic symptoms and unpleasantness of an unpleasant odor. We could not replicate this association, but differences in symptomatology between our sample and that reported by Hudry et al. (2002) could explain the divergent findings. More similar to our findings, higher pleasantness ratings were found in a psychosis-prone sample with high scores in physical anhedonia (Becker et al. 1993). Moreover, and consistent with our findings of higher pleasantness ratings in patients, a recent study by Moberg et al. (2003) observed that male schizophrenia patients tended to rate only low odor concentrations as less pleasant, while higher odor concentrations also showed higher pleasantness ratings. All evidence taken together, olfactory hedonic valence in schizophrenia merits further studies in more homogeneous patient samples and with a careful selection of odors and odor properties such as familiarity and (stimulus) intensity.

With regard to detection thresholds, our controversial observation concerning sensitivity reflects the existing literature (Gross-Isseroff et al. 1987; Serby et al. 1990; Geddes et al. 1991; Kopala et al. 1992; Good et al. 1998; Sirota et al. 1999; Striebel et al. 1999; Kohler et al. 2001). Because we found intact and reduced sensitivity within a sample, and over both sessions, a detrimental effect of medication (Sirota et al. 1999) or cognitive impairment associated with task complexity seems an unlikely explanation. The most salient difference between the odors used in our study is their hedonic valence. So far, all studies including pleasantness ratings have observed disturbances in the hedonic experience of odors in patients with schizophrenia (Crespo-Facorro et al. 2001; Hudry et al. 2002; Moberg et al. 2003). It can be hypothesized that our finding of reduced sensitivity for dimethyl disulfide (unpleasant) but not for phenyl ethanol (pleasant) is related to the odors' hedonic valence, namely, the unpleasantness of dimethyl disulfide. Research using imaging technologies (Becker et al. 1993; Crespo-Facorro et al. 2001) revealed dysfunctions particularly in the processing of unpleasant stimuli. Becker et al. (1993) hypothesized that their finding of smallest olfactory event-related potential amplitudes in a psychosis-prone subgroup after stimulation with the unpleasant odor can be explained as a higher threshold for the perception of unpleasant odors.

The current knowledge about human olfaction suggests that functional olfactory processing depends upon many factors, including olfactory functions (tasks) and odor properties (e.g., familiarity, pleasantness) (Savic et al. 1997; Zald and Pardo 1997, 2000; Savic and Berglund 2000; Brand et al. 2001; Savic 2002; Anderson et al. 2003). Different olfactory functions (tasks) and odors may be processed, and therefore impaired, differently. Prefrontal cortical areas and medial-temporal, subcortical connections are associated with the pathophysiology of schizophrenia (Christensen and Bilder 2000). The investigation of functions such as olfactory function, which are mediated by these neuronal pathways, are thought to provide some clues as to the nature of this heterogeneous disorder (Pantelis and Brewer 1995). The functional localization of odor identification is poorly understood. Only a few research groups have used functional neuroimaging techniques in olfaction in schizophrenia (Clark et al. 1991, 2001; Wu et al. 1993; Malaspina et al. 1998; Crespo-Facorro et al. 2001), mostly correlating psychometric olfactory measures (identification) with functional indices. Given that disruption anywhere along the olfactory pathways and other mediating cognitive processes may result in odor identification deficits, it is not surprising that patients with a wide variety of diseases show such impairments (see Martzke et al. 1997; Doty 2001). To date, the utility of odor identification performance as a marker for schizophrenia (and, i.e., to identify distinct subgroups of the disorder) remains unclear (e.g., Serby et al. 1996; Kopala et al. 2001). In addition, Moberg et al. (1997a) have reported that elderly patients with schizophrenia and Alzheimer's disease could not be distinguished by odor identification performance.

Our results demonstrate that deficits in olfactory processing in schizophrenia patients clearly go beyond higher order identification deficits. There was no generalized impairment in olfaction, but patients showed various dysfunctions specific to olfactory tasks and possibly also related to odor properties. We suggest that impaired quality discrimination ability in schizophrenia patients is of particular interest, as nonverbal odor discrimination, primarily assumed to have its neural correlate in the orbitofrontal cortex (Tanabe et al. 1975; Potter and Butters 1980; Eslinger et al. 1982; Zatorre and Jones-Gotman 1991; Savic et al. 1997), is necessary to succeed in an odor identification task. We believe that investigating different types of olfactory functions in patients with schizophrenia represents an intriguing avenue for further exploration. Together with neuroimaging techniques this may provide valuable diagnostic and theoretical information concerning this heterogeneous disorder.

