- Email: [email protected]
Treating anxious depression using repetitive transcranial magnetic stimulation
Journal of Affective Disorders 151 (2013) 365–368
Contents lists available at ScienceDirect
Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Preliminary communication
Treating anxious depression using repetitive transcranial magnetic stimulation Gretchen J. Diefenbach a,b,n, Laura Bragdon a, John W. Goethe a a b
The Institute of Living, 200 Retreat Avenue, Hartford, CT 06106, USA Yale University School of Medicine, New Haven, CT, USA
art ic l e i nf o
a b s t r a c t
Article history: Received 19 February 2013 Received in revised form 22 May 2013 Accepted 29 May 2013 Available online 27 June 2013
Background: A subset of patients given a clinical diagnosis of major depressive disorder (MDD) are described as having “anxious depression,” a presentation that, in some studies, has been an indicator of poor response to pharmacotherapy. The aim of this study was to determine if anxious depression is associated with attenuated response to repetitive transcranial magnetic stimulation (rTMS), an FDAapproved treatment for MDD. Methods: Participants were 32 adult outpatients with treatment resistant MDD who were referred for rTMS. The Hamilton Rating Scale for Depression (HAMD) was administered to assess treatment response, and anxious depression was defined as a score of seven or above on the anxiety/somatization factor of the HAMD. A quarter of the sample met the anxious depression criterion at pretreatment. Results: Both depression (total score) and anxiety symptoms improved from pre- to post-treatment with moderate to large treatment effects. Patients with and without anxious depression demonstrated similar rates of improvement in depression. Patients with versus without anxious depression demonstrated larger improvements in anxiety. Limitations: The sample size was small, and assessments did not include structured diagnostic interview or independent measures of anxiety symptoms. Conclusions: For the sample as a whole, there were significant improvements in both depression and anxiety. Anxious depression was not associated with attenuated treatment response to rTMS. & 2013 Elsevier B.V. All rights reserved.
Keywords: Anxiety Depression Transcranial magnetic stimulation
1. Introduction Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive somatic therapy that uses magnetic pulses to induce electrical currents in the brain. Treatment resistant major depressive disorder (MDD) is the only FDA-approved indication for rTMS. The FDA-approved product label treatment parameters are high frequency (10 hz) rTMS (5 days/week) applied to the left dorsolateral prefrontcal cortex (DLPFC) for 4–6 weeks (Horvath et al., 2010). Although the mechanism of action is not fully understood, evidence suggests that high frequency stimulation is associated with increased neural activation (Pascual-Leone et al., 1994), which may correct presumed prefrontal hypoactivation characteristic of MDD (Henriques and Davidson, 1991). Randomized controlled trials have demonstrated that rTMS is superior to placebo in MDD (O’Reardon et al., 2007; George et al., 2010; Ray et al., 2011; Triggs et al., 2010). Meta-analyses have shown n Corresponding author at: Anxiety Disorders Center, The Institute of Living, 200 Retreat Avenue, Hartford, CT 06106, USA. Tel.: +1 860 545 7685; fax: +1 860 545 7156. E-mail address: [email protected] (G.J. Diefenbach).
0165-0327/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jad.2013.05.094
that treatment effect sizes are in the moderate range and comparable to effect sizes for antidepressant pharmacotherapy (Slotema et al., 2010; Schutter, 2008). Pooled response and remission rates in randomized controlled trials for rTMS were 25% and 17%, compared with 9% and 6%, respectively, for the sham condition (Lam et al., 2008). “Anxious depression,” a commonly described presentation in MDD, has been associated with poor response to pharmacotherapy in some (Domschke et al., 2010; Fava et al., 2008) but not all studies (Nelson et al., 2009; Fava et al., 2007). Several studies have shown that anxiety symptoms improve more with rTMS than with sham in patients with MDD (O’Reardon et al., 2007; Ray et al., 2011). Comorbid anxiety disorder, but not severity of anxiety symptoms, has been associated with poor response to rTMS (Lisanby et al., 2009; Brakemeier et al., 2008). No published studies have specifically explored the outcome of rTMS for patients with anxious depression. For the present study of MDD patients with and without anxious depression it was predicted that (1) both depression (total score) and anxiety symptoms would improve from pre-to post-treatment, and (2) based upon findings from medication trials (Fava et al., 2008; Domschke et al., 2010), that patients with anxious depression would have significantly less improvement in depressive symptoms.
