Reduced olfactory bulb volume and olfactory sensitivity in patients with acute major depression.
ABSTRACT The purpose of this study was to assess olfactory function and olfactory bulb volume in patients with acute major depression in comparison to a normal population. Twenty-one patients diagnosed with acute major depressive disorder and 21 healthy controls matched by age, sex and smoking behavior participated in this study. Olfactory function was assessed in a lateralized fashion using measures of odor threshold, discrimination and identification. Olfactory bulb volumes were calculated by manual segmentation of acquired T2-weighted coronal slices according to a standardized protocol. Patients with acute major depressive disorder showed significantly lower olfactory sensitivity and smaller olfactory bulb volumes. Additionally, a significant negative correlation between olfactory bulb volume and depression scores was detected. Their results provide the first evidence, to our knowledge, of decreased olfactory bulb volume in patients with acute major depression. These results might be related to reduced neurogenesis in major depression that could be reflected also at the level of the olfactory bulb.
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ABSTRACT: Gestational methyl donor deficiency (MDD) leads to growth retardation as well as to cognitive and motor disorders in 21-d-old rat pups. These disorders are related to impaired neurogenesis in the cerebral neurogenic areas. Olfactory bulbs (OB), the main target of neuronal progenitors originating from the subventricular zone, play a critical role during the postnatal period by allowing the pups to identify maternal odour. We hypothesised that growth retardation could result from impaired suckling due to impaired olfactory discrimination through imbalanced apoptosis/neurogenesis in the OB. Since neurosteroidogenesis modulates neurogenesis in OB, in the present study, we investigated whether altered neurosteroidogenesis could explain some these effects. Pups born to dams fed a normal diet (n 24) and a MDD diet (n 27) were subjected to olfactory tests during the lactation and weaning periods (n 24 and 20, respectively). We studied the markers of apoptosis/neurogenesis and the expression levels of the key neurosteroidogenic enzyme aromatase, the cholesterol-transfer protein StAR (steroidogenic acute regulatory protein) and the ERα oestrogen receptor and the content of oestradiol in OB. The 21-d-old MDD female pups displayed lower body weight and impaired olfactory discrimination when compared with the control pups. MDD led to greater homocysteine accumulation and more pronounced apoptosis, along with impaired cell proliferation in the OB of female pups. The expression levels of aromatase, StAR and ERα as well as the content of oestradiol were lower in the OB of the MDD female pups than in those of the control female pups. In conclusion, gestational MDD may alter olfactory discrimination performances by affecting neurogenesis, apoptosis and neurosteroidogenesis in OB in a sex-dependent manner. It may be involved in growth retardation through impaired suckling.The British journal of nutrition 11/2013; · 3.45 Impact Factor
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ABSTRACT: Much research indicates that patients with schizophrenia have impaired olfaction detection ability. However, studies of individuals with psychometrically defined schizotypy reveal mixed results-some document impairments while others do not. In addition to deficits in objective accuracy in olfaction for patients with schizophrenia, there has been an interest in subjective experience of olfaction. Unfortunately, methods of assessing accuracy and subjective hedonic olfactory evaluations in prior studies may not have been sensitive enough to detect group differences in this area. This study employed a measure of olfactory functioning featuring an expanded scoring system to assess both accuracy and subjective evaluations of pleasant and unpleasant experience. Data were collected for patients with schizophrenia, young adults with psychometrically defined schizotypy, psychiatric outpatients, and healthy controls. Results of this study indicate that both the schizophrenia and outpatient psychiatric groups showed similar levels of impaired olfaction ability; however, the schizotypy group was not impaired in olfaction detection. Interestingly, with regard to subjective hedonic evaluation, it was found that patients with schizophrenia did not differ from psychiatric outpatients, whereas individuals with schizotypy tended to rate smells as significantly less pleasant than healthy control participants. This suggests that subjective olfactory assessment is abnormal in some manner in schizotypy. It also suggests that accuracy of olfaction identification may be a characteristic of severe mental illness across severe mental illness diagnoses. The results are potentially important for understanding olfaction deficits across the mental illness spectrum.Psychiatry Interpersonal & Biological Processes 01/2014; 77(1):57-66. · 2.58 Impact Factor
