01. Difficult-to-Treat Depression: First-Line Antidepressant Selection, Switch vs. Augment, and Augmentation Strategies

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Definition and Conceptual Framework

Flavio Guzman, M.D.: What is your current view of the treatment-resistant depression concept?

Michael Thase, M.D.: There is consensus at the regulatory level that patients with depression who have not responded to at least two standard proven therapies in the current episode can be considered to have the entry-level diagnosis of treatment-resistant depression.

However, there is no uniform belief among practitioners that this is the best definition. Many consider requiring only two ineffective treatments in the current episode too low a threshold, and believe stricter, more demanding definitions are warranted.

At a broader level, some patients are unlikely to improve from their depression even if they have never received any treatment. They may have a difficult-to-treat depression for a variety of reasons, despite never having failed a standard antidepressant.

Consider, for example, a patient who experienced sexual abuse in childhood or early adolescence, later developed substance dependence, and has a comorbid anxiety disorder. That patient has multiple reasons for being difficult to treat, even without a history of standard treatment nonresponse.

The term treatment-resistant depression was borrowed from medical microbiology. The process by which a bacterium becomes resistant to an antibiotic is far simpler than the process by which a human being cannot respond to a standard treatment for depression, making the term both borrowed and not entirely satisfactory.

Those who do not respond to standard treatments represent a subset of a larger group of patients who have difficult-to-treat depression because of various complications and comorbidities.

Difficult-to-Treat Depression

Flavio Guzman, M.D.: CANMAT and other groups have introduced the concept of difficult-to-treat depression to broaden the focus beyond strict definitions. How do you view this shift in terminology?

Michael Thase, M.D.: I am in favor of the shift from treatment-resistant depression to difficult-to-treat depression. Nonresponse to a number of standard treatments is one way of describing these patients, but it is not the most useful one.

Understanding the patient’s life story, history, complications, and the problems that may have made them harder to treat gives the clinician a better opportunity to build a treatment plan that addresses the whole person, as well as the broader context in which their depression has become difficult to treat.

First-Line Treatment and Medication Selection

Flavio Guzman, M.D.: When choosing a first SSRI or SNRI, what practical considerations (side effects, comorbidities, and patient preferences) matter most in your day-to-day prescribing?

Michael Thase, M.D.: I work within a framework in which insurance preferentially covers generic medications before branded ones, and the cost difference is significant.

I maintain one or two preferred SSRIs, one or two preferred SNRIs, plus bupropion and mirtazapine: roughly six first-line options. I try to match the patient to the agent that best fits the symptoms causing them the most trouble.

For example, I would not prescribe a sedating medication for someone with no sleep difficulty, nor one that suppresses appetite for a patient who already struggles to eat. The practical question is whether this patient should receive escitalopram or sertraline, venlafaxine or duloxetine, or bupropion or mirtazapine.

The first treatment experience is informative. I look at whether:

• The match was poor, with significant side effects
• The patient obtained no benefit whatsoever
• Tolerability was acceptable, but benefit was insufficient

By the second choice, I am better informed. I know the patient’s side effect profile and what happened with the first agent, and that knowledge shapes a more targeted selection.

Flavio Guzman, M.D.: What is your framework for choosing bupropion or mirtazapine as a first-line option instead of an SSRI or SNRI?

Michael Thase, M.D.: Bupropion has the best profile for avoiding sexual side effects among antidepressants. If a patient wants to avoid sexual side effects, or has experienced them with other antidepressants, bupropion is my first choice.

Bupropion also has no sedative properties and may carry energy- and motivation-enhancing effects beyond those of other antidepressants. It is a good fit for the patient who:

• Has no significant sleep problems
• Does not present with prominent anxiety
• Reports low energy and low motivation as the principal complaints

Mirtazapine sits at the opposite end of the spectrum. It can stimulate appetite and promote sleep, but is not effective at immediately fostering energy. Bupropion offers the reverse profile.

