Defining treatment-resistant depression: A comprehensive review of the literature

Transcription

1 ANNALS OF CLINICAL PSYCHIATRY 2014;26(3): REVIEW ARTICLE Defining tretment-resistnt depression: A comprehensive review of the literture Kenneth Trevino, PhD Shwn M. McClintock, PhD, MSCS Noelle McDonld Fischer, PhD Ankit Vor, MD, MPH Mustf M. Husin, MD BACKGROUND: Despite the common occurrence nd debilitting nture of tretment-resistnt depression (TRD), currently there is no universlly ccepted definition for TRD. This review summrizes the different methods used to define TRD, nd provides n overview of the TRD literture. METHODS: PsycInfo, Medline, nd Ovid were serched to identify relevnt rticles published in peer-reviewed journls. A combintion nd/or vrition of the following keywords were serched: tretment resistnt, tretment refrctory, depression, defining, stging, nd modeling. Identified rticles provided description of the methods utilized for defining nd/or mesuring TRD, prevlence nd impct of TRD, risk fctors for TRD, nd/or fctors tht contribute to the misclssifiction of non-trd ptients. RESULTS: Multiple methods for defining/mesuring TRD hve been proposed; however, vribility in these methods hs limited the comprbility between TRD studies. Although vrious risk fctors for TRD hve been suggested, few hve been consistently supported. The misclssifiction of non-trd ptients s hving TRD is relted to vrious clinicl nd tretment-relted fctors. CORRESPONDENCE Kenneth Trevino, PhD University of Texs Southwestern Medicl Center Deprtment of Psychitry 5323 Hrry Hines Boulevrd Dlls, TX USA kennethtrevinophd@gmil.com CONCLUSIONS: Adopting universl stndrd definition for TRD is necessry to reduce the vribility in how TRD is defined, nd the misclssifiction of non-trd ptients. A universl definition would benefit clinicl nd reserch settings by llowing dt to be esily compred cross these settings. KEYWORDS: tretment-resistnt depression, mjor depressive disorder, tretment filure, drug resistnce, stging models, risk fctors 222 August 2014 Vol. 26 No. 3 Annls of Clinicl Psychitry

2 ANNALS OF CLINICAL PSYCHIATRY INTRODUCTION Individuls with depression who re unble to chieve n dequte therpeutic response despite multiple ntidepressnt trils, re commonly referred to s hving tretment-resistnt depression (TRD). 1-5 The term tretment-refrctory depression lso hs been used to describe nd/or refer to ptients experiencing TRD. 6 Although the term refrctory suggests greter degree of resistnce, the terms resistnce nd refrctory pper to represent overlpping constructs nd hve been used interchngebly within the literture. 7 A review of the literture clerly supports the occurrence of TRD; however, currently there is no consensus regrding how best to define nd mesure TRD. 3,5,8-11 In the bsence of universl definition, mny different descriptions nd guidelines hve been proposed for defining or ctegorizing TRD. These guidelines hve conceptulized TRD in terms of ctegoricl or continuum-bsed condition. A ctegoricl pproch is designed to indicte the presence or bsence of TRD, while continuum-bsed pproch provides mens of mesuring TRD in terms of degree or level of severity. This high degree of vribility in how TRD hs been defined hs in prt contributed to the frequent misclssifiction of ptients s hving TRD, limited the generlizbility of TRD-relted studies, nd prevented the psychitric community from mking substntil further gins in the understnding nd tretment of TRD. Thus, the use, nd dopting of, stndrdized nd universl definition for TRD s well s n ccurte method of differentiting between TRD nd non-trd is necessry step towrd ddressing these issues. The purpose of this review is to summrize the existing methods used to define nd mesure TRD. To provide comprehensive understnding of TRD this review lso includes summry of the prevlence nd impct of TRD, potentil predictors of tretment resistnce, nd clinicl fctors tht contribute to the misclssifiction of ptients with mjor depressive disorder (MDD) s hving TRD. Specific fetures ssocited with TRD tht re still debted in the literture re reviewed to help guide future reserch. METHODS A literture serch ws conducted using PsycInfo, Medline, nd Ovid to identify relevnt TRD-relted rticles. This serch ws restricted to rticles published in peer-reviewed journls between 1980 nd 2012 nd vilble in English. In ddition, rticles tht primrily focused on niml or peditric reserch were excluded, s well s rticles tht involved primry dignosis other thn MDD. A combintion nd/or vrition of the following terms were used in this serch: tretment resistnt, tretment refrctory, depression, defining, stging, nd modeling. A totl of 283 rticles were identified bsed on the bovementioned serch criteri. The title nd bstrct of these rticles were reviewed to identify relevnt TRD rticles. Articles tht were predominntly focused on proposed/experimentl tretment options (93), neuroimging studies (30), or otherwise unrelted rticles (74) were excluded from this review. Articles tht were selected nd retrieved for further evlution were those tht provided description of t lest one of the following topics: 1) definitions, stging models, or other methods used to define nd/or mesure TRD; 2) prevlence nd impct of TRD; 3) predictors or risk fctors of tretment resistnce; nd 4) fctors tht contribute to the misclssifiction of ptients with MDD s hving TRD. Bsed on this selection criteri, totl of 86 TRD-relted rticles were identified nd reviewed, of which 28 were excluded due to lck of relevnce. The remining 58 rticles then were summrized for this review. RESULTS Prevlence nd impct of tretment-resistnt depression Prevlence/frequency. Studies hve reported tht 30% to 50% of ptients dignosed with MDD do not respond to n initil ntidepressnt tril of dequte dose nd durtion. Although most ptients respond to n dditionl ntidepressnt, some ptients fil to chieve ny significnt decrese in the severity of their depressive symptoms. Multiple studies found tht pproximtely 20% of depressed ptients continued to suffer from depression for up to 2 yers fter initil onset of mjor depressive episode (MDE). 9,12,13 Despite the completion of multiple ntidepressnt mediction tretments nd more ggressive tretment regimens, 15% of ptients dignosed with MDD will continue to suffer from depression. 7 Even mong ptients who experience significnt reduction in their depressive symptoms following n dequte ntidepressnt tril, 60% to 70% of these ptients fil to obtin complete remission of depressive symptoms AACP.com Annls of Clinicl Psychitry Vol. 26 No. 3 August

