Therapeutic Strategies for Treatment-resistant Depression: State of the Art and Future Perspectives

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.