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ABSTRACT: The large variety of available animal models has revealed much on the neurobiology of depression, but each model appears as specific to a significant extent, and distinction between stress response, pathogenesis of depression and underlying vulnerability is difficult to make. Evidence from epidemiological studies suggests that depression occurs in biologically predisposed subjects under impact of adverse life events. We applied the diathesis-stress concept to reveal brain regions and functional networks that mediate vulnerability to depression and response to chronic stress by collapsing data on cerebral long term neuronal activity as measured by cytochrome c oxidase histochemistry in distinct animal models. Rats were rendered vulnerable to depression either by partial serotonergic lesion or by maternal deprivation, or selected for a vulnerable phenotype (low positive affect, low novelty-related activity or high hedonic response). Environmental adversity was brought about by applying chronic variable stress or chronic social defeat. Several brain regions, most significantly median raphe, habenula, retrosplenial cortex and reticular thalamus, were universally implicated in long-term metabolic stress response, vulnerability to depression, or both. Vulnerability was associated with higher oxidative metabolism levels as compared to resilience to chronic stress. Chronic stress, in contrast, had three distinct patterns of effect on oxidative metabolism in vulnerable vs. resilient animals. In general, associations between regional activities in several brain circuits were strongest in vulnerable animals, and chronic stress disrupted this interrelatedness. These findings highlight networks that underlie resilience to stress, and the distinct response to stress that occurs in vulnerable subjects.Behavioural brain research 03/2014; · 3.22 Impact Factor
REDUCED OLFACTORY BULB VOLUME AND OLFACTORY
SENSITIVITY IN PATIENTS WITH ACUTE MAJOR DEPRESSION
S. NEGOIAS,aI. CROY,a,bJ. GERBER,cS. PUSCHMANN,a
K. PETROWSKI,bP. JORASCHKYbAND T. HUMMELa*
aSmell and Taste Clinic, Department of Otorhinolaryngology, University of
Dresden Medical School, Dresden, Germany
bClinic and Policlinic for Psychotherapy and Psychosomatic Therapy,
University of Dresden Medical School, Dresden, Germany
cDepartment of Neuroradiology, University of Dresden Medical
School, Dresden, Germany
Abstract—The purpose of this study was to assess olfactory
function and olfactory bulb volume in patients with acute
major depression in comparison to a normal population.
Twenty-one patients diagnosed with acute major depressive
disorder and 21 healthy controls matched by age, sex and
smoking behavior participated in this study. Olfactory func-
tion was assessed in a lateralized fashion using measures of
odor threshold, discrimination and identification. Olfactory
bulb volumes were calculated by manual segmentation of
acquired T2-weighted coronal slices according to a standard-
ized protocol. Patients with acute major depressive disorder
showed significantly lower olfactory sensitivity and smaller
olfactory bulb volumes. Additionally, a significant negative
correlation between olfactory bulb volume and depression
scores was detected. Their results provide the first evidence,
to our knowledge, of decreased olfactory bulb volume in
patients with acute major depression. These results might be
related to reduced neurogenesis in major depression that
could be reflected also at the level of the olfactory bulb.
© 2010 IBRO. Published by Elsevier Ltd. All rights reserved.
Key words: olfaction, smell, major depression, olfactory bulb,
In recent years a series of studies has investigated olfac-
tory function in various neuropsychiatric disorders (for re-
view see Atanasova et al., 2008). Motivating this research
is the partial overlap between emotional and olfactory brain
structures, especially the limbic system and prefrontal ar-
eas. Dysfunctions in emotional processing areas are con-
sequently expected to also affect the olfactory perception.
In turn, olfactory probes could provide a surrogate mea-
sure of some neuropsychiatric symptoms.