3 Individul nd societl impct. Although few studies hve exmined the impct nd burden of TRD, the debilitting nture of MDD nd chronic nture of tretment resistnce suggest tht TRD is the most debilitting or distressing form of MDD. 17 Petersen et l 18 found tht TRD ptients experienced mild impirment in their bility to enjoy sexul ctivity, mild to moderte impirment in work-relted ctivities, poor level of involvement in recretionl ctivities, nd poor globl socil functioning. An interesting finding ws the tendency for both ptients nd clinicins to rte globl rtings s more impired reltive to specific functionl res. Additionl reserch is needed to fully understnd the negtive impct of TRD on specific nd globl spects of psychosocil functioning. The societl burden of TRD includes decresed productivity, incresed cost of tretment, nd continuous demnds plced on psychitric services. The cost to receive nd provide dequte tretment for TRD ptients represents much greter finncil burden compred with the cost of tretment for non-trd ptients. In fct, 50% of the nnul cost ssocited with the tretment of depression is due to TRD. 19 This figure is striking given tht TRD ptients only ccount for 15% to 30% of ptients undergoing psychitric tretment for depression. 20,21 A study tht exmined the helth cre expenditures nd chnges in ntidepressnt mediction regimens of TRD ptients found tht overll helth cre expenditures (depression nd medicl relted) incresed in concordnce with the degree of tretment resistnce. 22 Regrding utiliztion of services, TRD ptients were twice s likely to be hospitlized nd hd 12% more outptient visits compred with non-trd ptients. 23 TRD ptients lso used 1.4 to 3 times more psychotropic medictions, which ws significntly greter compred with non-trd ptients. These findings provide cler evidence of the considerble finncil cost, societl burden, nd personl distress cused by TRD. 17,24,25 The disproportionte cost of TRD compred with other forms of depression highlights the need for dditionl reserch regrding the etiology, course, nd tretment of TRD. Risk fctors of tretment-resistnt depression Attempts to identify potentil predictors of TRD hve included the evlution of vrious clinicl nd sociodemogrphic vribles. Although multiple predictors of TRD hve been suggested, few hve been consistently supported in the literture. As such, the clinicl nd sociodemogrphic vribles described in this section should be viewed s risk fctors of TRD vs ctul predictors. One of the min methodologicl issues tht hs mde it difficult to identify nd study potentil risk fctors for TRD involves the use of different guidelines or criteri for defining TRD. 2 The use of different definitions for TRD hs introduced considerble vribility in the literture, which hs limited the comprbility mong different TRD-relted studies. Depression severity nd durtion of illness. Depression severity hs been identified s risk fctor for tretment resistnce. 2,10,26 Studies hve found tht ptients dignosed with MDD who hve greter depression severity, defined by either higher scores on depression mesures (eg, 17-Item Hmilton Rting Scle for Depression [HRSD 17 ]) or the presence of psychotic fetures, re less likely to respond to ntidepressnts, psychotherpy, nd electroconvulsive therpy (ECT) Regrding the reltionship between illness durtion nd tretment response, the current TRD literture hs consistently found greter chronicity or longer durtion of illness to be predictive of incresed unresponsiveness to ntidepressnt tretments. 1,26,28,31-33 Lifetime durtion of depressive illness, which is referred to s ge of onset, hs been found to hve positive reltionship with unresponsiveness to psychophrmcologicl tretments nd higher rtings of tretment-resistnt severity. 3,9 Psychitric nd medicl comorbidity. Psychitric nd medicl comorbidity consistently hve been described s contributing fctor to tretment resistnce. 1,24,26,34 Regrding psychitric comorbidity, personlity, nxiety, nd substnce-relted disorders hve ll been ssocited with TRD or reduced responsiveness to ntidepressnt tretments. 3,35,36 Personlity disorders hve been found to correlte with n erlier ge of onset of depression, which lso hs been found to hve positive reltionship with the degree of tretment resistnce. 3,26,37 Therefore, the presence of comorbid personlity disorder could influence the reltionship between lifetime durtion of illness nd the degree of tretment resistnce. Studies hve found nxious depression to be ssocited with higher degree of tretment resistnce, 36 lower response rtes, 38 nd less stisfctory response to tretment. 39 In ddition, studies compring individuls with nxious depression to those with non-nxious depression found it to be ssocited with incresed risk of functionl impirment, suicide ttempts, lengthier course of illness, nd greter depression severity Substnce-relted comorbidity cn cuse n increse in depressive symptom severity nd decrese in tretment complince. 26 Even moderte lcohol use 224 August 2014 Vol. 26 No. 3 Annls of Clinicl Psychitry

4 ANNALS OF CLINICAL PSYCHIATRY hs been ssocited with greter ntidepressnt tretment resistnce. 43,44 Generl medicl conditions tht my contribute to tretment resistnce due to not being dignosed or dequtely mnged, include dibetes, coronry rtery disese, cncer, nd chronic pin. 26,45 A comorbid medicl condition cn interfere with both ntidepressnt tretment efficcy nd ptient complince. 1,7,46,47 Sociodemogrphic fctors. Attempts to identify sociodemogrphic-relted risk fctors for TRD hve minly produced unrelible results, in prt becuse of the frequent methodologicl vribility when conducting TRD reserch. 2,6 Although ge nd sex hve been described s potentil risk fctors for TRD, these sociodemogrphic vribles hve not been consistently supported in the psychitric literture. Regrding the reltionship between ge nd TRD, mny studies hve indicted tht geritric ptients re t higher risk of nonresponse to ntidepressnt tretments nd delyed remission. 