Venlafaxine augmentation  There are only anecdotal reports of venlafaxine augmentation (75-300 mg/day) in SSRI nonresponders. One disadvantage with fluoxetine and paroxetine is that venlafaxine is a substrate of the cytochrome P450 (CYP) 2D6 isoenzyme, and accumulation of venlafaxine when coadministered with SSRIs inhibiting the 2D6 pathway could lead to serotonergic adverse effects (Bhatara et al. 1998) or to blood pressure elevation and other side effects (Benazzi 1999).

Mirtazapine augmentation  Mirtazapine is a dual-action antidepressant that increases both serotonergic and noradrenergic activity by blocking the α₂-adrenergic autoreceptors and heteroreceptors and blocking the serotonergic 5-HT₂ and 5-HT₃ receptors. The use of 15-30 mg qhs has been reported to be helpful in an open trial of augmentation of SSRIs (Price et al. 1998). This augmentation may also manage SSRI-induced sexual dysfunction (Farah 1999; Sussman 1997). The main disadvantages of this strategy are sedation and the potential for weight gain (Price et al. 1998).

Atypical antipsychotic drug augmentation  Ostroff and Nelson (1999) reported eight cases in which the addition of risperidone led to remission among nonpsychotic depressed patients who had not responded to treatment with either fluoxetine or paroxetine. The response was quite rapid—all patients achieved response within 1 week of starting the risperidone. A recent double-blind study (Tollefson et al. 1999) randomized 28 patients with treatment-resistant depression to fluoxetine alone, olanzapine alone, or the combination of fluoxetine plus olanzapine. The olanzapine augmentation of fluoxetine was significantly more effective (Montgomery-Asberg Depression Rating Scale [MADRS; Montgomery and Asberg 1979] total score) than either treatment alone (Tollefson et al. 1999). The main disadvantages of augmenting antidepressants with atypical antipsychotic agents are the risk of sedation and weight gain, although these drugs may offer the advantage of helping with anxiety and insomnia.

Anticonvulsant drug augmentation  Marked improvement in patients with treatment-resistant depression was observed when the anticonvulsant carbamazepine (300 mg/day) was added to desipramine (Cullen et al. 1991). Similarly, the addition of sodium valproate to fluoxetine in a nonresponder and to fluvoxamine in a partial responder was followed by marked improvement in both patients (Corrigan 1992). The potential usefulness of the augmentation of antidepressants with these and other anticonvulsants requires further study. On the other hand, it is common clinical practice to use anticonvulsants such as sodium valproate, carbamazepine, lamotrigine, gabapentin, and topiramate as adjuncts to antidepressants, particularly with unipolar depressed patients with significant affective instability or with comorbid Cluster B personality disorders. The main issues with this strategy are sedation and, in the case of valproic acid and carbamazepine, the need for therapeutic blood-level monitoring.

Benzodiazepine augmentation  The addition of benzodiazepine anxiolytics to antidepressant drugs is very common in clinical practice. Whereas in some cases the benzodiazepine is added to the antidepressant to manage such side effects as insomnia and nervousness, in other instances this combination is used to treat patients with anxious depression or depressed patients with comorbid anxiety disorders. Case reports describe efficacy in resistant depression with panic attacks when the combination of an MAOI and a high-potency benzodiazepine such as clonazepam or alprazolam is used (Deicken 1987; Reis and Wittkowsky 1986).

Conclusion  Although lithium is the best-studied augmentation strategy, no definitive algorithm based on controlled comparisons has emerged to guide the clinician in the choice of an augmentation strategy. Selection of a sequence of agents typically reflects the individual clinician’s preference. Moreover, no data are available on the commonly employed clinical strategy of combining different augmenting agents in patients with refractory depressions. Results from the clinical trials of augmentation strategies for patients with treatment-resistant unipolar depression are compiled in

Table 45-1.