Olfactory deficiencies have been established in schizo-
phrenia (Turetsky et al., 2009a) whereas in affective dis-
orders a review of the literature research provides contro-
versial results. Major depression is one such case, with
results covering almost the entire spectrum of olfactory
testing outcomes. Odor identification ability ranges from
normal (Amsterdam et al., 1987; Warner et al., 1990; Lom-
bion-Pouthier et al., 2006; Swiecicki et al., 2009) to de-
creased performance (Serby et al., 1990), compared to a
normosmic control group. For threshold measurements,
one study reported no difference and no correlation be-
tween olfactory sensitivity and depression quantification
scales for patients with acute depression, but better sen-
sitivity for patients after 42 days after initiation of treatment
(Gross-Isseroff et al., 1994) supporting the results from an
earlier study (Serby et al., 1990). In line with these results,
Swiecicki et al. showed no olfactory sensitivity impairments
in unipolar depression (Swiecicki et al., 2009). On the
contrary, Pause and colleagues reported strongly reduced
olfactory sensitivity in acute-phase major depressive dis-
order (MDD) that correlated negatively with depression
scores. When investigating the same group of patients
after successful therapy, no olfactory sensitivity difference
was found compared to controls (Pause et al., 2001). The
same dynamic was in cerebral processing as assessed by
reduced amplitudes of olfactory event related potentials
(ERPs) peaks in patients with MDD at the beginning of the
therapy, without reproduction of the effect after successful
treatment (Pause et al., 2003). Decreased olfactory sensi-
tivity in MDD has been replicated in a recent study (Lom-
bion-Pouthier et al., 2006). Seasonal affective disorder
studies have also studied the relationship between olfac-
tory function and depression, with the same contrasting
results. One study reported no difference in olfactory
thresholds and identification between patients and controls
(Postolache et al., 1999), while another showed better
thresholds for patients, regardless of season (Postolache
et al., 2002).
It seems that the relationship between olfaction and
depression is reciprocal. Olfactory impairment alters the
quality of life (Hummel and Nordin, 2005); loss of olfactory
function is typically associated with increased depressive
symptoms (Deems et al., 1991; Gudziol et al., 2009a; Seo
et al., 2009). A recent report showed depressive symptoms
correlate negatively with olfactory sensitivity in healthy
participants (Pollatos et al., 2007) analogous to the results
of Pause et al. on patients with MDD (Pause et al., 2001).
The question whether olfactory impairment alone could
lead to or trigger a major depression episode remains to be
answered. Two considerations are crucial when trying to
investigate olfactory function in MDD. First, it is important
to discriminate between testing patients with acute depres-
sion and patients in a remission, or between medicated
and unmedicated patients. Differences in methodological
approaches, number of participants and heterogeneity in
*Corresponding author. Tel: ?49-351-458-4189; fax: ?49-351-458-
E-mail address: firstname.lastname@example.org (T. Hummel).
Abbreviations: BDI, Beck’s depression inventory; MDD, major depres-
sive disorder; OB, olfactory bulb; SD, standard deviation; SVZ, sub-
Neuroscience 169 (2010) 415–421
0306-4522/10 $ - see front matter © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.
medication and moment of testing could account for the
inconsistencies in results seen in previous studies.
Second, some authors divide olfactory function tests
into those focusing on peripheral processing (threshold
measurement) and those focusing on cognitive processing
(e.g., odor discrimination or odor identification; Cain,
1979), concluding that they should be examined sepa-
rately. Most of the studies investigating olfactory function in
MDD used identification tests, mainly the University of
Pennsylvania Smell identification Test (UPSIT). While ol-
factory identification scores correlate with olfactory thresh-
olds (Doty et al., 1984; Hummel et al., 1997), independent
testing of various olfactory functions could provide infor-
mation on the level of the interaction between olfaction and
depression. On one hand, cognitive impairment associated
with major depression could interfere with odor identifica-
tion or discrimination abilities (Austin et al., 2001; Marvel
and Paradiso, 2004). On the other hand, it has been shown
that bulbectomized rodents provide a model for depression
(Song and Leonard, 2005), with correction of symptoms
after chronic administration of antidepressants. The au-
thors of this study presumed that bulbectomy induced
dysfunction in the cortical-hippocampal-amygdalar circuit,
responsible for modulating behavioral responses. Specifi-
cally, the olfactory bulb (OB) sends inhibitory projections to
the amygdala, which is involved preferentially in the pro-
cessing of fear and sadness (Costafreda et al., 2008). In
light of these ideas some authors have speculated that in
MDD, dysfunction at the level of the olfactory bulb could
cause not only the reduced olfactory sensitivity, but also
the increased sadness and fear, through disinhibition of
the amygdala (Pause et al., 2001).