6,48 However, it hs been proposed tht mny older ptients clssified s hving TRD my be incorrectly lbeled tretment resistnt becuse of vrious dignostic nd tretment-relted fctors. 49,50 Fctors tht my contribute to insufficient ntidepressnt response include incorrect or incomplete psychitric dignosis, unrecognized comorbid medicl conditions, nd indequte ntidepressnt mediction trils. The role of sex s potentil risk fctor for TRD hs been even less relible thn ge. According to erlier TRD literture, women tend to demonstrte higher degree of tretment-resistnt severity compred with men. 3,6 Despite initil support for this finding, the literture recently hs become more criticl of the reltionship between femle sex nd tretment resistnce by highlighting limittions of prior TRD reserch. 2,7 Fctors tht my hve contributed to the inclusion of femle sex s possible risk fctor include: 1) differences in prevlence rtes of depression for men nd women; 2) sex differences in tretment response bsed on tretment type; nd 3) methodologicl limittions frequently described in erly TRD studies (eg, TRD smples comprised of both unipolr nd bipolr ptients, vrition in how studies opertionlly defined TRD, results bsed on limited smple sizes, nd use of different outcome mesures). 2,7,9,22,26,51 Differentiting tretment resistnce from pseudoresistnce Findings from community-bsed survey reserch suggest tht pproximtely 60% of ptients initilly clssified s TRD my be experiencing pseudoresistnce. 26,52 Although t present there is no universlly ccepted definition for TRD, 3,5,8-10 there is generl consensus regrding how to differentite tretment resistnce from pseudoresistnce. 7,8,14,26 This process requires estblishing n ccurte psychitric dignosis, completing thorough evlution of ptient s prior tretments, nd determining dequte dosing nd durtion of ny filed ntidepressnt mediction trils. Dignostic issues nd concerns. Ptients who re misdignosed s hving unipolr depression or who re not comprehensively dignosed (eg, substnce-induced mood disorder, psychotic fetures, comorbid medicl conditions) re less likely to receive dequte tretment. They lso tend to experience greter number of tretment filures, which increses their risk of being misclssified s hving TRD. 1,8,26 Given the importnce of estblishing n ccurte dignosis to provide pproprite tretment, comprehensive dignostic evlution, possibly including stndrdized mesure, should be utilized before ptient is clssified s hving TRD. Review of medicl records. A comprehensive review of ptient s psychitric nd previous ntidepressnt mediction history must be completed to determine if ptient cn be clssified s hving TRD. A ptient s record must contin sufficient detils regrding strt nd stop dtes for ech psychitric mediction tril, s well s the dte of ny dose modifictions. 46 This tsk cn be complicted by vritions in record keeping, insufficient dt regrding durtion nd dosge, nd limited description regrding tretment response. Adequte therpeutic dosing nd durtion. Subtherpeutic dosing of ntidepressnt medictions hs been referred to s the primry reson for nonresponse or tretment filure. 7,46 There re vrious physicin-, ptient-, nd mediction-relted fctors tht contribute to subtherpeutic dosing of ntidepressnts. Physicinrelted fctors include misdignosing the primry psychitric disorder nd prescribing n ntidepressnt mediction t n indequte dose or durtion. Ptientrelted fctors include tretment noncomplince, which ccounts for pproximtely 20% of tretment resistnce in ptients with MDD, 6,26 underreporting symptom severity, nd limited ccess to mentl helth services becuse of finncil constrints. 7,26 Finlly, mediction-relted fctors include intolerble side effects nd concomitnt drug interctions. 1 Filure to ccount for these fctors cn result in misclssifiction of ptients with MDD s hving TRD, which in clinicl reserch cn reduce the vlidity nd relibility of ny TRD-relted study results. AACP.com Annls of Clinicl Psychitry Vol. 26 No. 3 August

5 TABLE 1 Thse nd Rush stging method: Antidepressnt tretment resistnce Stge Stge 0 Stge I Stge II Stge III Stge IV Stge V Description Source: Reference 56 Any mediction trils, to dte, determined to be indequte Filure of 1 dequte tril of 1 mjor clss of ntidepressnts Filure of 2 dequte trils of 2 distinctly different clsses of ntidepressnts Stge II resistnce plus filure of n dequte tril of tricyclic ntidepressnt Stge III resistnce plus filure of n dequte tril of n monomine oxidse inhibitor Stge IV resistnce plus course of bilterl electroconvulsive therpy Defining tretment-resistnt depression There exists considerble vribility in the definition nd mesurement of TRD. The generl concept of TRD is described s lck of response to n dequte tril of mediction or other ntidepressnt tretment. 1,46 Although this definition provides generl guideline for how to potentilly define nd mesure TRD, no specific guidelines or criteri hve been widely dopted. 2,7 Of the proposed methods for defining nd mesuring TRD, mny re bsed on mediction filure pproch 6 or the use of stging model. 8 Mediction filure method. The mediction filure method uses ctegoricl pproch to determine the presence or bsence of TRD. 6 This method involves estblishing minimum number nd/or type of ntidepressnt tretment filures tht must be obtined in order for ptient to be clssified s hving TRD. As reported by Berlim nd Turecki, 53 multiple studies hve used this pproch to define TRD; however, there hs been limited consistency mong these studies regrding the exct number nd/or type of tretment filures necessry to estblish the presence of TRD. For exmple, proposed guidelines hve included filure to respond to n dequte dose of the following: single tricyclic ntidepressnt (TCA), monomine oxidse inhibitor (MAOI), or dequte ntidepressnt tretment; 3 dequte trils of tretment including t lest one TCA; 5 dequte tretments; 1 tril of ECT; nd single tril of the newer heterocyclic ntidepressnt. As with ny definition of TRD, this pproch requires comprehensive review of ptient s ntidepressnt tretment history, including the number nd type of prior tretment filures. The use of stndrdized mesure of depressive symptom severity is recommended to evlute tretment outcomes nd determine tretment filures. Stging model method. The stging model methods of TRD re bsed on similr guidelines included in the mediction filure definition of TRD; however, min difference involves the ppliction of these stging methods s mens of mesuring tretment-resistnt severity. This is bsed on the ide tht greter tretment resistnce is ssocited with higher number of filed ntidepressnt tretments. 