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Commentary TMS FOR BIPOLAR DEPRESSION

Antidepressants, TMS, and the risk of affective switch in bipolar depression

Some evidence suggests that TMS plus a mood stabilizer might minimize this risk

ecause treatment resistance is a pervasive problem in bipolar depression, the use of neuromodulation treatments such as transcranial magnetic stimula- B 1-7 tion (TMS) is increasing for patients with this disorder. Patients with tend to spend the major- ity of the time with depressive symptoms, which under- scores the importance of providing effective treatment for bipolar depression, especially given the chronicity of this disease.2,3,5 Only a few medications are FDA-approved for treating bipolar depression (Table, page 21). In this article, we describe the case of a patient with treat- ment-resistant bipolar depression undergoing adjunctive TMS treatment who experienced an affective switch from © BENJAVISA/GETTY IMAGES © BENJAVISA/GETTY depression to . We also discuss evidence regarding the Lucia Smith-Martinez, MD likelihood of treatment-emergent mania for Clinical Assistant Professor vs TMS in bipolar depression. Department of Psychiatry and Behavioral

Kaylan Muppavarapu, MD CASE Clinical Assistant Professor Ms. W, a 60-year-old White female with a history of bipo- Department of Psychiatry and Behavioral Medicine lar I disorder and attention-deficit/hyperactivity disorder Michael Lang, MD (ADHD), presented for TMS evaluation during a depressive Assistant Professor Director, Medicine/Psychiatry Residency Program episode. Throughout her life, she had experienced numerous Vice Chair manic episodes, but as she got older she noted an increasing Department of Psychiatry and Behavioral Medicine frequency of depressive episodes. Over the course of her • • • • illness, she had completed adequate trials at therapeutic East Carolina University doses of many medications, including second-generation Greenville, North Carolina antipsycho­tics (SGAs) (, , ,

Disclosures The authors report no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products. Current Psychiatry 20 April 2021 doi: 10.12788/cp.0099 Table Medications that are FDA-approved for treating bipolar depression

Medication Brand name Year approved MDedge.com/psychiatry Olanzapine-fluoxetine Symbyax 2003 Seroquel 2006 Quetiapine XR Seroquel XR 2008 Lurasidone Latuda 2013 Vraylar 2019 XR: extended-release

quetiapine), mood stabilizers (lamotrigine, 7, indicating very severe depression, mild ), and antidepressants (, , and the absence of mania. Ms. W’s , , , tra- psychotropic regimen remained unchanged zodone). A course of electroconvulsive throughout the course of her TMS treatment. therapy was not effective. Ms. W had a After her motor threshold was determined, Clinical Point long-standing diagnosis of ADHD and had her TMS treatment began at 80% of motor The natural course of been treated with stimulants for >10 years, threshold and was titrated up to 95% at the although it was unclear whether formal first treatment. By the second treatment, it switching in bipolar neuropsychological testing had been con- was titrated up to 110%. By the third treat- disorder confounds ducted to confirm this diagnosis. She had ment, it was titrated up to 120% of motor interpretation of >10 attempts and multiple psychi- threshold, which is the percentage used for the evidence about atric hospitalizations. the remaining treatments. treatment-emergent At her initial evaluation for TMS, Ms. W Initially, Ms. W reported some improve- said she had depressive symptoms pre- ment in her depression, but this improvement mania dominating for the past 2 years, including was short-lived, and she continued to have low mood, hopelessness, poor sleep, poor elevated QIDS scores throughout treatment. , anhedonia, and suicidal ideation By treatment #21, her QIDS and GAD-7 scores without a plan. At the time, she was taking remained elevated, and her YMRS score had , 0.5 mg twice a day; lurasidone, increased to 12. Due to this increase in YMRS 40 mg/d at bedtime; fluoxetine, 60 mg/d; score, the YMRS was repeated on the next 2 trazodone, 50 mg/d at bedtime; and methyl- treatment days (#22 and #23), and her score phenidate, 40 mg/d, and was participating in was 6 on both days. When Ms. W presented psychotherapy consistently. for treatment #25, she was disorganized, After Ms. W and her clinicians discussed irritable, and endorsed racing thoughts and alternatives, risks, benefits, and adverse decreased sleep. She was involuntarily hos- effects, she consented to adjunctive TMS pitalized for mania, and TMS was discontin- treatment and provided written informed ued. Unfortunately, she did not complete consent. The treatment plan was outlined any clinical scales on that day. Upon admis- as 6 weeks of daily TMS therapy (NeuroStar; sion to the hospital, Ms. W reported that at Neuronetics, Malvern, PA), 1 treatment per approximately the time of treatment #21, day, 5 days a week. Her clinical status was she had a fluctuation in her mood that con- assessed weekly using the Quick Inventory sisted of increased goal-directed activity, of Depressive Symptomatology (QIDS) for decreased need for sleep, racing thoughts, depression, Generalized and increased frivolous spending. She was Discuss this article at 7-item scale (GAD-7) for anxiety, and Young treated with lithium, 300 mg twice a day. www.facebook.com/ Mania Rating Scale (YMRS) for mania. The Lurasidone was increased to 80 mg/d at MDedgePsychiatry Figure (page 22) shows the trends in Ms. bedtime, and she continued clonazepam, W’s QIDS, GAD-7, and YMRS scores over the trazodone, and at the pre- course of TMS treatment. vious doses. Over 14 days, Ms. W’s mania Prior to initiating TMS, her baseline gradually resolved, and she was discharged Current Psychiatry scores were QIDS: 25, GAD-7: 9, and YMRS: home. Vol. 20, No. 4 21 continued Figure Ms. W’s QIDS, GAD-7, and YMRS scores over the course of transcranial magnetic stimulation treatment