1The second substance listed in each grouping is the “odd” stimulus.

Table I.

Demographic and clinical characteristics

 Patients (n = 30)
 
Controls (n = 30)
 
Analysis1
 
Variable Mean SD Range n Mean SD Range n Value df p 
Demographic variables            
 Age 31.5 6.1 21–47  32.5 6.9 22–49  t = −0.633 58 ns 
 Education (yrs) 10.5 1.9 8–17  13.7 3.7 8–18  t = −4.321 58 <0.001 
 EHI (dextral)    24    25  ns 
Tobacco smoking history            
 Currently smoker (yes)    14    11  ns 
 Cigarettes (average no./day) 20.0 7.6 10–30  19.3 8.8 2–30  t = 0.222 23 ns 
 Duration of smoking (mos) 136.4 71.3 1–252  144.7 73.0 36–240  t = −0.288 23 ns 
Personal psychiatric history            
 Age at illness onset 22.4 5.3 14–37         
 Duration of hospitalization (days) 18.4 14.1 3–57         
 Number of hospitalizations 5.3 4.6 1–21         
Subtypes (DSM–IV           
 Paranoid/disorganized/residual    25/2/3        
Medication            
 Antipsychotic (mg/day CPZE)2 492.5 207.7 250–800         
 Lifetime antipsychotic treatment (mos) 86.4 60.8 3–222         
 PANSS scores            
 PANSS positive 17.4 5.5 8–27         
PANSS negative 21.7 7.1 10–37         
 Patients (n = 30)
 
Controls (n = 30)
 
Analysis1
 
Variable Mean SD Range n Mean SD Range n Value df p 
Demographic variables            
 Age 31.5 6.1 21–47  32.5 6.9 22–49  t = −0.633 58 ns 
 Education (yrs) 10.5 1.9 8–17  13.7 3.7 8–18  t = −4.321 58 <0.001 
 EHI (dextral)    24    25  ns 
Tobacco smoking history            
 Currently smoker (yes)    14    11  ns 
 Cigarettes (average no./day) 20.0 7.6 10–30  19.3 8.8 2–30  t = 0.222 23 ns 
 Duration of smoking (mos) 136.4 71.3 1–252  144.7 73.0 36–240  t = −0.288 23 ns 
Personal psychiatric history            
 Age at illness onset 22.4 5.3 14–37         
 Duration of hospitalization (days) 18.4 14.1 3–57         
 Number of hospitalizations 5.3 4.6 1–21         
Subtypes (DSM–IV           
 Paranoid/disorganized/residual    25/2/3        
Medication            
 Antipsychotic (mg/day CPZE)2 492.5 207.7 250–800         
 Lifetime antipsychotic treatment (mos) 86.4 60.8 3–222         
 PANSS scores            
 PANSS positive 17.4 5.5 8–27         
PANSS negative 21.7 7.1 10–37         

Note.—CPZE = chlorpromazine equivalent; EHI = Edinburgh Handedness Inventory; ns = nonsignificant; PANSS = Positive and Negative Syndrome Scale; SD = standard deviation.

1

t test, Fisher's exact test; ns (p > 0.05).

2

n = 28 (2 patients were medication-free); CPZE doses (Riederer et al. 1998) wherever applicable (haloperidol [n = 4], clozapine [n = 10], and pimozide [n = 2]); the others received risperidone (n = 9), sertindole (n = 2), and zotepine (n = 1).

Table II.