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acute or taper, but excluding maintenance rTMS sessions occurring 7 or more days apart).
2. Materials and methods 2.1. Participants Participants were 32 adult outpatients (age M ¼55.9, SD ¼12.5; 62.5% Women) with a principal diagnosis of MDD who had received rTMS therapy through routine clinical services at a large psychiatric hospital. All participants met criteria for treatment resistance (i.e., at least two failed adequate trials of antidepressant medication). Additional inclusion criteria for the current study were a Hamilton Rating Scale for Depression baseline total score ≥10 and ≥20 rTMS sessions completed. Current psychotropic medications in the sample were benzodiazepines (n¼ 17, 53.1%), serotonin norepinephrine reuptake inhibitors (n¼ 15%, 46.9%), mirtazapine (n ¼5%, 15.6%), anticonvulsants (n ¼ 5%, 15.6%), stimulants (n ¼5%, 15.6%), selective serotonin reuptake inhibitors (n ¼4%, 12.5%), bupropion (n ¼4%, 12.5%), antipsychotics (n ¼ 4%, 12.5%), lithium (n ¼ 3%, 9.4%), tricyclics (n¼ 2%, 6.3%), buspirone (n ¼1%, 3.1%), and trazadone (n ¼1%, 3.1%). 2.2. Hamilton rating scale for depression The Hamilton Rating Scale for Depression (HAMD, Hamilton, 1960) is one of the most commonly used and extensively validated outcome measures for depressive symptoms. A structured interview version of the HAMD, which demonstrates high concurrent validity with the original version of the HAMD, but superior interrater reliability (Williams et al., 2008), was administered. In the current study the total score was calculated to be consistent with the 17-item version of the HAMD. Remission status was defined as in previous work (Mcintyre et al., 2002) as a total score less than 8. 2.3. Anxious depression Patients were grouped into those with versus without anxious depression using the anxiety/somatization subscale of the HAMD (Cleary and Guy, 1977). The anxiety/somatization subscale is comprised of six items: Anxiety Somatic, Anxiety Psychic, Somatic Symptoms (GI), Somatic Symptoms (General), Hypochondriasis, and Insight. A score ≥7 on this scale is commonly used to define anxious depression (e.g., Fava et al., 2008), and 25% of the current sample (n¼ 8) met this criterion. 2.4. Procedure Participants were identified via retrospective chart review, which was approved by the hospital's Institutional Review Board (#2118). A psychiatrist (JG) completed all diagnostic assessments as part of routine clinical care. A research assistant trained to criterion (within 1 point of all ratings) with the treating psychiatrist (JG) administered the HAMD on a variable schedule throughout treatment. The baseline HAMD was administered within three days of treatment initiation for the vast majority of patients (90.6%). Post-treatment HAMD was defined as the last administration occurring within a week of the final rTMS session (either
2.5. Treatment parameters Treatment was administered using the FDA-Cleared Neuronetics NeuroStar TMS Therapy System, and parameters were consistent with those in the seminal study demonstrating safety and efficacy of this device (O’Reardon et al., 2007). Treatment was targeted at the left DLPFC with location identified using the 5 cm method: the coil was placed 5 cm anterior of the resting motor threshold (MT). Treatment was begun at 80% of the MT and was adjusted up to 130%. Treatment was administered with a repetition rate of 10 pulses per second and a stimulus train of 4 s on and 20–26 s off. Treatment sessions lasted for 37.5 min for a total of 3000–5000 pulses in each session (Horvath et al., 2010). On average, patients completed 31 treatment sessions (SD ¼5.39, range¼ 22–42), with an average minimum motor threshold of 91% (SD ¼14.4), for 4016 maximum pulses per session (SD ¼673.6), and 101,787 total pulses (SD ¼20,048.3). The groups did not differ on any treatment parameter.
2.6. Data analytic plan A two time (pre, post) by two group (with anxious depression, without anxious depression) repeated measures analysis of variance (ANOVA) was conducted to determine treatment response to rTMS. Two ANOVAs were conducted, one with the HAMD total score as the dependent variable, and one with the anxiety/ somatization factor score as the dependent variable. Chi-Square was used to analyze remission status at posttreatment by anxious depression group.
