Metab Brain Dis (2010) 25:369–374 DOI 10.1007/s11011-010-9218-6
ORIGINAL PAPER
Changes in regional brain volumes in social anxiety disorder following 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, including the selective serotonin reuptake inhibitors have neurotrophic effects. Nevertheless, the impact of treatment with a selective serotonin re-uptake inhibitor on regional brain volumes in social anxiety disorder has not been studied. 11 subjects with social anxiety disorder completed magnetic resonance imaging both before and after 12weeks of treatment with 20 mg/day escitalopram. No increases in structural grey matter were found, but there were decreases in bilateral superior temporal cortex, vermis and the left cerebellum volumes following 12 weeks of N. Cassimjee : K. J. Cloete (*) Department of Psychiatry, University of Stellenbosch, PO Box 19063, Tygerberg 7505, South Africa e-mail:
[email protected] e-mail:
[email protected] J.-P. Fouche Cape Universities Brain Imaging Centre, University of Stellenbosch, Tygerberg, South Africa M. Burnett : C. Lochner : J. Warwick : D. J. Stein : P. D. Carey MRC Research Unit on Anxiety Disorders, Department of Psychiatry, University of Stellenbosch, Tygerberg, South Africa J. Warwick Division of Nuclear Medicine, University of Stellenbosch, Tygerberg, South Africa P. Dupont Laboratory for Cognitive Neurology and Medical Imaging Research Center, K.U. Leuven, Leuven, Belgium D. J. Stein Department of Psychiatry, University of Cape Town, Cape Town, South Africa
treatment with escitalopram. These preliminary findings require replication to determine their reliability, and extension to determine whether or not they are disorder specific. Keywords Escitalopram . Regional brain volumes . Social anxiety disorder . Structural magnetic resonance imaging
Introduction Evidence for a range of effective medications for social anxiety disorder (SAD) has emerged in recent years (Ipser et al. 2008). Presently, the weight of evidence supports the use of selective serotonin reuptake inhibitors (SSRI) and serotonin norepinephrine reuptake inhibitors as first line agents in SAD. It is increasingly thought that the primary action of the SSRIs is not limited to the inhibition of synaptic serotonin reuptake, but also involves a complex interaction of post-synaptic receptors, secondary messenger systems and neurotrophic factors (NF), which act together to effect changes in the cellular milieu that result in a treatment response. Mounting evidence supports the hypothesis that neurotrophins interact with neurotransmitters to alter synaptic activity (Lang et al. 2004; Schinder and Poo 2000). More specifically, neurotrophins have a stimulatory or inhibitory effect on glutamatergic and gamma aminobutyric acid-ergic systems, which in turn results in changes to the production, secretion and activity of neurotrophins. Altered neurotrophin levels have been described in a variety of disorders, which have in turn been associated with altered brain neuroplasticity (Spedding and Gressens 2008). Extension of this hypothesis into the clinical arena has indicated that there is an association between lower levels of NF, increased psychiatric symptoms (Castrén and Rantamäki
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2008; Martinowich et al. 2007; Vetencourt et al. 2008), with increased NF levels associated with a treatment response (Rantamäki et al. 2007). In addition, early studies of anxiety disorders (Bremner et al. 2003) and depression have suggested an association of NF levels with regional brain volumes (Campbell and MacQueen 2006; Frodl et al. 2007). Taken together these studies raise the question of the link between disorders with apparently lower NF levels, and the ability of pharmacotherapy agents to lead to changes in NF levels, and consequently to changes in regional brain volume. Indeed, there is some evidence that antidepressant treatment does lead to increases in regional brain volumes (Chen et al. 2007; Fossati et al. 2004; Vermetten et al. 2003). However, it remains unclear whether these findings can be extended to other anxiety disorders, where different neuro-circuitry may be involved in mediating symptoms. Social anxiety disorder is an anxiety disorder characterized by marked and persistent fear of one or more performance situations (American Psychiatric Association 2000). Individuals fear being exposed to unfamiliar people/ situations in which the possibility of scrutiny and ensuing embarrassment is a possibility. This results in functionally impairing and distressing anticipation of social situations, consequent social avoidance, or endurance of situations with considerable discomfort. Previous work has suggested that an undefined dysfunction within the frontal and amygdalo-hippocampal circuitry is responsible for mediating symptoms of SAD (Aouizerate et al. 2004; Warwick et al. 2008). Research has also shown that effective treatment alters brain regions broadly linked to these brain regions suggesting disorder specific brain effects that correlate with the treatment effect (Furmark et al. 2002; Warwick et al. 2006). To date no studies in SAD have been reported in which the impact of treatment with an SSRI on regional brain volumes is investigated. We hypothesized that after 12 weeks of treatment with escitalopram, brain volumes in frontal and temporal brain regions would increase in participants with SAD.
