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Evidence-Based Reviews

Therapy-resistant major depression When to consider ECT: Algorithm seeks respect for neglected therapy

Using ECT early—instead of as a last resort—is highly effective for ‘therapy-resistant’ depression.

Vol. 2, No. 6 / June 2003

Patients with what’s called “therapy-resistant” depression (TRD)—with subtherapeutic response to medications and psychotherapy—are often actually suffering from unrecognized, inadequately treated psychotic depression. Psychiatrists could greatly diminish the clinical challenge of TRD by recognizing psychotic depression and treating it more effectively.1 And the most effective treatment for psychotic depression is neither antidepressants nor antipsychotic drugs but electroconvulsive therapy (ECT).

Despite ECT’s superior efficacy in TRD, however, algorithms for treating major depression relegate ECT to an option of last resort. By not considering ECT sooner, we consign many severely depressed patients to less-effective treatments and the risk of chronic illness.


Diagnostic signs of psychosis in patients with major depression



Somatic concern

Delusions of fatal illness


Special relation to God or royalty


Delusions of spousal infidelity


Foul body odor

Unusual thought

Bizarre, confused ideation

Depressive delusion

Worthlessness, guilt, feelings of deserving death or punishment

Source: Based on the Brief Psychiatric Rating Scale.14

It is time for a more realistic algorithm that recommends ECT earlier for major depressive episodes, with or without psychotic features. This article proposes such an algorithm and discusses the supporting evidence.


Patients with delusions or hallucinations were classified as suffering from schizophrenia until the mid-1970s. Researchers then found that depressed patients with psychotic features responded well to ECT but poorly to adequate serum levels of imipramine.2

These observations were confirmed by a large Italian study, in which 437 depressed patients were treated with high-dose imipramine (200 to 350 mg/d). Depression remitted in 244 patients (56%). Those who remained depressed were then treated with ECT, and depression remitted in 136 of 190 (72%). Psychosis was the marker of poor response to imipramine.3 DSM-III codified these findings by separating the syndrome of “major depression with psychosis” (296.34) from “major depression without psychosis” (296.33).

As psychiatry recognized psychotic depression as a distinct form of depression, it became clear that drugs often could not adequately treat it. Less than one-third of patients with psychotic depression respond to tricyclics alone.4-6

Response to antipsychotic monotherapy averaged 50% and increased to 75% with combined antipsychotics and antidepressants. However, high daily dosages —at least 32 mg of perphenazine and 225 mg of amitriptyline—were required for an adequate response,7 and side effects made sustaining such heroic dosing was difficult. The greatest improvement rates were seen with ECT.

Few other drug combinations have been reported to be effective in psychotic depression, but we lack proper studies. Schatzberg8 addressed the use of newer antidepressants and atypical antipsychotics without offering an algorithm based on the data. Evidence on combination therapies consists mainly of case reports, with few designed studies.


ECT is the most effective treatment for psychotic major depression—achieving remission rates >80% within 3 weeks—as demonstrated by the ongoing, four-hospital Consortium for Research in ECT (CORE), supported by the National Institute of Mental Health.

CORE researchers are studying the efficacy of bilateral ECT in treating severe unipolar depression in patients ages 18 to 85 and of continuation treatments with ECT or lithium plus nortriptyline.9 Under the CORE protocol, diagnoses are made by structured clinical interview using DSM-III-R criteria, and remission is defined as >60% reduction in Hamilton Rating Scale for Depression scores, with final scores 10 sustained for 1 week.

In the first 253 CORE patients treated with ECT, depression remitted in 75% and did not remit in 11%; 14% dropped out. Psychotic depression was identified in 30% (77 of 253), and the remission rate among these patients was 83%.

Among patients who completed the full ECT course (at least 12 sessions), remission rates were 96% for psychotic depression and 83% for nonpsychotic depression. The overall remission rate was 87%.

