How treatable is refractory depression?

J Affect Disord. 2014:167:148-52. doi: 10.1016/j.jad.2014.05.047. Epub 2014 Jun 4.


Introduction: Patients who do not remit following one or more attempts at treatment present a clinical challenge, as well as prolonged suffering and disability. Discouragement is common, so knowledge of likelihood of eventual remission as well as which treatments might ultimately be effective would help patient and clinician alike.

Method: Thirty-one patients with major depression were recruited, 28 beginning study treatment. All had remained significantly depressed following adequate (4 weeks taking ≥ PDR maximum dose) trials on ≥ two antidepressants having different presumed mechanisms. Patients were begun on tranylcypromine to 60 mg/d, were then treated with up to 120 mg/d and then had dextroamphetamine added. Following two week wash-out, patients were then treated with nortriptyline+lithium, and then phenelzine was added. Each successive phase was entered only if remission had not been achieved, and phases could be skipped.

Results: Eighteen of the 28 patients (65%) remitted in one of the five phases of the study, plus 5 additional patients with open post-study treatment (total remitting, 82%). By study phase, Eight of 27 (30%) patients remitted with initial dosing of tranylcypromine up to 60 mg/d, 6/18 (33%) remitted with above PDR dosing of tranylcypromine up to 120 mg/d, and 1/6 (17%) to adding dextroamphetamine. With nortriptyline, 1/10 (10%) remitted with nortriptyline+lithium, and 1/5 (20%) when phenelzine was added. Eighteen of the 28 patients (64%), or 78% of those who remitted, maintained their good benefit for at least six months.

Discussion: The majority of depressed patients refractory to two or more adequately utilized differently acting antidepressant medications can still remit and about half may maintain remission for extended periods. "Refractory depression" appears to be a relative description for many unresponsive depressed patients.

Trial registration: NCT00296686.

Keywords: Dextroamphetamine; Lithium; Nortriptyline; Phenelzine; Refractory depression; Tranylcypromine.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antidepressive Agents / pharmacology
  • Antidepressive Agents / therapeutic use*
  • Central Nervous System Stimulants / administration & dosage
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Treatment-Resistant / drug therapy*
  • Dextroamphetamine / administration & dosage
  • Drug Administration Schedule
  • Drug Therapy, Combination
  • Female
  • Humans
  • Lithium Compounds / administration & dosage
  • Male
  • Middle Aged
  • Nortriptyline / administration & dosage
  • Phenelzine / administration & dosage
  • Tranylcypromine / administration & dosage
  • Treatment Outcome


  • Antidepressive Agents
  • Central Nervous System Stimulants
  • Lithium Compounds
  • Tranylcypromine
  • Nortriptyline
  • Phenelzine
  • Dextroamphetamine

Associated data