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Metab Brain Dis (2010) 25:369–374DOI 10.1007/s11011-010-9218-6 Changes in regional brain volumes in social anxiety disorderfollowing 12 weeks of treatment with escitalopram Naseema Cassimjee & Jean-Pierre Fouche & Michael Burnett & Christine Lochner &James Warwick & Patrick Dupont & Dan J. Stein & Karen J. Cloete & Paul D. Carey Received: 23 April 2010 / Accepted: 24 August 2010 / Published online: 10 November 2010 # Springer Science+Business Media, LLC 2010 Abstract It has been suggested that antidepressants, treatment with escitalopram. These preliminary findings including the selective serotonin reuptake inhibitors have require replication to determine their reliability, and neurotrophic effects. Nevertheless, the impact of treatment extension to determine whether or not they are disorder with a selective serotonin re-uptake inhibitor on regional brain volumes in social anxiety disorder has not beenstudied. 11 subjects with social anxiety disorder completed Keywords Escitalopram . Regional brain volumes . Social magnetic resonance imaging both before and after 12- anxiety disorder . Structural magnetic resonance imaging weeks of treatment with 20 mg/day escitalopram. Noincreases in structural grey matter were found, but therewere decreases in bilateral superior temporal cortex, vermis and the left cerebellum volumes following 12 weeks of Evidence for a range of effective medications for socialanxiety disorder (SAD) has emerged in recent years (Ipser N. Cassimjee K. J. Cloete (*) et al. Presently, the weight of evidence supports the Department of Psychiatry, University of Stellenbosch, use of selective serotonin reuptake inhibitors (SSRI) and PO Box 19063, Tygerberg 7505, South Africae-mail: [email protected] serotonin norepinephrine reuptake inhibitors as first line agents in SAD. It is increasingly thought that the primaryaction of the SSRIs is not limited to the inhibition of synaptic serotonin reuptake, but also involves a complex Cape Universities Brain Imaging Centre,University of Stellenbosch, interaction of post-synaptic receptors, secondary messenger Tygerberg, South Africa systems and neurotrophic factors (NF), which act togetherto effect changes in the cellular milieu that result in a M. Burnett C. Lochner J. Warwick D. J. Stein P. D. Carey treatment response.
MRC Research Unit on Anxiety Disorders,Department of Psychiatry, University of Stellenbosch, Mounting evidence supports the hypothesis that neuro- Tygerberg, South Africa trophins interact with neurotransmitters to alter synapticactivity (Lang et al. ; Schinder and Poo ). More specifically, neurotrophins have a stimulatory or inhibitory Division of Nuclear Medicine, University of Stellenbosch,Tygerberg, South Africa effect on glutamatergic and gamma aminobutyric acid-ergicsystems, which in turn results in changes to the production, secretion and activity of neurotrophins. Altered neuro- Laboratory for Cognitive Neurology and Medical Imaging trophin levels have been described in a variety of disorders, Research Center,K.U. Leuven, which have in turn been associated with altered brain neuroplasticity (Spedding and Gressens ). Extension ofthis hypothesis into the clinical arena has indicated that there is an association between lower levels of NF, Department of Psychiatry, University of Cape Town,Cape Town, South Africa increased psychiatric symptoms (Castrén and Rantamäki Metab Brain Dis (2010) 25:369–374 ; Martinowich et al. Vetencourt et al. ), withdraw from fluoxetine due to lack of efficacy and was with increased NF levels associated with a treatment washed out for 5 weeks prior to the baseline treatment visit.
response (Rantamäki et al. ). In addition, early studies No participant had failed more than a single trial of of anxiety disorders (Bremner et al. and depression pharmacotherapy defined as a minimum of 8 weeks at an have suggested an association of NF levels with regional adequate dose. No participants had previously been exposed brain volumes (Campbell and MacQueen Frodl et to escitalopram.