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TMS for bipolar 20 depression 15 e Scor 10

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Clinical Point 0 One review found 5101520 QIDS that the rate of GAD-7 Treatment number affective switch in YMRS patients with bipolar GAD-7: Generalized Anxiety Disorder 7-item scale; QIDS: Quick Inventory of Depressive Symptomatology; YMRS: Young depression who were Mania Rating Scale treated with TMS was 3.1% Mixed evidence on the risk Interpretation of available literature is of switching limited due to inconsistencies in the defi- Currently, several TMS devices are nition of an affective switch, the variable FDA-cleared for treating unipolar major length of treatment with antidepressants, depressive disorder, obsessive-compulsive the use of concurrent medications such as disorder, and certain types of migraine. mood stabilizers, and confounders such as In March 2020, the FDA granted the natural course of switching in bipolar Breakthrough Device Designation for one disorder.17 Overall, the evidence for treat- TMS device, the NeuroStar Advanced ment-emergent mania related to antide- Therapy System, for the treatment of pressant use is mixed, and the reported rate bipolar depression.8 This designation cre- of treatment-emergent mania varies. In a ated an expedited pathway for prioritized and meta-analysis of >20 FDA review of the NeuroStar Advanced randomized controlled trials that included Therapy program. 1,316 patients with bipolar disorder who Few published clinical studies have received antidepressants, Fornaro et al18 evaluated using TMS to treat patients with found that the incidence of treatment-emer- bipolar depression.9-15 As with any anti- gent mania was 11.8%. It is generally rec- treatment for bipolar depres- ommended that if antidepressants are used sion, there is a risk of affective switch from to treat patients with bipolar disorder, they depression to mania when using TMS. should be given with a traditional mood Most of the literature available regarding stabilizer to prevent affective switches, the treatment of bipolar depression focuses although whether mood stabilizers can pre- on the risk of medications vent such switches is unproven.19 to induce an affective switch. This risk In a literature review by Xia et al,20 the depends on the class of the antidepressant,16 affective switch rate in patients with bipolar and there is a paucity of studies examining depression who were treated with TMS was Current Psychiatry 22 April 2021 the risk of switch with TMS. 3.1%, which was not statistically different from the affective switch rate with sham treatment. However, most of the patients Related Resources included in this analysis were receiving • Transcranial magnetic stimulation: clinical applications for psychiatric practice. Bermudes RA, Lanocha K, Janicak PG, other medications concurrently, and the eds. American Psychiatric Association Publishing; 2017. MDedge.com/psychiatry length of treatment was 2 weeks, which • Gold AK, Ornelas AC, Cirillo P, et al. Clinical applications of is shorter than the average length of TMS transcranial magnetic stimulation in bipolar disorder. Brain Behav. 