Both agents, however, carry a lower risk of sexual side effects, making them valuable options for patients trying to avoid sexual dysfunction.

Switch vs. Augment Decision

Flavio Guzman, M.D.: At what point do you decide it is time to switch antidepressants versus augment them?

Michael Thase, M.D.: I switch when the first medication has intolerable side effects, or when dose-limiting side effects prevent reaching an adequate dose for an adequate duration. Switching is the strategy when a medication does little good and produces bothersome side effects.

Augmenting is appropriate when the first medication is somewhat helpful and free of side-effect problems, so it can serve as the platform to which a second agent is added to improve the response.

Flavio Guzman, M.D.: When a patient does not respond to an initial SSRI, many clinicians assume a different mechanism is required. What is your view, and is this actually supported by evidence?

Michael Thase, M.D.: There is modest evidence suggesting that switching to a mechanistically dissimilar antidepressant is five to ten percent more effective than staying within the original SSRI class. That is a modest advantage.

If you believe you selected the right SSRI for a patient, a second within-class trial is reasonable. However, if the patient felt worse rather than better (for example, with worsened insomnia or new sexual side effects), there is no rationale for trying a second SSRI. In that case, moving outside the class, where bupropion or mirtazapine may be a better fit, is the more appropriate step.

Flavio Guzman, M.D.: When a patient shows only partial response to an SSRI or SNRI at a moderate dose, how do you decide whether to push the dose higher versus switching or augmenting?

Michael Thase, M.D.: The decision depends on how much dosing headroom remains.

• If there are no side effects and room to increase remains (for example, sertraline at 100 mg or paroxetine at only 30 mg), I feel obliged to go at least one step higher toward the maximum.
• If the patient is already near the maximum dose and not improving, I consider an adjunctive strategy that may offer the best chance of crossing over to a full therapeutic response.
• Alternatively, I may switch to a different SSRI, hoping for a somewhat better individual match.

Atypical Antipsychotic Augmentation

Flavio Guzman, M.D.: Let’s say a patient had only a minimal response to sertraline. We augment with aripiprazole, but after six weeks there is still no improvement. Does it make more sense to switch the antidepressant, the augmenting agent, or both?

Michael Thase, M.D.: In this scenario, we have a well-tolerated but ineffective first antidepressant followed by an adjunctive strategy that also failed. Assuming we reached at least 5 mg of aripiprazole with good tolerability but no improvement, several options are reasonable:

• Switch both medications and start over.
• Discontinue aripiprazole and try a newer-generation antipsychotic with a different mechanism of action.
• Keep sertraline and add a different, newer antidepressant as a combination strategy.

We do not have strong evidence to guide this choice. Because sertraline has been well tolerated, one path is to seek a stronger alternative to aripiprazole. Another is to conclude that this combination has not worked and move on, possibly to an older-generation antidepressant. The best decision depends in part on clinical urgency and past treatment history.

Flavio Guzman, M.D.: Can you discuss the differences among second-generation antipsychotics in terms of efficacy and tolerability when used to augment an antidepressant?

Michael Thase, M.D.: There are large, clinically meaningful differences in tolerability across this class, particularly in the likelihood of:

• Weight gain
• Metabolic dysfunction
• Insomnia
• Other dose-limiting side effects

In terms of efficacy, the differences are more modest. Lumateperone is among the more effective augmenters; quetiapine is among the relatively less effective. But I would argue we have more to work with clinically in the domain of tolerability than in universal efficacy: tailoring an agent to the patient’s individual needs and side-effect vulnerabilities is where the real differentiation occurs.

Flavio Guzman, M.D.: How do you differentiate among the D2 partial agonists (aripiprazole, brexpiprazole, and cariprazine), and are there patient features that guide your selection?

Michael Thase, M.D.: In the United States, aripiprazole is generically available and therefore less expensive, while brexpiprazole and cariprazine remain branded.