Materials and methods Participants Potentially eligible participants (n=14, 9=female, 5=male), aged 18–65 years with MINI-defined DSM-IV SAD (Sheehan et al. 1998) were recruited from our specialist anxiety disorder clinic at Stellenbosch University. Participants had been previously diagnosed with SAD, and all but one were medication free at the time of the study. The one participant on treatment at the time of screening voluntarily agreed to
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withdraw from fluoxetine due to lack of efficacy and was washed out for 5 weeks prior to the baseline treatment visit. No participant had failed more than a single trial of pharmacotherapy defined as a minimum of 8 weeks at an adequate dose. No participants had previously been exposed to escitalopram. Subjects with any current psychiatric co-morbidity, including current depression, were excluded. Women of childbearing potential were excluded if pregnant, and all subjects were required to be on contraception for the duration of the study. Having a recent (6 months) history of substance abuse/misuse, a serious/unstable medical disorder, a history of previous head injury, recent (90 days) electroconvulsive therapy, any metal implants, claustrophobia or a previous adverse response to magnetic resonance imaging (MRI), and use of any psychoactive substances other than non-problematic alcohol or nicotine use (< 14 days prior to study initiation) were all criteria for exclusion from participation in the study. The study protocol was approved by the Committee for Human Research of the University of Stellenbosch (M05/01/006) prior to study initiation. Following determination of eligibility, all participants were required to sign an information and consent document prior to any study specific procedure being conducted. Participants were not re-imbursed for their participation in the study. However we did cover transport costs incurred to attend clinic visits. Measures To determine baseline and subsequent severity of SAD we used the Liebowitz Social Anxiety Scale (LSAS) (Liebowitz 1987). To assess sub-syndromal depressive symptomatology, we used the Montgomery Äsberg Depression Rating Scale (MADRS) (Montgomery and Asberg 1979). Overall clinical severity of symptoms and response were assessed using the Clinical Global Impression (CGI) scale (Guy 1976). Study procedures The clinical screening interview was conducted by a psychiatrist or psychiatric resident (PC and NC), and was followed with a structural magnetic resonance scan prior to the initiation of open-label escitalopram therapy. Subsequent study visits were scheduled on completion of 4, 8, and 12 weeks of treatment. In addition, investigators made biweekly telephonic contact with participants to assess ongoing safety and compliance with study procedures. A second MRI was conducted before discontinuation of study medication after completion of a minimum of 12 weeks treatment. The clinical measures mentioned above were repeated at each of these visits. Medication tolerability and compli-
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ance (pill-count) with the treatment regime was assessed at each contact. Treatment Following completion of all scheduled baseline activities, open-label treatment with escitalopram was initiated at a dose of 10 mg daily for the first 5 days. This dose was increased to 20 mg daily for the remainder of the 12-week treatment period. All participants who started treatment completed the scheduled 12 weeks of treatment. Participants were given the option of continuing treatment at 12 weeks. Those that were discontinuing with the treatment were tapered to 10 mg per day for 10 days, and then medication was stopped. Structural MRI Magnetic resonance imaging was conducted on the 3T Siemens Magnetom Allegra located in the Cape Universities Brain Imaging Centre located at the University of Stellenbosch’s Tygerberg Campus. Scanning sessions lasted approximately 40 min. A high resolution 3D, T1weighted sequence was acquired and used in subsequent analyses. One hundred and sixty, sagittal 1 mm slices of the whole brain were acquired with imaging parameters as follows: 179×256 matrix, TR=2300 ms, TE=3.93 ms, inplane resolution of 1.0×1.0×1.0 mm and flip angle 12°. MRI preprocessing All of the 14 participants who started the study completed the 12 weeks of treatment. One subject was excluded due to poor image quality of the MRI, and two participants were not able to complete the Week 12 scan. Our final analysis was conducted on the remaining 11 subjects using baseline and week 12 scans. Preprocessing was performed in MATLAB R2007b (Mathworks, Natick, MA) within the statistical parametric mapping (SPM5) framework (Wellcome Department of Imaging Neuroscience, University College London, UK). Although standard voxel-based morphometry processes in SPM5 are adequate for comparing grey matter differences across groups, potential artefacts might occur during longitudinal analysis resulting from intra subject global changes in brain size over time (Chételat et al. 2005). As such we implemented the longitudinal protocol described by Chételat et al. (2005). This procedure first creates a customized whole brain template as described by Good et al. (2001). The template was smoothed with an 8 mm Gaussian full width at half maximum isotropic kernel. We then implemented the protocol as defined by Chételat et al. (2005) with the one exception being our use of the SPM5 international consortium for brain
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mapping (ICBM) priors instead of study-specific priors. In 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 the baseline scan using high-dimensional warping and also writing the Jacobian determinants for the deformation field of each warp. The deformation field was then applied to the follow-up image and this transformed image was then averaged with the baseline image to create a mean image for each subject. This mean image was then segmented into grey matter, white matter and cerebrospinal fluid using the ICBM priors of SPM5. The normalization parameters of the grey matter partition were then applied to the mean images as well as the Jacobian determinant data. The normalized mean image was then segmented into its grey matter partition using the ICBM template. This baseline data (partition) for each subject was then multiplied by the Jacobian determinants to create the follow-up data for each subject. With data from both time-points being smoothed using a 10 mm full width at half maximum Gaussian kernel. Statistical analysis A paired two-sample t-test was used for the statistical analysis. The significance threshold was set at p follow-up was tested.
