Evaluation of antidepressant polypharmacy and other interventions for treatment-resistant depression.

There is on-going controversy about the definition and sub-classification of treatment-resistant depression (TRD) that makes it difficult to assess the effectiveness of different proposed strategies for treating this chronic, often disabling condition. Sub-classification of TRD in terms of symptom severity and in terms of demographic and clinical characteristics may help in the recognition of homogeneous TRD subgroups and in the development of subgroup-specific interventions.

According to the World Health Organization, by 2020 major depressive disorder will become the second major cause of disease burden after heart disease.[1] The estimated annual direct and indirect costs of depression treatment in the United States exceeds 40 billion US dollars, partially due to the large proportion (>40%) of chronic treatment-resistant depression (TRD) among clinically treated individuals with depression.[2] Depression is also associated with substantial disease burden in China, [3] where it interferes with the social functioning of affected individuals resulting in a heavy burden on society. It is also associated with an elevated risk of suicide. Currently, treatment strategies for TRD typically include the simultaneous use of different medications and/or psychotherapy. Formal, scientific evaluation and comparison of the efficacy of these treatment regimens is essential for the improvement of treatment outcomes.

The lack of a globally accepted operational definition of TRD or guidelines for the treatment of TRD has made it difficult for clinicians and researchers in this area. Responding to this issue, in 2002 the European agency for the evaluation of medical products committee for proprietary medical products (EMACPMP) defined TRD as an insufficient treatment effect after full-dose and full-course treatment with at least two types of antidepressants.[4] Three years later (2005), the United States Massachusetts General Hospital (MGH) provided a more quantitative definition for TRD: limited treatment effect after full-dose (i.e., maximum dosage or blood concentration) treatment for at least six weeks with at least two types of antidepressants with different working mechanisms.[5] Although the MGH definition provided a fully quantifiable criterion in terms of the dosage and duration of the treatment, it did not mention several easily overlooked factors that can affect treatment outcomes in clinical practice, including patients’ adherence to medications and individual variations in metabolism rates of antidepressants. For example, the blood concentration of antidepressants would not reach the optimal treatment concentration among individuals with a high metabolism rate for these drugs if given the same dosage as those with a regular metabolism rate. Similarly, suboptimal concentration of antidepressants can occur when the levels of enzymes that break down the active compounds of antidepressants are elevated. These factors can lead to pseudo drug resistance, which should not be considered TRD in clinical practice.

Several steps could help improve clinical outcomes when using antidepressant polypharmacy to treat TRD. First, categorization of TRD could help identify more homogeneous subgroups of individuals with TRD; this would subsequently make it easier to identify the most effective treatment strategies for each subgroup. Thase and Rush proposed an ordinal system to sort individuals with TRD into five severity groups[6] based on the type of antidepressants used, duration of treatment, and effectiveness of electroconvulsive therapy (ECT). This system was later modified by researchers in Europe, Australia, and North America to better guide the combined treatment of TRD.[7] The identification of the clinical characteristics of TRD that are predictive of treatment outcomes can help in the design of different types of adjunctive treatments.[8] These characteristics include: (a) clinical presentations associated with poor efficacy of monotherapy antidepressant treatment, such as atypical depressive symptoms, endogenous depression, chronic depression (duration of disease greater than 2 years), or ‘double depression’ (concurrent depressive episode and dysthymia symptoms); (b) comorbid chronic physical conditions or mental conditions such as drug dependence, anxiety disorder, and borderline personality disorder; and (c) a poor social support system resulting in insufficient management and monitoring of treatment adherence. These characteristics are risk factors for relapses and for the exacerbation of depressive symptoms. Future research needs to quantify the relative importance of these different characteristics in the onset and course of TRD.

Clinical regimens of combined treatment with multiple antidepressants for TRD typically consist of the use of selective serotonin reuptake inhibitors (SSRIs) and another type of antidepressant such as bupropion, trazodone, venlafaxine, dutoxetine, or mirtazapine. Mirtazapine, bupropion, and agomelatine are generally well tolerated and have few drug-drug interactions. Therefore, they are the first choices for combined treatment. Other non-antidepressant drugs can also be used in combination with antidepressants to treat TRD, including anti-anxiety drugs (e.g., buspirone and tandopsirone) and some atypical antipsychotics (e.g., olanzapine, aripiprazole and quetiapine).[9], [10] Besides medications, non-pharmacological treatment, including cognitive-behavioral therapy and physical therapies (e.g., modified ECT and rTMS), have shown good treatment effect for TRD. In summary, the best treatment outcome is usually achieved after a detailed evaluation of the clinical characteristics of the patient, and the correct identification and management of core risk factors that affect the course of depressive illnesses.