Subjects with any current psychiatric co-morbidity, Taken together these studies raise the question of the link including current depression, were excluded. Women of between disorders with apparently lower NF levels, and the childbearing potential were excluded if pregnant, and all ability of pharmacotherapy agents to lead to changes in NF subjects were required to be on contraception for the levels, and consequently to changes in regional brain duration of the study. Having a recent (6 months) history of volume. Indeed, there is some evidence that antidepressant substance abuse/misuse, a serious/unstable medical disorder, treatment does lead to increases in regional brain volumes a history of previous head injury, recent (90 days) electro- (Chen et al. ; Fossati et al. ; Vermetten et al.
convulsive therapy, any metal implants, claustrophobia or a ). However, it remains unclear whether these findings previous adverse response to magnetic resonance imaging can be extended to other anxiety disorders, where different (MRI), and use of any psychoactive substances other than neuro-circuitry may be involved in mediating symptoms.
non-problematic alcohol or nicotine use (< 14 days prior to Social anxiety disorder is an anxiety disorder character- study initiation) were all criteria for exclusion from participa- ized by marked and persistent fear of one or more tion in the study.
performance situations (American Psychiatric Association The study protocol was approved by the Committee ). Individuals fear being exposed to unfamiliar people/ for Human Research of the University of Stellenbosch situations in which the possibility of scrutiny and ensuing (M05/01/006) prior to study initiation. Following deter- embarrassment is a possibility. This results in functionally mination of eligibility, all participants were required to impairing and distressing anticipation of social situations, sign an information and consent document prior to any consequent social avoidance, or endurance of situations study specific procedure being conducted. Participants with considerable discomfort. Previous work has suggested were not re-imbursed for their participation in the study.
that an undefined dysfunction within the frontal and However we did cover transport costs incurred to attend amygdalo-hippocampal circuitry is responsible for mediat- clinic visits.
ing symptoms of SAD (Aouizerate et al. ; Warwick etal. Research has also shown that effective treatment alters brain regions broadly linked to these brain regionssuggesting disorder specific brain effects that correlate To determine baseline and subsequent severity of SAD we with the treatment effect (Furmark et al. ; Warwick used the Liebowitz Social Anxiety Scale (LSAS) (Liebowitz To assess sub-syndromal depressive symptomatology, To date no studies in SAD have been reported in which we used the Montgomery Äsberg Depression Rating Scale the impact of treatment with an SSRI on regional brain (MADRS) (Montgomery and Asberg ). Overall clinical volumes is investigated. We hypothesized that after severity of symptoms and response were assessed using the 12 weeks of treatment with escitalopram, brain volumes Clinical Global Impression (CGI) scale (Guy ).
in frontal and temporal brain regions would increase inparticipants with SAD.
The clinical screening interview was conducted by a Materials and methods psychiatrist or psychiatric resident (PC and NC), and wasfollowed with a structural magnetic resonance scan prior to the initiation of open-label escitalopram therapy. Subsequentstudy visits were scheduled on completion of 4, 8, and Potentially eligible participants (n=14, 9=female, 5=male), 12 weeks of treatment. In addition, investigators made bi- aged 18–65 years with MINI-defined DSM-IV SAD (Sheehan weekly telephonic contact with participants to assess ongoing et al. were recruited from our specialist anxiety disorder safety and compliance with study procedures. A second MRI clinic at Stellenbosch University. Participants had been was conducted before discontinuation of study medication previously diagnosed with SAD, and all but one were after completion of a minimum of 12 weeks treatment.
medication free at the time of the study. The one participant The clinical measures mentioned above were repeated at on treatment at the time of screening voluntarily agreed to each of these visits. Medication tolerability and compli- Metab Brain Dis (2010) 25:369–374 ance (pill-count) with the treatment regime was assessed mapping (ICBM) priors instead of study-specific priors. In at each contact.
