Switching Treatments for Complicated Depression

Maurizio Fava, MD

Department of Psychiatry, Harvard Medical School and Massachusetts General Hospital, Boston


The treatment goal for patients with major depressive disorder is remission, but, as evidenced by the STAR*D trial,1 the majority of patients treated with a first-line antidepressant do not achieve remission, and only about half experience response. A survey2 of clinicians reported that the most common next-step strategy for patients who experience partial response after 8 weeks of SSRI treatment is to increase the dose of the medication, and secondly to augment or combine another medication with the initial antidepressant (AV 1AV 1). Clinicians are reluctant to switch agents and possibly jeopardize the partial benefit provided to these patients by the first medication. Patients in the STAR*D trial3 exhibited this same reluctance toward switching medications after achieving partial response. However, for nonresponders, clinicians in the survey chose switching medications as the next-step (see AV 1AV 1). Patients are also more likely to accept switching when they experience either no response or intolerable side effects from the first antidepressant.3

Switching medications has certain advantages over augmentation or combination therapies. Patient compliance may be enhanced by the generally lower cost of switching over combination and augmentation therapies, and by the ease of taking only 1 medication. Additionally, the second drug may have a more acceptable side effect profile than the first agent. However, besides losing any benefit of the first drug, disadvantages of switching include possible discontinuation reactions and the potential for adverse effects to be different, but not better.

Switching Strategies

Switching strategies include staying within the same class as the original medication or switching to another class. Switching between agents within the same class may maintain tolerability but obtain slightly different pharmacologic properties, such as switching from a relatively serotonergic TCA to a more noradrenergic TCA. Switching to a different class may be done to obtain a different neurochemical effect (eg, switching from a relatively selective agent to a dual-action agent) or to reduce specific side effects characteristic of a particular class of agents. Also, switching outside the class may be done because certain depressive subtypes appear to be more responsive to 1 antidepressant class than another. However, no unequivocal evidence showing a benefit of a within-class switch over an outside-class switch, or vice versa, has been reported.4

Switching within SSRI class. Patients with depression usually receive an SSRI as first-line treatment.5 Studies6 have shown that patients who experienced no response to an SSRI had remission rates of about 24% when switched to another SSRI and 28% when switched to a non-SSRI. An advantage to switching within the same class is that patients can typically tolerate the switch without a washout period. However, depending on the agents used, switching within the same class may not be as effective as switching between classes because the pharmacologic action of the second SSRI may be too similar to that of the first SSRI.

Switching to SNRIs. Dual-action agents are hypothesized to be more effective in certain depressive subtypes than single-action agents. With the SNRIs, efficacy may be due to the distinctive roles and potential synergistic effects of serotonin and norepinephrine. A study7 of the SNRI venlafaxine compared with the SSRI paroxetine in subjects who had suboptimal response to trials of 2 or more antidepressants (typically SSRIs) found that venlafaxine produced a 42% remission rate, compared with a remission rate of 20% for paroxetine (P = .01).


Switching to TCAs. A study8 was conducted in 92 patients who had not responded to initial antidepressant treatment (mostly SSRI) who were then treated with nortriptyline. Approximately 12% of the subjects achieved remission. Switching from a TCA (imipramine) to an SSRI (sertraline) led to similar remission rates as switching from the SSRI to the TCA, indicating that switching outside of the initial drug class is a useful strategy for nonresponders regardless of which drug class was used first (AV 2AV 2).9 However, adverse effects leading to dropout occurred more often with the switch to the TCA than to the SSRI.9 A meta-analysis10 indicated that TCAs are more effective than SSRIs for the depressive subtype melancholic depression. TCAs are relatively low-cost antidepressants, but disadvantages include anticholinergic side effects and the lethality of overdose.

Switching to MAOIs. The MAOIs may be particularly effective in patients with atypical unipolar depression11 and treatment-resistant patients with anergic bipolar depression.12 Disadvantages of MAOI treatment include dietary restrictions and the risk of hypertensive crises, as well as the need for a washout period before starting and after ending treatment.


Switching to other non-SSRI classes. An open-label study13 of patients who were switched to mirtazapine after not responding to or not being able to tolerate SSRIs showed a response rate of 48%. In another open-label trial,5 60% of patients resistant to the SSRI fluoxetine had a full or partial response when switched to bupropion; about 23% of the intent-to-treat population remitted, or 30% of completers.

STAR*D Trials


The STAR*D trials compared various switching and augmentation strategies to determine optimal next-step strategies for patients with treatment-resistant depression (AV 3AV 3).14,15 Patients who could not tolerate or who did not remit with citalopram in level 1 of STAR*D and chose to switch agents in level 2 were randomly assigned to take another SSRI (sertraline), bupropion, or venlafaxine.16 None of these agents produced a significantly greater remission rate compared with another agent. Overall remission rates in level 2 of STAR*D were slightly lower than in level 1.

At level 3 of the STAR*D trial,17 patients who had not responded to 2 previous antidepressant trials were randomly assigned to mirtazapine or nortriptyline treatment, if they chose the option to switch agents rather than add an augmenting agent. Neither treatment showed a statistical advantage in remission or response rates, and they were comparable in side effects and tolerability. However, overall remission rates were low, suggesting that remission rates may diminish with each successive treatment step.

At level 4 of the STAR*D trial,18 investigators randomly assigned a switch to either venlafaxine plus mirtazapine or tranylcypromine for patients who had an inadequate response to the 3 previous trials. Remission rates were low, and not statistically different between groups.


Switching appears to be a relatively well-tolerated and effective strategy for both partial and nonresponders to antidepressant treatment. Because a disadvantage of switching is the potential loss of partial benefit from the initial antidepressant, switching may be more commonly used for nonresponders; however, the presence of significant side effects from the initial antidepressant may favor switching for partial responders. Switching strategies should be guided by the individual patient’s circumstances and preferences.

Drug Names

bupropion (Wellbutrin, Aplenzin, and others), citalopram (Celexa and others), fluoxetine (Prozac and others), imipramine (Tofranil and others), mirtazapine (Remeron and others), nortriptyline (Pamelor, Aventyl, and others), paroxetine (Paxil and others), sertraline (Zoloft and others), tranylcypromine (Parnate and others), venlafaxine (Effexor and others)


MAOI = monamine oxidase inhibitor, QIDS-SR-16 = 16 item Quick Inventory of Depressive Symptomatology—Self Report, SNRI = serotonin-norepinephrine reuptake inhibitor, SSRI = selective serotonin reuptake inhibitor, STAR*D = Sequenced Treatment Alternatives to Relieve Depression, TCA = tricyclic antidepressant

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