Common strategies for treatment resistance.

Electroconvulsive therapy

An important and effective treatment for depression, electroconvulsive therapy (ECT) is effective in about 90% of cases of major depression. The success rate drops when it is used for drug-refractory cases. Using ECT depends on patient-related factors: it clearly is the treatment of choice for depression with psychomotor slowing, stupor, psychotic symptoms, or depression requiring rapid response because of suicidal risk or malnutrition. Use of ECT should be considered whenever therapeutic management is being reviewed and revised.

Triiodothyronine (T₃) augmentation

Thyroid hormone potentiation of tricyclic antidepressants (TCAs) can be useful. The thyrotropin-releasing hormone stimulation test should be done first, if available and convenient, to rule out grade three (subclinical) hypo thy roidism. If hypo thy roidism is present, it should be treated with thyroid replacement therapy. If the patient is euthyroid, low doses of T₃ (25 to 50 µg/d) can be given with the antidepressant for 10 to 14 days. Up to a third of depressed patients, particularly women, respond. Most experience with this approach has involved tricyclic antidepressants (TCAs), and the effect on the selective serotonin reuptake inhibitors (SSRIs) or other new agents is not well studied.

Tricyclic-fluoxetine combination

Some reports indicate that fluoxetine, when added to a TCA such as desipramine, can produce a robust and rapid response in many patients. This augmentation effect could be a result of increased TCA levels due to fluoxetine inhibition of the cytochrome P 450 system. Because fluoxetine can raise blood levels of tricyclic antidepressants (TCAs), routine serum levels of TCAs are recommended. Other TCA-SSRI combinations can also be tried. All selective serotonin reuptake inhibitors (SSRIs), however, effect the cytochrome P 450 System by raising TCA levels.

Tricyclic-MAOI combination

Some evidence suggests that this combination is more effective than either drug used alone for some patients. Ideally both drugs should be started simultaneously or the MAOI added to a TCA regimen. The safest combination seems to be phenelzine with either amitriptyline or doxepin. Clomipramine, imipramine, and the new agents, such as fluoxetine, should be avoided. Give low doses initially and pay rigid attention to dietary restrictions.

The SSRI combinations

Although no literature supports the practice, clinical experience suggests that lower doses of two selective serotonin reuptake inhibitors (SSRIs) together might work better than either alone.

Augmentation with L-tryptophan

L-tryptophan is the dietary precursor of brain serotonin. Reports confirm that L-tryptophan can enhance the antidepressant effect of monoamine oxidase inhibitors (MAOIs) as well as tricyclic antidepressants (TCAs) and lithium. This might apply to the new antidepressant agents as well. The high doses required (more than 3 to 4 g/d) make this approach cumbersome because the tablets are quite large.

Psychostimulants

Dextroamphetamine, methylphenidate, and to a lesser degree magnesium pemoline all have mood-elevating, psychoenergizing properties and have a place in the management of mood disorders. These drugs can be used alone or combined with antidepressants. Apathetic, elderly, and medically ill depressed patients often respond to psychostimulants when they cannot tolerate the side effects of antidepressants or a rapid response is necessary.

Psychostimulants are also useful for patients who do not respond to any antidepressant and are truly treatment resistant. Non-response to one psychostimulant does not predict non-response to another. There is no evidence of addiction or dose escalation although clearly this class of drugs needs to be prescribed cautiously and monitored carefully. Using psychostimulants is somewhat similar to prescribing analgesics for chronic pain conditions and can be justified considering the morbidity associated with major depression.

Cognitive behavioural therapy (CBT)

This therapy can be very useful for treating chronic depression, such as dysthymia, and can be helpful as an augmentation strategy in conjunction with pharmacotherapy for treatment-resistant patients. Several studies have demonstrated the effectiveness of CBT, a technique that family physicians can easily learn.

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