3. Results 3.1. HAMD Table 1 shows the means and standard deviations of the HAMD for patients with versus without anxious depression. There was a main effect for group [F (1, 30)¼6.80, po0.014] and time [F (1, 30)¼ 26.22, p o0.001] but no group by time interaction [F (1, 30)¼ 2.52, p¼ 0.123]. Patients with versus without anxious depression scored higher on the HAMD total score. HAMD scores were significantly lower after treatment for the entire sample, and change from preto post-treatment did not differ by anxious depression group. The pre- to post-treatment effect sizes for the entire sample and for the anxious depression group were large (d ¼0.87 and 1.47, respectively) while the effect size for patients without anxious depression was moderate (d¼ 0.76). The percentages of patients meeting remission status were similar in patients with (n ¼2%, 25.0%) and without (n¼ 7%, 29.2%) anxious depression [Χ2 (1, N ¼ 32) ¼0.05, p ¼0.82].
Table 1 Pre- and post-treatment HAMD total and anxiety/somatization factor scores by MDD group with and without anxious depression. Group
n
Pretreatment HAMD Total
Posttreatment HAMD total
Pretreatment anxiety/somatization factor
Posttreatment anxiety/somatization factor
With anxious depression Without anxious depression Total sample
8 24 32
22.38 (3.93) 15.71 (4.35) 17.38 (5.11)
14.63 (6.35) 11.63 (6.23) 12.38 (6.30)
8.50 (1.77) 3.96 (1.46) 5.09 (2.51)
5.75 (2.66) 3.17 (1.81) 3.81 (2.31)
Note: Means are shown with standard deviations in parentheses.
G.J. Diefenbach et al. / Journal of Affective Disorders 151 (2013) 365–368
3.2. Anxiety/somatization factor score Means and standard deviations for the Anxiety/Somatization factor are also displayed in Table 1 by group. There was a significant main effect of group [F (1, 30) ¼38.38, p o0.001], time [F (1, 30) ¼ 14.71, p o0.001], and group by time interaction [F (1, 30) ¼4.50, p o0.05]. Patients with versus without anxious depression had higher scores, reported lower anxiety/somatization factor scores after treatment, and had a larger decrease in scores from pre- to post-treatment. The pre- to post-treatment effect size was large for patients with anxious depression (d ¼1.22) and was moderate for patients without anxious depression (d ¼0.48) as well as the sample as a whole (d¼ 0.53). Three-fourths of the patients in the anxious depression group no longer met criteria for anxious depression at posttreatment (n ¼6).
4. Discussion These results are consistent with previous reports showing that rTMS is an effective treatment for MDD. In the current study, 28.1% of the sample achieved remission. The remission rate across randomized controlled trials of rTMS is 17% (Lam et al., 2008), and remission rates as high as 37.1% have been reported in naturalistic studies (Carpenter et al., 2012; Connolly et al., 2012). However, these results are not consistent with studies that suggest that patients with anxious depression have, as suggested in some medication trials for MDD (Domschke et al., 2010; Fava et al., 2008), an attenuated treatment response. By contrast, the current study suggests that rTMS may also be effective for treating anxiety symptoms in MDD patients. Most rTMS studies have not addressed anxious depression per se. Two randomized clinical trials reported superior improvements in anxiety with rTMS compared to placebo (O’Reardon et al., 2007; Ray et al., 2011). In a naturalistic study, anxiety symptoms improved with a moderate treatment effect (Berlim et al., 2011). The current study lends further support to the evidence-base that rTMS is effective for anxious depression. This study found that anxiety improved significantly from pre- to post-treatment, with larger improvements in patients with anxious depression. While this finding may be due to grouping patients by anxiety symptom severity, thus leading to a floor effect for patients without anxious depression, it is notable that improvements in anxiety symptoms for the sample as a whole were also substantial. Limitations are the small sample, that diagnoses were not based on a structured interview, and comorbidities were not included in the analyses. In addition, anxiety symptoms were assessed using a factor scale of the HAMD, an approach that is typical of research on anxious depression (McClintock et al., 2011; Fava et al., 2008), but stronger conclusions regarding changes in anxiety symptoms could be drawn if more extensive anxiety assessments had been used.
