In this narrative review, we intended to summarize the evidence of pharmacological and somatic
treatment choices for treatment-resistant depression (TRD). There are several types of therapeutic strategies to
improve inadequate response to antidepressant treatment. The first step for patients with TRD is to optimize the
dosage and duration of antidepressants as well as to ensure their drug compliance. The shift to antidepressant and
antidepressant combination therapy for patients with TRD cannot be regarded as an evidence-based strategy.
Only the combination of a monoamine reuptake inhibitor with a presynaptic α2-autoreceptor antagonist might
have better efficacy than other antidepressant combinations. Currently, the most evidence-based treatment options
for TRD are augmentation strategies. Among augmentative agents, second-generation antipsychotics and lithium
have the strongest evidence for the management of TRD. Further studies are needed to evaluate the augmentative
efficacy of anticonvulsants, thyroid hormone, glutamatergic agents, anti-inflammatory agents, and nutraceuticals
for TRD. Among somatic therapies, electroconvulsive therapy and repetitive transcranial magnetic stimulation are
effective for TRD. Further studies are warranted to provide clinicians with a better recommendation in making
treatment choices in patients with TRD.