Results Eleven participants were included in the analysis. Participants demonstrated > 90% compliance overall, as determined by pill count. The cohort comprised nine males and five females with a mean age of 40.64 years (SD 11.74). All participants tolerated the higher (20 mg/day) dose of escitalopram as prescribed in the study protocol. Baseline severity of Table 1 Clinical measures at baseline and week 12 demonstrate a markedly ill cohort with very limited depressive symptom comorbidity and relatively modest overall improvements with 12 weeks of escitalopram Measure
Mean (SD)— Mean (SD)— Baseline Week 12
Liebowitz Social Anxiety Scale Montgomery Äsberg Depression Rating Scale Clinical Global Impression -Severity
84.36 (21.92) 57.91 (32.74) 7.64 (6.64) 2.46 (2.98) 5.25 (0.50)
4.00 (1.41)
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a R
R
T
b R
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 baseline’. This showed no significant clusters meeting our a priori thresholds. Even if we used a less stringent threshold of p < 0.01 (voxel level) and an uncorrected p Follow-up’ demonstrated structural grey matter decreases in the bilateral superior temporal cortex, vermis and the left cerebellum following 12 weeks of treatment with escitalopram (Fig. 1, Table 2). Small group size precluded a meaningful ‘responder vs non-responder’ contrast.
Discussion
R
T
Fig. 1 Clusters corresponding to a significant decrease in grey matter following 12 weeks of treatment with escitalopram in the right (a) and left (b) superior temporal cortex. Clusters are overlayed on the single subject brain provided within SPM5 for visualisation
The main findings in our study were structural grey matter decreases in bilateral superior temporal cortex, vermis and left cerebellum following 12 weeks of treatment with escitalopram. These findings are, to the best of our knowledge, the first to demonstrate structural brain changes in response to SSRI treatment in SAD. The clinical measures used in our study (LSAS, MADRS, CGI-severity) demonstrate a modest overall improvement following 12 weeks of treatment. Contrary to our hypothesis, the findings here do not replicate the effects on brain structure seen in previous studies in mood and anxiety disorders when treated with SSRI’s. The amygdalo-hippocampal brain regions, which are usually associated with high levels of plasticity, did not appear 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 for baseline LSAS scores Brain region Right superior temporal cortex Vermis Left superior temporal cortex Left cerebellum crus
Coordinates x,y,z (mm)a
Cluster volume (mm3)
Cluster p valueb
T value
66–14 4 10–46–2 −64–2–2 −56–60–38
2392 2648 2408 1224
0.000 0.000 0.000 0.015
14.00 8.76 8.13 7.53
a
Coordinates (x,y,z) in millimeters correspond to Montreal Neurological Institute space
b
Corrected for multiple comparisons
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sample, as has been the case in previous functional work on SAD (Furmark et al. 2005; Engel et al. 2009; Freitas-Ferrari et al. 2010) or structural work on other anxiety disorders (Bremner and Vermetten 2004; Engel et al. 2009). The neuroplasticity of the adult brain may well be limited (Nass 2002). It is also possible that the sample size in our study was underpowered to find such differences. Changes in temporal lobe regional volumes after SSRI treatment may, however, be consistent with various data pointing to the role of these structures in anxiety in general and SAD in particular (Tillfors et al. 2002; Lorberbaum et al. 2004; Furmark et al. 2005; Warwick et al. 2006; Engel et al. 2009; Freitas-Ferrari et al. 2010). It is notable that citalopram reduced public speaking anxiety in patients with social phobia, and that this symptom improvement was associated with reduced regional cerebral blood flow mainly in the medial temporal lobe, but including the amygdala, hippocampus and surrounding rhinal cortices (Furmark et al. 2005; Engel et al. 2009; Freitas-Ferrari et