5. Conclusions MDD patients with and without anxious depression responded similarly to rTMS in this study. Both depressive and anxiety symptoms improved following rTMS among these treatment resistant MDD patients. Future research should use larger samples and more extensive assessments of anxiety symptoms.
Conflict of interest Drs. Diefenbach and Goethe receive material support from Neuronetics as part of a separate research study. Dr. Goethe also receives Grant support from Bristol-
367
Myers Scquibb, Forest, Hoffman-La Roche, Janssen, Marck Schering Plough, Neuronetics, Neosync, Otsuka, Shire and Takeda. Ms. Bragdon has no conflict to disclose.
Role of funding source There is no funding body agreement to report.
Acknowledgments There are no acknowledgments to report.
References Berlim, M.T., Mcgirr, A., Beaulieu, M., Turecki, G., 2011. High frequency repetitive transcranial magnetic stimulation as an augmenting strategy in severe treatment-resistant depression: a prospective 4-week naturalistic trial. Journal of Affective Disorders 130, 312–317. Brakemeier, E., Wibertz, G., Rodax, S., Danker-Hopfe, H., Zinka, B., Zwanzger, P., Grossheinrich, N., Varkuti, B., Rupprecht, R., Bajbouj, M., Padberg, F., 2008. Patterns of response to repetitive transcranial magnetic stimulation (rTMS) in major depression: replication study in drug-free patients. Journal of Affective Disorders 108, 59–70. Carpenter, L.L., Janicak, P.G., Aaronson, S.T., Boyadijis, B., Brock, D.G., Cook, I.A., Dunner, D.L., Lanocha, K., Solvason, H.B., Demitrack, M.A., 2012. Transcranial magnetic stimulation (TMS) for major depression: a multisite, naturalistic, observational study of acute treatment outcomes in clinical practice. Depression and Anxiety 29, 587–596. Cleary, P., Guy, W., 1977. Factor analysis of the Hamilton depression scale. Drugs Under Experimental and Clinical Research 1, 115–120. Connolly, K.R., Helmer, A., Cristancho, M.A., Cristancho, P., O’Reardon, J.P., 2012. Effectiveness of transcranial magnetic stimulation in clinical practice post-FDA approval in the United States: Results observed with the first 100 consecutive cases of depression at an academic center. Journal of Clinical Psychiatry 73, e567–e573. Domschke, K., Deckert, J., Arolt, V., Baune, B.T., 2010. Anxious versus non-anxious depression: difference in treatment outcome. Journal of Psychopharmacology (Oxford) 24, 621–622. Fava, M., Martinez, J.M., Greist, J., Marangell, L.B., Brown, E., Chen, L., Wohlreich, M.M., 2007. The efficacy and tolerability of duloxetine in the treatment of anxious versus non-anxious depression: a post-hoc analysis of an open-label outpatient study. Annals of Clinical Psychiatry 19, 187–195. Fava, M., Rush, A.J., Alpert, J.E., Balasubramani, G.K., Wisniewski, S.R., Carmin, C.N., Biggs, M.M., Zisook, S., Leuchter, A., Howland, R., Warden, D., Trivedi, M.H., 2008. Difference in treatment outcome in outpatients with anxious versus nonanxious depression: a STARnD report. American Journal of Psychiatry 165, 342–351. George, M.S., Lisanby, S.H., Avery, D., Mcdonald, W.M., Durkalski, V., Pavlicova, M., Anderson, B., Nahas, Z., Bulow, P., Zarkowski, P., Holtzheimer, P.E., Schwartz, T., Sackeim, H.A., 2010. Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder. Archives of General Psychiatry 67, 507–516. Hamilton, M., 1960. A rating scale for depression. Journal of Neurology, Neurosurgery and Psychiatry 23, 56–62. Henriques, J.B., Davidson, R.J., 1991. Left frontal hypoactivation in depression. Journal of Abnormal Psychology 100, 535–545. Horvath, J.C., Mathews, J., Demitrack, M.A., Pascual-Leone, A., 2010. The NeuroStar TMS device: conducting the FDA approved protocol for treatment of depression. Journal of Visualized Experiments 45, pp 2345.. Lam, R.W., Chan, P., Wilkins-Ho, M., Yatham, L.N., 2008. Repetitive transcranial magnetic stimulation for treatment-resistant depression: a systematic review and metaanalysis. Canadian Journal of Psychiatry 53, 621–631. Lisanby, S.H., Husain, M.M., Rosenquist, R.B., Maixner, D., Gutierrex, R., Krystal, A., Gilmer, W., Marangell, L.B., Aaronson, S., Daskalakis, Z.J., Canterbury, R., Richelson, E., Sackeim, H.A., George, M.S., 2009. Daily left prefrontal repetitive transcranial magnetic stimulation in the acute treatment of major depression: clinical predictors of outcome in a multisite, randomized controlled clinical trial. Neuropsychopharmacology 34, 522–534. McClintock, S.M., Husain, M.M., Bernstein, I.H., Wisniewski, S.R., Trivedi, M.H., Morris, D., Alpert, J., Warden, D., Luther, J.F., Kornstein, S.G., Biggs, M.M., Fava, M., Rush, A.J., 2011. Assessing anxious features in depressed outpatients. International Journal of Methods in Psychiatric Research 20, e69–e82. Mcintyre, R., Kennedy, S., Bagby, R.M., Bakish, D., 2002. Assessing full remission. Journal of Psychiatry and Neuroscience 27, 235–239. Nelson, J.C., Delucchi, K., Schneider, L.S., 2009. Anxiety does not predict response to antidepressant treatment in late life depression: Results of a meta-analysis. International Journal of Geriatric Psychiatry 24, 539–544. O’Reardon, J.P., Solvanson, H.B., Janicak, P.G., Sampson, S., Isenberg, K.E., Nahas, Z., Mcdonald, W.M., Avery, D., Fitzgerald, P.B., Loo, C., Demitrack, M.A., George, M.S., Sackeim, H.A., 2007. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biological Psychiatry 62, 1208–1216. Pascual-Leone, A., Valls-Sole, J., Wasserman, E.M., Hallett, M., 1994. Responses to rapid-rate transcranial magnetic stimulation of the human motor cortex. Brain 117, 847–858.
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Ray, S., Nizamie, S.H., Akhtar, S., Praharaj, S.K., Mishra, B.W., Zia-Ul-Haq, M., 2011. Efficacy of adjunctive high freuqency repetitive transcranial magnetic stimulation of left prefrontal cortex in depression: a randomized sham controlled study. Journal of Affective Disorders 128, 153–159. Schutter, D.J.L.G., 2008. Antidepressant efficacy of high-frequency transcranial magnetic stimulation over the left dorsolateral prefrontal cortex in double-blind sham-controlled designs: a meta-analysis. Psychological Medicine 39, 65–75. Slotema, C.W., Blom, J.D., Hoek, H.W., Sommer, I.E.C., 2010. Should we expand the toolbox of psychiatric treatment methods to include repetitive transcranial
magnetic stimulation (rTMS)? A meta-analysis of the efficacy of rTMS in psychiatric disorders. Journal of Clinical Psychiatry 71, 873–884. Triggs, W.J., Ricciuti, N., Ward, H.E., Cheng, J., Bowers, D., Goodman, W.K., Kluger, B.M., Nadeau, S.E., 2010. Right and left dorsolateral pre-frontal rTMS treatment of refractory depression: a randomized, sham-controlled trial. Psychiatry Research 178, 467–474. Williams, J.B., Kobak, K.A., Bech, P., Engelhardt, N., Evans, K., Lipsitz, J., Olin, J., Pearson, J., Kalali, A., 2008. The GRID-HAMD: Standardization of the Hamilton Depression Rating Scale. International Clinical Psychopharmacology 23, 120–129.