2019;9(10):e01419. doi: 10.1002/brb3.1419 treatment in clinical practice. In a recent Drug Brand Names literature review by Rachid,21 TMS was Aripiprazole • Abilify Methylphenidate • Ritalin, found to possibly induce manic episodes Bupropion • Wellbutrin Concerta when used as monotherapy or in combina- Cariprazine • Vraylar Mirtazapine • Remeron Clonazepam • Klonopin Olanzapine • Zyprexa tion with antidepressants in patients with Fluoxetine • Prozac Olanzapine-fluoxetine • bipolar depression. To reduce the risk of Lamotrigine • Lamictal Symbyax treatment-emergent mania, current recom- Lithium • Eskalith, Quetiapine • Seroquel Lithobid Trazodone • Desyrel mendations advise the use of a mood sta- Lurasidone • Latuda Venlafaxine • Effexor bilizer for a minimum of 2 weeks before initiating TMS.1 In our case, Ms. W was receiving antide- Clinical Point pressants (fluoxetine and trazodone), lur- magnetic stimulation: clinical applications for psychiatric Ms. W was receiving asidone (an SGA that is FDA-approved for practice. American Psychiatric Association Publishing; bipolar depression), and methylphenidate 2017:127-156. several medications 2. Geddes JR, Miklowitz DJ. Treatment of bipolar disorder. before starting TMS treatment. Fluoxetine, Lancet. 2013;381(9878):1672-1682. that might have trazodone, and methylphenidate may pos- 3. Gitlin M. Treatment-resistant bipolar disorder. Molecular contributed to her risk Psychiatry. 2006;11(3):227-240. sibly contribute to an increased risk of 4. Harrison PJ, Geddes JR, Tunbridge EM. The emerging of an affective switch an affective switch.1,22 Further studies are neurobiology of bipolar disorder. Trends Neurosci. 2018;41(1): 18-30. while undergoing TMS needed to clarify whether mood stabilizers 5. Merikangas KR, Jin R, He JP, et al. Prevalence and or SGAs can prevent the development of correlates of bipolar spectrum disorder in the World Mental Health Survey Initiative. Arch Gen Psychiatry. mania in patients with bipolar depression 2011;68(3):241-251. who undergo TMS treatment.20 6. Myczkowski ML, Fernandes A, Moreno M, et al. Cognitive outcomes of TMS treatment in bipolar depression: safety Because bipolar depression poses a data from a randomized controlled trial. J Affect Disord. major clinical challenge,23,24 it is impera- 2018;235: 20-26. 7. Tavares DF, Myczkowski ML, Alberto RL, et al. tive to consider alternate treatments. When Treatment of bipolar depression with deep TMS: results evaluating alternative treatment strate- from a double-blind, randomized, parallel group, sham- controlled clinical trial. Neuropsychopharmacology. gies, one may consider TMS in conjunction 2017;42(13):2593-2601. with a traditional mood stabilizer because 8. Neuronetics. FDA grants NeuroStar® Advanced Therapy System Breakthrough Device Designation this regimen may have a lower risk of to treat bipolar depression. Accessed February 2, 2021. https://www.globenewswire.com/news-release/2020/ treatment-emergent mania compared with 03/06/1996447/0/en/FDA-Grants-NeuroStar-Advanced- antidepressants.1,25 Therapy-System-Breakthrough-Device-Designation-to- Treat-Bipolar-Depression.html 9. Cohen RB, Brunoni AR, Boggio PS, et al. Clinical Acknowledgment predictors associated with duration of repetitive The authors thank Dr. Sy Saeed for his expertise and guidance on transcranial magnetic stimulation treatment for this article. remission in bipolar depression: a naturalistic study. J Nerv Ment Dis. 2010;198(9):679-681. 10. Connolly KR, Helmer A, Cristancho MA, et al. Effectiveness References of transcranial magnetic stimulation in clinical practice post- 1. Aaronson ST, Croarkin PE. Transcranial magnetic FDA approval in the United States: results observed with stimulation for the treatment of other mood disorders. In: the first 100 consecutive cases of depression at an academic Bermudes RA, Lanocha K, Janicak PG, eds. Transcranial medical center. J Clin Psychiatry. 2012;73(4):e567-e573. continued