al. 2010). Although there is little work on the role of the cerebellum in anxiety disorders, previous research has suggested an association between anxiety disorders and cerebellarvestibular dysfunction (Levinson 1989a, b), and a positron emission tomography study demonstrated that anticipatory anxiety in SAD subjects was associated with decreased cerebellar perfusion bilaterally (Tillfors et al. 2002; FreitasFerrari et al. 2010). These areas also correspond with changes demonstrated by Kilts et al. (2006). Nevertheless, the relative lack of involvement in cerebellum in previous anxiety disorder imaging studies, and the less reliable GM segmentation of the cerebellum, raises the question of whether the cerebellum findings here are artefactual. Our study is limited by the fact that we do not have direct evidence of changes in potentially relevant mediating molecular pathways, such as altered neurotrophin factor levels in response to treatment, and as such cannot make any direct inference about the mechanism of change. Our small sample size also precluded us drawing conclusions about the relationship between treatment response, and changes in brain volume. The preliminary findings here require replication to determine their reliability, and extension to determine whether or not they are disorder specific. Acknowledgements We would also like to acknowledge equipment support from Siemens. Funding for this study was received from the Medical Research Council of South Africa and the Harry Crossley Foundation.
References American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders, 4th ed Text Revision (DSMIV-TR). American Psychiatric Publishing, Washington DC
373 Aouizerate B, Martin-Guehl C, Tignol J (2004) Neurobiology and pharmacotherapy of social phobia. Encephale 30:301–313 Bremner JD, Vermetten E (2004) Neuroanatomical changes associated with pharmacotherapy in posttraumatic stress disorder. Ann NY Acad Sci 1032:154–157 Bremner JD, Vythilingam M, Vermetten E, Southwick SM, McGlashan T, Nazeer A, Khan S, Vaccarino V, Soufer R, Garg PK, Ng CK, Staib LH, Duncan JS, Charney DS (2003) MRI and PET study of deficits in hippocampal structure and function in women with childhood sexual abuse and posttraumatic stress disorder. Am J Psychiatry 160:924–932 Campbell S, MacQueen G (2006) An update on regional brain volume differences associated with mood disorders. Curr Opin Psychiatry 19:25–33 Castrén E, Rantamäki T (2008) Neurotrophins in depression and antidepressant effects. Novartis Found Symp 289:43–52 Chen CH, Ridler K, Suckling J, Williams S, Fu CH, Merlo-Pich E, Bullmore E (2007) Brain imaging correlates of depressive symptom severity and predictors of symptom improvement after antidepressant treatment. Biol Psychiatry 62:407–414 Chételat G, Landeau B, Eustache F, Mézenge F, Viader F, De La Sayette V, Desgranges B, Baron JC (2005) Using voxel-based morphometry to map the structural changes associated with rapid conversion in MCI: a longitudinal MRI study. Neuroimage 27:934–946 Engel K, Bandelow B, Gruber O, Wedekind D (2009) Neuroimaging in anxiety disorders. J Neural Transm 116:703–716 Fossati P, Radtchenko A, Boyer P (2004) Neuroplasticity: from MRI to depressive symptoms. Eur Neuropsychopharmacol 14:S503– S510 Freitas-Ferrari MC, Hallak JEC, Trzesniak C, Filho AS, Machadode-Sousa JP, Chagas MHN, Nardi AE, Crippa JAS (2010) Neuroimaging in social anxiety disorder: a systematic review of the literature. Prog Neuropsychopharmacol Biol Psychiatry 34:565–580 Frodl T, Schule C, Schmitt G, Born C, Baghai T, Zill P, Bottlender R, Rupprecht R, Bondy B, Reiser M, Möller HJ, Meisenzahl EM (2007) Association of the brain-derived neurotrophic factor Val66Met polymorphism with reduced hippocampal volumes in major depression. Arch Gen Psychiatry 64:410–416 Furmark T, Tillfors M, Marteinsdottir I, Fischer H, Pissiota A, Långström B, Fredrikson M (2002) Common changes in cerebral blood flow in patients with social phobia treated with citalopram or