Buspirone augmentation The augmentation of SSRIs and other antidepressants with the antianxiety azaperone buspirone is supported by impressive response rates in several open trials. But the only placebo-controlled trial evaluating buspirone augmentation in resistant depression failed to find a significant drug:placebo difference.12 Still, its tolerability and anxiolytic efficacy, and potential for ameliorating sexual dysfunction in some patients, support its judicious use as an augmenting agent pending further study.
Pindolol Studies of this beta-agonist, 5HT-1A antagonist, as an antidepressant-augmenting combination have yielded promising results in some studies, including a negative 10-day, placebo-controlled trial.13 Some patients experience jitteriness or irritability on pindolol. Its role in treating resistant depression remains to be established.
Noradrenergic TCAs The combination of SSRIs with these agents is a good example of a strategy based on pairing complimentary antidepressant mechanisms. Double-blind, controlled trials of fluoxetine plus desipramine6,7 have tempered the enthusiasm generated by earlier open studies, however. Response rates in these trials range from 25% to 30%, no higher than lithium augmentation and slightly lower than higher-dose fluoxetine.
Mirtazapine A more recent combination is mirtazapine with SSRIs or with high-dose venlafaxine.14 In some patients, this combination may attenuate sexual dysfunction, insomnia, and gastrointestinal side effects of SSRIs and venlafaxine by virtue of a 5-HT2, 5-HT3, and histamine receptor blockade by mirtazapine. This combination may also capitalize on the combined antidepressant effects of direct norepinephrine (NE) and serotonin (5-HT) reuptake inhibition as well as an alpha2 adrenergic auto- and hetero-receptor blockade—facilitating presynaptic NE and 5HT release—and 5-HT2 receptor antagonism.
Antipsychotics The use of antipsychotics for nonpsychotic unipolar depression has been controversial. However, in the context of lower apparent risks of tardive dyskinesia with the newer, atypical antipsychotics, their use as antidepressant augmenting agents has been revisited. In one double-blind, placebo-controlled trial, the combination of fluoxetine plus olanzapine was more effective in a well-defined refractory depressed population than was either medication alone.15 (See Box 1 for a discussion of fluoxetine and folic acid.)
Ostroff and Nelson16 reported an extremely rapid (1 week) response after the addition of risperidone among 8 depressed individuals who had not responded to fluoxetine or paroxetine alone. The activating properties of ziprasadone for some patients, combined with its lower propensity for producing weight gain than other atypical antipsychotics, make it another potentially attractive candidate for antidepressant augmentation, though one that requires further study.
Anticonvulsant augmentation While controlled studies of anticonvulsant augmentation of newer-generation antidepressants are lacking, the efficacy of lamotrigine for treating bipolar depression17 has encouraged clinicians to combine the agent with antidepressants in unipolar depression. The potential sedative/anxiolytic effects of other anticonvulsants, including gabapentin and valproate, have also supported their use in resistant depression complicated by anxiety or irritability. Omega-3-fatty acids may work as mood-stabilizing substances when used for antidepressant augmentation.
Antidepressant switches: In class or out?
Switching from TCAs to SSRIs or vice versa following nonresponse has yielded generally high (50% to 60%) response rates.3 But the more common question now is whether to switch from an initial SSRI to another SSRI, to an SSRI-like agent with an additional noradrenergic mechanism (such as venlafaxine), or to an atypical antidepressant such as bupropion or mirtazapine.
Traditional teaching and regular psychiatric practice5 have favored a switch outside of class. More recently, however, a number of uncontrolled studies looking at response rates to a second SSRI following inadequate response to and/or tolerance of an initial SSRI have shown response rates of 40% to 75%.18 This coincides with response rates seen in studies involving crossover to antidepressants with differing mechanisms. Inferences from these studies are limited by, first, determining nonresponse retrospectively and, second, lumping together patients who did not remain on the first SSRI because of nonresponse with others who curtailed treatment because of intolerance.
Because of its dual 5-HT/NE reuptake inhibitory activity, particularly at higher doses, venlafaxine is a popular choice following failure of an initial SSRI. One-third of subjects with extremely resistant depression (3 or more trials of antidepressants) responded to venlafaxine.19 DeMontigny et al20 also demonstrated its efficacy (with a 58% response rate) as a switching agent among resistant, depressed patients.
But comparative response rates for switching to venlafaxine from an SSRI vs. from other antidepressant classes have not been well delineated, nor have response rates for switching from SSRIs and other antidepressants to venlafaxine vs. to other non-SSRI agents.
Switches from SSRIs to nefazodone and mirtazapine or the selective NE reuptake inhibitor reboxetine have shown reasonably high response rates.3 Studies comparing these various strategies head to head are lacking. In the absence of data, reasonable guides for switching agents include projected tolerability and existence of comorbid conditions that may respond well to one agent over another.