Brexpiprazole was synthesized to improve upon some of aripiprazole’s shortfalls. If I want an agent with a similar profile but advantages in specific areas, brexpiprazole is a good choice when the patient needs something:

• Better for anxiety
• Less likely to cause akathisia
• Better for sleep

Aripiprazole and brexpiprazole are closely related; cariprazine is not, though there is overlap in mechanism of action. If I need to leave the aripiprazole family entirely (because of weight gain, excessive sedation, or another side effect), switching to cariprazine, the more dissimilar agent, is a rational approach.

Residual Symptoms and Adjunctive Targeting

Flavio Guzman, M.D.: When a patient improves in some domains but has residual symptoms in others, do you adapt augmentation choices to target the remaining symptom cluster, or do you think primarily in terms of global efficacy evidence?

Michael Thase, M.D.: This is the ideal scenario for symptom-targeted adjunctive therapy. The probability that switching the antidepressant would greatly improve the patient’s circumstances is lower than the probability of benefit from adding an agent that specifically addresses what remains.

This is the classic rationale for preferring adjunctive treatment over switching when there is a partial response:

• For residual anxiety, I can prescribe an anxiolytic.
• For residual insomnia, I can prescribe a sedative-hypnotic.
• For low energy and low motivation, I can add an adjunct that targets those specific symptoms.

Buspirone Augmentation

Flavio Guzman, M.D.: Do you see a place for buspirone as an augmenting agent in depression today, or has it been eclipsed by more effective strategies?

Michael Thase, M.D.: Compared with a newer-generation antipsychotic, buspirone is less expensive and has an established track record in this setting, though it is probably less well-proven for antidepressant benefit.

If the primary residual target is anxiety, I may choose buspirone augmentation (at 15 mg BID, 20 mg BID, or 25 mg BID) over a newer-generation antipsychotic. Much depends on the patient’s history and prior medication responses.

Buspirone is not well-suited for patients with intense panic attacks, where it simply does not work as well as other options. As the clinical observation goes, buspirone has nearly every desirable property of a psychoactive medication except reliable efficacy. In this augmentation context, it is likely less effective than a newer-generation antipsychotic but may be better tolerated.

Pramipexole and Dopamine Agonists

Flavio Guzman, M.D.: How do pramipexole and other dopamine agonists compare to antipsychotic augmentation in terms of efficacy and tolerability? Do you see a niche role in patients with anergia?

Michael Thase, M.D.: Until a few years ago, I did not see a niche role: the available studies were equivocal, showing only modest benefits as adjuncts.

In the past couple of years, however, better-designed studies of pramipexole have demonstrated that higher (but still tolerable) doses carry significant antidepressant effects. Use in my difficult-to-treat depression clinic has increased considerably.

A starting dose of 0.5 mg two to three times daily, titrated slowly upward and occasionally going higher, is a reasonable approach, though it remains an off-label use.

Flavio Guzman, M.D.: There is a safety concern worth addressing: the risk of compulsive behaviors such as gambling, hypersexuality, and binge eating. How concerning is this risk when considering pramipexole for depression?

Michael Thase, M.D.: Based on the available case reports, the incidence of new-onset compulsive behavior is probably somewhere between 1 in 1,000 and 1 in 2,000. These medications do not predominantly produce this side effect in depressed patients.

That said, the comorbidities commonly associated with depression can place some individuals at elevated liability for a treatment-facilitated (iatrogenic) increase in compulsive behavior. It does happen, and it warrants explicit discussion during informed consent.

Psychostimulants as Augmentation

Flavio Guzman, M.D.: In which scenarios, if any, do you consider psychostimulants as augmentation?

Michael Thase, M.D.: I prioritize psychostimulants when the patient has comorbid ADHD or has previously responded well to a stimulant.

When patients gain benefit in concentration, focus, and adherence, even without a well-established prior ADHD diagnosis, the intervention has served its purpose. Because most stimulants are generically available and relatively inexpensive, they offer a practical opportunity to improve functional status without further disadvantaging the patient from a depression standpoint.

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