There is little benefit in making treatment changes before three weeks, other than to mitigate side effects. Changes in treatment strategy should be considered after the physician is satisfied that the patient has been treated with an adequate dosage of the antidepressant for an adequate time, with current medications increased to the limit of side effect tolerance.

In patients showing an inadequate response after a reasonable time, the decision is either to continue with the same medication and augment with an additional agent, or to switch medications altogether, depending on whether the patient has shown any response to the current strategy. Partial responders may be more likely to benefit from treatment augmentations, whereas patients who show no response or worsen during treatment warrant a new agent.

Antidepressant Augmentation

Typical augmentation strategies shown in Table: Augmentation Strategies include the addition of lithium carbonate, thyroid hormone, a stimulant, an atypical antipsychotic, or by the use of antidepressant combinations.

Table: Augmentation Strategies

† Inadequate data.

LITHIUM AUGMENTATION

Lithium has been used successfully with most antidepressants, including tricyclic antidepressants (TCAs), serotonin reuptake inhibitors, and bupropion, with response rates as high as 65%. The blood level of lithium necessary for adjunctive use has not been well established. It is probably best to start at a low dose (300 mg b.i.d) and increase to a therapeutic blood level (0.8 to 1.2 mEq/L) if there is no response. It may take three to six weeks for augmenting effect. If augmentation is successful, it should be continued throughout the acute phase of treatment. This strategy can be limited by side effects and lithium’s narrow therapeutic index. It is associated with hypothyroidism, tremor, increased thirst, increased urination, nausea, weight gain, and acne. Patients should be cautioned to avoid dehydration, which can precipitate toxic lithium blood levels.

THYROID HORMONE AUGMENTATION

Starting dose is 25 µg/day of triiodothyronine, which can be increased to 50 µg/day in a week if there is no response. The trial should continue for at least three weeks. Reported response rates for thyroid augmentation are lower than those for lithium augmentation (25%). As with lithium augmentation, if there is a positive response, it occurs relatively early.

STIMULANT AUGMENTATION

Methylphenidate and dextroamphetamine at dosages between 5 and 20 mg have been used for antidepressant augmentation, but there are few systematic data regarding the proper dose or length of treatment for this potential use.

ANTIDEPRESSANT DRUG AUGMENTATION

Second-generation antipsychotic drugs are increasingly being used adjunctively with antidepressants for residual or treatment-resistant symptoms. APDs are generally used within their therapeutic range.

COMBINED ANTIDEPRESSANT THERAPY

Open trials have supported the use of combined therapy of a TCA and a serotonin reuptake inhibitor in patients for whom either class alone has failed. When antidepressants are combined, it is important to remember that the serotonin reuptake inhibitors can potentiate TCA levels, and this should be monitored carefully. Monoamine oxidase inhibitors (MAOIs) have also been used in combination with tricyclic antidepressants (TCAs), although this should be monitored closely given the risk of potential toxic interactions. Given the risk of a serotonin syndrome, MAOIs should not be combined with serotonin reuptake inhibitors. Bupropion is frequently added to an SSRI to enhance efficacy or to alleviate side effects such as decreased libido, fatigue, and sedation.

NONPHARMACOLOGICAL APPROACHES

A number of nonpharmacological augmentation options exist, particularly the concomitant use of psychotherapy. The combination of psychotherapy and medication may offer benefits that either therapy alone cannot offer, including additional efficacy as well as prevention of relapse. This has been shown to some degree for both cognitive-behavioral therapy and interpersonal therapy.

Changing to a New Agent

Patient showing no response or whose condition deteriorates during therapy should trial an alternative single agent. Recent studies support the belief that it is best to switch to an agent of a different class, and approximately 50% of patients unresponsive to a first trial respond to an antidepressant of a different class.

When the switch involves an MAOI, sufficient time must be given for medication clearance. Although seldom used, monoamine oxidase inhibitors (MAOIs) may be very effective in patients not responsive to other classes of antidepressants. Generally, 10 to 14 days is required for clearance of tricyclic antidepressants (TCAs) and MAOIs. Fluoxetine requires a much longer period — 6 weeks — whereas sertraline and paroxetine require about two weeks when switching to an MAOI. Another alternative is changing from an SSRI medication to an SNRI. There is some evidence that serotonin-norepinephrine reuptake inhibitors (SNRIs) may lead to higher rates of response and remission than selective serotonin reuptake inhibitors (SSRIs).

ECT ECT and other forms of stimulant therapies (e.g., vagal nerve stimulation) should be considered for patients who are non-responsive to pharmaco- and psychotherapies.

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