Bottom Line For patients with bipolar depression, treatment with transcranial magnetic stimulation in conjunction with a mood stabilizer may have lower rates of Current Psychiatry treatment-emergent mania than treatment with antidepressants. Vol. 20, No. 4 23 11. Dell’osso B, D’Urso N, Castellano F, et al. Long-term efficacy 18. Fornaro M, Anastasia A, Novello S, et al. Incidence, after acute augmentative repetitive transcranial magnetic prevalence and clinical correlates of antidepressant‐ stimulation in bipolar depression: a 1-year follow-up study. emergent mania in bipolar depression: a systematic review J ECT. 2011;27(2):141-144. and meta‐analysis. Bipolar Disord. 2018;20(3):195-227. 12. Dell’Osso B, Mundo E, D’Urso N, et al. Augmentative 19. Pacchiarotti I, Bond DJ, Baldessarini RJ, et al. The repetitive navigated transcranial magnetic stimulation International Society for Bipolar Disorders (ISBD) task force (rTMS) in drug-resistant bipolar depression. Bipolar Disord. report on antidepressant use in bipolar disorders. Am J 2009;11(1):76-81. Psychiatry. 2013;170(11):1249-1262. 13. Harel EV, Zangen A, Roth Y, et al. H-coil repetitive 20. Xia G, Gajwani P, Muzina DJ, et al. Treatment-emergent transcranial magnetic stimulation for the treatment of mania in unipolar and bipolar depression: focus on bipolar depression: an add-on, safety and feasibility study. repetitive transcranial magnetic stimulation. Int J TMS for bipolar World J Biol Psychiatry. 2011;12(2):119-126. Neuropsychopharmacol. 2008;11(1):119-130. 14. Nahas Z, Kozel FA, Li X, et al. Left prefrontal transcranial 21. Rachid F. Repetitive transcranial magnetic stimulation and depression magnetic stimulation (TMS) treatment of depression in treatment-emergent mania and hypomania: a review of the bipolar affective disorder: a pilot study of acute safety and literature. J Psychiatr Pract. 2017;23(2):150-159. efficacy. Bipolar Disord. 2003;5(1):40-47. 22. Victorin A, Rydén E, Thase M, et al. The risk of treatment- 15. Tamas RL, Menkes D, El-Mallakh RS. Stimulating emergent mania with methylphenidate in bipolar disorder. research: a prospective, randomized, double-blind, sham- Am J Psychiatry. 2017;174(4):341-348. controlled study of slow transcranial magnetic stimulation 23. Hidalgo-Mazzei D, Berk M, Cipriani A, et al. Treatment- in depressed bipolar patients. J Neuropsychiatry Clin resistant and multi-therapy-resistant criteria for bipolar Neurosci. 2007;19(2):198-199. depression: consensus definition. Br J Psychiatry. 2019;214(1): 16. Tundo A, Cavalieri P, Navari S, et al. Treating bipolar 27-35. depression - antidepressants and alternatives: a critical 24. Baldessarini RJ, Vázquez GH, Tondo L. Bipolar depression: a review of the literature. Acta Neuropsychiatrica. 2011: major unsolved challenge. Int J Bipolar Disord. 2020;8(1):1. 23(3):94-105. 25. Phillips AL, Burr RL, Dunner DL. Repetitive transcranial Clinical Point 17. Gijsman HJ, Geddes JR, Rendell JM, et al. Antidepressants magnetic stimulation in the treatment of bipolar depression: for bipolar depression: a systematic review of randomized, Experience from a clinical setting. J Psychiatr Pract. 2020; Compared with controlled trials. Am J Psychiatry. 2004;161(9):1537-1547. 26(1):37-45. antidepressants, TMS plus a mood stabilizer may have a lower risk of treatment- emergent mania

Current Psychiatry 24 April 2021