Journal of Affective Disorders 131 (2011) 92–103

Contents lists available at ScienceDirect

Journal of Affective Disorders

j ourna l homepage: www.e lsev ie r.com/ locate / j ad

Research report

Prospective evaluation of specialist inpatient treatment for refractoryaffective disorders

Sarah C. Wooderson a,b, Mario F. Juruena a, Abebaw Fekadu a,b, Clodagh Commane b,Catherine Donaldson b, Mary Cowan b, Moya Tomlinson b, Lucia Poon b, Kalypso Markopoulou a,b,Lena Rane a,b, Jacek Donocik b, Catherine Tunnard b, Brendan Masterson b, Anthony J. Cleare a,b,c,⁎a King's College London, Institute of Psychiatry, Department of Psychological Medicine, Section of Neurobiology of Mood Disorders, 103 Denmark Hill, London SE5 8AZ, UKb The National Affective Disorders Unit, South London and Maudsley NHS Foundation Trust, Bethlem Royal Hospital, Monks Orchard Road, Beckenham, Kent BR3 3BS, UKc The NIHR Biomedical Research Centre at the South London and Maudsley NHS Foundation Trust and the Institute of Psychiatry, King's College London, UK

a r t i c l e i n f o

⁎ Corresponding author. Section of Neurobiology oP074, Department of Psychological Medicine, InstitutCollege London, 103 Denmark Hill, London SE5 8AF, U5130; fax: +44 207 848 0783.

E-mail address: anthony.cleare@kcl.ac.uk (A.J. Clea

0165-0327/$ – see front matter © 2010 Elsevier B.V.doi:10.1016/j.jad.2010.11.002

a b s t r a c t

Article history:Received 21 April 2009Received in revised form 6 October 2010Accepted 2 November 2010Available online 7 December 2010

Background: Little data exist to inform the treatment of severe and resistant affective disorders.We report here the effectiveness of specialist multimodal inpatient treatment for refractoryaffective disorders.Methods: Prospective evaluation of 225 consecutive patients admitted to the National AffectiveDisorders Unit between 2001 and 2008.Results: Patients were highly treatment-resistant: most had already received ECT, lithiumaugmentation and over 10 prior treatment trials. Even so, sequential assessment with theHamilton Depression Rating Scale found that 69% showed a clinical response (≥50% reductionin Hamilton score) to intensive therapy during admission; 50% continued to sustain a fullresponse and 71% at least a partial response on discharge. Patients' self-ratings (57% very muchor much improved, 24% slightly improved) and relative and referrer reports (75% and 68%respectively rated patients as improved) gave similar levels of improvement.Limitations: This was an observational study, without any untreated control group. Thegeneralisability of the findings is limited by the highly specialised nature of the unit.Conclusions: Most patients with depression highly resistant to prior treatment respond tospecialist and intensive multimodal inpatient therapy.

© 2010 Elsevier B.V. All rights reserved.

Keywords:Treatment resistant depressionRefractory depressionUnipolar depressionBipolar depressionCombination therapyInpatient treatmentPsychopharmacologyClinical outcomes

1. Introduction

Chronic, unremitting major depression is common (WHO,2001) and leads to substantial suffering, disability andfinancial costs (Greenberg et al., 1993; Scott and Dickey,2003; Thomas and Morris, 2003). With 50–60% of patientswith depression failing to respond adequately to antidepres-sants (Fava, 2003), treatment-resistant depression (TRD) is

f Mood Disorders, Boxe of Psychiatry, King'sK. Tel.: +44 207 848

re).

All rights reserved.

likely to contribute considerably to the overall impact ofdepression (Greden, 2001; Malhi et al., 2005). TRD presents asubstantial challenge with a significant risk of suicide(Dunner et al., 2006), and poor long-term prognosis (Fekaduet al., 2009a,b).

However, many general adult psychiatrists do not havesufficient expertise, experience or access to resources tomanage effectively severe and resistant affective disorders(Ker and Anderson, 2006). In the UK, the National Institute forClinical Excellence (NICE) recommends ‘When a patient'sdepression has failed to respond to various strategies foraugmentation and combination treatments, referral to aclinician with a specialist interest in treating depressionshould be considered’.

93S.C. Wooderson et al. / Journal of Affective Disorders 131 (2011) 92–103

Studies to date on the effectiveness of treatment for TRDhave typically used patients failing one or two antidepressanttreatments, i.e. relativelymild TRD(BerlimandTurecki, 2007).Few studies have reported onmore severely resistant patients,and there is also little data on the effectiveness of inpatienttreatment for TRD. In this paper we report the results of a 7-year prospective evaluation of the outcome of specialist,multimodal, inpatient treatment in patients admitted to aNational Unit specializing in the assessment and treatment ofrefractory affective disorders. We hypothesized that previ-ously unresponsive depressive illnesses would respond tomultimodal inpatient treatment both symptomatically andfunctionally.