Olfactory measures

 Patients
 
Controls
 
Analysis2
 
 Left
 
Right
 
Left
 
Right
 
Effect size3 Group
 
Group x Side
 
Variable1 Mean SD Mean SD Mean SD Mean SD df p df p 
Olfactory performance4          3.819 6, 52 0.003 1,397 6, 53 ns 
Detection thresholds (MOT) (1–8)                
Phenyl ethanol 3.6 2.1 3.3 1.7 3.1 1.5 3.2 1.6 −0.25 1.048 1, 57 ns    
Dimethyl disulfide 3.9 1.7 3.4 1.8 2.7 1.6 3.0 1.6 −0.68 6.040 1, 57 0.017    
Discrimination (MOT) (0–8)5 5.4 1.4 5.2 1.3 6.3 1.6 6.6 1.0 −1.08 20.021 1, 57 <0.001    
Identification (everyday odors) (0–8) 6.9 1.0 7.0 1.2 7.5 1.0 7.5 0.8 −0.65 5.260 1, 57 0.026    
Familiarity (everyday odors) (0–8) 6.8 1.2 7.1 1.4 7.4 0.8 7.5 0.6 −0.77 4.649 1, 57 0.035    
Edibility (everyday odors) (0–8) 5.9 1.6 6.2 1.3 6.8 1.1 6.7 1.2 −0.66 4.682 1, 57 0.035    
Olfactory ratings6 (MOT) (−5 to 5)          3.995 4, 55 0.006 1,204 4, 55 ns 
Familiarity 1.2 2.5 1.5 2.2 1.7 1.5 1.6 1.8 −0.23 0.331 1, 58 ns    
Pleasantness 0.4 1.3 0.5 1.0 −0.4 1.0 −0.3 1.2 0.84 9.054 1, 58 0.004    
Edibility −1.4 2.0 −0.9 1.9 −1.9 1.7 −1.7 1.7 0.30 1.885 1, 58 ns    
Intensity 2.2 1.4 2.6 1.0 2.9 1.0 2.8 1.2 −0.24 2.565 1, 58 ns    
 Patients
 
Controls
 
Analysis2
 
 Left
 
Right
 
Left
 
Right
 
Effect size3 Group
 
Group x Side
 
Variable1 Mean SD Mean SD Mean SD Mean SD df p df p 
Olfactory performance4          3.819 6, 52 0.003 1,397 6, 53 ns 
Detection thresholds (MOT) (1–8)                
Phenyl ethanol 3.6 2.1 3.3 1.7 3.1 1.5 3.2 1.6 −0.25 1.048 1, 57 ns    
Dimethyl disulfide 3.9 1.7 3.4 1.8 2.7 1.6 3.0 1.6 −0.68 6.040 1, 57 0.017    
Discrimination (MOT) (0–8)5 5.4 1.4 5.2 1.3 6.3 1.6 6.6 1.0 −1.08 20.021 1, 57 <0.001    
Identification (everyday odors) (0–8) 6.9 1.0 7.0 1.2 7.5 1.0 7.5 0.8 −0.65 5.260 1, 57 0.026    
Familiarity (everyday odors) (0–8) 6.8 1.2 7.1 1.4 7.4 0.8 7.5 0.6 −0.77 4.649 1, 57 0.035    
Edibility (everyday odors) (0–8) 5.9 1.6 6.2 1.3 6.8 1.1 6.7 1.2 −0.66 4.682 1, 57 0.035    
Olfactory ratings6 (MOT) (−5 to 5)          3.995 4, 55 0.006 1,204 4, 55 ns 
Familiarity 1.2 2.5 1.5 2.2 1.7 1.5 1.6 1.8 −0.23 0.331 1, 58 ns    
Pleasantness 0.4 1.3 0.5 1.0 −0.4 1.0 −0.3 1.2 0.84 9.054 1, 58 0.004    
Edibility −1.4 2.0 −0.9 1.9 −1.9 1.7 −1.7 1.7 0.30 1.885 1, 58 ns    
Intensity 2.2 1.4 2.6 1.0 2.9 1.0 2.8 1.2 −0.24 2.565 1, 58 ns    

Note.—ANOVA = analysis of variance; MANOVA = multiple analysis of variance; MOT = Munich Olfaction Test; ns = nonsignificant; SD = standard deviation.

1

Possible score ranges in parentheses.

2

Results of MANOVA and subsequent ANOVAs; ns (p > 0.05).

3

Difference of the means of the two groups, divided by the SD of the control group (r and 1 pooled). In the first block (olfactory performance), the minus sign means that patients showed the poorer performance. In the second block, the minus sign indicates lower mean ratings in the patient group compared with controls.

