Daihui PENG, Yiru FANG*

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

Daihui PENG, Yiru FANG*

treatment-resistant depression; classification; adjunctive treatment; combined treatment

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 theEuropean 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.

Conflict of interest

The authors declare no conflict of interest related to this article.

Funding

The preparation of this article was supported by the National Natural Science Foundation of China(91232719), the ‘12th Five-year Plan’ of National Key Technologies R&D Program (2012BAI01B04), the National Key Clinical Disciplines at Shanghai Mental Health Center (OMA-MH, 2011-873), the Science Fund of Shanghai Jiao Tong University (YG2012MS11), and Fund of the Science and Technology Commission of the Shanghai Municipality (134119a6200).

1. Lopez AD, Murray CC. The global burden of disease, 1990-2020.Nat Med. 1998; 4 (11): 1241-1243. doi: http://dx.doi.org/10.1038/3218

2. Thase ME. What role do atypical antipsychotic drugs have in treatment-resistant depression?J Clin Psychiatry. 2002; 63(2):95-103

3. Yang G, Wang Y, Zeng Y, Gao GF, Liang X, Zhou M, et al.Rapid health transition in China, 1990-2010: findings from the Global Burden of Disease Study 2010.Lancet. 2013;381(9882): 1987-2015. doi: http://dx.doi.org/10.1016/S0140-6736(13)61097-1

4. [EMACPMP] The European agency for the evaluation of medical products committee for proprietary medical products.Note for Guidance on Clinical Investigation of Medical Products in the Treatment of Depression. Report:CPMP/EWP/518/97. 2002; 4: 4

5. Petersen T, Papakostas GI, Posternak MA, Kant A, Guyker WM, Iosifescu DV, et al. Empirical testing of two models for staging antidepressant treatment resistance.J Clin Psychopharmacol. 2005; 25(4): 336-341

6. Thase ME, Rush AJ. When at first you don’t succeed:sequential strategies for antidepressant nonresponders.J Clin Psychiatry. 1997; 58(Suppl 13): 23-29

7. Fava M. Diagnosis and definition of treatment-resistant depression.Biol Psychiatry. 2003; 53: 649–659. doi: http://dx.doi.org/10.1016/S0006-3223(03)00231-2

8. Joyce PR, Mulder RT, Luty SE, Sullivan PF, McKenzie JM, Abbott RM, et al. Patterns and predictors of remission,response and recovery in major depression treated with fluoxetine or nortriptyline.Aust N Z J Psychiatry. 2002;36(3): 384-391. doi: http://dx.doi.org/10.1046/j.1440-1614.2001.01026.x

9. Liu FR, Xia YP, Zhang JX. [Case-control study of paroxetine with small doses of olanzapine in the treatment of depression].Shanghai Arch Psychiatry. 2005; 5: 13-15.Chinese

10. Dodd S, Berk M. Olanzapine/fluoxetine combination for treatment resistant depression: efficacy and clinical utility.Expert Rev Neurother. 2008; 8(9): 1299-1306

, 2014-12-05; accepted, 2014-12-12)

Dr. Daihui Peng has been working at the Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine since he graduated from Fudan University School of Medicine with a Doctorate in Medicine in 2006. He is now an attending doctor and the Vice Director of the Mood Disorders Division.His main research interests are clinical and neuroimaging studies on mood disorders.

抗抑郁藥聯(lián)合用藥以及其他干預(yù)策略治療難治性抑郁癥的評價

彭代輝，方貽儒

難治性抑郁癥，分類，輔助治療，聯(lián)合治療

Summary: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.

[Shanghai Arch Psychiatry. 2014;26(6): 365-367.

http://dx.doi.org/10.11919/j.issn.1002-0829.214180]

Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China

*correspondence: yirufang@aliyun.com; yirufang@gmail.com

A full-text Chinese translation of this article will be available at www.shanghaiarchivesofpsychiatry.org on January 25, 2015.

概述：有關(guān)難治性抑郁癥（treatment-resistant depression，TRD）的定義及其亞類一直有爭議，從而難以評估治療這種慢性致殘性病癥的不同方案的療效。根據(jù)TRD的癥狀嚴重程度等臨床特征以及人口學(xué)特征方面進行分類可能有助于對同一亞類TRD的識別，并有助于制定針對特定亞類的干預(yù)措施。

本文全文中文版從2015年01月25日起在www.shanghaiarchivesofpsychiatry.org可供免費閱覽下載