Treatments were given three times per week. Among patients who completed treatment in weeks 1 through 4, remission rates were 5%, 45%, 81%, and 100%, respectively. Psychotic depression remitted more rapidly than nonpsychotic depression.

Suicide risk. CORE findings suggest that ECT also may reduce suicide risk. In item 3 of the Hamilton Rating Scale for Depression, scores of 2 to 4 indicate preoccupation with death or suicide, or a recent suicide attempt. Nearly 60% of 404 patients (237) reported baseline scores of 2 to 4, but their scores dropped rapidly with ECT. Scores of 0 were reported in 68% after 1 week of ECT, in 87% after 2 weeks, and in 93% after 3 weeks.10

Summary. In patients with severe depressive illness, CORE’s remission rates of 95% for psychotic depression and 83% for nonpsychotic depression are remarkable. Another group is independently reporting a 92% remission rate for psychotic depression treated with ECT.11


Clinical signs that point to psychotic major depression

Psychotic depression is difficult to recognize and treat, even for clinicians with advanced training. For example:

  • only 2 of 52 psychotic depressed patients were determined to have been adequately treated before referral to a National Institute of Mental Health-supported study of ECT15
  • only 3 of 46 psychotic depressed patients had been adequately treated prior to enrollment in the Consortium for Research in ECT (CORE) study.9

The three most useful diagnostic criteria are spelled out in the Brief Psychiatric Rating Scale:

  • any sign of psychosis is sufficient for designating a major depression as “psychotic”
  • one well-developed sign is sufficient to prescribe treatment for psychotic depression
  • well-developed vegetative signs also indicate the need to treat psychotic depression.14


Many eligible patients never receive ECT, despite its track record of producing high remission rates in psychotic depression. Reasons include:

Limited access. Few psychiatrists—less than 8%—offer ECT as a treatment option, and most who do offer it practice in private hospitals.12-14

Academic low regard. Psychiatry’s academic lecturers largely ignore ECT’s efficacy in psychotic depression and therapy-resistant depression. This low regard for ECT is codified in expert algorithms, which cite ECT as an option of last resort.

Social stigma. In a recent essay summarizing medication’s weak effect in treating psychotic depression, Schatzberg states, “While ECT is a remarkably effective treatment for psychotic depression, requirements for its use are stringent, and public perception about the overall appropriateness of shock treatment is negative.”8

Algorithm Treatment of major depression, with or without psychotic features


Because patients with psychotic and nonpsychotic major depression clearly require different treatments, differentiating between these two types is critical. Although psychotic depression can be difficult to diagnose,15,16 commonly recognized criteria are listed in the Table

Assessment. Assess each severely depressed patient for psychotic features, such as delusions and hallucinations. A useful assessment guide is the Brief Psychiatric Rating Scale (Box).17 Also treat those with melancholia, inanition, severe weight loss and insomnia, concentration and memory difficulty, stupor, or suicidal ideation as if they had psychotic depression. These symptoms and signs are evidence that the patient’s neuroendocrine system is disturbed, an indication of severe depression that responds poorly to antidepressant drugs alone.

Treatment. Nonpsychotic depressed patients are best offered antidepressants—tricyclics or selective serotonin reuptake inhibitors (SSRIs)—as recommended by conventional guidelines. Insufficient response to two adequate trials calls for a careful assessment for psychosis and, if found, treatment with effective drug combinations or ECT (Algorithm).18 For patients with psychotic depression—especially those who fail medication trials or whose severe symptoms would likely respond to ECT as a primary treatment—bilateral ECT is the effective standard.19

ECT is the appropriate first option for hospitalized patients with psychotic depression—especially those who are suicidal or require supplementary feeding and sedation. It may also be considered the first option in patients who have:

  • attempted suicide
  • lost more than 10% of body weight (approximately 15 lbs for adults) in the weeks of their illness
  • or show signs of severe melancholia, such as catatonia or pseudodementia.