4

MANOVA (detection thresholds: phenyl ethanol and dimethyl disulfide, discrimination, identification, and familiarity and edibility judgments); significant effect of the covariate age (F = 2.849, df = 6, 52, p = 0.018).

5

Significant effect of the covariate age (F = 11.916, df = 1, 57, p = 0.001).

6

MANOVA (ratings of familiarity, pleasantness, edibility, and intensity).

This research was sponsored by the Austrian Nationalbank, Jubiläumsfondsprojekt No. 5143. The authors thank the pharmacy laboratory of the Innsbruck Medical University, and we are especially grateful to Elisabeth Semenitz, Ph.D. We also thank Josef Ilmberger, Ph.D., Frithjof Kruggel, M.D., Matthias Laska, Ph.D., and Johannes Lehrner, Ph.D., for their valuable help. We greatly appreciated the donation of substances from BASF. We also thank all study participants.

Preliminary results and parts of results were presented at the Sixth International Congress on Schizophrenia Research, Colorado Springs, CO, 1997; and the Twentieth Symposium of AChemS (Association for Chemoreception Sciences), Sarasota, FL, 1998.

References

American Psychiatric Association.
DSM–IV: Diagnostic and Statistical Manual of Mental Disorders
  4th ed. Washington, DC APA
1994
.
Anderson, AK, Christoff, K, Stappen, I, Panitz, D, Ghahremani, DG, Glover, G, Gabrieli, JDE, Sobel, N. Dissociated neural representations of intensity and valence in human olfaction.
Nature Neuroscience
 
6
pp.
196
–202
2003
.
Ayabe-Kanamura, S, Schicker, I, Laska, M, Hudson, R, Distel, H, Kobayakawa, T, Saito, S. Differences in perception of everyday odors: A Japanese-German-cross cultural study.
Chemical Senses
 
23
31
–38
1998
.
Becker, E, Hummel, T, Piel, E, Pauli, E, Kobal, G, Hautzinger, M. Olfactory event-related potentials in psychosis-prone subjects.
International Journal of Psychophysiology
 
15
51
–58
1993
.
Bradley, EA. Olfactory acuity to a pheromonal substance and psychotic illness.
Biological Psychiatry
 
19
899
–905
1984
.
Brand, G, Millot, JL, Henquell, D. Complexity of olfactory lateralization processes revealed by functional imaging: A review.
Neuroscience and Biobehavioral Reviews
 
25
159
–166
2001
.
Brewer, WJ, Edwards, J, Anderson, V, Robinson, T, Pantelis, C. Neuropsychological, olfactory, and hygiene deficits in men with negative symptom schizophrenia.
Biological Psychiatry
 
40
1021
–1031
1996
.
Brewer, WJ, Pantelis, C, Anderson, V, Velakoulis, D, Singh, B, Copolov, DL, McGorry, PD. Stability of olfactory identification deficits in neuroleptic-naive patients with first-episode psychosis.
American Journal of Psychiatry
 
158
107
–115
2001
.
Cain, WS, Cometto-Muniz, E, de Wijk, RA. Techniques in the quantitative study of human olfaction. In Serby, MJ and Chobor, KL (Eds.).
Science of Olfaction
  New York, NY Springer pp.
279
–308
1992
.
Cain, WS, de Wijk, R, Lulejian, C, Schiet, F, See, LC. Odor identification: Perceptual and semantic dimensions.
Chemical Senses
 
23
309
–326
1998
.
Cain, WS, Gent, JF, Goodspeed, RB, Leonard, G. Evaluation of olfactory dysfunction in the Connecticut Chemosensory Clinical Research Center.
Laryngoscope
 
98
83
–88
1988
.
Christensen, BK and Bilder, RM. Dual cytoarchitectonic trends: An evolutionary model of frontal lobe functioning and its application to psychopathology.
Canadian Journal of Psychiatry
 
45
247
–256
2000
.
Clark, C, Kopala, L, Hurwitz, T, Li, D. Regional metabolism in microsmic patients with schizophrenia.
Canadian Journal of Psychiatry
 
