Non-pharmacological Somatic Treatments for Bipolar Depression

  • Harold A. SackeimEmail author
Part of the Milestones in Drug Therapy book series (MDT)


There has been an explosion of research interest in noninvasive and invasive forms of brain stimulation as treatments for bipolar depression and major depressive disorder (MDD). Electroconvulsive therapy (ECT) has the strongest evidence base. In the short term, ECT is more effective than any other intervention for MDD. MDD patients and those with bipolar disorder (BD) do not differ in response or remission rates, but BD patients respond more quickly. Magnetic Seizure Therapy (MST) and Focal Electrically Administered Seizure Therapy (FEAST) provide greater focality of stimulation than can be achieved with traditional ECT. Both techniques appear to have reduced cognitive effects, but equivalence in efficacy with traditional ECT is not established. Repetitive Transcranial Magnetic Therapy (rTMS) is an approved and widely used treatment for MDD. Efficacy appears stronger in the community than in the randomized controlled trials, perhaps due to concomitant use of pharmacotherapy. While commonly used in bipolar depression, as yet there is little information on efficacy specifically in this subgroup. Small studies have suggested that transcranial Direct Current Stimulation (tDCS) has antidepressant properties, including in bipolar depression. While promising, multisite randomized sham controlled trials are needed to test these claims. Vagus Nerve Stimulation (VNS) showed long-term antidepressant effects and good durability of benefit in treatment-resistant depression, including BD. Lack of insurance reimbursement has limited use in the USA for this indication. Initial open-label studies of Deep Brain Stimulation (DBS) at several targets were encouraging. However, two recent pivotal trials were terminated due to lack of an efficacy signal. These negative findings are leading to rethinking the role of DBS in the treatment of severe, treatment-resistant depression.


Electroconvulsive therapy (ECT) Bipolar depression Response rate Magnetic seizure therapy (MST) Focal electrically administered seizure therapy (FEAST) Repetitive transcranial magnetic stimulation (rTMS) Deep brain stimulation (DBS) Vagus nerve stimulation (VNS) Transcranial direct current stimulation (tDCS) 


  1. American Psychiatric Association (2001) The practice of ECT: recommendations for treatment, training and privileging, 2nd edn. American Psychiatric Press, Washington, DCGoogle Scholar
  2. Berman RM, Prudic J, Brakemeier EL, Olfson M, Sackeim HA (2008) Subjective evaluation of the therapeutic and cognitive effects of electroconvulsive therapy. Brain Stimul 1(1):16–26CrossRefPubMedGoogle Scholar
  3. Brakemeier EL, Berman R, Prudic J, Zwillenberg K, Sackeim HA (2011) Self-evaluation of the cognitive effects of electroconvulsive therapy. J ECT 27(1):59–66CrossRefPubMedGoogle Scholar
  4. Brunoni AR, Ferrucci R, Bortolomasi M, Vergari M, Tadini L, Boggio PS, Giacopuzzi M, Barbieri S, Priori A (2011) Transcranial direct current stimulation (tDCS) in unipolar vs. bipolar depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 35(1):96–101CrossRefPubMedGoogle Scholar
  5. Burt T, Prudic J, Peyser S, Clark J, Sackeim HA (2000) Learning and memory in bipolar and unipolar major depression: effects of aging. Neuropsychiatry Neuropsychol Behav Neurol 13(4):246–253PubMedGoogle Scholar
  6. Burt T, Lisanby SH, Sackeim HA (2002) Neuropsychiatric applications of transcranial magnetic stimulation: a meta analysis. Int J Neuropsychopharmacol 5(1):73–103CrossRefPubMedGoogle Scholar