2. Method

2.1. Brief description of the service

The National Affective Disorders Unit (ADU) at the SouthLondon and Maudsley NHS Foundation Trust (SLaM) offers aspecialised tertiary referral service for patients with complexand difficult-to-treat affective disorders including TRD andBipolar Disorder (BD). Although not a nationally commis-sioned service, it receives patients from all parts of the UK, intandem with other services in the National Division of SLaM.The ADU also offers a service to Health Care Professionalswith affective disorders requiring specialist input. Theservice's inpatient unit provides a comprehensive assess-ment, and if appropriate subsequent treatment package, forthe most challenging cases.

Patients are admitted for a comprehensivemultidisciplinaryassessment that takes 4–6 weeks and involves medical,psychological, occupational therapy, nursing and couple ther-apy input. Blood levels of prescribed psychotropic medicationare routinely taken to assess compliance and detect potentialpharmacokineticmechanisms for treatment resistance (such asfast metabolisers or drug–drug interactions). Following assess-ment, a detailed treatment plan is made, and usually under-taken on the unit.

Multimodal treatment incorporating the major evidencebased therapies for affective disorder is offered, including:pharmacotherapy (where indicated using complex combina-tions and high dose therapy), psychological therapy (Cogni-tive Behavioural Therapy (CBT), Schema-based CBT andInterpersonal Therapy), occupational therapy (involvingbehavioural activation), couple therapy and physical thera-pies (ECT and assessment for suitability for neurosurgicalinterventions). Supportive and enabling nursing care is animportant part of the treatment package. Treatment and/orreferral for general health problems is undertaken given thetwo-way interaction between physical and mental health. Afuller description of the service is available on-line at https://www.national.slam.nhs.uk/services/adult-services/affective-disorders/.

Treatment for each patient is individualised, and alsobased on an agreement between patient and clinician, butchosen interventions are based on structured guidance.Hence, the choice of medication follows the guidance onfirst, second and third line interventions as detailed in theMaudsley Prescribing Guidelines (Taylor et al., 2007).However, there is not a rigid adherence, as other factors are

also considered in the choice of medications including patientpreference, suitability/motivation for a discontinuation fol-lowed by washout period (e.g. for the use of MAOIs); presentmedication (e.g. a medication already started but not fullytitrated being continued — often applying to the particularlyslow titration period for lamotrigine); other indicators (e.g.presence of subthreshold bipolar symptoms in those withunipolar depression; or comorbidities indicating particularstrategies asmore likely to benefit); and the concurrent use ofother thyroid hormone therapy (leading to a decision to useother augmentation strategies in place of T3).

Psychological, couple and occupational therapy decisionsare made in accordance with NICE guidelines supplementedby other published literature, and are necessarily individua-lised according to a patient's illness given the range ofpresentations within this population.

2.2. Subjects

Data were collected from all patients discharged between01/01/2001 and 15/10/2008. This was a naturalistic study andhence all subjects were included with no exclusion criteria.However, we also defined a more homogeneous sample fordetailed outcome assessment, for which the inclusion criteriawere: 1) receipt of a period of intensive inpatient treatment(rather than assessment); 2) diagnosis of a primary affectivedisorder; 3) failure to respond to at least one prior adequatemedication trial; and 4) HRSD score of ≥16 on admission.Clinical and outcome data were collected contemporaneouslyunless stipulated and supplemented by a retrospective casenote review for additional/missing variables. Full diagnosticreview using ICD-10 criteria was undertaken using patienthistory, collateral history, old case notes and any otheravailable information including diagnostic interview sched-ules where indicated, usually for diagnostic uncertainty (Weused the Structured Clinical Interview for DSM-IV, axis I andaxis II versions, and the Standardised Assessment of Person-ality: 95/225 subjects underwent a formal structured assess-ment). Diagnostic assessment was also aided by a prolongedperiod of observation, including objective measures such asdaily mood ratings, sleep charts, fluid/food intake monitoringand weight charts. When determining the number ofprevious depressive episodes, a minimum of 2 monthsabsence of depressive symptoms was necessary to determinerecovery of the previous episode.

Patients' medication history was obtained using a checklist of all relevant psychotropic medication includinggeneric and brand names which patients completed priorto admission from their records and memory, includingdates, doses and duration. This was then supplemented byan in-depth clinical interview to clarify the data. During theadmission, old case notes were reviewed to check thehistory and obtain any missing data on prior trials.Minimum dose and duration to define an adequate trialwas based on the Maudsley Prescribing Guidelines (Tayloret al., 2007), supplemented by (in order) the Antidepres-sant Treatment History Form (Sackeim et al., 1990) and theBritish National Formulary (BNF_55, 2008) where data onan individual drug was not specified in the Maudsleyguidelines.