36
645
–650
1991
.
Clark, C, Kopala, L, Li, DK, Hurwitz, T. Regional cerebral glucose metabolism in never-medicated patients with schizophrenia.
Canadian Journal of Psychiatry
 
46
340
–345
2001
.
Crespo-Facorro, B, Paradiso, S, Andreasen, NC, O'Leary, DS, Watkins, GL, Ponto, LLB, Hichwa, RD. Neural mechanisms of anhedonia in schizophrenia.
JAMA
 
286
427
–435
2001
.
De Wijk, RA and Cain, WS. Odor quality: Discrimination versus free and cued identification.
Perception & Psychophysics
 
56
12
–18
1994
.
Diekmann, H, Walger, M, von Wedel, H. Die Riechleistung von Gehörlosen und Blinden.
HNO
 
42
264
–269
1994
.
Distel, H, Ayabe-Kanamura, S, Martínez-Gómez, M, Schicker, I, Kobayakawa, T, Saito, S, Hudson, R. Perception of everyday odors—correlation between intensity, familiarity and strength of hedonic judgement.
Chemical Senses
 
24
191
–199
1999
.
Doty, RL. Olfaction.
Annual Review of Psychology
 
52
423
–452
2001
.
Doty, RL, Shaman, P, Dann, M. Development of the University of Pennsylvania Smell Identification Test: A standardized microencapsulated test of olfactory function.
Physiology & Behavior
 
32
489
–502
1984
.
Dunn, TP and Weller, MPI. Olfaction in schizophrenia.
Perceptual and Motor Skills
 
69
833
–834
1989
.
Eskenazi, B, Cain, WS, Novelly, RA, Friend, KB. Olfactory functioning in temporal lobectomy patients.
Neuropsychologia
 
21
365
–374
1983
.
Eskenazi, B, Cain, WS, Novelly, RA, Mattson, R. Odor perception in temporal lobe epilepsy patients with and without temporal lobectomy.
Neuropsychologia
 
24
553
–562
1986
.
Eslinger, PJ, Damasio, AR, Van Hoesen, GW. Olfactory dysfunction in man: Anatomical and behavioral aspects.
Brain and Cognition
 
1
259
–285
1982
.
Geddes, J, Huws, R, Pratt, P. Olfactory acuity in the positive and negative syndromes of schizophrenia.
Biological Psychiatry
 
29
774
–778
1991
.
Good, KP, Martzke, JS, Honer, WG, Kopala, LC. Left nostril olfactory identification impairment in a subgroup of male patients with schizophrenia.
Schizophrenia Research
 
33
35
–43
1998
.
Good, KP, Martzke, JS, Milliken, HI, Honer, WG, Kopala, LC. Unirhinal olfactory identification deficits in young male patients with schizophrenia and related disorders: Association with impaired memory function.
Schizophrenia Research
 
56
211
–223
2002
.
Gross-Isseroff, R, Stoler, M, Ophir, D, Lancet, D, Sirota, P. Olfactory sensitivity to androstenone in schizophrenic patients.
Biological Psychiatry
 
22
922
–925
1987
.
Herz, RS, McCall, C, Cahill, L. Hemispheric lateralization in the processing of odor pleasantness versus odor names.
Chemical Senses
 
24
691
–695
1999
.
Houlihan, DJ, Flaum, M, Arnold, SE, Keshavan, M, Alliger, R. Further evidence for olfactory identification deficits in schizophrenia.
Schizophrenia Research
 
12
179
–182
1994
.
Hudry, J, Saoud, M, d'Amato, T, Daléry, J, Royet, JP. Ratings of different olfactory judgements in schizophrenia.
Chemical Senses
 
27
407
–416
2002
.
Hudson, R, Laska, M, Berger, T, Heye, B, Schopohl, J, Danek, A. Olfactory function in patients with hypogonadotropic hypogonadism: An all-or-none phenomenon?
Chemical Senses
 
19
57
–69
1994
.
Hummel, T, Sekinger, B, Wolf, SR, Pauli, E, Kobal, G. ‘Sniffin’ Sticks': Olfactory performance assessed by the combined testing of odor identification, odor discrimination and olfactory threshold.
Chemical Senses
 