  7. Carpenter LL, Janicak PG, Aaronson ST, Boyadjis T, Brock DG, Cook IA, Dunner DL, Lanocha K, Solvason HB, Demitrack MA (2012) Transcranial magnetic stimulation (TMS) for major depression: a multisite, naturalistic, observational study of acute treatment outcomes in clinical practice. Depress Anxiety 29(7):587–596CrossRefPubMedGoogle Scholar
  8. Cycowicz YM, Luber B, Spellman T, Lisanby SH (2008) Differential neurophysiological effects of magnetic seizure therapy (MST) and electroconvulsive shock (ECS) in non-human primates. Clin EEG Neurosci 39(3):144–149CrossRefPubMedGoogle Scholar
  9. Daly JJ, Prudic J, Devanand DP, Nobler MS, Lisanby SH, Peyser S, Roose SP, Sackeim HA (2001) ECT in bipolar and unipolar depression: differences in speed of response. Bipolar Disord 3(2):95–104CrossRefPubMedGoogle Scholar
  10. Deng ZD, Lisanby SH, Peterchev AV (2015) Effect of anatomical variability on electric field characteristics of electroconvulsive therapy and magnetic seizure therapy: a parametric modeling study. IEEE Trans Neural Syst Rehabil Eng 23(1):22–31CrossRefPubMedGoogle Scholar
  11. Dougherty DD, Rezai AR, Carpenter LL, Howland RH, Bhati MT, O’Reardon JP, Eskandar EN, Baltuch GH, Machado AD, Kondziolka D, Cusin C, Evans KC, Price LH, Jacobs K, Pandya M, Denko T, Tyrka AR, Brelje T, Deckersbach T, Kubu C, Malone DA Jr (2015) A randomized sham-controlled trial of deep brain stimulation of the ventral capsule/ventral striatum for chronic treatment-resistant depression. Biol Psychiatry 78(4):240–248CrossRefPubMedGoogle Scholar
  12. Dunner DL, Aaronson ST, Sackeim HA, Janicak PG, Carpenter LL, Boyadjis T, Brock DG, Bonneh-Barkay D, Cook IA, Lanocha K, Solvason HB, Demitrack MA (2014) A multisite, naturalistic, observational study of transcranial magnetic stimulation for patients with pharmacoresistant major depressive disorder: durability of benefit over a 1-year follow-up period. J Clin Psychiatry 75(12):1394–1401CrossRefPubMedGoogle Scholar
  13. Folkerts HW, Michael N, Tolle R, Schonauer K, Mucke S, Schulze-Monking H (1997) Electroconvulsive therapy vs. paroxetine in treatment-resistant depression – a randomized study. Acta Psychiatr Scand 96(5):334–342CrossRefPubMedGoogle Scholar
  14. George MS, Lisanby SH, Avery D, McDonald WM, Durkalski V, Pavlicova M, Anderson B, Nahas Z, Bulow P, Zarkowski P, Holtzheimer PE III, Schwartz T, Sackeim HA (2010) Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: a sham-controlled randomized trial. Arch Gen Psychiatry 67(5):507–516CrossRefPubMedGoogle Scholar
  15. Greenberg BD, Malone DA, Friehs GM, Rezai AR, Kubu CS, Malloy PF, Salloway SP, Okun MS, Goodman WK, Rasmussen SA (2006) Three-year outcomes in deep brain stimulation for highly resistant obsessive-compulsive disorder. Neuropsychopharmacology 31(11):2384–2393CrossRefPubMedGoogle Scholar
  16. Hardesty DE, Sackeim HA (2007) Deep brain stimulation in movement and psychiatric disorders. Biol Psychiatry 61(7):831–835CrossRefPubMedGoogle Scholar
  17. Heijnen WT, Birkenhager TK, Wierdsma AI, van den Broek WW (2010) Antidepressant pharmacotherapy failure and response to subsequent electroconvulsive therapy: a meta-analysis. J Clin Psychopharmacol 30(5):616–619CrossRefPubMedGoogle Scholar
  18. Holtzheimer PE, Kelley ME, Gross RE, Filkowski MM, Garlow SJ, Barrocas A, Wint D, Craighead MC, Kozarsky J, Chismar R, Moreines JL, Mewes K, Posse PR, Gutman DA, Mayberg HS (2012) Subcallosal cingulate deep brain stimulation for treatment-resistant unipolar and bipolar depression. Arch Gen Psychiatry 69(2):150–158CrossRefPubMedPubMedCentralGoogle Scholar