The human OB is a highly plastic structure whose
volume reflects changes in olfactory sensitivity, as shown
in patients with post-traumatic chemosensory deficits
(Yousem et al., 1996a, 1999; Rombaux et al., 2006), post-
al., 2006), congenital anosmia (Yousem et al., 1996b;
et al., 2005a) and in normosmic participants (Yousem et al.,
1998). A recent study provided normative data in a normos-
mic population (Buschhuter et al., 2008). To our knowl-
edge, no study has yet been published addressing the
connection between the OB and depression in humans.
The purpose of the present study was to assess olfac-
tory function and OB volume in patients with acute MDD
compared to a normal population matched for age, sex,
and smoking behavior, using a standardized test for odor
threshold, discrimination and identification.
Participants and experimental protocol
The study was performed in accordance to the Declaration of
Helsinki on Biomedical Studies Involving Human Subjects (World
Medical Association, 1997) and was approved by the University of
Dresden Medical Faculty Ethics Review Board. All participants
provided written informed consent before inclusion in the study.
Twenty-five inpatients of the Clinic for Psychosomatic Disor-
ders and 22 healthy controls were invited to participate in this
study. All patients had been admitted to the hospital and treated
because of acute MDD. They had been previously diagnosed with
acute MDD by the treating physician /clinical psychologist (KP)
after completing a Composite International Diagnostic Interview
(CIDI, DIA-X German version; Wittchen and Pfister, 1997) accord-
ing to DSM IV criteria. Healthy controls were recruited via posters
set in the University Clinic area and reimbursed for their partici-
pation. Before proceeding with olfactory and volumetric measure-
ments, the testing protocol for all participants included a detailed
medical history review as well as otorhinolaryngological examina-
tion, comprising nasal endoscopy, which ensured exclusion of
nasal or internal pathology potentially causing olfactory dysfunc-
tion. All participants underwent a mini mental state examination
(MMSE; Folstein et al., 1975) to screen for possible cognitive
impairment. Additionally, all participants were asked to complete
the German version of Beck’s Depression Inventory (BDI; Beck et
al., 1961 German version; Hautzinger et al., 1995) and to rate their
olfactory function on a 7 points scale ranging from “extremely bad”
to “very good.”
Four patients were excluded because of concomitant nasal
pathology or existence of comorbidities known to interfere with
olfactory function (severe septum deviation, sinonasal disease).
The final group included four men and 17 women, aged between
21 and 55 years (mean?standard deviation (SD)?36.86?10.13
years); 14 were non-smokers, and seven smokers. Demographic
and illness-related parameters are shown in Table 1. Comorbidi-
ties included: somatoform disorders (12 cases) posttraumatic
stress disorder (nine cases) and anxiety disorders (17 cases).