22
39
–52
1997
.
Hurwitz, T, Kopala, L, Clark, C, Jones, B. Olfactory deficits in schizophrenia.
Biological Psychiatry
 
23
123
–128
1988
.
Jones-Gotman, M and Zatorre, RJ. Olfactory identification deficits in patients with focal cerebral excision.
Neuropsychologia
 
26
387
–400
1988
.
Kay, SR, Fiszbein, A, Opler, LA. The Positive and Negative Syndrome Scale (PANSS) for schizophrenia.
Schizophrenia Bulletin
 
13
261
–276
1987
.
Kohler, CG, Moberg, PJ, Gur, RE, O'Connor, MJ, Sperling, MR, Doty, RL. Olfactory dysfunction in schizophrenia and temporal lobe epilepsy.
Neuropsychiatry, Neuropsychology and Behavioral Neurology
 
14
83
–88
2001
.
Kopala, L, Good, K, Martzke, J, Hurwitz, T. Olfactory deficits in schizophrenia are not a function of task complexity.
Schizophrenia Research
 
17
195
–199
1995
.
Kopala, LC, Clark, C, Hurwitz, T. Olfactory deficits in neuroleptic-naive patients with schizophrenia.
Schizophrenia Research
 
8
245
–250
1992
.
Kopala, LC, Clark, CC, Bassett, A. Olfactory deficits in schizophrenia and chromosome 5.
Biological Psychiatry
 
29
732
–733
1991
.
Kopala, LC, Good, KP, Honer, WG. Olfactory hallucinations and olfactory identification ability in patients with schizophrenia and other psychiatric disorders.
Schizophrenia Research
 
12
205
–211
1994
.
Kopala, LC, Good, KP, Morrison, K, Bassett, AS, Alda, M, Honer, WG. Impaired olfactory identification in relatives of patients with familial schizophrenia.
American Journal of Psychiatry
 
158
1286
–1290
2001
.
Kopala, LC, Good, KP, Torrey, EF, Honer, WG. Olfactory function in monozygotic twins discordant for schizophrenia.
American Journal of Psychiatry
 
155
134
–136
1998
.
Kruggel, F. “Die Untersuchung des olfaktorischen Systems bei Patienten mit fokalen Hirnschädigungen.” Unpublished doctoral dissertation, Ludwig-Maximilians-Universität, München, 1989.
Kruggel, F. Riechen und Schmecken. In Cramon, DY, Mai, M, Ziegler, W (Eds.).
Neuropsychologische Diagnostik
  Weinheim, Germany VCH-Verlag pp.
53
–63
1993
.
Kwapil, TR, Chapman, JP, Chapman, LJ, Miller, MB. Deviant olfactory experiences as indicators of risk for psychosis.
Schizophrenia Bulletin
 
22
371
–382
1996
.
Larsson, M. Semantic factors in episodic recognition of common odors in early and late adulthood: A review.
Chemical Senses
 
22
623
–633
1997
.
Larsson, M and Bäckman, L. Age-related differences in episodic odour recognition: The role of access to specific odour names.
Memory
 
5
361
–378
1997
.
Laska, M and Hudson, R. A comparison of the detection thresholds of odour mixtures and their components.
Chemical Senses
 
16
651
–662
1991
.
Laska, M and Teubner, P. Olfactory discrimination ability of human subjects for ten pairs of enantiomers.
Chemical Senses
 
24
161
–170
1999
.
Lehrner, J and Deecke, L. Die Wiener Olfaktorische Testbatterie (WOTB).
Aktuelle Neurologie
 
27
170
–177
2000
.
Lehrner, JP, Brücke, T, Dal-Bianco, P, Gatterer, G, Kryspin-Exner, I. Olfactory functions in Parkinson's disease and Alzheimer's disease.
Chemical Senses
 
22
105
–110
1997
.
Lehrner, JP, Glück, J, Laska, M. Odor identification, consistency of label use, olfactory threshold and their relationships to odor memory over the human lifespan.
Chemical Senses
 
24
337
–346
1999
.
Malaspina, D, Perera, GM, Lignelli, A, Marshall, RS, Esser, PD, Storer, S, Furman, V, Wray, AD, Coleman, E, Gorman, JM, Van Heertum, RL. SPECT imaging of odor identification in schizophrenia.
Psychiatry Research
 
