Decades of research have focused on the identification of risk factors associated with treatment-resistant depression (TRD). The most reliable include:
• Duration of the episode: the longer the episode of depression, the greater the atrophy in specific brain regions (eg, hippocampus); the cognitive and behavioral changes that take place during long episodes make a return to previous well-being difficult
• Severity of the episode: both ends of the depression spectrum (most severe, mildest) are hypothesized to increase the risk of poor response—severe depression is associated with biological unbalances; mild depression, with lower drug versus placebo response
• Melancholic features: TRD is more prevalent in bipolar depression than in MDD; the specific investigation of subthreshold manic symptoms is pivotal
• Lack of symptomatic improvement within the first couple of weeks since the start of treatment
• Comorbidity: anxious symptoms and full anxiety disorders (especially generalized anxiety disorder) were found to be predictors of lower rates of response and remission; personality disorders, especially avoidant and borderline, are negative prognostic factors
• Old age
Biological factors have also been studied as possible predictors of TRD. Genetic variants within the serotonin transporter—serotonin receptors and genes involved in neurodevelopment—have been found to modulate the risk of TRD.1 Although this very promising predictive tool is still under development, a number of research centers worldwide are currently using gene-targeted antidepressant prescription (eg, the Canadian Centre for Addiction and Mental Health Pharmacogenetics Program). A further development is the identification of peripheral blood biomarkers or imaging predictors.
Before treating TRD, however, due diligence is advised. A number of conditions are possible causes of relative or “pseudo” TRD:
• Subtherapeutic doses of antidepressants (approximately 20%)
• Patient nonadherence (approximately 40%)
• Intolerable adverse effects (20% to 30%)
• Wrong diagnosis (10% to 15%) (such as, thyroid disease, nutritional deficiencies, sleep apnea, “latent” bipolarity)
Once TRD is established on the basis of one or more of the risk factors and the exclusion of other conditions, the question arises: what to do next? Unfortunately the answer is not clear, but a number of options are available. The Figure presents a treatment algorithm for TRD.
A combination of 2 antidepressants or augmentation with another drug, such as lithium, a thyroid hormone, or an atypical antipsychotic, can be tried. The most robust evidence is augmentation of conventional antidepressant therapy with atypical antipsychotics.2 Switching to another antidepressant may also help. However, there is no clear evidence to guide the choice between augmentation and switching. Clinical experience and preliminary scientific evidence support the option of augmenting when partial symptomatic improvement is observed during the current antidepressant treatment.
Vortioxetine is an FDA-approved pharmacological option for the treatment of MDD. It is a serotonin modulator and stimulator that blocks the serotonin transporter, a partial agonist of serotonin receptor 1B and antagonist of serotonin receptors 3A and 7. Vortioxetine demonstrated good tolerability and a beneficial effect on cognition that appears largely independent from the effect on depressive symptoms.3
The combination of antidepressant pharmacotherapy and psychotherapy (usually cognitive-behavioral therapy) is an effective option; however, the cost-effectiveness of this strategy has not been evaluated.2 Other nonpharmacological treatments have been widely studied. The use of light therapy, possibly in combination with physical exercise, has demonstrated a considerable antidepressant and anxiolytic effect.4
Neurostimulation represents a more invasive option that can be helpful in highly refractory patients. Repetitive transcranial magnetic stimulation (rTMS) provided promising results in the treatment of TRD after 2 or more antidepressant treatment trials failed.5 Moreover, rTMS reduced cognitive impairment and improved patient acceptability compared with electroconvulsive therapy. Vagus nerve stimulation was shown to be effective in chronic TRD, with a 12-month response of 30% or more.6 The evidence for deep brain stimulation is compelling as a promising but still experimental treatment strategy in highly resistant patients. Findings indicate a response rate of 40% to 70%.7
Dr Serretti is Associate Professor and Dr Fabbri is a Resident in the department of biomedical and neuromotor sciences at the Institute of Psychiatry, University of Bologna, Bologna, Italy. They report no conflicts of interest concerning the subject matter of this article.
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