1,3,6,46 Therefore, ptient s level of tretmentresistnt severity, which is bsed on their response to previous ntidepressnt tretments, cn be used to predict their likelihood of responding to dditionl ntidepressnt tretments. 54 Some of the proposed stging methods lso incorporte ugmenttion nd combined ntidepressnt tretment strtegies, which re consistently recommended nd used s tretment option for TRD. 55 A description of the 4 existing TRD stging models, including their respective strengths nd limittions, hs been provided. Thse nd Rush stging method. 56 The Thse nd Rush stging method consists of 5 levels of tretment resistnce, with higher levels representing greter levels of resistnce (TABLE 1). 56 The ppliction of this stging method involves strtifying ptients dignosed with MDD bsed on the number nd type of ntidepressnt medictions nd ECT tht hve been identified s tretment filures. Bsed on the guidelines outlined for this method, only filed ntidepressnt mediction trils of dequte dose nd durtion cn be used to determine ptient s level of tretment resistnce severity. The progression to higher levels of tretment resistnce involves progression from the more commonly used ntidepressnt tretments, such s selective serotonin reuptke inhibitors (SSRIs), to less frequently used ntidepressnt tretments (eg, MAOIs). Although the Thse nd Rush stging method provides systemtic pproch to the clssifiction of TRD severity, certin limittions re present in this stging method. These include the indirect impliction of hierrchy towrd ntidepressnt mediction efficcy, which suggests tht SSRIs re less effective thn TCAs, nd both re less effective thn MAOIs. 7 In ddition, this stging method excludes certin tretment nd clinicl fctors relted to tretment resistnce. At this time the Thse nd Rush stging method hs not been comprehensively evluted in term of its predictive vlue. Msschusetts Generl Hospitl stging method. The Msschusetts Generl Hospitl stging method 226 August 2014 Vol. 26 No. 3 Annls of Clinicl Psychitry

6 ANNALS OF CLINICAL PSYCHIATRY TABLE 2 Msschusetts Generl Hospitl stging method for tretment-resistnt depression Stge Description Points towrd resistnce score 1 No response to ech dequte ( 6 weeks of n dequte dosge of n ntidepressnt) tril of mrketed ntidepressnt 2 Optimiztion of dose, optimiztion of durtion, nd ugmenttion or combintion of ech tril (bsed on the Msschusetts Generl Hospitl or Antidepressnt Tretment Response Questionnire) 3 Electroconvulsive therpy 3 points Source: Reference point per tril (overll score of resistnce) 0.5 point per tril per optimiztion/strtegy (MGH-S) 57 ws designed to ddress the limittions of the Thse nd Rush stging method. This method stges tretment resistnce severity bsed on the number of previously filed ntidepressnt trils, with higher number of filed medictions representing greter tretment resistnce. Unlike the Thse nd Rush stging method, the MGH-S method considers the intensity nd optimiztion of ech prior tretment through evlution of the dose nd durtion. The MGH-S ssigns points for ech ntidepressnt tril, including combined nd ugmenttion strtegies, bsed on certin criteri or detils regrding ech tretment (TABLE 2 57 ). As such, this method does not imply hierrchy of efficcy regrding the vrious ntidepressnt clsses. This pproch provides continuous vrible tht represents the level of tretment resistnce. The vlidity of the MGH-S ws demonstrted in smll-scle study tht found significnt positive correltion between the MGH-S nd Thse nd Rush stging methods. 57 Further nlysis found tht the MGH-S scores hd significntly greter bility to predict nonremission compred with the Thse nd Rush stging method, suggesting tht continuous scoring system my be more dvntgeous. 57 Although these results re encourging, the generlizbility of these findings is limited due to certin methodologicl fctors (eg, smll smple size, relince on dt derived from chrt review). Moreover, it is uncler how the MGH-S guidelines were determined for ssigning points. 7 Europen stging method. The Europen stging method 6 includes both clssifiction nd stging pproch to TRD. Ptients cn be clssified s nonresponders, experiencing TRD, or s experiencing chronic resistnt depression (CRD). As with the previously described TRD stging methods, the Europen stging method lso requires n evlution of previous ntidepressnt tretments nd tretment response. Depressed ptients who hve filed to respond to one ntidepressnt mediction of dequte dose nd durtion re clssified s nonresponders to tht clss of mediction (SSRI, TCA, MAOI, etc.). Bsed on the Europen stging method, ptients re considered tretment resistnt fter filing to respond to 2 trils of different ntidepressnts of dequte dose nd durtion. An dequte durtion is defined s tking n ntidepressnt mediction t n dequte dose for period of 6 to 8 weeks. After clssifiction of TRD hs been estblished, the stging of TRD severity is bsed on the number of dditionl filed ntidepressnt medictions. The Europen stging method provides considertion for the prolonged durtion or chronic nture ssocited with TRD. Ptients who hve experienced MDE for more thn yer, despite completing severl ntidepressnt trils of dequte dose nd durtion, re clssified s hving CRD (TABLE 3). 6 The 2 min fetures of the Europen stging method tht re bsent from other stging methods re 1) the estblishment of required minimum number (2) of filed ntidepressnt medictions to clssify ptient s hving TRD; nd 2) the considertion given to the chronic nture of TRD. 6,7 Although single filed tretment my represent some degree of tretment resistnce, 6 requiring 2 filed ntidepressnt medictions from different clsses is generlly ccepted in the psychitric literture s more representtive of TRD. 7,24,35,46,54,58 Despite these dded benefits, the Europen stging method does not ddress symptom severity or mediction ugmenttion strtegies. Mudsley Stging Method. The Mudsley Stging Method (MSM) is the most recent stging method, nd is bsed on the principle tht tretment resistnce occurs s continuum, nd is gretly influenced by vrious dimensionl fctors. 59 The MSM ws developed s multi dimensionl stging method for TRD tht incorported vrious tretment nd clinicl fctors. The tretment fctors incorported in the MSM include number of AACP.com Annls of Clinicl Psychitry Vol. 26 No. 3 August