Medication of the patients included selective serotonin reuptake
inhibitors (SSRI: Citalopram, Escitalopram, Paroxetine) in five
cases, tricyclic antidepressants in three cases (Mirtazapin, Dox-
epin, Primipramin), serotonin-norepinephrine reuptake inhibitors
(SNRI: Venlafaxin) in three cases, anticonvulsants in seven cases
(Carbamazepin, Pregabalin, Valproat), one with zinc and one with
lithium. Additionally four patients received neuroleptic drugs (Ris-
peridon and Quetiapin), as well as analgesics (five cases) and
proton pump inhibitors (three cases), while five patients were free
One subject from the control group was excluded because of
presumption of incidental MRI findings and failure to complete
required tests. The final control group was composed out of
6 males and 15 females, aged between 20 and 52 years
(mean?SD? 39.62?11.39 years), including 19 non-smokers and
two smokers. None of the controls scored higher than nine on the
BDI questionnaire (mean?SD?3.12?2.91) or reported psychiat-
ric diagnoses in their personal history. Data for part of the control
group (15 participants) were randomly selected according to age
groups from a database of a previous study that followed the same
inclusion criteria as the present study (Buschhuter et al., 2008).
The groups did not differ in terms of age (T40?0.83, P?0.41),
sex distribution (Chi-square?.52, P?0.47) and smoking habits
(Chi-square?4.30, P?0.12) but significantly differed regarding
BDI scores (T40??9.8, P?.001).
Olfactory function was assessed using the “Sniffin’ Sticks” test
battery (Burghart GmbH, Wedel, Germany) following a standard-
Table 1. Demographic and illness related parameters for patients
Minimum Maximum MeanSD
Age at debut of
Duration of disease (y)
Duration of current
S. Negoias et al. / Neuroscience 169 (2010) 415–421416
ized procedure (Hummel et al., 1997; Kobal et al., 2000). The test
included measurements for odor thresholds (T ?16 dilutions of
PEA, single staircase procedure, with No. 16 marking the lowest
available odor concentration, therefore the best olfactory sensitiv-
ity), odor discrimination (D ?16 triplets, 3-alternative forced
choice) and odor identification (I ?16 common odors, four alter-
native forced choice). Threshold measurements were performed
separately for the left and right nostril (Buschhuter et al., 2008),
while discrimination and identification were assessed in a birhinal
mode. The sum of the scores from the three individual tests (TDI
score) defined the olfactory function (Wolfensberger et al., 2000).
The results of the best nostril were used to calculate the overall
TDI score for group comparisons (compare; Frasnelli et al., 2002).
MRI measurements were performed with a 1.5-Tesla scanner
(Sonata Vision; Siemens, Erlangen, Germany) using an eight
channel-head coil. The investigation protocol included one whole
brain anatomical sequence without interslice gap (5-mm-thick
standard T1-weighted 3D sequence) for every participant to rule
out any organic brain disorders. The OB sequence included ac-
quisition of 2-mm-thick T2-weighted fast spin-echo images without
interslice gap in the coronal plane covering the anterior and middle
segments of the base of the skull. Images were processed offline
and left and right OBs limits were drawn manually on each coronal
slice using the AMIRA 3D visualization and modeling system
(Visage Imaging, Carlsbad, USA). OB volumes were calculated by
planimetric manual contouring (surface in mm2) and all surfaces
were added and multiplied by 2 (2-mm slice thickness) to obtain a
volume in cubic millimeters. The change of diameter at the begin-
ning of the olfactory tract was used as the distal demarcation of
the OB. OB measurements of all data were performed by the
same experimenter (SN), blinded to the group category or olfac-
tory test results. It included re-analyses of the data selected from
the laboratory database (15 participants). For reliability purposes,
intra-class correlation coefficients for these data were calculated
(ICC?0.70, P?0.003). The OB volume corresponding to the best
nostril was defined as “best OB” and was used for correlation
analyses with different functional parameters.
Data was analyzed using SPSS 15.0 for Windows (SPSS Inc.,
Chicago, IL, USA). Results were submitted to analyses of vari-
ance for repeated measures, adopting “side of testing” (left/right),
“test” (threshold, OB volume) as within-subjects-factors; the factor
“group” (patients/controls) was used as a between-subject-factor.
Degrees of freedom were adjusted according to Greenhouse-
Geisser. Additional comparisons for the functional and volumetric
data were performed using t-tests for independent samples. The
results may be prone to type 1 statistical error because the level
of significance was not corrected for multiple tests. Pearson cor-
relations between volumetric and functional measurements were
also calculated. The level of significance was set at 0.05.
