When to change first-line treatment: Debating an everyday dilemma

If there is partial response after two to four weeks, persist with current therapy. If not, there are plenty of options for change -- whether that is changing antidepressant, or using a combination, or an adjunctive agent. Although the best time to do this is uncertain, do not keep patients for months on a treatment that is clearly ineffective.

The ECNP session was cast in the form of a debate. The case for prompt and decisive action in cases of partial response was put by Bernhard Baune (University of Melbourne Medical School, Melbourne, Australia), while a more cautious approach was advocated by Peter Falkai (Ludwig-Maximilians University, Munich, Germany).

When asked their view at the start of the session, the majority of the audience preferred to wait before expressing an opinion. After the presentation, there was a slight majority in favor of changing antidepressant early rather than late. But persuasive points had been made on both sides.

What is best to do can be discussed; but all agree that patients should not be left for 6-8 weeks without response

Combine or augment: an alternative to early changing

With regard to areas of disagreement, Peter Falkai argued that there is only very limited evidence for an early change to a different antidepressant which improves outcome. More often than not, randomized trials of the early change strategy have failed to meet their primary outcome.1

Besides, lack of 20% reduction on MADRS or HAM-D score at weeks 2-4 does not necessarily mean a patient is not improving. We should also take into account of what our patients say. Perhaps there been a helpful shift in at least one area, such as mood or activity.

Andrea Cipriani’s recent meta-analysis shows there are many effective antidepressants,2 but we should not risk jumping too quickly from one to another, he argued.

Increasing dose can often be a way forward since many patients are put on insufficient doses at the start of treatment. Measuring serum drug level can identify rapid metabolizers.

We should take note that STAR*D offers support for the idea that certain classes of antidepressant can usefully be combined.3 And there is also a case for augmentation with an agent that is not a conventional antidepressant.

Patients whose depression improves early are more than three times as likely to become sustained responders. 

In favor of a treatment progression

In reply, Bernhard Baune made these points in favor of decisive action:

  • Early response is a must: compared to non-responders, patients whose depression improves early are more than three times as likely to become sustained responders 
  • Lack of early response predicts poor response later in the course of disease
  • Poor response can have adverse effects on the long-term course of disease and result in chronicity, with increased risk of relapse
  • Alternatives to changing the initial depressant – i.e. dose increase, combination and augmentation – can have adverse effects that may lead to disengagement with treatment. For instance, the higher rate of non-adherence found when antidepressants are combined.4
  • Changing from monotherapy with an SSRI or SNRI to a drug with multimodal activity can enhance response further by interacting with a number of serotonin receptors as well as inhibiting the serotonin transporter.

There are certain patients whose antidepressant needs to be changed and needs to be changed early, he concluded.

A question of timing

Considering the points of both sides acknowledged, Professors Baune and Falkai agreed that:

  • Initial therapy should take into account the individual circumstances of the patient including disease history, depression severity and comorbidities
  • Intolerance of current medication is clear reason for change
  • 2-4 weeks is an appropriate time at which to reconsider treatment in the case of non-response
  • Existing guidelines vary and do not provide consistent advice on when to add to or change treatment.

Educational financial support for the session was provided by H.Lundbeck A/S

  1. Kudlow PA, McIntyre RS, Lam RW. CNS Drugs 2014;28:601-9.
  2. Cipriani A et al. Lancet 2018;391:1357-1366
  3. Rush AJ et al. Am J Psychiatry 2006;163:1905-1917
  4. Warden D et al. J Psychiatric Practice 2014;20:118-132.
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