Contents lists available at ScienceDirect
Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Preliminary communication
Treating anxious depression using repetitive transcranial magnetic stimulation Gretchen J. Diefenbach a,b,n, Laura Bragdon a, John W. Goethe a a b
The Institute of Living, 200 Retreat Avenue, Hartford, CT 06106, USA Yale University School of Medicine, New Haven, CT, USA
art ic l e i nf o
a b s t r a c t
Article history: Received 19 February 2013 Received in revised form 22 May 2013 Accepted 29 May 2013 Available online 27 June 2013
Background: A subset of patients given a clinical diagnosis of major depressive disorder (MDD) are described as having “anxious depression,” a presentation that, in some studies, has been an indicator of poor response to pharmacotherapy. The aim of this study was to determine if anxious depression is associated with attenuated response to repetitive transcranial magnetic stimulation (rTMS), an FDAapproved treatment for MDD. Methods: Participants were 32 adult outpatients with treatment resistant MDD who were referred for rTMS. The Hamilton Rating Scale for Depression (HAMD) was administered to assess treatment response, and anxious depression was defined as a score of seven or above on the anxiety/somatization factor of the HAMD. A quarter of the sample met the anxious depression criterion at pretreatment. Results: Both depression (total score) and anxiety symptoms improved from pre- to post-treatment with moderate to large treatment effects. Patients with and without anxious depression demonstrated similar rates of improvement in depression. Patients with versus without anxious depression demonstrated larger improvements in anxiety. Limitations: The sample size was small, and assessments did not include structured diagnostic interview or independent measures of anxiety symptoms. Conclusions: For the sample as a whole, there were significant improvements in both depression and anxiety. Anxious depression was not associated with attenuated treatment response to rTMS. & 2013 Elsevier B.V. All rights reserved.
Keywords: Anxiety Depression Transcranial magnetic stimulation
1. Introduction Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive somatic therapy that uses magnetic pulses to induce electrical currents in the brain. Treatment resistant major depressive disorder (MDD) is the only FDA-approved indication for rTMS. The FDA-approved product label treatment parameters are high frequency (10 hz) rTMS (5 days/week) applied to the left dorsolateral prefrontcal cortex (DLPFC) for 4–6 weeks (Horvath et al., 2010). Although the mechanism of action is not fully understood, evidence suggests that high frequency stimulation is associated with increased neural activation (Pascual-Leone et al., 1994), which may correct presumed prefrontal hypoactivation characteristic of MDD (Henriques and Davidson, 1991). Randomized controlled trials have demonstrated that rTMS is superior to placebo in MDD (O’Reardon et al., 2007; George et al., 2010; Ray et al., 2011; Triggs et al., 2010). Meta-analyses have shown n Corresponding author at: Anxiety Disorders Center, The Institute of Living, 200 Retreat Avenue, Hartford, CT 06106, USA. Tel.: +1 860 545 7685; fax: +1 860 545 7156. E-mail address: [email protected] (G.J. Diefenbach).
0165-0327/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jad.2013.05.094
that treatment effect sizes are in the moderate range and comparable to effect sizes for antidepressant pharmacotherapy (Slotema et al., 2010; Schutter, 2008). Pooled response and remission rates in randomized controlled trials for rTMS were 25% and 17%, compared with 9% and 6%, respectively, for the sham condition (Lam et al., 2008). “Anxious depression,” a commonly described presentation in MDD, has been associated with poor response to pharmacotherapy in some (Domschke et al., 2010; Fava et al., 2008) but not all studies (Nelson et al., 2009; Fava et al., 2007). Several studies have shown that anxiety symptoms improve more with rTMS than with sham in patients with MDD (O’Reardon et al., 2007; Ray et al., 2011). Comorbid anxiety disorder, but not severity of anxiety symptoms, has been associated with poor response to rTMS (Lisanby et al., 2009; Brakemeier et al., 2008). No published studies have specifically explored the outcome of rTMS for patients with anxious depression. For the present study of MDD patients with and without anxious depression it was predicted that (1) both depression (total score) and anxiety symptoms would improve from pre-to post-treatment, and (2) based upon findings from medication trials (Fava et al., 2008; Domschke et al., 2010), that patients with anxious depression would have significantly less improvement in depressive symptoms.
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G.J. Diefenbach et al. / Journal of Affective Disorders 151 (2013) 365–368
acute or taper, but excluding maintenance rTMS sessions occurring 7 or more days apart).