The results for psychophysical and volumetric measure-
ments are listed in Table 2 separately for patients and
No difference was found in terms of self-rated olfactory
function (Chi-square?6.72, P?0.35). A significant effect of
the factor “group” was present only for thresholds and OB
volume (F[1,37]?5.32, P?0.027, and F[1,40]?5.73, P?
0.021, respectively), unlike for measures of odor discrimi-
nation and identification. No “group X side” interactions
were found significant. Regarding olfactory thresholds, t-
tests for paired samples revealed significantly lower sen-
sitivity for patients compared to controls for both later-
alized (right: T?2.15, P?0.038, left: T?2.11,
P?0.041) (Fig. 1) and best nostril measurements (T?
The patients group also exhibited smaller OB volumes
for side-to-side comparisons with controls (right T?
2.27, P?0.028; left T?2.21, P?0.026) (Fig. 2), while a
trend towards significance was revealed for “best bulb”
comparison (T?1.93, P?0.061). OB volumes varied
over a wide range: 37.4–98.1 mm3for controls and
36.4–86 mm3for patients. Intraindividual variation for
Fig. 1. Box plot of olfactory thresholds measured separate for left and
right nostril in patients and controls (where 16 represents the lowest
available odor concentration). The box-whisker plots show the 5th,
25th, 50th, 75th and 95th percentiles. The asterisk (*) indicates signif-
icant differences between patients and controls at a level of P?0.05.
Table 2. Results (mean, SD) and group comparison (t-Test) for odor
thresholds (T-left, right and best), discrimination (D), identification (I)
and olfactory bulb volume (OB-left, right and best) between controls
and patients (df?degrees of freedom)
S. Negoias et al. / Neuroscience 169 (2010) 415–421417
OB volume was much smaller, with a significant correla-
tion emerging (P?.001) between left and right-sided mea-
surements for both patients and controls (r21?0.87 and
A significant correlation between left-sided OB vol-
umes and left-sided odor thresholds (r39?0.37, P?0.02)
was observed: the lower the olfactory sensitivity, the
smaller the OB volume. However the correlation between
right-sided OB volumes and right-sided odor thresholds
was not significant (r39?0.19, P?0.26) (Fig. 3). No signif-
icant correlations were found between OB volume and
odor discrimination or odor identification scores. Further
on, depression scores (BDI) showed high negative corre-
lations with OB volumes (left: r37??0.40, P?0.014; right:
r37??0.37, P?0.025, best: r34??0.34, P?0.044) (Fig. 4).
Only the olfactory sensitivity as reflected in the best nostril
threshold was found to significantly correlate with the BDI
score (r37??0.34, P?0.04), while lateralized threshold
measures missed statistical significance (left or right:
The present study points to the following major results: (1)
patients with acute MDD have a reduced olfactory sensi-
tivity and smaller OB volumes than a normosmic control
group; (2) BDI scores correlate negatively with OB volume
and olfactory sensitivity.
These results are in line with previous findings of re-
duced olfactory sensitivity in acute MDD (Pause et al.,
2001, 2003; Lombion-Pouthier et al., 2006). A correlation
between olfactory function and depression scores/symp-
toms has also been shown in previous studies (Pause et
al., 2001; Pollatos et al., 2007). In addition, we demon-
strate for the first time that the decrease of olfactory func-
tion is accompanied by smaller OB volumes in MDD pa-
tients, and that depression scores correlate with OB
A range of theories has been proposed to explain a
potential olfactory deficit in MDD. Some authors point to
Fig. 2. Box plot of olfactory bulb volumes measured separately for left
and right nostril in patients and controls. The box-whisker plots show
the 5th, 25th, 50th, 75th and 95th percentiles. The asterisk (*) indicates
significant differences between patients and controls at a level of
P?0.05 for the same measures between patients and controls.
