We identified robust sex differences in olfactory processing in both individuals with schizophrenia and healthy comparison subjects. The differences include the association, or lack thereof, between the sensitivity for detecting the test odor and smell identification ability. Healthy males showed a strong positive correlation between increasing acuity and better smell identification scores. Conversely, greater odor sensitivity predicted worse smell identification ability for males with schizophrenia in multiple regressions. However, neither female patients nor healthy females showed any relationship between odor detection sensitivity and smell identification, even though these female patients and controls had a slight advantage on both olfactory tasks, as is commonly reported (Doty and Cameron, 2009
There was a female sex specific relationship for olfaction and negative symptoms in schizophrenia, whereby increased sensitivity for odor detection was strongly correlated with diminished emotional expression. We demonstrated a distinct male specific relationship for smell identification deficits and PANSS negative symptoms, which is consistent with the literature (Atanasova et al., 2008
), with significant findings for blunted affect, emotional withdrawal, poor rapport, and lack of spontaneity/flow of conversation.
Since odor sensitivity and smell identification were significantly associated in males, we also used multiple regression to identify the specific symptoms linked to each olfactory test. In males, controlling for acuity showed that emotional withdrawal was uniquely associated with smell identification. Controlling for smell identification showed a more complex pattern for odor detection threshold, as blunted affect was linked to more sensitive acuity and lack of spontaneity was linked to less sensitive acuity. Comparably in females, controlled analyses showed diminished emotional range linked with very sensitive acuity and poverty of speech with less sensitive acuity. We earlier found that smell identification deficits were associated with social drive in a study that combined male and female cases and did not adjust for odor sensitivity. In the current analyses, smell identification was only associated with social drive factors in the male cases. After accounting for odor detection sensitivity, smell identification predicted expressive negative symptoms in male and female cases. It is of note that females only showed this association with respect to the enduring and severe “trait” negative symptoms of the deficit syndrome. This likely speaks to the sex differences in negative symptom expression that are well described in the disease.
The finding that both high and low odor sensitivity predicted different domains of negative symptoms is consistent with latent heterogeneity. Of further interest, factor analytic studies of negative symptoms consistently identify only two domains of symptoms: expressive deficits, which include emotion, linguistic and paralinguistic expressions, and avolition or asociality for daily-life activities (reviewed in Blanchard and Cohen, 2006
, and Messinger et al., 2011
). In both males and females with schizophrenia in this study, more sensitive acuity tapped items related to emotional expression; diminished emotional range in females and flat affect in males. In contrast, less sensitive accuracy predicted asociality/avolition items: social withdrawal in females and decreased spontaneity in males. These findings bolster the hypothesis that deficits in expressiveness and avolition are non-overlapping domains of negative symptoms by showing that they are differentially associated with odor detection acuity.
The experience of symptoms in schizophrenia is described as “flooding” by intense sensory stimuli (Swerdlow and Geyer, 1998
) that secondarily causes emotional blunting, which is consistent with our findings linking hyperosmia to emotional expression deficits. This sensory overload may be a result of deficient central inhibition, or “gating” of stimuli (see Tregellas et al., 2007
). Odor sensitivity is known to be modulated by central mechanisms (Mainland et al., 2002
) which could malfunction in schizophrenia. Such a failure might explain why more sensitive acuity predicted worse smell identification in males with schizophrenia, in direct contradistinction from healthy males. On the other hand, in the alternate setting of diminished olfactory input, elements of volition and sociality appear to be compromised in the patients. This observation would be particularly intriguing if social signaling molecules are shown to drive aspects of motivated behavior in humans. If so, then olfactory dysfunction might play a key pathogenic role in explaining this core disease feature.