7 TABLE 3 The Europen stging method for tretment-resistnt depression Stge Definition Durtion of tril A. Nonresponder Nonresponse to 1 dequte ntidepressnt tril of: TCA, SSRI, MAOI, SNRI, ECT, or other ntidepressnt(s) 6 to 8 weeks B. TRD Resistnce to 2 dequte ntidepressnt trils TRD 1: 12 to 16 weeks TRD 2: 18 to 24 weeks TRD 3: 24 to 32 weeks TRD 4: 30 to 40 weeks TRD 5: 36 weeks to 1 yer C. CRD Resistnce to severl ntidepressnt trils, including ugmenttion strtegy Source: Reference months CRD: chronic resistnt depression; ECT: electroconvulsive therpy; MAOI: monomine oxidse inhibitor; SNRI: serotonin-norepinephrine reuptke inhibitor; SSRI: selective serotonin reuptke inhibitor; TCA: tricyclic ntidepressnt; TRD: tretment-resistnt depression. tretment filures, use of ugmenttion tretment strtegies, nd use of ECT. Regrding clinicl fctors, the MSM includes illness durtion nd symptom severity in the stging process for TRD (TABLE 4 59 ). As with other stging methods, the MSM only considers ntidepressnt mediction trils, including ugmenting strtegies, of dequte dose nd durtion to determine the totl number of tretment filures. 59 A higher number of filed tretments of dequte dose nd durtion generlly is viewed s representing greter degree of tretment resistnce. 1,6,7,24,35,46,54,58 The MSM does not differentite between tretment filures of different mediction clsses, nor does it hierrchiclly rrnge mediction clsses. Thus, the MSM does not mke ssumptions regrding the efficcy of ntidepressnt mediction bsed on clss. This is in contrst to the Thse nd Rush stging method, 56 which tcitly implies hierrchy mong the clsses of ntidepressnt gents. 7 The inclusion of depression severity nd durtion ccounts for the nture nd course of depressive illness. Symptom severity nd illness durtion both hve been ssocited with decresed efficcy nd persistence of depressive residul symptoms. 28,29,32,33,60 Although reserch using the MSM is limited, 2 smllscle studies hve produced promising results regrding its predictive vlidity. The initil study tht developed nd tested the MSM involved cse review of smll (N = 88) TRD cohort of ptients who were recently dischrged from n inptient unit tht specilized in tretment-resistnt mood disorders. 59 The MSM predicted tretment resistnce in pproximtely 86% of the cohort. Importntly, ll 3 fctors of the MSM (number of tretment filures, severity, nd durtion) independently predicted tretment resistnce. These findings were substntited in study tht exmined the long-term outcome of TRD ptients bsed on length of depressive episode nd level of functionl impirment. 61 The study found the MSM hd resonble predictive vlidity for TRD ptients, becuse higher MSM scores were ssocited with the persistence of the MDE. Summry of stging models. The development of TRD stging models ws n importnt step towrd developing more systemtic method of defining TRD nd mesuring tretment-resistnt severity. Newly developed stging models hve continued to ddress vrious limittions of previous stging models, which hs been encourging given the comprehensive nd complex nture of TRD. To dte, however, few lrge-scle studies hve been conducted to vlidte ny 1 stging model. 7,8,15 A fctor tht hs contributed to the limited number of lrge-scle TRD studies involves the lck of consensus regrding specific fetures ssocited with TRD. 6,7,35 Unresolved issues nd concerns Number nd type of tretment filures. Although the number nd type of prior mediction filures re generlly considered n indiction of TRD, t this time there is continued debte regrding the exct number nd type of tretment filures required to estblish TRD. 14,62 In ddition, despite the development nd utility of vrious forms of psychotherpy nd neurostimultion modlities, nonpsychophrmcologicl ntidepressnt tretments serve only miniml role in determining tretment resistnce. 1,7 Among mny of the proposed guidelines for defining TRD, ECT is the only nonphrmcologicl tretment routinely evluted s mesure of TRD. 6,14,56,57, August 2014 Vol. 26 No. 3 Annls of Clinicl Psychitry

8 ANNALS OF CLINICAL PSYCHIATRY Vrition in prescription guidelines. There is lck of consensus in terms of which prescription guidelines constitute n dequte therpeutic dose nd durtion. 6,7,35 For exmple, mong 2 commonly used ntidepressnt prescription guidelines the minimum effective dose for the ntidepressnt sertrline differed from 50 to 100 mg. 4,63 To further compre the differences in ntidepressnt dosing guidelines, the minimum effective dosge for severl ntidepressnts hs been provided in TABLE The minimum effective dose for these ntidepressnts is bsed on 2 commonly used prescription guidelines, the Antidepressnt Tretment History Form 4 nd the Mudsley Prescribing Guidelines. 63 The length of time tht hs been used to estblish n ntidepressnt tretment s being of dequte durtion hs rnged from 4 to 12 weeks. 1,4,46 The consequence of using different prescription guidelines to determine ptient s totl number of tretment filures includes loss of comprbility mong different TRD-relted studies. Future reserch is wrrnted to determine which prescription guidelines nd durtion of tretment to dopt. Mesuring tretment outcome nd defining tretment filure. The occurrence of multiple tretment filures is considered defining feture of TRD. For this reson, evluting tretment outcomes nd determining tretment filures is n essentil prt of ny mesure or definition used to ctegorize or identify ptients with TRD. Unfortuntely, t this time there is no consensus regrding wht constitutes or how to define filed tretment. 24 A method commonly used in clinicl reserch settings to determine if tretment hs filed involves n evlution of the presence nd severity of vrious depressive symptoms following the completion of n dequte tretment course. Depressive symptoms generlly re mesured with the use of stndrdized nd vlidted depression rting instrument (eg, HRSD 17, Inventory of Depressive Symptomology). Although depression symptom severity mesures re useful in determining how prticulr tretment ffected ptient s level of depression severity, there is debte regrding wht degree of chnge in depression scores should be used to differentite filed tretment from successful tretment. 