Desvenlafaxine and escitalopram for the treatment of

postmenopausal women with major depressive disorder.

Soares CN1, Thase ME, Clayton A, Guico-Pabia CJ, Focht K, Jiang Q, Kornstein SG, Ninan
P, Kane CP, Cohen LS.
Author information

Abstract
OBJECTIVE:
This study assessed the efficacy, safety, and tolerability of the serotonin-norepinephrine reuptake inhibitor
desvenlafaxine and the selective serotonin reuptake inhibitor escitalopram for major depressive disorder (MDD)
in postmenopausal women.
METHODS:
In this randomized, double-blind study, postmenopausal outpatients (aged 40-70 y) with Diagnostic and
Statistical Manual of Mental Disorders, Fourth Edition MDD received flexible-dose desvenlafaxine (100-200
mg/d) or escitalopram (10-20 mg/d) for 8 weeks. Acute-phase responders, that is, women with a 50% or greater
reduction from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D17) total score, were
eligible to continue the same double-blind treatment in the 6-month continuation phase. The primary efficacy
outcomes were mean change from baseline in HAM-D17 total score (acute phase), analyzed using a mixedeffects model for repeated measures, and the proportion of women who maintained response (continuation
phase), analyzed using logistic regression.
RESULTS:
Reductions in HAM-D17 total score at acute-phase endpoint were similar for desvenlafaxine- and escitalopramtreated women (-13.6 vs -14.3, respectively; P = 0.24). No significant difference was observed between groups
at continuation-phase endpoint in the proportion of women who maintained response (desvenlafaxine, 82%;
escitalopram, 80%; P = 0.70). In both phases, desvenlafaxine and escitalopram were generally safe and well
tolerated.
CONCLUSIONS:
Among postmenopausal outpatients with MDD, there were no significant differences in the efficacy of
desvenlafaxine and escitalopram based on primary efficacy analyses. The results do not support the overall
hypothesis that the serotonin-norepinephrine reuptake inhibitor desvenlafaxine has an efficacy advantage for
the treatment of MDD in postmenopausal women because, in this particular subgroup, desvenlafaxine failed to
prove superiority over escitalopram. Safety and tolerability were comparable.

The Human Ortholog of Acid-Sensing Ion Channel Gene ASIC1a

Is Associated with Panic Disorder and Amygdala Structure and
Function.
Smoller JW1, Gallagher PJ2, Duncan LE3, McGrath LM2, Haddad SA2, Holmes AJ4, Wolf
AB2, Hilker S5, Block SR6, Weill S2, Young S7, Choi EY8, Rosenbaum JF9, Biederman J10, Faraone
SV11, Roffman JL12, Manfro GG13, Blaya C14, Hirshfeld-Becker DR9, Stein MB15, Van Ameringen
M16, Tolin DF17, Otto MW18,Pollack MH19, Simon NM20, Buckner RL21, Ongr D22, Cohen BM22.
Author information

Abstract
BACKGROUND:
Individuals with panic disorder (PD) exhibit a hypersensitivity to inhaled carbon dioxide, possibly reflecting a
lowered threshold for sensing signals of suffocation. Animal studies have shown that carbon dioxide-mediated
fear behavior depends on chemosensing of acidosis in the amygdala via the acid-sensing ion channel ASIC1a.
We examined whether the human ortholog of the ASIC1a gene, ACCN2, is associated with the presence of PD
and with amygdala structure and function.
METHODS:
We conducted a case-control analysis (n = 414 PD cases and 846 healthy controls) of ACCN2 single
nucleotide polymorphisms and PD. We then tested whether variants showing significant association with PD
are also associated with amygdala volume (n = 1048) or task-evoked reactivity to emotional stimuli (n = 103) in
healthy individuals.
RESULTS:
Two single nucleotide polymorphisms at the ACCN2 locus showed evidence of association with PD: rs685012
(odds ratio = 1.32, gene-wise corrected p = .011) and rs10875995 (odds ratio = 1.26, gene-wise corrected p = .
046). The association appeared to be stronger when early-onset (age 20 years) PD cases and when PD
cases with prominent respiratory symptoms were compared with controls. The PD risk allele at rs10875995
was associated with increased amygdala volume (p = .035) as well as task-evoked amygdala reactivity to
fearful and angry faces (p = .0048).
CONCLUSIONS:
Genetic variation at ACCN2 appears to be associated with PD and with amygdala phenotypes that have been
linked to proneness to anxiety. These results support the possibility that modulation of acid-sensing ion
channels may have therapeutic potential for PD.