  19. Horvath JC, Forte JD, Carter O (2015) Quantitative review finds no evidence of cognitive effects in healthy populations from single-session transcranial Direct Current Stimulation (tDCS). Brain Stimul 8(3):535–550CrossRefPubMedGoogle Scholar
  20. Janicak P, Davis J, Gibbons R, Ericksen S, Chang S, Gallagher P (1985) Efficacy of ECT: a meta-analysis. Am J Psychiatry 142(3):297–302CrossRefPubMedGoogle Scholar
  21. Jelovac A, Kolshus E, McLoughlin DM (2013) Relapse following successful electroconvulsive therapy for major depression: a meta-analysis. Neuropsychopharmacology 38(12):2467–2474CrossRefPubMedPubMedCentralGoogle Scholar
  22. Kalinowsky LB, Hoch PH (1946) Shock treatments and other somatic procedures in psychiatry. Grune & Stratton, New YorkGoogle Scholar
  23. Kellner CH, Knapp RG, Petrides G, Rummans TA, Husain MM, Rasmussen K, Mueller M, Bernstein HJ, O’Connor K, Smith G, Biggs M, Bailine SH, Malur C, Yim E, McClintock S, Sampson S, Fink M (2006) Continuation electroconvulsive therapy vs pharmacotherapy for relapse prevention in major depression: a multisite study from the Consortium for Research in Electroconvulsive Therapy (CORE). Arch Gen Psychiatry 63(12):1337–1344CrossRefPubMedPubMedCentralGoogle Scholar
  24. Lisanby SH, Schlaepfer TE, Fisch HU, Sackeim HA (2001) Magnetic seizure therapy of major depression. Arch Gen Psychiatry 58(3):303–305CrossRefPubMedGoogle Scholar
  25. Lisanby SH, Luber B, Schlaepfer TE, Sackeim HA (2003) Safety and feasibility of magnetic seizure therapy (MST) in major depression: randomized within-subject comparison with electroconvulsive therapy. Neuropsychopharmacology 28(10):1852–1865CrossRefPubMedGoogle Scholar
  26. Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, Schwalb JM, Kennedy SH (2005) Deep brain stimulation for treatment-resistant depression. Neuron 45(5):651–660CrossRefPubMedGoogle Scholar
  27. Meduna LJ (1935) Versuche über die biologische Beeinflussung des Abaufes der Schizophrenie: I. Campher und Cardiozolkrämpfe. Z Neurol Psychiatry 152:235–262CrossRefGoogle Scholar
  28. Mulsant BH, Haskett RF, Prudic J, Thase ME, Malone KM, Mann JJ, Pettinati HM, Sackeim HA (1997) Low use of neuroleptic drugs in the treatment of psychotic major depression. Am J Psychiatry 154(4):559–561CrossRefPubMedGoogle Scholar
  29. Nahas Z, Short B, Burns C, Archer M, Schmidt M, Prudic J, Nobler MS, Devanand DP, Fitzsimons L, Lisanby SH, Payne N, Perera T, George MS, Sackeim HA (2013) A feasibility study of a new method for electrically producing seizures in man: focal electrically administered seizure therapy [FEAST]. Brain Stimul 6(3):403–408CrossRefPubMedGoogle Scholar
  30. O’Reardon JP, Solvason HB, Janicak PG, Sampson S, Isenberg KE, Nahas Z, McDonald WM, Avery D, Fitzgerald PB, Loo C, Demitrack MA, George MS, Sackeim HA (2007) Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biol Psychiatry 62(11):1208–1216CrossRefPubMedGoogle Scholar
  31. Pereira Junior Bde S, Tortella G, Lafer B, Nunes P, Bensenor IM, Lotufo PA, Machado-Vieira R, Brunoni AR (2015) The bipolar depression electrical treatment trial (BETTER): design, rationale, and objectives of a randomized, sham-controlled trial and data from the pilot study phase. Neural Plast 2015:684025PubMedGoogle Scholar
  32. Perera TD, Coplan JD, Lisanby SH, Lipira CM, Arif M, Carpio C, Spitzer G, Santarelli L, Scharf B, Hen R, Rosoklija G, Sackeim HA, Dwork AJ (2007) Antidepressant-induced neurogenesis in the hippocampus of adult nonhuman primates. J Neurosci 27(18):4894–4901CrossRefPubMedGoogle Scholar