7,24 This debte hs involved the concepts of response nd remission, which re terms commonly used in clinicl reserch. The concept of response generlly is defined s 50% reduction in depressive symptom severity; however, there is less consensus regrding the concept of remission, which lcks n TABLE 4 Mudsley Stging Method for tretment-resistnt depression: Recommended scoring conventions Prmeter/ dimension Prmeter specifiction Score Durtion Acute ( 12 months) 1 Symptom severity (t bseline) Tretment filures Sub-cute (13 to 24 months) 2 Chronic (>24 months) 3 Subsyndroml 1 Syndroml Mild 2 Moderte 3 Severe without psychosis 4 Severe with psychosis 5 Antidepressnts Level 1: 1 to 2 Medictions 1 Level 2: 3 to 4 Medictions 2 Level 3: 5 to 6 Medictions 3 Level 4: 7 to 10 Medictions 4 Level 5: >10 Medictions 5 Augmenttion Not used 0 Electroconvulsive therpy Used 1 Not used 0 Used 1 Totl 15 Source: Reference 59. empiriclly vlidted definition. 24,64,65 Some reserchers hve described remission s complete bsence of depressive symptoms, 65 while others hve proposed specific cutoff scores for the vrious depression rting instruments. 64 The primry rgument ginst response-bsed criteri for determining tretment filure involves the issue of residul depressive symptoms. 26,46,65 Although 50% reduction in depressive symptoms demonstrtes substntil improvement, it is uncler if this ccurtely represents successful tretment. A 50% reduction in depressive symptoms my be less relevnt or cliniclly significnt for ptients with extremely high depression scores t bseline. 46 However, it lso is difficult to clssify ny tretment responsible for such sizble reduction in depressive symptoms s filure. In fct, for TRD some reserchers hve postulted tht lower overll reduction in depressive symptoms (25% to 40%) is sufficient to represent meningful clinicl response. 58,64 AACP.com Annls of Clinicl Psychitry Vol. 26 No. 3 August

9 TABLE 5 Antidepressnt mediction: Minimum effective dosing Drug clss Antidepressnt Minimum effective dose (mg/d) ATHF DISCUSSION MPG SSRI Citloprm Escitloprm Fluoxetine Fluvoxmine Proxetine Sertrline TCA Amitriptyline Clomiprmine Doxepin Imiprmine Nortriptyline Trimiprmine Desiprmine 200 Mprotiline 200 Protriptyline MAOI Isocrboxzid Phenelzine Trnylcypromine Selegiline Selegiline (TD) 9 SNRI Duloxetine Venlfxine TeCA Mirtzpine Amoxpine 400 SARI Nefzodone 300 Trzodone NRI Reboxetine 8 8 NDRI Bupropion 300 Minimum effective dose ws not indicted in the Mudsley Prescription Guidelines. Source: References 4,63. ATHF: Antidepressnt Tretment History Form; MAOI: monomine oxidse inhibitors; MPG: Mudsley Prescription Guidelines; NDRI: norepinephrine-dopmine reuptke inhibitor; NRI: norepinephrine reuptke inhibitor; SARI: serotonin ntgonist nd reuptke inhibitors; SNRI: serotonin-norepinephrine reuptke inhibitor; SSRI: selective serotonin reuptke inhibitor; TCA: tricyclic ntidepressnt; TD: trnsderml; TeCA: tetrcyclic ntidepressnt. Becuse of its chronic nture, TRD is considered the most distressing nd disbling form of depression, representing both n individul nd societl burden. Multiple predictors or risk fctors of TRD hve been proposed; however, few hve been consistently supported in the TRD literture. Psychitric comorbidity (eg, personlity, nxiety, nd substnce-relted disorders), depression severity, nd durtion of illness hve consistently been ssocited with tretment-resistnce. 1,26,28,31-33,35,36 A methodologicl issue tht hs mde it difficult to identify potentil risk fctors for TRD involves bsence of universlly ccepted criteri for defining TRD. The vribility in how TRD hs been defined hs resulted in significnt nd t times uncknowledged heterogeneity mong TRD studies nd smples, which limits the vlidity nd relibility of these studies. Becuse of the frequent misclssifiction of depressed ptients s experiencing TRD, focus hs been brought to the phenomenon of pseudoresistnce, which refers to the nonresponse of n ntidepressnt tretment dministered t n indequte dose nd/or durtion. 26,52 Fctors tht contribute to indequte dosing of ntidepressnt medictions includes physicin- nd mediction-relted fctors. In ddition to indequte dosing, which is considered the primry reson for tretment filures, 7,46 ptients nondherence to tretment ccounts for pproximtely 20% of the tretment resistnce in ptients with MDD. 6,26 In contrst to pseudoresistnce, less ttention hs been given to the potentil misclssifiction of TRD ptients s not hving TRD, which cn occur if depressed ptient is inccurtely viewed s tretment responder. The issue of identifying other fctors tht my contribute to the misclssifiction of TRD ptients s not hving TRD wrrnts further considertion. Although severl guidelines nd methods for defining TRD hve been proposed, currently there is no stndrd, universlly ccepted definition or criteri for TRD. 2,7 Mny of the proposed methods to define nd/or mesure TRD re bsed on mediction filure pproch 6 or the use of stging model. 8 The mediction filure method determines the presence or bsence of TRD bsed on n estblished minimum number nd/or type of ntidepressnt tretment filures tht must be obtined. In comprison, stging models re systemtic methods with specific scoring guidelines tht cn be used to define TRD nd mesure tretment-resistnt severity. The MSM is the newest TRD stging model. 59 The multidimensionl nd comprehensive nture of the MSM mkes it n idel method for stging tretment-resistnt severity nd differentiting TRD from non-trd. Although initil studies hve produced fvorble results regrding the predictive vlidity of the MSM, 59,66 dditionl reserch 230 August 2014 Vol. 26 No. 3 Annls of Clinicl Psychitry