cognitive-behavioral therapy. Arch Gen Psychiatry 59:425– 433 Furmark T, Appel L, Michelgård A, Wahlstedt K, Ahs F, Zancan S, Jacobsson E, Flyckt K, Grohp M, Bergström M, Pich EM, Nilsson LG, Bani M, Långström B, Fredrikson M (2005) Cerebral blood flow changes after treatment of social phobia with the neurokinin-1 antagonist GR205171, citalopram, or placebo. Biol Psychiatry 58:132–142 Good CD, Johnsrude IS, Ashburner J, Henson RN, Friston KJ, Frackowiak RS (2001) A voxel-based morphometric study of ageing in 465 normal adult human brains. Neuroimage 14:21–36 Guy W (1976) ECDU assessment manual for psychopharmacology. National Institute of Mental Health, Research Branch, pp 313–331 Ipser JC, Kariuki CM, Stein DJ (2008) Pharmacotherapy for social anxiety disorder: a systematic review. Expert Rev Neurother 8:235–257 Kilts CD, Kelsey JE, Knight B, Ely TD, Bowman FD, Gross RE, Selvig A, Gordon A, Newport DJ, Nemeroff CB (2006) The neural correlates of social anxiety disorder and response to pharmacotherapy. Neuropsychopharmacol 3:2243–2253 Lang UE, Jockers-Scherubl MC, Hellweg R (2004) State of the art of the neurotrophin hypothesis in psychiatric disorders: implications and limitations. J Neural Transm 111:387–411
374 Levinson HN (1989a) A cerebellar-vestibular explanation for fears/ phobias: hypothesis and study. Percept Mot Skills 68:67–84 Levinson HN (1989b) The cerebellar-vestibular predisposition to anxiety disorders. Percept Mot Skills 68:323–338 Liebowitz MR (1987) Social phobia. Mod Probl Pharmacopsychiatry 22:141–173 Lorberbaum JP, Kose S, Johnson MR, Arana GW, Sullivan LK, Hamner MB, Ballenger JC, Lydiard RB, Brodrick PS, Bohning DE, George MS (2004) Neural correlates of speech anticipatory anxiety in generalized social phobia. NeuroReport 15:2701–2705 Martinowich K, Manji H, Lu B (2007) New insights into BDNF function in depression and anxiety. Nat Neurosci 10:1089–1093 Montgomery SA, Asberg M (1979) A new depression scale designed to be sensitive to change. Br J Psychiatry 134:382–389 Nass R (2002) Plasticity: mechanisms, extent and limits. In: Segalowitz SJ, Rapin I (eds) Handbook of neuropsychology, 2nd ed, vol 8(1), Child neuropsychology, part 1. Elsevier, Amsterdam, pp 29–68 Rantamäki T, Hendolin P, Kankaanpää A, Mijatovic J, Piepponen P, Domenici E, Chao MV, Männistö PT, Castrén E (2007) Pharmacologically diverse antidepressants rapidly activate brain-derived neurotrophic factor receptor TrkB and induce phospholipase-Cgamma signaling pathways in mouse brain. Neuropsychopharmacol 32:2152–2162 Schinder AF, Poo M (2000) The neurotrophin hypothesis for synaptic plasticity. Trends Neurosci 23:639–645
Metab Brain Dis (2010) 25:369–374 Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC (1998) The MiniInternational Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 59:22–33 Spedding M, Gressens P (2008) Neurotrophins and cytokines in neuronal plasticity. Novartis Found Symp 289:222–233 Tillfors M, Furmark T, Marteinsdottir I, Fredrikson M (2002) Cerebral blood flow during anticipation of public speaking in social phobia: a PET study. Biol Psychiatry 52:1113–1119 Vermetten E, Vythilingam M, Southwick SM, Charney DS, Bremner JD (2003) Long-term treatment with paroxetine increases verbal declarative memory and hippocampal volume in posttraumatic stress disorder. Biol Psychiatry 54:693–702 Vetencourt JFM, Sale A, Viegi A, Baroncelli L, De Pasquale R, O’Leary OF, Castrén E, Maffei L (2008) The antidepressant fluoxetine restores plasticity in the adult visual cortex. Science 320:385–388 Warwick JM, Carey P, Van der Linden G, Prinsloo C, Niehaus D, Seedat S, Dupont P, Stein DJ (2006) A comparison of the effects of citalopram and moclobemide on resting brain perfusion in social anxiety disorder. Metab Brain Dis 21:241–252 Warwick JM, Carey P, Jordaan GP, Dupont P, Stein DJ (2008) Resting brain perfusion in social anxiety disorder: a voxel-wise whole brain comparison with healthy control subjects. Prog Neuropsychopharmacol Biol Psychiatry 32:1251–1256
