Evidence-Based Reviews

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

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



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 concernDelusions of fatal illness
GrandiositySpecial relation to God or royalty
SuspiciousnessDelusions of spousal infidelity
HallucinationsFoul body odor
Unusual thoughtBizarre, confused ideation
Depressive delusionWorthlessness, 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



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