Psychiatric Annals

CME Article 

The ‘Treatment-resistant’ Label in Bipolar Disorder Is a Misnomer

Max Fink, MD

Abstract

Three decades before the introduction of lithium therapy, electroconvulsive therapy (ECT) was the main treatment for patients with mania. Relief of mania and depression, as well as reduced mortality, highlighted the early reports.1,2 The introduction of chlorpromazine, its successor neuroleptic agents, and lithium replaced ECT.

The replacement of ECT with medications was not for want of efficacy or safety. Rather, it was because medications were easier to use, cost less, had lower requirements for patient consent, and carried less stigma than ECT. The enthusiasm that psychopharmacology was the key to mental health also contributed to psychiatrists' abandonment of ECT. The increasing incidence of therapy resistance among patients with mania in recent years makes it timely to re-examine the evidence for the efficacy of ECT and re-orient our treatment algorithms.3

The intimate relationship of mania and depression as a single disorder was first described in 1854 by the French psychopathologists Falret4 and Baillerger.5 Their descriptions set the stage for the concept of manic-depressive insanity that was distinguished from dementia praecox by Kraepelin in 1896.6

The concept of a single disorder served the profession well until the Diagnostic and Statistical Manual of Mental Disorders, third edition (DSMIII),7 separated bipolar disorder from major depressive disorder. The separation was prompted by the experience that the manic phases, but not the depressive phases, of the illness were best treated with lithium, while the depressive phases were responsive to tricyclic antidepressants and monoamine oxidase inhibitors. Observations that ECT was effective in both the manic and depressive phases of the illness were ignored. That ECT was effective in both phases of the illness should have indicated to the authors that the separation was on weak grounds, but this experience with ECT was disregarded.

The division of two disorders continued in DSM's fourth edition, in the belief that the two disorders had different pathophysiologies, different therapeutics, and now, different genetics and brain imaging. Such a belief increasingly is being recognized as misguided.3

The separation of bipolar disorder and major depressive disorder next was encouraged by reports that anticonvulsants reduced the duration and frequency of manic episodes.8 The separation assumed greater significance as more detailed treatment algorithms were developed for major depression based on newly introduced selective serotonin reuptake inhibitor (SSRI) and selective norepinephrine reuptake inhibitor (SNRI) agents.

Complaints that antidepressant agents fostered “switching” from depression to mania further prompted separation between the two disorders.2,8 Switches in the presenting mood occur spontaneously, most often for reasons that are obscure. The switches may be frequent, occurring within a day, or a week, or within a few months. The more rapid switches are labeled “rapid cycling.” The switches also occur during the course of treatment, and the relation of the spontaneous switch to the treatment-induced switch is not resolved.

The evidence for medication-induced switching from depression into mania is thin.2,8 In a retrospective review of 1,057 hospital admissions during a 60-year period, a switch to mania occurred in 12% in patients with “endogenous depression” and in 10% of patients with psychotic recurrent depressive illness. Of the nonpsychotic patients treated with medication, 3.6% switched to mania. In patients with psychotic manic-depressive illness, the switch rates were 32% for medications and 30% for ECT.9

Of patients with major depressive disorders, 40% to 50% develop mania or hypomania during the course of their illness.10 There is little justification to see the switch as more than a change in the phase of a manic-depressive illness.

“Treatment-resistance” is a term that is applied loosely to patients who do not respond to medication treatment trials. Neither the number or duration of treatments attempted, nor tests of patient…

Three decades before the introduction of lithium therapy, electroconvulsive therapy (ECT) was the main treatment for patients with mania. Relief of mania and depression, as well as reduced mortality, highlighted the early reports.1,2 The introduction of chlorpromazine, its successor neuroleptic agents, and lithium replaced ECT.

The replacement of ECT with medications was not for want of efficacy or safety. Rather, it was because medications were easier to use, cost less, had lower requirements for patient consent, and carried less stigma than ECT. The enthusiasm that psychopharmacology was the key to mental health also contributed to psychiatrists' abandonment of ECT. The increasing incidence of therapy resistance among patients with mania in recent years makes it timely to re-examine the evidence for the efficacy of ECT and re-orient our treatment algorithms.3

Bipolar Disorder

The intimate relationship of mania and depression as a single disorder was first described in 1854 by the French psychopathologists Falret4 and Baillerger.5 Their descriptions set the stage for the concept of manic-depressive insanity that was distinguished from dementia praecox by Kraepelin in 1896.6

The concept of a single disorder served the profession well until the Diagnostic and Statistical Manual of Mental Disorders, third edition (DSMIII),7 separated bipolar disorder from major depressive disorder. The separation was prompted by the experience that the manic phases, but not the depressive phases, of the illness were best treated with lithium, while the depressive phases were responsive to tricyclic antidepressants and monoamine oxidase inhibitors. Observations that ECT was effective in both the manic and depressive phases of the illness were ignored. That ECT was effective in both phases of the illness should have indicated to the authors that the separation was on weak grounds, but this experience with ECT was disregarded.

