1. Distinguish between 'Treatment Resistant' and 'Difficult to Treat' depression;
2. Current practical augmentation strategies for difficult to treat depression; and
3. Role of inflammation in difficult to treat depression.
Most depressed patients referred to psychiatrists have failed to respond to one or more antidepressant medications. By convention, the label of ‘treatment resistant depression’ (TRD) is applied to depressive conditions where there has been a failure to secure significant benefit from two trials of separate medications in the current episode. This definition has been criticised as being overly focused on medication and lacking psychosocial context. An alternative concept of ‘difficult to treat depression’ (DTD) is probably more satisfactory.
In DTD, if switching antidepressants does not produce benefit, then various pharmacological augmentation strategies are usually tried. The best evidence base is for the addition of atypical antipsychotic drugs to SSRI/SNRI treatment with aripiprazole and quetiapine the most widely used. One putative mechanism underpinning this therapeutic effect is blockade of cortical 5-HT2A receptors- an explanation supported by the apparent utility of the 5-HT2A receptor antagonist, pimavanserin, as an add-on treatment in SSRIresistant depressed patients. The NMDA receptor antagonists, ketamine and esketamine, are being increasingly used as augmentation in more refractory depressive states.
The pathophysiology of difficult to treat depression is unclear. One influential finding is that a proportion of patients with DTD have raised blood inflammatory markers such as Interleukin-6 (IL-6) and C-reactive protein (CRP). However, it is not yet established that specific targeting of such patients with anti-inflammatory agents results in significant benefit. Nevertheless, there are studies to suggest that noradrenergic agents might be more effective than serotonergic antidepressants in patients with raised levels of CRP.
1. Cowen PJ, Anderson IM. New approaches to treating resistant depression. BJPsych Advances. 2015 Sep;21(5):315-23.
2. Cowen PJ. Backing into the future: pharmacological approaches to the management of resistant depression. Psychological Medicine. 2017 Nov;47(15):2569-77.
3. McAllister-Williams RH, Arango C, Blier P, Demyttenaere K, Falkai P, Gorwood P, Hopwood M, Javed A, Kasper S, Malhi GS, Soares JC. The identification, assessment and management of difficult-to-treat depression: an international consensus statement. Journal of Affective Disorders. 2020 Apr 15;267:264-82.