10 ANNALS OF CLINICAL PSYCHIATRY is needed to better understnd the psychometric properties nd clinicl utility of the MSM. The development of TRD stging models hs been n importnt step towrd estblishing more systemtic method of defining TRD nd mesuring tretment-resistnce severity. Although newly developed stging models hve continued to ddress the limittions of previous stging models, this lso hs resulted in more complicted stging models. The incresed complexity of TRD stging model or definition my indvertently reduce the likelihood of its widespred use or universl cceptnce. In ddition, few lrge-scle studies hve been conducted to vlidte ny one of the proposed stging models. 7,8,15 The current lck of consensus in terms of how to opertionlly define TRD is the result of multiple unresolved issues ssocited with TRD. First, despite the development nd utility of vrious forms of psychotherpy nd neurostimultion modlities, nonpsychophrmcologicl ntidepressnt tretments serve only miniml role in determining tretment resistnce. 1,7 Second, there is no consensus regrding the extent of chnge in depression symptom severity needed to determine if tretment is filure or success. 24 Third, there is continued debte regrding wht constitutes n dequte ntidepressnt tril in terms of dose nd durtion. These limittions hve contributed to the wide vrition in how TRD hs been defined both in clinicl nd reserch settings. 8,53,67 CONCLUSIONS The disproportionte cost of TRD compred with other forms of depression highlights the need for dditionl reserch regrding the etiology, course, nd tretment of TRD. However, fctor tht hs limited such reserch is the lck of consensus regrding how to define nd mesure TRD. The bsence of n ccurte nd universl definition of TRD lso hs contributed to the frequent misclssifiction of ptients s hving TRD. Given the incresed risk of relpse ssocited with this ptient popultion, better identifiction of TRD is necessry to determine pproprite tretment strtegies for these ptients. Estblishing universl definition of TRD is essentil for ensuring homogeneity mong reserch smples, nd to determine the ppliction of clinicl reserch findings to clinicl prctice. TRD continues to chllenge mentl helth providers; therefore, further reserch is wrrnted to dopt stndrdized, universlly ccepted definition or criteri for TRD. DISCLOSURES: Dr. Trevino hs received reserch grnt support funding from the Ntionl Institute of Mentl Helth. Dr. McClintock hs received reserch grnt support funding from the Brin nd Behvior Foundtion, the Ntionl Center for Reserch Resources, nd the Ntionl Institutes of Helth, nd ws consultnt for Shire, Inc. Drs. McDonld Fischer nd Vor report no finncil reltionships with ny compny whose products re mentioned in this rticle or with mnufcturers of competing products. Dr. Husin hs received reserch grnt support/funding from Alkermes, Brinswy, Cyberonics, MgStim (equipment only), NeoSync, Neuronetics (previous), NARSAD, NIA, NIDA, NIH/NIMH, NINDS, the Stnley Foundtion, nd St. Jude Medicl (ANS). ACKNOWLEDGMENTS: This review ws supported in prt from grnt/fellowship from the Ntionl Institute of Mentl Helth (T32 MH ) to Dr. Trevino. REFERENCES 1. Fv M. Dignosis nd definition of tretmentresistnt depression. Biol Psychitry. 2003;53: Bermn RM, Nrsimhn M, Chrney DS. Tretmentrefrctory depression: definitions nd chrcteristics. Depress Anxiety. 1997;5: Fgiolini A, Kupfer DJ. Is tretment-resistnt depression unique subtype of depression? Biol Psychitry. 2003;53: Sckeim HA. The definition nd mening of tretment-resistnt depression. J Clin Psychitry. 2001;62(suppl 16): Shrn P, Sxen S. Tretment-resistnt depression: clinicl significnce, concept nd mngement. Ntl Med J Indi. 1998;11: Souery D, Amsterdm J, de Montigny C, et l. Tretment resistnt depression: methodologicl overview nd opertionl criteri. Eur Neuropsychophrmcol. 1999;9: Berlim MT, Turecki G. Definition, ssessment, nd stging of tretment-resistnt refrctory mjor depression: review of current concepts nd methods. Cn J Psychitry. 2007;52: Souery D, Ppkosts GI, Trivedi MH. Tretmentresistnt depression. J Clin Psychitry. 2006;67(suppl 6): Mlhi GS, Prker GB, Crwford J, et l. Tretmentresistnt depression: resistnt to definition? Act Psychitr Scnd. 2005;112: Nelsen MR, Dunner DL. Clinicl nd differentil dignostic spects of tretment-resistnt depression. J Psychitr Res. 1995;29: Guscott R, Grof P. The clinicl mening of refrctory depression: review for the clinicin. Am J Psychitry. 1991;148: Keller MB, Shpiro RW, Lvori PW, et l. Relpse in mjor depressive disorder: nlysis with the life tble. Arch Gen Psychitry. 1982;39: Pykel ES. Historicl overview of outcome of depression. Br J Psychitry Suppl. 1994;165(suppl 26): Souery D, Vn der Auwer K. The multiple fcets of tretment-resistnt depression. CNS Spectr. 2004;9: O Rerdon JP, Amsterdm JD. Tretment-resistnt depression: progress nd limittions. Psychitric Annls. 1998;28: Nierenberg AA, Husin MM, Trivedi MH, et l. Residul symptoms fter remission of mjor depressive disorder with citloprm nd risk of relpse: STAR*D report. Psychol Med. 2010;40: Greden JF. The burden of disese for tretmentresistnt depression. J Clin Psychitry. 2001;62(suppl 16): Petersen TJ, Ppkosts GI, Mhl Y, et l. Psychosocil functioning in ptients with tretment resistnt depression. Eur Psychitry. 2004;19: Rost K, Zhng M, Fortney J, et l. Expenditures for the tretment of mjor depression. Am J Psychitry. 1998; 155: AACP.com Annls of Clinicl Psychitry Vol. 26 No. 3 August

11 20. Ros S, Agüer L, de l Gándr J, et l. Potentition strtegies for tretment-resistnt depression. Act Psychitr Scnd. 2005;112:14-24, Burrows GD, Normn TR, Judd FK. Definition nd differentil dignosis of tretment-resistnt depression. Int Clin Psychophrmcol. 1994;9(suppl 2): Russell JM, Hwkins K, Ozminkowski RJ, et l. The cost consequences of tretment-resistnt depression. J Clin Psychitry. 2004;65: Crown WH, Finkelstein S, Berndt ER, et l. The impct of tretment-resistnt depression on helth cre utiliztion nd costs. J Clin Psychitry. 2002;63: Keller MB. Issues in tretment-resistnt depression. J Clin Psychitry. 2005;66(suppl 8): Hirschfeld RM, Keller MB, Pnico S, et l. The Ntionl Depressive nd Mnic-Depressive Assocition consensus sttement on the undertretment of depression. JAMA. 1997;277: Kornstein SG, Schneider RK. Clinicl fetures of tretment-resistnt depression. J Clin Psychitry. 2001; 62(suppl 16): de Vreede IM, Burger H, vn Vliet IM. Prediction of response to ECT with routinely collected dt in mjor depression. J Affect Disord. 2005;86: Blom MB, Spinhoven P, Hoffmn T, et l. Severity nd durtion of depression, not personlity fctors, predict short term outcome in the tretment of mjor depression. J Affect Disord. 