In the current study, we extend prior research on olfactory anhedonia in schizophrenia by examining unirhinal hedonic and intensity ratings in males and females with schizophrenia, as well as unaffected first-degree family members. Our results indicate, first, that both male and female patients demonstrate abnormalities in perceived olfactory hedonic valence. Specifically, patients undervalued the pleasantness of amyl acetate at low concentrations and did not appreciate its increasing unpleasantness at high concentrations, as experienced by healthy control subjects. This finding replicates our previous results for male patients.15
However, in contrast to our previous finding that female patients had normal hedonic valence perception, the female patients in the current study also experienced a disturbance in the appreciation of hedonic valence. One notable explanation for this discrepancy in findings between the current and prior study was the method of odor presentation. Compared with Moberg’s15
study, the current study employed unirhinal assessment whereby each nostril was tested in isolation. While few studies have compared differences between unirhinal and birhinal assessment, at least 1 study noted that the female advantage for birhinal odor identification disappears during unirhinal testing.32
As birhinal odor assessment is thought to involve interhemispheric facilitation compared with unirhinal conditions,30,33
it is possible that unirhinal testing suppressed the compensation of the contralateral hemisphere, and without this advantage female patients exhibited the same hedonic disturbance as male patients. Further research directly comparing birhinal and unirhinal conditions with measures for interhemispheric transfer times could help elucidate these differences.
The unaffected family members of schizophrenia patients, in contrast, did not show any disruption in odor hedonic perception. This was unexpected because previous investigations have noted both increased anhedonia18
and deficits in olfactory task performance in family members with schizophrenia.19,20
In addition, significant associations between physical anhedonia and neuropsychological probes of executive function have been noted in unaffected siblings of schizophrenia patients.34
Given these findings, we anticipated that family members would also exhibit a disturbance in attaching hedonic valence to odors. However, the current literature on heritability for olfactory ability is complex because heritability may vary depending on the olfactory task type and odorants assessed. Finkel and colleagues35
noted modest heritability for odor identification and odor intensity perception but found that ratings for the perceived pleasantness of odorants did not show significant genetic mediation in a non-clinical sample. Knaapila et al36
reported that both intensity and pleasantness perception are predominantly environmentally mediated, with minimal genetic contribution. Still others have noted that heritability of hedonic perception may depend on the nature and chemical composition of the particular odorant being assessed because hedonic perception of certain odorants (eg, androstenone, cinnamon) appear to be genetically mediated.37,38
Our findings suggest, though, that the odor hedonic abnormalities associated with schizophrenia are not genetically mediated but rather represent a functional deterioration associated with the illness state.
Patients’ abnormal pleasantness ratings could not be attributed to their inability to perceive the odors. Although we observed a statistically significant group difference in odor intensity ratings, the pattern of results was not consistent with decreased patient intensity perception. Rather, control subjects rated the strongest odor concentration as more intense and the weakest odor concentration as less intense. This suggests that control subjects used a greater range in their attribution of odor intensity but were not actually better at perceiving the odors. All groups showed a robust relationship between odor concentrations and intensity ratings, suggesting intact appreciation for basic intensity differences across adjacent concentrations. In addition, intensity ratings were not a significant predictor of pleasantness ratings, and controlling for individual intensity ratings for corresponding pleasantness ratings did not alter the effects.
Patient hedonic ratings were also not associated with antipsychotic medication dosage, illness duration, age of onset, depressive symptomatology, or current smoking behavior. However, a significant relationship was observed between pleasantness perception and anhedonia such that patients with higher levels of anhedonia/asociality showed a blunted perception of amyl acetate pleasantness
, specifically at those concentrations that were perceived as most pleasant by control subjects. This association remained significant after controlling for current level of depressive symptomatology, suggesting a relationship between trait anhedonia/asociality and impaired odor valence processing. In contrast, increased disorganization (bizarre behavior and positive thought disorder) was associated with blunted appreciation of amyl acetate unpleasantness
at the high concentrations that were perceived by controls as most unpleasant. The association between negative symptoms and impaired odor identification has been noted repeatedly.39,40
A prior study by Malaspina and Coleman41
noted a significant relationship between smell identification deficits and diminished social drive in schizophrenia patients. These data provide a logical and anticipated extension of this relationship into the domain of olfactory hedonic perception. However, the association between disorganized symptoms and impaired unpleasantness perception is not one that was either expected or readily understood. We did previously observe an association between disorganized symptoms and impaired odor identification.42
More recently, a study by Strauss et al10
noted that Nondeficit Syndrome patients (ie, those with positive, but not enduring negative, symptoms) showed a similar selective impairment in judging unpleasant odors to be less unpleasant compared with controls, whereas deficit syndrome (ie, primary and enduring negative symptoms) patients also underrated the pleasantness of pleasant odors. Collectively, these findings suggest that negative symptoms of anhedonia/asociality and positive symptoms of disorganization are independently associated with the perception of opposing valence characteristics in schizophrenia. Further studies comparing patient groups within these symptoms clusters are needed to elucidate the complexity of odor hedonic perception in schizophrenia.