The division of two disorders continued in DSM's fourth edition, in the belief that the two disorders had different pathophysiologies, different therapeutics, and now, different genetics and brain imaging. Such a belief increasingly is being recognized as misguided.3

The separation of bipolar disorder and major depressive disorder next was encouraged by reports that anticonvulsants reduced the duration and frequency of manic episodes.8 The separation assumed greater significance as more detailed treatment algorithms were developed for major depression based on newly introduced selective serotonin reuptake inhibitor (SSRI) and selective norepinephrine reuptake inhibitor (SNRI) agents.

Complaints that antidepressant agents fostered “switching” from depression to mania further prompted separation between the two disorders.2,8 Switches in the presenting mood occur spontaneously, most often for reasons that are obscure. The switches may be frequent, occurring within a day, or a week, or within a few months. The more rapid switches are labeled “rapid cycling.” The switches also occur during the course of treatment, and the relation of the spontaneous switch to the treatment-induced switch is not resolved.

The evidence for medication-induced switching from depression into mania is thin.2,8 In a retrospective review of 1,057 hospital admissions during a 60-year period, a switch to mania occurred in 12% in patients with “endogenous depression” and in 10% of patients with psychotic recurrent depressive illness. Of the nonpsychotic patients treated with medication, 3.6% switched to mania. In patients with psychotic manic-depressive illness, the switch rates were 32% for medications and 30% for ECT.9

Of patients with major depressive disorders, 40% to 50% develop mania or hypomania during the course of their illness.10 There is little justification to see the switch as more than a change in the phase of a manic-depressive illness.

“Treatment-resistance” is a term that is applied loosely to patients who do not respond to medication treatment trials. Neither the number or duration of treatments attempted, nor tests of patient compliance to the prescribed treatments, nor the specification that all effective treatments be applied, are required before the patient is labeled “treatment-resistant.” As the term is used, it is applied to the patient rather than the treatment. Thus, it is pejorative, blaming the patient for failure. “Treatment failure” is the more appropriate term, recognizing the serendipitous nature of the available treatments for mood disorders.

Nowhere is the use of the term “treatment-resistant” more capricious than in the failure to recognize the efficacy of ECT in relieving both the manic and the depressive phases of bipolar disorders.11 In treatment algorithms for major depression, ECT usually is cited among a list of alternative treatments, with the implication that it is best used as a “last resort” option.12,13 If the efficacy of ECT in manic disorders were as well recognized as it is for the depressive disorders, the incidence of patients with chronic illness labeled “treatment-resistant” surely would be reduced, as they would have had the opportunity to undergo effective treatment.

Manic-Depressive Illness

Convulsive therapy, based on chemically induced seizures (using pentylenetetrazol), was introduced for the treatment of dementia praecox in 1934.1 The efficacy of induced seizures in relieving the excitement and psychosis of four manic patients was first reported in 1938.14 In a larger study of 27 patients with manic-depressive psychosis in the manic phase, seven recovered but 20 did not.15 The duration of illness in the nonresponders was, on average, double that of responders (21.5 months versus 10.5 months).

Compelling data came from the studies by Ziskind et al.16,17 In their first report, they compared the immediate and long-term effects of medication-induced seizures in 38 patients with manic-depressive illness who accepted this novel treatment with 47 who refused treatment. Remission occurred in 82% (92% if partial remissions are added) of the treated group, with one death, compared with 38% remission (72% if partial remission is included) and five deaths in the nontreated group.

Updating their experience in 1945, and including ECT, Ziskind and colleagues described full remission in 78%, improvement in 18%, and failure of improvement in 4% of 88 patients in whom seizures were induced over 3 to 6 weeks. In the total group of 109 patients who refused ECT, nine died from suicide and four from exhaustion, compared with a single death by suicide in the treated patients. The investigators cited two salient factors that limited the benefit of convulsive therapy — missed or partial seizures (subconvulsive doses), and a foreshortened course of therapy.