When medications are first-line treatment for nonpsychotic depression, how long should a trial be continued before taking another tack? How many courses should you try before you declare therapy resistance and consider ECT?

Studies of clozapine provide a useful model.20 Because of clozapine’s association with agranulocytosis and induced seizures, patients with schizophrenia usually do not receive this antipsychotic unless two 4- to 6-week trials of other neuroleptics have proven ineffective. Ethicists have deemed two failed medication trials to be sufficient before a more hazardous treatment is offered.

Figure Remission of major depression with ECT

We can apply a similar standard when considering ECT in patients first treated with medication.18 A patient’s depression could be defined as therapy-resistant after an inadequate response to 4-week courses (in either order) of:

  • an SSRI at dosages equivalent to fluoxetine, 40 mg/d
  • a tricyclic at 200 mg/d.

In depressed patients with bipolar disorder, a trial of lithium or an anticonvulsant may replace an antidepressant.

ECT is appropriate when debilitating depression persists after two adequate medication trials. Only after an adequate ECT trial has failed—and such failure is infrequent—is it reasonable to offer poorly tested augmentation and combination strategies.

What is ‘adequate’ ECT? For patients with major depression, the definition of an adequate ECT trial is complex. Although many doctors expect six ECT sessions to be sufficient, the CORE studies are finding that only 45% of patients remitted with six ECT, 81% with nine ECT, and almost all with 12 ECT sessions (Figure).9 These patients were treated with bitemporal electrode placement, the more effective form of ECT. When unilateral electrode placements are used, ECT courses may be inadequate, as this form requires special attention to electrical dosing.

Further, the quality of the seizure—like the dosing of medications—directly influences outcome. Seizure monitoring is essential for assessing the adequacy of each treatment and the treatment course.21,22

Related resources

  • Petrides G, Fink M, Husain MM, et al. ECT remission rates in psychotic versus non-psychotic depressed patients: a report from CORE. J ECT 2001;17:244-53.

Drug brand names

  • Amitriptyline • Elavil
  • Clozapine • Clozaril
  • Imipramine • Tofranil
  • Nortriptyline • Pamelor
  • Perphenazine • Trilafon


The author reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.


Preparation of this manuscript was aided by grants from the Scion Natural Science Association, Inc., St. James, NY.


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9. Petrides G, Fink M, Husain MM, et al. ECT remission rates in psychotic versus non-psychotic depressed patients: a report from CORE. J ECT 2001;17:244-53.

10. Kellner CH, Fink M, Knapp R, et al. Bilateral ECT rapidly relieves suicidality: findings from phase I of the CORE ECT study. Am J Psychiatry (submitted).

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14. Kramer BA. Use of ECT in California revisited: 1984-1994. J ECT 1999;15:245-51.

15. Prudic J, Sackeim HA, Devanand DP. Medication resistance and clinical response to electroconvulsive therapy. Psychiatry Res 1990;31:287-96.

16. Mulsant BH, Haskett RF, Prudic J, et al. Low use of neuroleptic drugs in the treatment of psychotic major depression. Am J Psychiatry 1997;154:559-61.

17. Overall JE, Gorham DR. The Brief Psychiatric Rating Scale. Psychol Rep 1962;10:799-812.

18. Fink M. Electroconvulsive therapy in medication-resistant depression. In: Amsterdam J, Hornig-Rohan M, Nierenberg A (eds.): Treatment-resistant mood disorders. Cambridge, UK: Cambridge University Press, 2001;223-38.

19. Fink M. The efficacy of ECT and “treatment resistance.” J ECT 2002;18:1-2.

20. Lieberman JA, Kane JM, Johns CA. Clozapine: guidelines for clinical management. J Clin Psychiatry 1989;50:329-38.

21. Abrams R. Electroconvulsive therapy. (4th ed). New York: Oxford University Press, 2002.

22. Fink M. Optimizing ECT. Encephale 1994;20:297-302.

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