the longitudinal analysis, the second scan of each subject(Week 12 scan) was co-registered with the first scan (baseline) without any re-slicing, and then warped to thebaseline scan using high-dimensional warping and also Following completion of all scheduled baseline activities, writing the Jacobian determinants for the deformation field open-label treatment with escitalopram was initiated at a of each warp. The deformation field was then applied to the dose of 10 mg daily for the first 5 days. This dose was follow-up image and this transformed image was then increased to 20 mg daily for the remainder of the 12-week averaged with the baseline image to create a mean image treatment period. All participants who started treatment for each subject. This mean image was then segmented into completed the scheduled 12 weeks of treatment. Participants grey matter, white matter and cerebrospinal fluid using the were given the option of continuing treatment at 12 weeks.
ICBM priors of SPM5. The normalization parameters of the Those that were discontinuing with the treatment were grey matter partition were then applied to the mean images tapered to 10 mg per day for 10 days, and then as well as the Jacobian determinant data. The normalized medication was stopped.
mean image was then segmented into its grey matterpartition using the ICBM template. This baseline data (partition) for each subject was then multiplied by theJacobian determinants to create the follow-up data for each Magnetic resonance imaging was conducted on the subject. With data from both time-points being smoothed 3T Siemens Magnetom Allegra located in the Cape using a 10 mm full width at half maximum Gaussian Universities Brain Imaging Centre located at the University of Stellenbosch's Tygerberg Campus. Scanning sessionslasted approximately 40 min. A high resolution 3D, T1- Statistical analysis weighted sequence was acquired and used in subsequentanalyses. One hundred and sixty, sagittal 1 mm slices of the A paired two-sample t-test was used for the statistical whole brain were acquired with imaging parameters as analysis. The significance threshold was set at p<0.001 (at follows: 179×256 matrix, TR=2300 ms, TE=3.93 ms, in- the voxel level) combined with a family wise error plane resolution of 1.0×1.0×1.0 mm and flip angle 12°.
corrected p<0.05 for the size of the clusters. To excludenon-brain voxels, a brain mask was used during the MRI preprocessing analysis. The contrast follow-up > baseline and the reversecontrast of baseline > follow-up was tested.
All of the 14 participants who started the study completedthe 12 weeks of treatment. One subject was excluded due topoor image quality of the MRI, and two participants were not able to complete the Week 12 scan. Our final analysiswas conducted on the remaining 11 subjects using baseline Eleven participants were included in the analysis. Participants and week 12 scans. Preprocessing was performed in demonstrated > 90% compliance overall, as determined by MATLAB R2007b (Mathworks, Natick, MA) within the pill count. The cohort comprised nine males and five females statistical parametric mapping (SPM5) framework (Wellcome with a mean age of 40.64 years (SD 11.74). All participants Department of Imaging Neuroscience, University College tolerated the higher (20 mg/day) dose of escitalopram as London, UK). Although standard voxel-based morphometry prescribed in the study protocol. Baseline severity of processes in SPM5 are adequate for comparing grey matterdifferences across groups, potential artefacts might occur Table 1 Clinical measures at baseline and week 12 demonstrate a during longitudinal analysis resulting from intra subject global markedly ill cohort with very limited depressive symptom co- changes in brain size over time (Chételat et al. ). As such morbidity and relatively modest overall improvements with 12 weeks we implemented the longitudinal protocol described by Chételat et al. This procedure first creates a Mean (SD)— Mean (SD)— customized whole brain template as described by Good et al. ). The template was smoothed with an 8 mmGaussian full width at half maximum isotropic kernel.
Liebowitz Social Anxiety Scale 84.36 (21.92) 57.91 (32.74) We then implemented the protocol as defined by Montgomery Äsberg Depression Chételat et al. (with the one exception being our Clinical Global Impression -Severity use of the SPM5 international consortium for brain

Metab Brain Dis (2010) 25:369–374 SAD was marked to severe with a mean LSAS score of 84.36 (SD 21.92). While a significant improvement was noted overall (31% reduction in LSAS, p<0.009), themean LSAS score after Week 12 [57.91 (SD 32.74)] stillsuggests this cohort was moderately ill overall (Table Fewer than half (4/11) participants were classified asresponders with a CGI-Improvement score of "Much"(Score of 2, n=1) or "very much" (score of 1, n=3)improved. Treatment was well tolerated in all cases and noserious adverse effects were recorded.