In males, detecting and processing odor appears to be directly linked, whereas the modulation of odor sensitivity in female patients may be under different constraints. A role for odor processing in mate selection and child rearing by females may underlie both an olfactory advantage and a more enigmatic modulation of odor threshold. Sex differences in olfaction are of obvious importance in reproduction, since olfaction is the trigger for mating in many mammals and is supremely important in maternal behavior. It is plausible that females engage more memory and emotion in processing odor stimuli than males, leading to a more nuanced, top-down modulation of odor threshold. Sex differences in evaluating sexual attractiveness might also extend to evaluating olfactory signals. Human females, therefore, may employ cognitive processing and judgments of a man’s status in evaluating his sexual attractiveness that males do not employ when evaluating female attractiveness (Rupp et al., 2009
). Indeed sex differences are reported in the neural underpinnings of human olfaction (Frasnelli et al., 2009
), including in the gray matter density of olfactory structures (Garcia-Falgueras et al., 2006
). Since the orbitofrontal region that is activated by olfactory tasks (Savic, 2002
) is consistently larger in females (Gur et al., 2002
; Garcia-Falgueras et al., 2006
; Luders et al., 2009
) and is known to participate in the human sex differences for social and emotional capacities that favor females (Rupp, 2010
), it may also contribute to a greater high level modulation of odor acuity in females.
These data extend the story of human sex differences in olfactory processing. They suggest that the detection of odors and the central processing of odors are less directly linked in females than in males, perhaps due to finer intervening cognitive processes or menstrual influences in females. Other clues to differential modulation of olfactory function are the sex differences in which types of symptoms relate to olfaction: only PANSS (state) negative symptom items in males and only deficit syndrome (trait) symptoms in females. Another sex specific effect was that younger age and later age of illness onset predicted better smell identification in females.
The wider variability of odor threshold in females with schizophrenia in this study may shed light on some of the contradictory findings on odor detection acuity from earlier studies (Atanasova et al., 2008
). Most studies assess smell identification without testing odor threshold, as we did in an earlier patient cohort (Malaspina and Coleman, 2003
). These have underestimated the relationship of olfactory processing abnormalities with schizophrenia symptoms for females. In addition, studies that combine male and female schizophrenia patients can obscure the sex specific findings.
These current findings come with possible limitations and should be considered to be preliminary. Although the schizophrenia patients and the comparison subjects were matched on age, ethnicity, gender, and cognition, the patients were less educated than controls. Given the comparable intelligence scores of the groups, we ascribed this difference to features of the illness, such as avolition or other symptoms. As these were key study outcomes, we did not adjust the analyses for education; although doing so did not substantially alter the results (data not shown but available upon request). Smell identification scores and mean sensitivity did not distinguish between the schizophrenia and control groups. Rather, our correlation and regression analyses focused on the sex differences in relationship of these measures and their associations with illness features. Deficits in smell identification and alterations in odor threshold are useful tools for conducting sex-specific analyses in schizophrenia but are not necessarily tests for the disease. Another limitation is that we only used phenyl ethyl alcohol to test the threshold for odor detection sensitivity. Although there is a strong inter-odorant threshold correlation in humans (Hasin-Brumshtein et al., 2009
), other odorants should be examined in future studies. It should be noted that our cases were all on stable medications and in a stable clinical state. Although there is no evidence linking medication status to performance on smell identification (Coleman et al., 2002
), there is a report of a medication treatment effect on asymmetrical olfactory thresholds in schizophrenia (Purdon & Flor-Henry, 2000
). These analyses did not separately consider right and left nostril thresholds, as this information converges at the anterior olfactory nucleus (Kikuta et al., 2008
) and event related potential studies of central olfactory processing have not revealed main effects for right versus left nostril odor presentations (Olofsson et al., 2006
; Stuck et al., 2006
). We also did not control for menstrual cycle, which might underlie the sex differences linking threshold to smell identification, but would not explain the differential relationships of odor threshold and smell identification to symptoms in men and women with schizophrenia. Finally, some results of the controlled regression analyses were counterintuitive, which perhaps is a result of heterogeneity in physiological subtypes within our subject sample.
In summary, this study showed that the relationship between odor detection sensitivity and smell identification ability is sexually dimorphic; that negative symptoms are related to more sensitive odor detection in females, but to smell identification deficits in males; that odor threshold values are variable in schizophrenia; that very sensitive and insensitive acuity differentially tap the negative symptom domains of emotional expression and avolition/asociality, respectively; and that smell identification is better in younger females who have a later age of illness onset.
Olfaction is a promising probe for the social and emotional symptoms of schizophrenia but sex specific processing must be considered in these studies. Sex differences clearly underlie social and emotional functioning in humans and should be analyzed in neuropsychiatric research investigating these domains.