Major depression is a common and debilitating disorder that affects 10% to 15% of the population each year. Advances in understanding the psychopharmacology of depression has lead to the introduction of several new classes of antidepressant medication in the past decade. Despite these advances, however, patients’ overall response to any given pharmacologic approach continues to be unsatisfactory. Only 50% of patients recover fully from depression with antidepressant therapy; 35% to 40% recover partially and continue to have residual symptoms; and 10% to 15% do not improve at all despite adequate trials (diagnosis, selection of medication, treatment time, and compliance) of *antidepressant medication.

The clinical importance of these figures is underscored by the fact that incomplete recovery from a primary depressive episode is associated with serious personal, economic, and psychosocial morbidity. Complications include prolonged suffering of patient and family, higher risk of suicide, increased medical and psychiatric comorbidity, loss of productivity, loss of income, erosion of social support, social withdrawal, and increased levels of dependency. Refractory patients, therefore, represent a dilemma for primary care providers.

How is refractory defined? One proposed operational definition of refractory depression is a poor or unsatisfactory response to two adequate trials (optimal dosage and duration) of two different classes of antidepressant medication after ruling out possible medical or organic causes of the condition (Table 1).

Table 1. Common medical contributors to refractory depression

Endocrine disorders: thyroid disease, hypercortisolism (Cushing’s syndrome)

Infections: postviral syndromes (Epstein-Barr, cytomegalovirus, influenza), human immunodeficiency virus

Neoplastic syndromes

Neurologic conditions: previous stroke or recent transient ischemic attack, Parkinson’s disease, primary sleep disorders

Autoimmune diseases: systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis

Medication related to depression: vincristine, high-dose benzodiazepines (eg, diazepam >30 mg, clonazepam >1.5 mg, lorazepam >6 mg), steroids (prednisone >40 mg), antihypertensives (high-dose propranolol, atenolol), angiotensin-converting enzyme inhibitors (except captopril), calcium channel blockers, and very high-dose estrogen

Strategies for treating refractory depression include augmentation and combination therapy and switching (changing to a different agent). Although both strategies are currently employed, there are few parallel comparison studies that directly test these two approaches. Interventions, therefore, must take into account the diversity of clinical presentation and be tailored to each clinical circumstance.


Switching therapeutic agents is supported by the data on continuation and maintenance of antidepressant monotherapy and could be favoured for patients whose compliance might be jeopardized by the introduction of polypharmacy with its accompanying risks of adverse events secondary to drug interactions. lose all gains made by discontinuing the first antidepressant medication. Such a setback could be especially important for partial responders, where loss of even small gains might lead to serious consequences.

Augmentation and combination

Augmentation and combination strategies refer to use of two or more agents to target the core symptoms of depression by targeting different neurotransmitter systems, different aspects of neurotransmission, or a combination of these actions. Augmentation strategies involve addition of drugs that are not antidepresants, whereas combination strategies involve addition of antidepressants from a different class. Augmentation and combination approaches are distinguished from adjunctive therapy, which employs a second agent to reverse an emergent side effect or obtain a complementary clinical effect (ie, restricted, short-term use of benzodiazepines for insomnia or symptoms of anxiety).

Despite limited empirical evidence for the efficacy of augmentation and combination strategies, this option holds several advantages over switching. First, patients who do not respond to a first antidepressant might respond when a second agent is added. Second, the strategy builds on therapeutic gains obtained with the first antidepressant. Third, there is potential for rapid onset of antidepressant effect. Response could take as few as 2 days or up to 3 to 6 weeks (considerably shorter than the delay expected with switching, which involves tapering the first drug, wash-out, and delay in onset of effects of the second drug). Last, addition of a second compound is generally well tolerated and does not substantially alter the side-effect profile of the initial antidepressant.

Table 2. Augmenting agents


Established agent*

  • Lithium……300–900 mg……48 h – 2 wk……Can be used with TCAs, SSRIs, MOAIs, pregnancy tests, TH-Abs, RFT, TFT, and electrolytes

Well established agents†

  • Triiodothyronine……12.5–50µg……2 wk……Monitor cardiac after effects
  • L-Tryptophan……2–5 g……2 wk……Monitor serotonin syndrome
  • Buspirone……10–60 mg……2–3 wk
  • Pindolol……2.5 mg……twice daily 1–2 wk……Contraindicated in COPD or bronchial asthma
  • Methylphenidate……5–40 mg……1–2 wk Monitor sleep quality, anxiety

Evidence accumulating‡

  • Olanzapine……2.5–5 mg……Not established Prefer fluoxetine?
  • Risperidone……0.5–2 mg……Not established
  • Ketoconazole……200–400 mg (?)……Not established Monitor LFT, TFT, RFT, ECG, WBC

Open case reports §

  • Aminoglutethimide……250–500 mg?……Not established Monitor LFT, TFT, RFT, ECG, WBC
  • Naltrexone……50 mg?……Not established Monitor LFT, TFT, RFT, ECG, WBC
  • Pergolide……1–5mg?……Not established

COPD—chronic obstructive pulmonary disease, ECG—electrocardiogram, LFT—liver function test, MAOIs—monoamine oxidase inhibitors, RFT—renal function tests, SSRIs—serotonin reuptake inhibitors, TCA—tricyclic antidepressants, TFT—thyroid function tests, TSH—thyroid-stimulating hormone, TH-Abs—thyroid hormone antibodies, WBC—whole blood count.

*Criterion standard: evidence level 1A. †Evidence level 1A-2B. ‡Evidence level 2B-3. §Evidence level

The best studied augmentation strategy has been addition of lithium to a tricyclic antidepressant. Other strategies have investigated the addition of triiodothyronine (T3), L-tryptophan, buspirone, pindolol, psychostimulants, atypical antipsychotics, and other classes of antidepressants (Table 2). Although meta-analysis has supported the effectiveness of lithium and T3 augmentation strategies, robust evidence for other strategies is lacking. In addition, empirical data addressing optimal duration of therapy with augmentation agents is not yet available, and it is unclear whether results of trials investigating the efficacy of augmentation in one class of antidepressant can be extrapolated to other classes. Augmentation strategies to consider appear in Table 3.

Table 3. Drug combinations and cocktails

Serotonin reuptake inhibitor + tricyclic antidepressant (ie, fluoxetine + desipramine)

Serotonin reuptake inhibitor + bupropion

Tricyclic antidepressant + monoamine oxidase inhibitor (avoid imipramine, desipramine, clomipramine)

Serotonin reuptake inhibitor + noradrenaline reuptake inhibitor (eg, citalopram + reboxetine)

Phenelzine + L-tryptophan + lithium (“Newcastle cocktail”)

Nefazodone + pindolol + L-tryptophan (“Dalhousie serotonin cocktail”)

Electroconvulsive therapy + pindolol

Nefazodone + venlafaxine

Serotonin reuptake inhibitor + atypical antipsychotic (fluoxetine + olanzapine)


Given the limited evidence available at this time, the decision on which strategy to choose or which agents
to combine is somewhat arbitrary. One suggestion is to carefully assess unresolved or residual psychopathology and, if possible, to cluster it with correlates within the monoamine system (dopamine, noradrenaline, serotonin) and choose an augmenting or combining agent accordingly. A simplified approach to refractory depression is presented in Figure 1.

Source: CFP. 2001 January; 47: 50–52.

Category: Depression / Tags: agents, antidepressants, disorder, Drugs, Major depression, medication

Leave a Reply

Your email address will not be published. Required fields are marked *