Confirmation of these benefits quickly followed.18–21 In an experience with 1,500 patients, Kalinowsky22 reported that, of 60 depressed patients with manic-depressive psychosis, 52 (87%) recovered, and of 32 manic patients, 27 (84%) recovered or were much improved. Of 76 with a diagnosis of involutional melancholia, 66 (87%) recovered, and of 32 with the diagnosis of involutional paranoia, 14 (44%) showed recovery.

The introduction of the antidepressant and antipsychotic drugs in the mid-1950s set the stage for comparative studies. In a controlled, random assignment study comparing ECT with chlorpromazine in patients with manic-depressive illness, efficacy was equal for both treatments.23 A retrospective review of patients matched on age, sex, and severity of illness contrasted the efficacy of ECT in manic patients with those later treated with chlorpromazine.24 For ECT, 28 out of 28 were responders, while for chlorpromazine, 18 out of 28 responded. Each of the 10 nonresponders to chlorpromazine later received ECT and each responded, suggesting superior efficacy for ECT. Another study found an equivalence in outcome in a comparison of ECT, lithium, and chlorpromazine in chronic mania.25

A retrospective review of the naturalistic treatment of patients at the Iowa Psychopathic Hospital over 4 decades identified 438 patients with manic-depressive illness who had been treated with ECT, lithium, or neither.26 Lithium was assessed as dosed adequately (203 patients) or inadequately (163 patients). ECT was administered in 37 patients, and 35 patients received neither treatment. The chart records reported much improved discharge ratings for ECT of 78%, compared with adequate lithium courses (62%), inadequate lithium courses (56%), and neither treatment (37%).

Two prospective studies compared lithium and ECT. An Indianapolis study compared the efficacy of ECT and lithium over 8 weeks in patients with a suboptimal response to lithium therapy.27 Each of the 17 patients treated with ECT were rated as remitted at the end of the trial. When individual rating scale items showed group differences, ECT was superior to lithium in each comparison.

In a Columbia University study, patients with mania who failed lithium or neuroleptic medication were treated with either ECT or the combination of lithium and haloperidol.28 Of the patients treated with ECT, 59% showed complete remission for at least 7 days without medication, while none of those who received the combined medications remitted.

A summary review of the published assessments of convulsive therapy in mania reported that 470 of 589 patients (80%) remitted or showed marked clinical improvement with ECT.29 A similar literature review of young people identified 154 patients younger than18 with a wide range of psychiatric diagnoses who were treated with ECT.30 The authors reported assessments of remission and much improved ratings in 81 (53%) of the patients. Of 20 patients in manic episodes, 16 (80%) were evaluated as remitted and much improved. Of 51 bipolar patients (manic, depressed, and catatonic), 37 (73%) remitted.

In addition, numerous reports of successful treatment of individual patients with mania using ECT dot the literature.2,8,31 One instructive case report describes the merit of ECT in a patient with chronic relapsing bipolar disorder.32 During a 10-year period, a woman had been in the hospital 41% of the time. She was considered medication refractory, failing almost all psychoactive medications in various combinations, dosages, and augmentations. In 2001, at age 56, she was treated with ECT, remitted, and was discharged. For the next 3 years, she was maintained at home with periodic ambulatory ECT. In 2004, the appearance of bronchospasm during anesthesia inhibited further ECT, and valproate and haloperidol decanoate were prescribed. Within 3 months she was re-admitted to the hospital in a manic state. ECT was again prescribed, mania remitted, and continuation ECT had sustained her for 1 year at the time of the report.

Reasons for Hesitancy in Using ECT

In the face of such supportive clinical experience, how are we to account for the lack of interest in ECT in patients with mania? One reason is in the necessity of anesthesia and all the paraphernalia of a surgical procedure for ECT. Treatments are no longer available in doctor's offices, and the requirement for the physician to attend to the rules of surgical suites makes the treatment more serious consideration.

Another reason is theoretical. Many believe that antidepressant drugs are associated with worsening of mania. Because most researchers identify ECT with its antidepressant efficacy, simplistic thinking leads to the expectation that the antidepressant action of ECT will make mania worse, discouraging its use.

Expert algorithms acknowledge the efficacy of ECT as a last resort or at the same level of efficacy as light therapy.12,13 In the algorithms for bipolar disorder, ECT is not recognized in the formal decision tree but is cited as an alternative “last resort.”13 Many authors excuse their failure to recommend ECT with the note that no formal random assignment studies of ECT in bipolar disorder assure its efficacy. While this is true, such a standard is not required for the marketing of new pharmacologic agents, nor for the position of medications in the treatment algorithm. Why is ECT held to a higher standard?