  33. Prudic J, Sackeim HA, Devanand DP (1990) Medication resistance and clinical response to electroconvulsive therapy. Psychiatry Res 31(3):287–296CrossRefPubMedGoogle Scholar
  34. Prudic J, Olfson M, Marcus SC, Fuller RB, Sackeim HA (2004) Effectiveness of electroconvulsive therapy in community settings. Biol Psychiatry 55(3):301–312CrossRefPubMedGoogle Scholar
  35. Rush AJ (2007) STAR*D: what have we learned? Am J Psychiatry 164(2):201–204CrossRefPubMedGoogle Scholar
  36. Rush AJ, Marangell LB, Sackeim HA, George MS, Brannan SK, Davis SM, Howland R, Kling MA, Rittberg BR, Burke WJ, Rapaport MH, Zajecka J, Nierenberg AA, Husain MM, Ginsberg D, Cooke RG (2005) Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial. Biol Psychiatry 58(5):347–354CrossRefPubMedGoogle Scholar
  37. Sachs GS, Nierenberg AA, Calabrese JR, Marangell LB, Wisniewski SR, Gyulai L, Friedman ES, Bowden CL, Fossey MD, Ostacher MJ, Ketter TA, Patel J, Hauser P, Rapport D, Martinez JM, Allen MH, Miklowitz DJ, Otto MW, Dennehy EB, Thase ME (2007) Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med 356(17):1711–1722CrossRefPubMedGoogle Scholar
  38. Sackeim HA (1994) Magnetic stimulation therapy and ECT. Convulsive Ther 10:255–258Google Scholar
  39. Sackeim HA (2000) Repetitive transcranial magnetic stimulation: What are the next steps? Biol Psychiatry 48(10):959–961CrossRefPubMedGoogle Scholar
  40. Sackeim HA (2003) Electroconvulsive therapy and schizophrenia. In: Hirsch SR, Weinberger D (eds) Schizophrenia, 2nd edn. Balckwell, Oxford, pp 517–551CrossRefGoogle Scholar
  41. Sackeim HA (2004) The convulsant and anticonvulsant properties of electroconvulsive therapy: towards a focal form of brain stimulation. Clin Neurosci Rev 4:39–57CrossRefGoogle Scholar
  42. Sackeim HA (2014) Autobiographical memory and electroconvulsive therapy: Do not throw out the baby. J ECT 30(3):177–186CrossRefPubMedPubMedCentralGoogle Scholar
  43. Sackeim HA, Prudic J (2005) Length of the ECT course in bipolar and unipolar depression. J ECT 21(3):195–197CrossRefPubMedGoogle Scholar
  44. Sackeim HA, Decina P, Prohovnik I, Malitz S, Resor SR (1983) Anticonvulsant and antidepressant properties of electroconvulsive therapy: a proposed mechanism of action. Biol Psychiatry 18(11):1301–1310PubMedGoogle Scholar
  45. Sackeim HA, Decina P, Kanzler M, Kerr B, Malitz S (1987) Effects of electrode placement on the efficacy of titrated, low-dose ECT. Am J Psychiatry 144(11):1449–1455CrossRefPubMedGoogle Scholar
  46. Sackeim HA, Prudic J, Devanand DP, Decina P, Kerr B, Malitz S (1990) The impact of medication resistance and continuation pharmacotherapy on relapse following response to electroconvulsive therapy in major depression. J Clin Psychopharmacol 10(2):96–104CrossRefPubMedGoogle Scholar
  47. Sackeim HA, Prudic J, Devanand DP, Kiersky JE, Fitzsimons L, Moody BJ, McElhiney MC, Coleman EA, Settembrino JM (1993) Effects of stimulus intensity and electrode placement on the efficacy and cognitive effects of electroconvulsive therapy. N Engl J Med 328(12):839–846CrossRefPubMedGoogle Scholar
  48. Sackeim HA, Prudic J, Devanand DP, Nobler MS, Lisanby SH, Peyser S, Fitzsimons L, Moody BJ, Clark J (2000) A prospective, randomized, double-blind comparison of bilateral and right unilateral electroconvulsive therapy at different stimulus intensities. Arch Gen Psychiatry 57(5):425–434CrossRefPubMedGoogle Scholar
  49. Sackeim HA, Haskett RF, Mulsant BH, Thase ME, Mann JJ, Pettinati HM, Greenberg RM, Crowe RR, Cooper TB, Prudic J (2001a) Continuation pharmacotherapy in the prevention of relapse following electroconvulsive therapy: a randomized controlled trial. JAMA 285(10):1299–1307CrossRefPubMedGoogle Scholar