To address our main hypothesis we assessed the contrast ‘Follow-up > baseline'. This showed no significant clustersmeeting our a priori thresholds. Even if we used a lessstringent threshold of p < 0.01 (voxel level) and anuncorrected p<0.05 (cluster level), we did not find anysignificant increase. However, the reverse contrast of ‘Baseline > Follow-up' demonstrated structural grey matter decreases in the bilateral superior temporal cortex, vermisand the left cerebellum following 12 weeks of treatment with escitalopram (Fig. Table Small group sizeprecluded a meaningful ‘responder vs non-responder' The main findings in our study were structural grey matterdecreases in bilateral superior temporal cortex, vermis andleft cerebellum following 12 weeks of treatment withescitalopram. These findings are, to the best of ourknowledge, the first to demonstrate structural brain changesin response to SSRI treatment in SAD. The clinical measuresused in our study (LSAS, MADRS, CGI-severity) demon-strate a modest overall improvement following 12 weeks of Contrary to our hypothesis, the findings here do not replicate the effects on brain structure seen in previous Fig. 1 Clusters corresponding to a significant decrease in grey matter studies in mood and anxiety disorders when treated with following 12 weeks of treatment with escitalopram in the right (a) and left (b) superior temporal cortex. Clusters are overlayed on the single 's. The amygdalo-hippocampal brain regions, which subject brain provided within SPM5 for visualisation are usually associated with high levels of plasticity, did notappear to be impacted following SSRI treatment in our Table 2 Group-wise contrast (Baseline > Follow-up) showing clusters of brain volume decreases following 12 weeks of treatment co-varied forbaseline LSAS scores Coordinates x,y,z (mm)a Cluster volume (mm3) Right superior temporal cortex Left superior temporal cortex Left cerebellum crus a Coordinates (x,y,z) in millimeters correspond to Montreal Neurological Institute spaceb Corrected for multiple comparisons Metab Brain Dis (2010) 25:369–374 sample, as has been the case in previous functional work on Aouizerate B, Martin-Guehl C, Tignol J (2004) Neurobiology and pharmacotherapy of social phobia. Encephale 30:301–313 SAD (Furmark et al. ; Engel et al. ; Freitas-Ferrari Bremner JD, Vermetten E (2004) Neuroanatomical changes associated et al. or structural work on other anxiety disorders with pharmacotherapy in posttraumatic stress disorder. Ann NY (Bremner and Vermetten ; Engel et al. ). The Acad Sci 1032:154–157 neuroplasticity of the adult brain may well be limited (Nass Bremner JD, Vythilingam M, Vermetten E, Southwick SM, McGlashan T, Nazeer A, Khan S, Vaccarino V, Soufer R, Garg PK, Ng CK, ). It is also possible that the sample size in our study Staib LH, Duncan JS, Charney DS (2003) MRI and PET study of was underpowered to find such differences.
deficits in hippocampal structure and function in women with Changes in temporal lobe regional volumes after SSRI childhood sexual abuse and posttraumatic stress disorder. Am J treatment may, however, be consistent with various data Psychiatry 160:924–932 Campbell S, MacQueen G (2006) An update on regional brain volume pointing to the role of these structures in anxiety in general differences associated with mood disorders. Curr Opin Psychiatry and SAD in particular (Tillfors et al. ; Lorberbaum et al. Furmark et al. Warwick et al. Engel et Castrén E, Rantamäki T (2008) Neurotrophins in depression and al. ; Freitas-Ferrari et al. It is notable that antidepressant effects. Novartis Found Symp 289:43–52 Chen CH, Ridler K, Suckling J, Williams S, Fu CH, Merlo-Pich E, citalopram reduced public speaking anxiety in patients with Bullmore E (2007) Brain imaging correlates of depressive social phobia, and that this symptom improvement was symptom severity and predictors of symptom improvement after associated with reduced regional cerebral blood flow mainly antidepressant treatment. Biol Psychiatry 62:407–414 in the medial temporal lobe, but including the amygdala, Chételat G, Landeau B, Eustache F, Mézenge F, Viader F, De La Sayette V, Desgranges B, Baron JC (2005) Using voxel-based hippocampus and surrounding rhinal cortices (Furmark et al.