2. Materials and methods 2.1. Participants Participants were 32 adult outpatients (age M ¼55.9, SD ¼12.5; 62.5% Women) with a principal diagnosis of MDD who had received rTMS therapy through routine clinical services at a large psychiatric hospital. All participants met criteria for treatment resistance (i.e., at least two failed adequate trials of antidepressant medication). Additional inclusion criteria for the current study were a Hamilton Rating Scale for Depression baseline total score ≥10 and ≥20 rTMS sessions completed. Current psychotropic medications in the sample were benzodiazepines (n¼ 17, 53.1%), serotonin norepinephrine reuptake inhibitors (n¼ 15%, 46.9%), mirtazapine (n ¼5%, 15.6%), anticonvulsants (n ¼ 5%, 15.6%), stimulants (n ¼5%, 15.6%), selective serotonin reuptake inhibitors (n ¼4%, 12.5%), bupropion (n ¼4%, 12.5%), antipsychotics (n ¼ 4%, 12.5%), lithium (n ¼ 3%, 9.4%), tricyclics (n¼ 2%, 6.3%), buspirone (n ¼1%, 3.1%), and trazadone (n ¼1%, 3.1%). 2.2. Hamilton rating scale for depression The Hamilton Rating Scale for Depression (HAMD, Hamilton, 1960) is one of the most commonly used and extensively validated outcome measures for depressive symptoms. A structured interview version of the HAMD, which demonstrates high concurrent validity with the original version of the HAMD, but superior interrater reliability (Williams et al., 2008), was administered. In the current study the total score was calculated to be consistent with the 17-item version of the HAMD. Remission status was defined as in previous work (Mcintyre et al., 2002) as a total score less than 8. 2.3. Anxious depression Patients were grouped into those with versus without anxious depression using the anxiety/somatization subscale of the HAMD (Cleary and Guy, 1977). The anxiety/somatization subscale is comprised of six items: Anxiety Somatic, Anxiety Psychic, Somatic Symptoms (GI), Somatic Symptoms (General), Hypochondriasis, and Insight. A score ≥7 on this scale is commonly used to define anxious depression (e.g., Fava et al., 2008), and 25% of the current sample (n¼ 8) met this criterion. 2.4. Procedure Participants were identified via retrospective chart review, which was approved by the hospital's Institutional Review Board (#2118). A psychiatrist (JG) completed all diagnostic assessments as part of routine clinical care. A research assistant trained to criterion (within 1 point of all ratings) with the treating psychiatrist (JG) administered the HAMD on a variable schedule throughout treatment. The baseline HAMD was administered within three days of treatment initiation for the vast majority of patients (90.6%). Post-treatment HAMD was defined as the last administration occurring within a week of the final rTMS session (either
2.5. Treatment parameters Treatment was administered using the FDA-Cleared Neuronetics NeuroStar TMS Therapy System, and parameters were consistent with those in the seminal study demonstrating safety and efficacy of this device (O’Reardon et al., 2007). Treatment was targeted at the left DLPFC with location identified using the 5 cm method: the coil was placed 5 cm anterior of the resting motor threshold (MT). Treatment was begun at 80% of the MT and was adjusted up to 130%. Treatment was administered with a repetition rate of 10 pulses per second and a stimulus train of 4 s on and 20–26 s off. Treatment sessions lasted for 37.5 min for a total of 3000–5000 pulses in each session (Horvath et al., 2010). On average, patients completed 31 treatment sessions (SD ¼5.39, range¼ 22–42), with an average minimum motor threshold of 91% (SD ¼14.4), for 4016 maximum pulses per session (SD ¼673.6), and 101,787 total pulses (SD ¼20,048.3). The groups did not differ on any treatment parameter.
2.6. Data analytic plan A two time (pre, post) by two group (with anxious depression, without anxious depression) repeated measures analysis of variance (ANOVA) was conducted to determine treatment response to rTMS. Two ANOVAs were conducted, one with the HAMD total score as the dependent variable, and one with the anxiety/ somatization factor score as the dependent variable. Chi-Square was used to analyze remission status at posttreatment by anxious depression group.
3. Results 3.1. HAMD Table 1 shows the means and standard deviations of the HAMD for patients with versus without anxious depression. There was a main effect for group [F (1, 30)¼6.80, po0.014] and time [F (1, 30)¼ 26.22, p o0.001] but no group by time interaction [F (1, 30)¼ 2.52, p¼ 0.123]. Patients with versus without anxious depression scored higher on the HAMD total score. HAMD scores were significantly lower after treatment for the entire sample, and change from preto post-treatment did not differ by anxious depression group. The pre- to post-treatment effect sizes for the entire sample and for the anxious depression group were large (d ¼0.87 and 1.47, respectively) while the effect size for patients without anxious depression was moderate (d¼ 0.76). The percentages of patients meeting remission status were similar in patients with (n ¼2%, 25.0%) and without (n¼ 7%, 29.2%) anxious depression [Χ2 (1, N ¼ 32) ¼0.05, p ¼0.82].