  50. Sackeim HA, Rush AJ, George MS, Marangell LB, Husain MM, Nahas Z, Johnson CR, Seidman S, Giller C, Haines S, Simpson RK Jr, Goodman RR (2001b) Vagus nerve stimulation (VNS) for treatment-resistant depression: efficacy, side effects, and predictors of outcome. Neuropsychopharmacology 25(5):713–728CrossRefPubMedGoogle Scholar
  51. Sackeim HA, Brannan SK, John Rush A, George MS, Marangell LB, Allen J (2007a) Durability of antidepressant response to vagus nerve stimulation (VNSTM). Int J Neuropsychopharmacol 10:817–826Google Scholar
  52. Sackeim HA, Prudic J, Fuller RB, Keilp J, Lavori PW, Olfson M (2007b) The cognitive effects of electroconvulsive therapy in community settings. Neuropsychopharmacology 32:244–254CrossRefPubMedGoogle Scholar
  53. Sackeim HA, Prudic J, Nobler MS, Fitzsimons L, Lisanby SH, Payne N, Berman RM, Brakemeier EL, Perera T, Devanand DP (2008) Effects of pulse width and electrode placement on the efficacy and cognitive effects of electroconvulsive therapy. Brain Stimul 1(2):71–83CrossRefPubMedPubMedCentralGoogle Scholar
  54. Sackeim HA, Dillingham EM, Prudic J, Cooper T, McCall WV, Rosenquist P, Isenberg K, Garcia K, Mulsant BH, Haskett RF (2009) Effect of concomitant pharmacotherapy on electroconvulsive therapy outcomes: short-term efficacy and adverse effects. Arch Gen Psychiatry 66(7):729–737CrossRefPubMedGoogle Scholar
  55. Schlaepfer TE, Cohen MX, Frick C, Kosel M, Brodesser D, Axmacher N, Joe AY, Kreft M, Lenartz D, Sturm V (2008) Deep brain stimulation to reward circuitry alleviates anhedonia in refractory major depression. Neuropsychopharmacology 33(2):368–377CrossRefPubMedGoogle Scholar
  56. Schoeyen HK, Kessler U, Andreassen OA, Auestad BH, Bergsholm P, Malt UF, Morken G, Oedegaard KJ, Vaaler A (2015) Treatment-resistant bipolar depression: a randomized controlled trial of electroconvulsive therapy versus algorithm-based pharmacological treatment. Am J Psychiatry 172(1):41–51CrossRefPubMedGoogle Scholar
  57. Shiozawa P, Fregni F, Bensenor IM, Lotufo PA, Berlim MT, Daskalakis JZ, Cordeiro Q, Brunoni AR (2014) Transcranial direct current stimulation for major depression: an updated systematic review and meta-analysis. Int J Neuropsychopharmacol 17(9):1443–1452CrossRefPubMedGoogle Scholar
  58. Sienaert P, Vansteelandt K, Demyttenaere K, Peuskens J (2009) Ultra-brief pulse ECT in bipolar and unipolar depressive disorder: differences in speed of response. Bipolar Disord 11(4):418–424CrossRefPubMedGoogle Scholar
  59. Tor P-C, Bautovich A, Wang M-J, Martin D, Harvey SB, Loo C (2015) A systematic review and meta-analysis of brief versus ultrabrief right unilateral electroconvulsive therapy for depression. J Clin Psychiatry 76(9):e1092–e1098CrossRefPubMedGoogle Scholar
  60. Truman CJ, Goldberg JF, Ghaemi SN, Baldassano CF, Wisniewski SR, Dennehy EB, Thase ME, Sachs GS (2007) Self-reported history of manic/hypomanic switch associated with antidepressant use: data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). J Clin Psychiatry 68(10):1472–1479CrossRefPubMedGoogle Scholar
  61. Wehr TA, Goodwin FK (1979) Rapid cycling in manic-depressives induced by tricyclic antidepressants. Arch Gen Psychiatry 36(5):555–559CrossRefPubMedGoogle Scholar

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© Springer International Publishing Switzerland (outside the USA)  2016

Authors and Affiliations

  1. 1.Departments of Psychiatry and RadiologyCollege of Physicians and Surgeons of Columbia UniversityFleetwoodUSA

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