82
53
–61
1998
.
Malaspina, D, Wray, AD, Friedman, JH, Amador, X, Yale, S, Hasan, A, Gorman, JM, Kaufmann, CA. Odor discrimination deficits in schizophrenia: Association with eye movement dysfunction.
Journal of Neuropsychiatry and Clinical Neurosciences
 
6
273
–278
1994
.
Martinez, BA, Cain, WS, de Wijk, RA, Spencer, DD, Novelly, RA, Sass, KJ. Olfactory functioning before and after temporal lobe resection for intractable seizures.
Neuropsychology
 
7
351
–363
1993
.
Martzke, JS, Kopala, LC, Good, KP. Olfactory dysfunction in neuropsychiatric disorders: Review and methodological considerations.
Biological Psychiatry
 
42
721
–732
1997
.
Moberg, PJ, Agrin, R, Gur, RE, Gur, RC, Turetsky, BI, Doty, RL. Olfactory dysfunction in schizophrenia: A qualitative and quantitative review.
Neuropsychopharmacology
 
21
325
–340
1999
.
Moberg, PJ, Arnold, SE, Doty, RL, Kohler, C, Kanes, S, Seigel, S, Gur, RE, Turetsky, BI. Impairment of odor hedonics in men with schizophrenia.
American Journal of Psychiatry
 
160
1784
–1789
2003
.
Moberg, PJ, Doty, RL, Mahr, RN, Mesholam, RI, Arnold, SE, Turetsky, BI, Gur, RE. Olfactory identification in elderly schizophrenia and Alzheimer's disease.
Neurobiology of Aging
 
18
163
–167 a
1997
.
Moberg, PJ, Doty, RL, Turetsky, BI, Arnold, SE, Mahr, RN, Gur, RC, Bilker, W, Gur, RE. Olfactory identification deficits in schizophrenia: Correlation with duration of illness.
American Journal of Psychiatry
 
154
1016
–1018 b
1997
.
Mohr, C, Roehrenbach, CM, Laska, M, Brugger, P. Unilateral olfactory perception and magical ideation.
Schizophrenia Research
 
47
255
–264
2001
.
Oldfield, RC. The assessment and analysis of handedness: The Edinburgh Inventory.
Neuropsychologia
 
9
97
–113
1971
.
Olsson, MJ and Fridén, M. Evidence of odor priming: Edibility judgements are primed differently between the hemispheres.
Chemical Senses
 
26
117
–123
2001
.
Pantelis, C and Brewer, W. Neuropsychological and olfactory dysfunction in schizophrenia: Relationship of frontal syndromes to syndromes of schizophrenia.
Schizophrenia Research
 
17
35
–45
1995
.
Potter, H and Butters, N. An assessment of olfactory deficits in patients with damage to prefrontal cortex.
Neuropsychologia
 
18
621
–628
1980
.
Purdon, SE. Olfactory identification and Stroop interference converge in schizophrenia.
Journal of Psychiatry & Neuroscience
 
23
163
–171
1998
.
Purdon, SE and Flor-Henry, P. Asymmetrical olfactory acuity and neuroleptic treatment in schizophrenia.
Schizophrenia Research
 
44
221
–232
2000
.
Riederer, P, Laux, G, Pöldinger, W.
Neuro-Psychopharmaka. Ein Therapie-Handbuch
  Wien, Austria Springer-Verlag
1998
.
Royet, JP, Croisile, B, Williamson-Vasta, R, Hibert, O, Serclerat, D, Guerin, J. Rating of different olfactory judgements in Alzheimer's disease.
Chemical Senses
 
26
pp.
409
–417
2001
.
Royet, JP, Koenig, O, Gregoire, MC, Cinotti, L, Lavenne, F, Le Bars, D, Costes, N, Vigouroux, M, Farget, V, Sicard, G, Holley, A, Mauguière, F, Comar, D, Froment, JC. Functional anatomy of perceptual and semantic processing for odors.
Journal of Cognitive Neuroscience
 
11
94
–109
1999
.
Rupp, CI. Dysfunctions in olfactory processing in schizophrenia.
Current Opinion in Psychiatry
 