Unfortunately, the needed information on the relative merits of ECT and the newer pharmacologic agents will not be gleaned in either of the two government-supported contract studies meant to naturalistically assess the treatment of depression and bipolar disorder. Neither of the two studies — STAR*D (Sequenced Treatment Alternatives to Relieve Depression) for major depression and STEP-BD (Systematic Treatment Enahncement Program for Bipolar Disorder) for bipolar disorder — includes an assessment of ECT, even as a last-resort option.

Finally, the public demand for a formal written consent in ECT, a demand not made for lithium or the neuroleptic drugs, inhibits its clinical application in patients with mania.33 The grandiosity, denial of illness, and paranoia that interfere with the patients' compliance with medications also affect their ability to consent formally for ECT. This would make it necessary to seek a court order for treatment, a procedure that is carried out only reluctantly.

Summary

In the 1980s, when the experimental trials of clozapine had been curtailed for fear of toxicity, clinicians sought to reinstate clinical trials. To overcome the ethical issue of offering a trial with an agent of potential toxicity, the studies were limited to patients who had failed two adequate clinical trials of antipsychotic agents of different chemical classes.34 The studies were successful, and clozapine was reinstated in the clinic.

A similar guideline for treatment algorithms of bipolar patients would call for a consideration of ECT after the failure of two adequate clinical trials. For patients who are suicidal or in delirium or persistent excitement, ECT would be considered earlier.

We are not so rich in effective treatments for bipolar disorder that we can arbitrarily reject an effective treatment, no matter how it is stigmatized, and no matter its inelegance and surgical nature. Our patients deserve the best care that is known to the profession, and the present disregard of ECT is no longer tenable.33

