As many as 50% of depressed patients do not achieve a 50% or greater reduction in severity of symptoms after an adequate antidepressant trial.1 Moreover, among those who do respond to acute treatment, longer-term residual depressive symptoms are quite common. Persistent subsyndromal depressive symptoms are associated with impaired psychosocial functioning and increased risk of relapse. This possibility has reinforced an evolving consensus that full depressive remission rather than response is the proper goal of treatment.2
When your patient’s depressive symptoms fail to remit following an initial pharmacotherapy course, you must decide which of numerous possible next steps to pursue, in what combinations, and following what sequence. The range of strategies include the following:
- Pursuing an extended trial with the initial agent using higher than usual dosages (e.g., fluoxetine 40 to 80 mg/qd);
- Augmenting an antidepressant with an agent that offers no established antidepressant efficacy on its own, such as buspirone, lithium, thyroid, or estrogen;
- Combining an antidepressant with another antidepressant, with another somatic therapy such as electroconvulsive treatment or phototherapy, or with some form of psychotherapy;
- Switching to an antidepressant within the same class (e.g., from one selective serotonin reuptake inhibitor [SSRI] to another), or outside of class (from an SSRI to an atypical antidepressant), or switching to non-pharmacological somatic therapy or psychotherapy.3
A predictable lag exists between innovative clinical applications and the randomized, controlled trials (RCTs) designed to evaluate them. The result: Approaches that are thoroughly described in the literature involve medication regimens that are no longer first-line, such as lithium or thyroid augmentation of tricyclic antidepressants (TCAs), or the combination of TCAs with SSRIs. Conversely, approaches most widely used in current psychiatric practice (e.g., addition of bupropion to SSRIs) have received relatively little systematic attention.4
Further, while predictors of initial antidepressant response have been hard to come by, even less is known about predictors of antidepressant response after lack of response to previous antidepressants. The working hypotheses that clinicians use to decide which strategies to pursue, though plausible, are largely untested, whether based on characteristics of a patient’s initial response (e.g., non-response or partial response)5 or on side effects or comorbid diagnoses.
This review will describe new research and emerging strategies that address the common clinical problem of unremitted depression despite one or more adequate courses of antidepressant treatment.
A look at new augmentations and combinations
Adding a second agent is an appealing strategy when patients have tolerated an initial antidepressant without troublesome side effects or have shown partial response (≥ 25% and <50% symptom reduction) and/or when a second agent may serve an important additional goal such as treating a comorbid condition—attention-deficit disorder or smoking, for example—or a side effect (e.g., nausea or insomnia).
CAN FOLIC ACID IMPROVE RESPONSE TO FLUOXETINE?
Evidence supporting a relation between folate and depression has accrued over decades. Low folate levels may be associated with poorer response to fluoxetine.
Coppen and Bailey25 found that depressed patients had higher initial response rates to fluoxetine when combined with supplemental folic acid (500 mcg) than they did with placebo. The effect was significant only among female subjects. Study participants were naïve to fluoxetine and did not have established treatment resistance.
Still, the safety, tolerability, cost-effectiveness, and high patient acceptability of folic acid should stimulate further study of augmentation with folic acid supplementation and other naturally occurring agents related to folate in the one-carbon cycle, including S-adenosyl-methionine (SAMe).
The primary drawbacks to augmentation/combination strategies are an increased risk of drug interactions, cost, and potential decrement in adherence to treatment as the regimen’s complexity increases.
Thyroid augmentation Although thyroid augmentation of TCAs has been the subject of numerous RCTs, no controlled trials of thyroid augmentation of SSRIs or other newer-generation antidepressants are available.
Lithium augmentation Studies of lithium augmentation of SSRIs have yielded generally modest response rates with questionable durability.6,7
Noradrenergic and/or dopaminergic agonist agents Open trials and case series in the treatment of patients with unremitted depression have supported combining SSRIs and venlafaxine with agents that possess primarily noradrenergic and/or dopaminergic agonist properties. These include bupropion,8 psychostimulants,9 and direct dopamine agonists, including pergolide and pramipexole.10
These combinations have the advantage of potentially ameliorating several common SSRI side effects, particularly sedation, sexual dysfunction, and putative SSRI-related apathy. In the case of psychostimulants and/or bupropion, the combinations may treat such common comorbidities as attention-deficit/hyperactivity disorder and smoking.
Modafinil The combination of the antinarcoleptic modafinil with SSRIs and other newer-generation antidepressants has also attracted interest. Its efficacy as an antidepressant adjunct and as a remedy for side effects must still be established, however.11