Table 1 Pre- and post-treatment HAMD total and anxiety/somatization factor scores by MDD group with and without anxious depression. Group
n
Pretreatment HAMD Total
Posttreatment HAMD total
Pretreatment anxiety/somatization factor
Posttreatment anxiety/somatization factor
With anxious depression Without anxious depression Total sample
8 24 32
22.38 (3.93) 15.71 (4.35) 17.38 (5.11)
14.63 (6.35) 11.63 (6.23) 12.38 (6.30)
8.50 (1.77) 3.96 (1.46) 5.09 (2.51)
5.75 (2.66) 3.17 (1.81) 3.81 (2.31)
Note: Means are shown with standard deviations in parentheses.
G.J. Diefenbach et al. / Journal of Affective Disorders 151 (2013) 365–368
3.2. Anxiety/somatization factor score Means and standard deviations for the Anxiety/Somatization factor are also displayed in Table 1 by group. There was a significant main effect of group [F (1, 30) ¼38.38, p o0.001], time [F (1, 30) ¼ 14.71, p o0.001], and group by time interaction [F (1, 30) ¼4.50, p o0.05]. Patients with versus without anxious depression had higher scores, reported lower anxiety/somatization factor scores after treatment, and had a larger decrease in scores from pre- to post-treatment. The pre- to post-treatment effect size was large for patients with anxious depression (d ¼1.22) and was moderate for patients without anxious depression (d ¼0.48) as well as the sample as a whole (d¼ 0.53). Three-fourths of the patients in the anxious depression group no longer met criteria for anxious depression at posttreatment (n ¼6).
4. Discussion These results are consistent with previous reports showing that rTMS is an effective treatment for MDD. In the current study, 28.1% of the sample achieved remission. The remission rate across randomized controlled trials of rTMS is 17% (Lam et al., 2008), and remission rates as high as 37.1% have been reported in naturalistic studies (Carpenter et al., 2012; Connolly et al., 2012). However, these results are not consistent with studies that suggest that patients with anxious depression have, as suggested in some medication trials for MDD (Domschke et al., 2010; Fava et al., 2008), an attenuated treatment response. By contrast, the current study suggests that rTMS may also be effective for treating anxiety symptoms in MDD patients. Most rTMS studies have not addressed anxious depression per se. Two randomized clinical trials reported superior improvements in anxiety with rTMS compared to placebo (O’Reardon et al., 2007; Ray et al., 2011). In a naturalistic study, anxiety symptoms improved with a moderate treatment effect (Berlim et al., 2011). The current study lends further support to the evidence-base that rTMS is effective for anxious depression. This study found that anxiety improved significantly from pre- to post-treatment, with larger improvements in patients with anxious depression. While this finding may be due to grouping patients by anxiety symptom severity, thus leading to a floor effect for patients without anxious depression, it is notable that improvements in anxiety symptoms for the sample as a whole were also substantial. Limitations are the small sample, that diagnoses were not based on a structured interview, and comorbidities were not included in the analyses. In addition, anxiety symptoms were assessed using a factor scale of the HAMD, an approach that is typical of research on anxious depression (McClintock et al., 2011; Fava et al., 2008), but stronger conclusions regarding changes in anxiety symptoms could be drawn if more extensive anxiety assessments had been used.
5. Conclusions MDD patients with and without anxious depression responded similarly to rTMS in this study. Both depressive and anxiety symptoms improved following rTMS among these treatment resistant MDD patients. Future research should use larger samples and more extensive assessments of anxiety symptoms.
Conflict of interest Drs. Diefenbach and Goethe receive material support from Neuronetics as part of a separate research study. Dr. Goethe also receives Grant support from Bristol-
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Myers Scquibb, Forest, Hoffman-La Roche, Janssen, Marck Schering Plough, Neuronetics, Neosync, Otsuka, Shire and Takeda. Ms. Bragdon has no conflict to disclose.
Role of funding source There is no funding body agreement to report.
Acknowledgments There are no acknowledgments to report.
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