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conversion in MCI: a longitudinal MRI study. Neuroimage Although there is little work on the role of the cerebellum in anxiety disorders, previous research has suggested an Engel K, Bandelow B, Gruber O, Wedekind D (2009) Neuroimaging in anxiety disorders. J Neural Transm 116:703–716 association between anxiety disorders and cerebellar- Fossati P, Radtchenko A, Boyer P (2004) Neuroplasticity: from MRI vestibular dysfunction (Levinson ), and a positron to depressive symptoms. Eur Neuropsychopharmacol 14:S503– emission tomography study demonstrated that anticipatory anxiety in SAD subjects was associated with decreased Freitas-Ferrari MC, Hallak JEC, Trzesniak C, Filho AS, Machado- de-Sousa JP, Chagas MHN, Nardi AE, Crippa JAS (2010) cerebellar perfusion bilaterally (Tillfors et al. ; Freitas- Neuroimaging in social anxiety disorder: a systematic review Ferrari et al. These areas also correspond with changes of the literature. Prog Neuropsychopharmacol Biol Psychiatry demonstrated by Kilts et al. ). Nevertheless, the relative lack of involvement in cerebellum in previous anxiety Frodl T, Schule C, Schmitt G, Born C, Baghai T, Zill P, Bottlender R, Rupprecht R, Bondy B, Reiser M, Möller HJ, Meisenzahl EM disorder imaging studies, and the less reliable GM segmen- (2007) Association of the brain-derived neurotrophic factor tation of the cerebellum, raises the question of whether the Val66Met polymorphism with reduced hippocampal volumes in cerebellum findings here are artefactual.
major depression. Arch Gen Psychiatry 64:410–416 Our study is limited by the fact that we do not have direct Furmark T, Tillfors M, Marteinsdottir I, Fischer H, Pissiota A, Långström B, Fredrikson M (2002) Common changes in cerebral evidence of changes in potentially relevant mediating blood flow in patients with social phobia treated with citalopram molecular pathways, such as altered neurotrophin factor or cognitive-behavioral therapy. Arch Gen Psychiatry 59:425– levels in response to treatment, and as such cannot make any direct inference about the mechanism of change. Our small Furmark T, Appel L, Michelgård A, Wahlstedt K, Ahs F, Zancan S, Jacobsson E, Flyckt K, Grohp M, Bergström M, Pich EM, sample size also precluded us drawing conclusions about the Nilsson LG, Bani M, Långström B, Fredrikson M (2005) relationship between treatment response, and changes in Cerebral blood flow changes after treatment of social phobia brain volume. The preliminary findings here require replica- with the neurokinin-1 antagonist GR205171, citalopram, or tion to determine their reliability, and extension to determine placebo. Biol Psychiatry 58:132–142 Good CD, Johnsrude IS, Ashburner J, Henson RN, Friston KJ, whether or not they are disorder specific.
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Laboratorios Silanes, S.A. de C.V. Información para prescribir Nombre del producto y F.F.: Versión de IPP: N° de Registro: Versión número: CLOSTEDAL* 86718 SSA-IV N° de Autorización: tabletas KEAR 06330060101992/RM2006 INFORMACIÓN PARA PRESCRIBIR AMPLIA (IPP-A)


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