References

  1. Fink M. Convulsive Therapy: Theory and Practice. New York, NY: Raven Press; 1979.
  2. Fink M, Taylor MA. Catatonia: A Clinician's Guide to Diagnosis and Treatment. Cambridge UK: Cambridge University Press; 2003. doi:10.1017/CBO9780511543777 [CrossRef]
  3. Taylor MA, Fink M. Melancholia: Diagnosis, Pathophysiology and Treatment of Depressive Mood Disorder. Cambridge, England: Cambridge University Press. In press.
  4. Falret JP. A note on circular insanity [in French]. Bulletin de l'Academie de Médecine. 1854;19:382–415.
  5. Baillerger J. On a double form of insanity [in French]. Ann Med Psychol. 1854;6:367–391.
  6. Kraepelin E. Clinical Psychiatry: A Textbook for Students and Physicians. 6th ed (abstracted and reprinted). New York, NY: Macmillan; 1902.
  7. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 3rd ed. Washington, DC: APA; 1980.
  8. Goodwin FK, Jamison KR. Manic Depressive Illness. New York, NY: Oxford University Press; 1990.
  9. Angst J, Angst K, Baruffol I, Meinherz-Surbeck R. ECT-induced and drug-induced hypomania. Convulsive Ther. 1992;8(3):179–185.
  10. Benazzi F. Depressive mixed state: a feature of the natural course of bipolar II (and major depressive) disorder?Psychopathology. 2004;37(5):207–212. doi:10.1159/000080715 [CrossRef]15353886
  11. Fink M. The efficacy of ECT and “treatment resistance.”J ECT. 2002;18(1):1–2. doi:10.1097/00124509-200203000-00001 [CrossRef]11925510
  12. American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder (revision). Am J Psychiatry. 2000;157(4 Suppl):1–45.
  13. American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 2002;159(4 Suppl):1–50.11958165
  14. Cook LC. The range of mental reaction states influenced by Cardiozol convulsions. J Ment Sci. 1938;84:664–667. doi:10.1192/bjp.84.352.664 [CrossRef]
  15. Read CF, Steinberg L, Liebert E, Finkelman I. Use of Metrazol in the functional psychoses. Am J Psychiatry. 1939;95:781–786. doi:10.1176/ajp.95.4.781 [CrossRef]
  16. Ziskind E, Somerfeld-Ziskind E, Ziskind L. Metrazol therapy in the affective psychoses. Study of a controlled series of cases. J Nerv Ment Dis. 1942;95:460–73. doi:10.1097/00005053-194204000-00007 [CrossRef]
  17. Ziskind E, Somerfeld-Ziskind E, Ziskind L. Metrazol and electric convulsive therapy of the affective psychoses. A controlled series of observations covering a period of five years. Arch Neurol Psychiatry. 1945;53:212–217. doi:10.1001/archneurpsyc.1945.02300030049007 [CrossRef]
  18. Rennie TAC. Prognosis in manic-depressive and schizophrenic conditions following shock treatment. Psychiatr Quart. 1943;17:642–654. doi:10.1007/BF01561844 [CrossRef]
  19. Myerson A. Prolonged cases of grief reaction treated by electric shock. N Engl J Med. 1944; 230:255–256. doi:10.1056/NEJM194403022300903 [CrossRef]
  20. Bianchi JA, Chiarello CJ. Shock therapy in the involutional and manic-depressive psychoses. Psych Quart. 1944;18:118–26. doi:10.1007/BF01569028 [CrossRef]
  21. Tillotson KJ, Sulzbach W. A comparative study and evaluation of electric shock therapy in depressive states. Am J Psychiatry. 1944;101:455–459. doi:10.1176/ajp.101.4.455 [CrossRef]
  22. Kalinowsky LB. Electric convulsive therapy, with emphasis on importance of adequate treatment. Arch Neurol Psychiatry. 1943;50:652–660. doi:10.1001/archneurpsyc.1943.02290240036002 [CrossRef]
  23. Langsley DG, Enterline JD, Hickerson GX. A comparison of chlorpromazine and ECT in treatment of acute schizophrenic and manic patients. Arch Neurol Psychiatry. 1959;81(3): 384–391. doi:10.1001/archneurpsyc.1959.02340150116015 [CrossRef]
  24. McCabe MS, Norris B. ECT versus chlorpromazine in mania. Biol Psychiatry. 1977; 12(2):245–254.870095
  25. Thomas J, Reddy B. The treatment of mania: a retrospective evaluation of the effects of ECT, chlorpromazine and lithium. J Affect Disord. 1982;4(2):85–92. doi:10.1016/0165-0327(82)90038-6 [CrossRef]6213694
  26. Black DW, Winokur G, Nasrallah A. Treatment of mania: a naturalistic study of electroconvulsive therapy versus lithium in 438 patients. J Clin Psychiatry. 1987;48(4):132–139.3104316
  27. Small JG, Klapper MH, Kellams JJ, et al. Electroconvulsive treatment compared with lithium in the management of manic states. Arch Gen Psychiatry. 1988;45(8):727–732. doi:10.1001/archpsyc.1988.01800320037004 [CrossRef]2899425
  28. Mukherjee S, Sackeim HA, Lee C. Unilateral ECT in the treatment of manic episodes. Convuls Ther. 1988;4(1):74–80.11940944
  29. Mukherjee S, Sackeim HA, Schnur DB. Electroconvulsive therapy of acute manic episodes: a review of 50 years' experience. Am J Psychiatry. 1994;151(2):169–176. doi:10.1176/ajp.151.2.169 [CrossRef]8296883
  30. Rey JM, Walter G. Half a century of ECT use in young people. Am J Psychiatry. 1997; 154(5):595–602. doi:10.1176/ajp.154.5.595 [CrossRef]9137112
  31. Fink M. Electroshock. Restoring the Mind. New York, NY: Oxford University Press; 1999.
  32. Sienaert M, Peuskens J. Electroconvulsive therapy as prophylactic treatment in treatment-resistant bipolar disorder. Bipolar Disord. In press.
  33. Ottosson JO, Fink M. Ethics in Electroconvulsive Therapy. New York, NY: Brunner/Routledge; 2004.
  34. Lieberman JA, Kane JM, Johns CA. Clozapine: guidelines for clinical management. J Clin Psychiatry. 1989;50(9):329–338.2670914

Educational Objectives

  1. Cite evidence illustrating that electroconvulsive therapy (ECT) is as effective in the treatment of mania as in depression.

  2. Summarize the argument that ECT's relegation to a “last-resort” therapy is unjustified.

  3. Discuss reasons that the separation of major depression and bipolar disorder is artificial and poorly founded.

Authors

Dr. Fink is professor of Psychiatry and Neurology emeritus, State University of New York at Stony Brook, Stony Brook, NY.

Address reprint requests to: Max Fink, MD, PO Box 457, St. James, NY 11780-0457; or e-mail mafink@attglobal.net.

This article was supported in part by grants from the Scion Natural Science Association. Dr. Fink has no industry relationships to disclose.

10.3928/00485713-20051201-03

Sign up to receive

Journal E-contents