This relationship between anhedonia and olfactory hedonic deficits was limited to odor presentations to the left nostril. This is consistent with the overall effect we observed in which all subjects tended to rate odors as more pleasant when presented to the left, rather than the right, nostril. While the neural basis for odor hedonic abnormalities is unclear, odor valence processing in healthy people, particularly for pleasant odors, has shown left hemisphere dominance.43
In schizophrenia, reduced hedonic ratings for pleasant odors has been associated with decreased activation in left temporo-limbic and left orbital olfactory regions13
and increased physical anhedonia has been linked with decreased activation in the amygdala.44
The authors of the latter report note that aberrant amygdala activation results in a failure to mark the salience of pleasant events. If one were to extrapolate these findings to the current analysis, it is possible that aberrant processing in OFC and amygdala networks results in reduced representation of affective value and a failure to signify the pleasantness of amyl acetate as salient. Further investigation of aberrant processing in these brain regions as neural correlates of anhedonia is warranted.
Prior laboratory studies in schizophrenia using olfactory stimuli have repeatedly noted abnormalities in valence ratings,8–13,15
while studies examining subjective ratings of stimuli from other modalities (eg, pictures, film clips) have not consistently elicited patient-control differences in subjective hedonic reactions (for a review, see Cohen and Minor45
). It is possible that the relative integration that exists between olfactory and limbic circuitry, coupled with the evolutionary salience of olfaction to social behavior, makes olfactory stimuli especially sensitive probes of hedonic perception. While this is of course speculative, there is evidence for an evolutionary role of olfactory cues in directing humans toward food, identifying mates and offspring, and signaling threat or danger. Furthermore, olfaction is distinct from other senses because only 1 synapse lies between olfactory receptors and olfactory cortex, providing a direct pathway between the sensory environment and cortex, bypassing the thalamus. Therefore, olfactory probes may offer a unique advantage over other forms of emotional stimuli when probing emotional disturbance and hedonic capacity in schizophrenia.
Limitations of this study include the use of a single odor to ascertain intensity and pleasantness ratings. While the use of 1 odor remedies the potential confound of using disparate odors that differ with respect to chemical makeup and odor dimensions (eg, familiarity, edibility, intensity), it does not allow for generalizability to other classes of odorants or for an examination of genetic mediation across different odor classes. Second, we characterized anhedonia in schizophrenia using a subscale of the SANS. The use of multiple measures of anhedonia, including those that distinguish between social and physical anhedonia (eg, Chapman Scales46
), or anticipatory and consummatory pleasure (eg, Temporal Experience of Pleasure Scale47
), and relating these measures to odor hedonic capacity would help to elucidate what aspects of anhedonia are associated with odor hedonic capacity in schizophrenia. Though we observed no significant effect of medication status or type of antipsychotic agent used on odor hedonic ratings, our analysis was likely underpowered given the relatively small number of patients within each subgroup. Therefore, these results must be interpreted with caution given the possibility for false-negative findings. Future studies examining odor valence processing in larger groups of medicated and unmedicated patients are warranted. Similarly, the first-degree family member cohort was considerably smaller than the patient and control group. This limited our ability to examine differences in odor hedonic ratings by degree of relationship (eg, sibling vs parent vs offspring) and resulted in a higher degree of variability in their hedonic responses. Thus, follow-up studies on odor hedonic abnormalities in larger family member groups would be especially useful in understanding how odor valence perception is influenced by degree of genetic relationship to schizophrenia probands.
Our findings indicate that individuals with schizophrenia experience difficulty when assigning valence characteristics to amyl acetate and this difficulty is related at opposing ends of the spectrum, to increased anhedonia and increased disorganization. In contrast to our prior report,15
female patients showed a similar abnormality to male patients when hedonic ratings were elicited during unirhinal odor presentation. Unaffected family members of schizophrenia patients did not show a disruption in valence appreciation for amyl acetate, which suggests that this disruption represents an environmentally mediated abnormality. Anhedonia is a treatment-resistant and enduring feature of schizophrenia that is associated with poor functional outcome in patients and individuals at-risk for psychosis. New treatments that target anhedonia in schizophrenia are underway,48
and thus, behavioral measures that have predictive value in identifying those at risk for anhedonia are necessary. The use of olfaction as a probe of hedonic capacity is a novel and promising avenue to explore anhedonia in schizophrenia and could be especially useful in identifying people at-risk for anhedonia and in need of targeted intervention for poor social, emotional, and functional outcomes.