What is the best option in Treatment-resistant depression? Jl Aff disorders.March 2014


Remission of  symptoms is the goal of treatment in depression.Remission significantly increases the probability of recovery from the disorder.However remission rates are poor with current treatments. Overall remission rates reported in STAR-D for the medication options were 28%, 25%, 18%, and 10% at steps 1, 2, 3, and 4, respectively, meaning most patients require multiple trials.Identifying treatment resistance  at the earliest is required to plan further trials.Unfortuntaley there is no universally accepted definition of TRD. Failure to achieve remission with two or more adequate antidepressant trials is the most accepted definition. Various staging systems are also proposed for TRD.European staging model differentiate between TRD and CRD (Resistant to several antidepressant trials, including augmentation strategy, for more than 12 months).

Roger S. McIntyre  et al review the state of knowledge regarding evidence based options in TRD in this article.

1.Atypical antipsychotics: Approved as adjunct (i.e., aripiprazole and quetiapine) or in combination (olanzapine-fluoxetine combination [OFC]) with antidepressant therapy. The target dosing for aripiprazole in MDD appears to be between 5 and 20 mg per day with 2 mg representing a reasonable starting dose in most patients.Quetiapine is reported to be efficacious at 50–300 mg per day with a greater reduction in symptoms seen across more depressive items at a quetiapine dosing of 150 and 300 mg daily. OFC is recommended at 3 mg/25 mg to 12 mg/ 50 mg tailored to the individual patient.

2. Combination antidepressants and augmenting  agents: No antidepressant is FDA approved and/or established as reliably effective as an “add-on”/ combination treatment strategy in TRD. However this remains a popular approach. Most studies of augmenting with Lithium or thyroid hormone have involved TCAs and MAOIs rather than commonly used agents now.Treatment guidelines  position combination antidepressants and lithium as a first-line treatment strategy with thyroid hormone and buspirone as next-line treatment options.

3. Stimulants: Several negative studies with modafanil  and methylphenidate . Prodrug lisdexamfetamine may be capable of offering symptom improvement in TRD.

4. Glutamatergic agents:  Interventions which directly (e.g., ketamine and riluzole) or indirectly (e.g., scopolamine) modulate glutamate function may mitigate depressive symptoms . Ketamine is appearing to be very promising. 

4. Complementary alternative medicine (CAM)/nutraceuticals: Some evidence for S-adenosyl-methionine (SAMe) as well as L-methylfolate as augmenting agents.

5. Anti-inflammatory-immune based treatments: Small open and controlled studies suggest that celecoxib, some NSAIDs and Tumor necrosis factor (TNF) antagonist, infliximab, could be of use.

6. Psychotherapy: No studies on TRD.  CBT shown effective  as an adjunct to conventional treatment in primary care patients insufficiently responsive to pharmacotherapy.

7. Stimulation treatments: Benefits of ECT is well documented.Promising results are also reported for rTMS in TRD with the advantage of reduced cognitive impairment and improved patient acceptability.  DBS is compelling as an acute treatment strategy in highly resistant populations .

8.Aerobic exercise: Some evidence to suggest that this may be a viable augmentation strategy for individuals with depression not responding to pharmacotherapy.

Conclusion: Lack of symptomatic improvement in the first couple of weeks may be a more robust predictor of non- remission after 6–8 weeks. So monitoring during this period is essential to plan for further strategies at the earliest. Review concludes that atypical antipsychotics have most evidence base as augmenting agents for resistant depression.

Summary of the article:

Treatment-resistant depressionDefinitionsreview of the evidence, and algorithmic approach.

McIntyre RS, Filteau MJ, Martin L, Patry S, Carvalho A, Cha DS, Barakat M, Miguelez M. J Affect Disord. 2014 Mar;156:1-7.

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