16
181
–185
2003
.
Rupp, CI, Klimbacher, M, Scholtz, A, Lechner, T, Walch, T, Kremser, C, Hinterhuber, H. Olfactory quality discrimination deficits in schizophrenia using the ‘Sniffin’ Sticks.’ [Abstract].
Chemical Senses
 
25
658
2000
.
Rupp, CI, Kurz, M, Kemmler, G, Mair, D, Hausmann, A, Hinterhuber, H, Fleischhacker, WW. Reduced olfactory sensitivity, discrimination, and identification in patients with alcohol dependence.
Alcoholism: Clinical and Experimental Research
 
27
432
–439
2003
.
Savic, I. Imaging of brain activation by odorants in humans.
Current Opinion in Neurobiology
 
12
455
–461
2002
.
Savic, I and Berglund, H. Right-nostril dominance in discrimination of unfamiliar, but not familiar odours.
Chemical Senses
 
25
517
–523
2000
.
Savic, I, Bookheimer, SY, Fried, I, Engel, J Jr. Olfactory bedside test. A simple approach to identify temporo-orbitofrontal dysfunction.
Archives of Neurology
 
54
162
–168
1997
.
Schab, FR. Odor memory: Taking stock.
Psychological Bulletin
 
109
242
–251
1991
.
Schab, FR and Cain, WS. Memory for odors. In Laing, DG, Doty, RL, Breipohl, W (Eds.).
The Human Sense of Smell
  New York, NY Springer-Verlag pp.
217
–240
1991
.
Seidman, LJ, Goldstein, JM, Goodman, JM, Koren, D, Turner, WM, Faraone, SV, Tsuang, MT. Sex differences in olfactory identification and Wisconsin Card Sorting performance in schizophrenia: Relationship to attention and verbal ability.
Biological Psychiatry
 
42
104
–115
1997
.
Serby, M, Larson, P, Kalkstein, D. Olfactory sense in psychoses. [Letter].
Biological Psychiatry
 
28
830
1990
.
Serby, M, Mohan, C, Aryan, M, Williams, L, Mohs, RC, Davis, KL. Olfactory identification deficits in relatives of Alzheimer's disease patients.
Biological Psychiatry
 
39
375
–377
1996
.
Shipley, MT and Ennis, M. Functional organization of olfactory system.
Journal of Neurobiology
 
30
123
–176
1996
.
Sirota, P, Davidson, B, Mosheva, T, Benhatov, R, Zohar, J, Gross-Isseroff, R. Increased olfactory sensitivity in first episode psychosis and the effect of neuroleptic treatment on olfactory sensitivity in schizophrenia.
Psychiatry Research
 
86
143
–153
1999
.
Stedman, TJ and Clair, AL. Neuropsychological, neurological and symptom correlates of impaired olfactory identification in schizophrenia.
Schizophrenia Research
 
32
23
–30
1998
.
Striebel, KM, Beyerstein, B, Remick, RA, Kopala, L, Honer, WG. Olfactory identification and psychosis.
Biological Psychiatry
 
45
1419
–1425
1999
.
Tanabe, T, Iino, M, Takagi, SF. Discrimination of odors in olfactory bulb, pyriform-amygdaloid areas, and orbitofrontal cortex of the monkey.
Journal of Neurophysiology
 
38
1284
–1296
1975
.
Wu, J, Buchsbaum, MS, Moy, K, Denlea, N, Kesslak, P, Tseng, H, Plosnaj, D, Hetu, M, Potkin, S, Bracha, S, Cotman, C. Olfactory memory in unmedicated schizophrenics.
Schizophrenia Research
 
9
41
–47
1993
.
Zald, DH and Pardo, JV. Emotion, olfaction, and the human amygdala: Amygdala activation during aversive olfactory stimulation.
Proceedings of the National Academy of Sciences of the United States of America
 
94
4119
–4124
1997
.
Zald, DH and Pardo, JV. Functional neuroimaging of the olfactory system in humans.
International Journal of Psychophysiology
 
36
165
–181
2000
.
Zatorre, RJ and Jones-Gotman, M. Human olfactory discrimination after unilateral frontal or temporal lobectomy.
Brain
 
114
71
–84
1991
.