2007;104: Rubenstein LV, Ryburn NR, Keeler EB, et l. Predicting outcomes of primry cre ptients with mjor depression: development of depression prognosis index. Psychitr Serv. 2007;58: Howlnd RH, Wilson MG, Kornstein SG, et l. Fctors predicting reduced ntidepressnt response: experience with the SNRI duloxetine in ptients with mjor depression. Ann Clin Psychitry. 2008;20: Joyce PR, Mulder RT, Luty SE, et l. Ptterns nd predictors of remission, response nd recovery in mjor depression treted with fluoxetine or nortriptyline. Aust N Z J Psychitry. 2002;36: Mynors-Wllis L, Gth D. Predictors of tretment outcome for mjor depression in primry cre. Psychol Med. 1997;27: McGrth PJ, Stewrt JW, Quitkin FM, et l. Predictors of relpse in prospective study of fluoxetine tretment of mjor depression. Am J Psychitry. 2006; 163: Viet E, Colom F. Therpeutic options in tretmentresistnt depression. Ann Med. 2011;43: Jnick PG, Dowd SM. Tretment-resistnt depression: n updte on dignosis nd mngement. Psychophrm Review. 2009;44: Kennedy SH. Treting ech nd every depressed ptient. J Psychophrmcol. 2008;22(suppl 7): Thse ME. The role of Axis II comorbidity in the mngement of ptients with tretment-resistnt depression. Psychitr Clin North Am. 1996;19: Fv M, Uebelcker LA, Alpert JE, et l. Mjor depressive subtypes nd tretment response. Biol Psychitry. 1997;42: Fv M, Rush AJ, Alpert JE, et l. Difference in tretment outcome in outptients with nxious versus nonnxious depression: STAR*D report. Am J Psychitry. 2008;165: Kessler RC, McGongle KA, Zho SP, et l. Lifetime nd 12-month prevlence of DSM-III-R psychitric disorders in the United Sttes. Results from the Ntionl Comorbidity Survey. Arch Gen Psychitry. 1994;51: Joffe RT, Bgby R, Levitt A. Anxious nd nonnxious depression. Am J Psychitry. 1993;150: Fv M, Rush AJ, Alpert JE, et l. Wht clinicl nd symptom fetures nd comorbid disorders chrcterize outptients with nxious mjor depressive disorder: repliction nd extension. Cn J Psychitry. 2006;51: Worthington JJ, Fv M, Agustin C, et l. Consumption of lcohol, nicotine, nd cffeine mong depressed outptients. Reltionship with response to tretment. Psychosomtics. 1996;37: Cstned R, Sussmn N, Westreich L, et l. A review of the effects of moderte lcohol intke on the tretment of nxiety nd mood disorders. J Clin Psychitry. 1996;57: Sonwll SB, Ppkosts GI, Petersen TJ, et l. Elevted cholesterol levels ssocited with nonresponse to fluoxetine tretment in mjor depressive disorder. Psychosomtics. 2002;43: Bird D, Hddd PM, Dursun SM. An overview of the definition nd mngement of tretment-resistnt depression. Bulletin of Clinicl Psychophrmcology. 2002;12: Pohle K, Domschke K, Roehrs T, et l. Medicl comorbidity ffects ntidepressnt tretment response in ptients with melncholic depression. Psychother Psychosom. 2009;78: Nemeroff CB. Prevlence nd mngement of tretment-resistnt depression. J Clin Psychitry. 2007; 68(suppl 8): Mulsnt BH, Pollock BG. Tretment-resistnt depression in lte life. J Geritr Psychitry Neurol. 1998; 11: Flint AJ. Tretment-resistnt depression in lte life. CNS Spectr. 2002;7: Dyck MJ. Tretment-resistnt depression: critique of current pproches. Aust N Z J Psychitry. 1994;28: Nierenberg AA, Amsterdm JD. Tretment-resistnt depression: definition nd tretment pproches. J Clin Psychitry. 1990;51:39-47; discussion Berlim MT, Turecki G. Wht is the mening of tretment resistnt/refrctory mjor depression (TRD)? A systemtic review of current rndomized trils. Eur Neuropsychophrmcol. 2007;17: Rush AJ, Thse ME, Dubé S. Reserch issues in the study of difficult-to-tret depression. Biol Psychitry. 2003;53: Crvlho AF, Mchdo JR, Cvlcnte JL. Augmenttion strtegies for tretment-resstnt depression. Curr Opin Psychitry. 2009;22: Thse ME, Rush AJ. When t first you don t succeed: sequentil strtegies for ntidepressnt nonresponders. J Clin Psychitry. 1997;58(suppl 13): Petersen T, Ppkosts GI, Posternk MA, et l. Empiricl testing of two models for stging ntidepressnt tretment resistnce. J Clin Psychophrmcol. 2005;25: Annth J. Tretment-resistnt depression. Psychother Psychosom. 1998;67: Fekdu A, Wooderson SC, Donldson C, et l. A multidimensionl tool to quntify tretment resistnce in depression: the Mudsley stging method. J Clin Psychitry. 2009;70: Kton W, Lin E, von Korff M, et l. The predictors of persistence of depression in primry cre. J Affect Disord. 1994;31: Fekdu A, Wooderson SC, Mrkopoulou K, et l. The Mudsley Stging Method for tretment-resistnt depression: prediction of longer-term outcome nd persistence of symptoms. J Clin Psychitry. 2009;70: O Rerdon JP, Brunswick DJ, Amsterdm JD. Tretment-resistnt depression in the ge of serotonin: evolving strtegies. Curr Opin Psychitry. 2000;13: Tylor D, Pton C, Kpur S. The Mudsley prescribing guidelines. 10th ed. London, United Kingdom: Inform Helthcre; Rush AJ, Kremer HC, Sckeim HA, et l; ACNP Tsk Force. Report by the ACNP Tsk Force on response nd remission in mjor depressive disorder. Neuropsychophrmcology. 2006;31: Nierenberg AA, DeCecco LM. Definitions of ntidepressnt tretment response, remission, nonresponse, prtil response, nd other relevnt outcomes: focus on tretment-resistnt depression. J Clin Psychitry. 2001;62(suppl 16): Fekdu A, Wooderson SC, Mrkopoulo K, et l. Wht hppens to ptients with tretment-resistnt depression? A systemtic review of medium to long term outcome studies. J Affect Disord. 2009;116: Crvlho AF, Cvlcnte JL, Cstelo MS, et l. Augmenttion strtegies for tretment-resistnt depression: literture review. J Clin Phrm Ther. 2007; 32: Kenneth Trevino, PhD Neurostimultion Reserch Lb Deprtment of Psychitry University of Texs Southwestern Medicl Center Dlls, Texs, USA Shwn M. McClintock, PhD, MSCS Neurostimultion Reserch Lb Deprtment of Psychitry University of Texs Southwestern Medicl Center Dlls, Texs, USA Neurocognitive Reserch Lbortory Division of Brin Stimultion nd Neurophysiology Deprtment of Psychitry nd Behviorl Sciences, nd Psychology nd Neuroscience Duke University School of Medicine Durhm, North Crolin, USA Noelle McDonld Fischer, PhD Neurostimultion Reserch Lb Deprtment of Psychitry University of Texs Southwestern Medicl Center Dlls, Texs, USA Ankit Vor, MD, MPH Neurostimultion Reserch Lb Deprtment of Psychitry University of Texs Southwestern Medicl Center Dlls, Texs, USA Mustf M. Husin, MD Neurostimultion Reserch Lb Deprtment of Psychitry University of Texs Southwestern Medicl Center Dlls, Texs, USA 232 August 2014 Vol. 26 No. 3 Annls of Clinicl Psychitry