Shift in the brain network of emotional regulation in midlife

women: is the menopausal transition the turning point?
Frey BN1, Hall GB, Attard S, Yucel K, Skelin I, Steiner M, Soares CN.
Author information

Abstract
OBJECTIVE:
The menopausal transition is marked by hormonal changes and is quite often accompanied by cognitive and
emotional complaints. Recent data also suggest a heightened risk for depression. Little is known about the
changes in emotional regulation that might contribute to the increased risk of depression in this population. The
aim of this study was to examine the brain correlates of emotional regulation in healthy, nondepressed midlife
women.
METHODS:
Functional magnetic resonance imaging was obtained in response to a standardized emotional regulation task.
Levels of congruency were set and brain activation was measured during high- and low-conflict-resolution
trials.
RESULTS:
Fourteen women aged 40 to 60 years were enrolled into the study, and 11 were included in the final analyses.
Activity associated with resolution of emotional conflict was observed in the dorsolateral prefrontal cortex (P <
0.05). No regions were engaged in the generation/monitoring of emotional conflict. Moreover, there was a
significant deactivation of the amygdala in response to fearful faces (P < 0.05).
CONCLUSIONS:
Unlike similar studies in younger populations, these results suggest a more significant engagement of the
dorsolateral prefrontal cortex and less amygdala activation in emotional regulation in midlife women. These
findings are, however, consistent with previous studies in older populations. We hypothesize that a shift in
emotional regulation circuitry might therefore occur in women during the menopausal transition and possibly
contribute to the occurrence of mood and anxiety symptoms in women during/after this period in life.

Role of serotonin transporter inhibition in the regulation of tryptophan

hydroxylase in brainstem raphe nuclei: time course and regional
specificity.
MacGillivray L1, Lagrou LM, Reynolds KB, Rosebush PI, Mazurek MF.
Author information

Department of Medicine-Neurology, McMaster University Medical Centre, 1200 Main Street West,

Hamilton, ON, L8N 3Z5, Canada. macgille@mcmaster.ca

Abstract
Drugs that selectively inhibit the serotonin transporter (SERT) are widely prescribed for treatment of depression
and a range of anxiety disorders. We studied the time course of changes in tryptophan hydroxylase (TPH) in
four raphe nuclei after initiation of two different SERT inhibitors, citalopram and fluoxetine. In the first
experiment, groups of Sprague-Dawley rats received daily meals of rice pudding either alone (n=9) or mixed
with citalopram 5 mg/kg/day (n=27). Rats were sacrificed after 24 h, 7 days or 28 days of treatment. Sections of
dorsal raphe nucleus (DRN), median raphe nucleus (MRN), raphe magnus nucleus (RMN) and caudal linear
nucleus (CLN) were processed for TPH immunohistochemistry. Citalopram induced a significant reduction in
DRN TPH-positive cell counts at 24 h (41%), 7 days (38%) and 28 days (52%). Similar reductions in TPHpositive cell counts were also observed at each timepoint in the MRN and in the RMN. In the MRN, citalopram
resulted in significant reductions at 24 h (26%), 7 days (16%) and 28 days (23%). In the RMN, citalopram
induced significant reductions of TPH-positive cell counts at 24 h (45%), 7 days (34%) and 28 days (43%). By
contrast, no significant differences between control and treatment groups were observed in the CLN at any of
the time points that we studied. To investigate whether these changes would occur with other SERT inhibitors,
we conducted a second experiment, this time with a 28-day course of fluoxetine. As was observed with
citalopram, fluoxetine induced significant reductions of TPH cell counts in the DRN (39%), MRN (38%) and
RMN (41%), with no significant differences in the CLN. These results indicate that SERT inhibition can alter the
regulation of TPH, the rate limiting enzyme for serotonin biosynthesis. This persistent and regionally specific
downregulation of serotonin biosynthesis may account for some of the clinical withdrawal symptoms associated
with drugs that inhibit SERT.