Fig. 3. Left and right odor thresholds plotted against left and right OB
volume, respectively (where 16 represents the lowest available odor
concentration). Left-sided OB volumes exhibited a significant correla-
tion with left-sided odor thresholds (r39?0.37, P?0.02) (dotted regres-
sion line), while correlations between right-sided OB volumes and
right-sided odor thresholds did not reach the level of significance
(r39?0.19, P?0.26, continuous regression line).
Fig. 4. BDI scores plotted separately against left and right OB volume.
OB volume shows significant correlation with BDI scores (left:
r37??.40, P?0.01; right: r37??.37, P?0.02).
S. Negoias et al. / Neuroscience 169 (2010) 415–421 418
the primary olfactory cortex and the OB as the site of
dysfunction, since tests involving cognitive levels of pro-
cessing, like olfactory discrimination and identification, do
not reveal any difference in patients with MDD compared
to controls. These results are also confirmed by the
present study. An additional model postulates that primary
OB dysfunction in MDD is responsible for reduced olfac-
tory perception leading to amygdala disinhibition which
consequently would affect emotional responses (Pause et
al., 2001), in analogy to the bulbectomy model of depres-
sion in rats (see Introduction). Abnormal functionality in the
para-limbic brain areas (mainly amygdala and orbitofrontal
cortex) has also been hypothesized to affect early olfactory
processing in MDD (Pause et al., 2003).
The present results raise the possibility of a relation
between neurogenesis and MDD. Neurogenesis is present
at the level of dentate nucleus of the hippocampus and
subventricular zone (SVZ) in mammalian brains (Eriksson
et al., 1998; Gould and Gross, 2002). Interestingly, some
authors consider the dentate nucleus of the hippocampus
to be closely linked to the olfactory system (Vanderwolf,
1992, 2001). Decreased neurogenesis at the level of the
hippocampus has been shown in animal models of depres-
sion (Jaako-Movits et al., 2006; Kronenberg et al., 2009),
while human studies report atrophic hippocampus in MDD
(McKinnon et al., 2009). Neurogenesis in the hippocampus
formation is suppressed by factors that predispose to
MDD, like prolonged stress and this process is reversed by
antidepressant therapy (see; Paizanis et al., 2007a; Perera
et al., 2008; Boldrini et al., 2009). Consequently, the idea
that impaired neurogenesis could be involved in the
pathoetiology of MDD has drawn substantial attention and
controversy (see; Paizanis et al., 2007b; Perera et al.,
2008). It has been suggested that newborn cells might be
needed in the adult hippocampus for linking external con-
text to emotions; disruption of this process by stress-in-
duced suppression of neurogenesis is thought to lead to
negative mood that could be resolved by the stimulation of
neurogenesis by antidepressant drugs. In the same theo-
retical framework, we might discuss the connection be-
tween OB, neurogenesis and MDD. Animal studies show
the rostral migratory stream provides progenitor cells from
the SVZ to the olfactory bulb in both rodents and primates
(Altman, 1969; Gheusi and Lledo, 2007). Although under
debate, some authors include the OB within the regions
showing cell proliferation in the human brain by analogy to
animal studies (Curtis et al., 2007; Kam et al., 2009). A
high incidence of OB ventricles found in a recent study
supports this theory (Smitka et al., 2009). The OB in hu-
mans has been shown to be a highly plastic structure
responding to sensory input. Mueller et al. showed re-
duced OB volumes in patients with post viral and posttrau-
matic olfactory loss compared to a normosmic population
(Mueller et al., 2005b). The same population measured
after 15 months showed significant increase of the OB
volume that paralleled the recovery of olfactory sensitivity
(Haehner et al., 2008). Similarly, a recent longitudinal
study provided evidence of increased OB volume and
olfactory function in patients with chronic rhinosinusitis
after functional endoscopic sinus surgery (Gudziol et al.,
2009b). It has been speculated that the increase of OB
volume is partly regulated by a bottom-up process involv-
ing sensory input from the olfactory epithelium. Our current
evidence suggests potential simultaneous top-down regu-
lation of the OB volume. In MDD, suppressed neurogen-
esis could also be reflected at the OB level and cause the
reduced olfactory sensitivity. Support for this idea comes
from animal studies, where reduced neurogenesis has
been shown also at the level of the SVZ which provides
progenitor cells to the OB, in mice exposed to chronic
stress (Mineur et al., 2007). This speculation is sustained
by a correlation of BDI scores with OB volume, found in the
present study. Similar to decreased hippocampus volumes
that resolve after antidepressant treatment, one could pre-
dict an increase of the OB volume with successful therapy.
Improvement of olfactory sensitivity with treatment of an
acute depressive episode, regarding of the level of the
starting point (reduced, the same or increased) compared
to a normosmic control population has been previously
reported (Suffin and Gitlin, 1986; Gross-Isseroff et al.,
1994; Pause et al., 2001; Postolache et al., 2002). A
follow-up study is currently ongoing to further investigate
whether this effect is reflected also in the OB volume. An
alternative hypothesis was proposed by Turetsky et al.
who observed decreased OB and decreased olfactory sen-
sitivity in patients with schizophrenia (Turetsky et al.,
2000). Recent results coming from the same laboratory
point to a potential olfactory receptor neuron dysfunction in
these patients (Turetsky et al., 2009) as showed by the
increased ORN depolarization responses following olfac-
tory stimulation. Corroborating the clinical and morpholog-
ical data, the authors interpreted these findings as proof of
increased neuronal proliferation associated with dysfunc-
tional olfactory receptor development in schizophrenia.
Analogously, the reduced bulb volume in patients with
acute depression could reflect a pre-existing condition at
the level of the olfactory epithelium.
A limitation of the present study may relate to the
patients’ use of drugs. Although antidepressants are
known to affect gustatory function in humans (Schiffman
and Graham, 2000), there is no evidence of quantitative
olfactory impairment coming from human studies. One
case report on Citalopram associates this drug with induc-
tion of parosmia (“unfavourable and intolerable smell”) that
appeared 7 weeks after the treatment initiation and disap-
peared upon termination (Ghanizadeh, 2007). Some ani-
mal studies suggest, nevertheless, that SSRIs might affect
olfactory function: Rolipram was shown in mice to impair
detection accuracy of 1-propanol at relatively low concen-
trations (Pho et al., 2005). Citalopram and Clomipramine
induced a decrease in olfactory sensitivity after 3 weeks of
treatment in mice (Lombion et al., 2008). The patients
included in this study had a long history of the disease.
Therefore possible chronic effects of the medication can-
not be excluded. However, as in the present study, re-
duced olfactory sensitivity was also reported in antidepres-
sant drug free patients with MDD (Pause et al., 2005).
Consequently a potential confounding effect of the antide-
S. Negoias et al. / Neuroscience 169 (2010) 415–421419
pressant medication does not seem to play a significant
role in the present study. Lack of motivation in patients with
depression could have possibly led to poorer performance
in the olfactory tests; the correlation with depression se-
verity seems to support this possibility. Nevertheless, pa-
tients participated on a voluntary basis and were free to
abandon the study at any time. In fact, the investigated
patients showed a clear interest in the olfactory tests
which—apparently—was not different from that of healthy
The present results provide further evidence supporting a
reduced olfactory sensitivity with maintained olfactory dis-
crimination and identification abilities in patients with se-
vere MDD compared to healthy controls. Furthermore,
decreased OB volume was shown in MDD patients, ac-
companied by a significant correlation between OB vol-
ume, olfactory thresholds and depression scores, respec-
tively. A hypothetical mechanism explaining these results
might involve reduced neurogenesis in MDD that could be
reflected also at the OB level.
Acknowledgments—We would like to thank Artin Arshamian, Anja
Symank and Dorothee Buschhüter for their contribution to collec-
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(Accepted 5 May 2010)
(Available online 13 May 2010)
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