94 S.C. Wooderson et al. / Journal of Affective Disorders 131 (2011) 92–103

2.3. Measures

The primary outcome measure to assess symptomaticimprovement was the 21-item Hamilton Rating Scale forDepression (HRSD) (Hamilton, 1960) a semi-structured,clinician-administered scale regarded as the “gold-standard”in the field. We used a structured interview guide for thisscale to aid reliability (SIGH-D) (Williams, 1988)). Wedefined remission as a discharge HRSD score of 10 points orless; response as a more than 50% reduction in HRSD or ascore of 10 or less; and partial response as a 25–49% reductionin HRSD. To define a sufficient level of depression to beincluded in the detailed outcome assessment, we used a cutoff score of 16. The basis for this was that, first, this is a scoregenerally in keeping with treatment trials in depression,and specifically equates to that used in STAR*D, which used a17-item HRSD cut off of 14, which is equivalent to a cut off of16 on a 21-item HRSD (e.g. Rush et al., 2006 and please seeequivalence charts available in multiple languages at (http://www.ids-qids.org/index2.html#table3). Second, this was atrial of treatment resistant depression, regardless of symptomseverity, and a score of 16 comfortably includes those withclinical levels of depressive illness. Third, patients wereadmitted while already taking psychotropic medication, andoften some of the depressive symptoms (e.g. biologicalsymptoms) had shown some degree of improvement despitethe patient remaining clinically depressed. Time to firstresponse was defined similarly to STAR*D as the firstobservation with a reduction ≥50% from the baseline score,though using the HRSD rather than the QIDS-SR score(Nierenberg et al., 2006).

Wealsousedanumber of secondary outcomemeasures.Weobtained patient self-ratings of illness improvement either attime of discharge or retrospectively after discharge. Patientsfilled out the Patient Global Impression-Improvement (PGI-I)scale being asked “Overall, how would you rate your illnesscompared to when you were admitted?”, and having 7 optionsranging from “very much improved” to “very much worse”based on the Clinical Global Impression Scale (Guy, 1976).Patients also rated their satisfaction with their stay and howtheir stay compared to any previous experiences of being apsychiatric inpatient.

We assessed the change in patients' functioning in asubset of 39 patients using the Canadian OccupationalPerformance Measure (COPM) (Law et al., 1998). This semi-structured interview quantifies patients' perceptions of theirindividualised occupational performance and satisfactionfrom 1 to 10 and has been validated in a variety of conditions(Ay-Woan et al., 2006). Data were collected contemporane-ously before and after occupational therapy intervention.

Patients' relatives and referring health professionals weresent a 3-item questionnaire asking: (a) whether they felt thepatient was better (b) whether they felt the patient'sdepression had improved; and (c) whether they felt thepatient had benefited overall from the admission.

2.4. Administration, scoring and inter-rater reliability

Admission, fortnightly and discharge HRSD interviewswere conducted by the ward doctors. In order to standardisethe interviews we used a structured guide (Williams, 1988)

and all raters were trained by the same senior consultant(AJC). In addition, a training video utilising cases of varyingseverity was used to discuss and standardise ratings.Concurrent ratings from clinicians involved were taken onseveral occasions: inter-rater reliability was found to beexcellent with the maximum discrepancy between ratersbeing 2 points.

2.5. Statistical analyses

For the consecutive HRSD scores, last-observation carriedforward (LOCF) was used to account for missing data. TheStatistical Package for Social Sciences (SPSS) software v13(SPSS, 2001) was used to analyse the data: means, medians,standard deviation and percentages were used as appropriatedependingon thenormality of distribution. The change inHRSDscores from admission to discharge was assessed using aWilcoxon test as these data were non-parametric in distribu-tion. Performance and satisfaction scores at time 1 weresubtracted from performance and satisfaction scores at time 2in order to ascertainCOPMchange scores. Paired samples t-testswere employed to assess differences between scores at the twotime points.We assessed the time to first clinical response (50%fall in HRSD) as undertaken in STAR*D (Nierenberg et al., 2006).Alsowe investigated clinical and treatment differences betweensubgroups (e.g. responders andnon-responders, and thosewithand without comorbidity) using Chi square, t-tests and Mann–Whitney U-tests as appropriate.

3. Results

Data were collected from 225 admissions, including sixpatients admitted twice and one patient admitted four times.Patients were referred from London/Greater London (30.3%);Home Counties (42.5%); Other English Counties (21.2%);Northern Ireland (0.5%); Scotland (0.9%); Wales (2.3%) andEurope/Channel Islands (2.3%). The mean duration of hospitalstaywas 23 weeks, but this was skewed by 20 cases that stayed≥12 months; the median stay was 16 weeks (IQR 8–33). Eightcases stayed ≤2 weeks.

3.1. Socio-demographic and clinical characteristics (Table 1)

As expected from the epidemiology of depression, therewas a female preponderance. Themean agewas 48 years; fewpatients were working, but most were in a cohabitingrelationship. Health professionals comprised a quarter. Ofthe Non-British ethnicity, 6% were other Caucasian, 3% Asianor mixed Asian, 0.4% African and 0.8% other or not specified.

3.2. Diagnosis

In just over 15%, the primary diagnosis was changed awayfroman affective disorder (Table 1). Of the 41 patientswhodidnot have a primary affective disorder, but whose depressionwas felt to be secondary to another primary disorder, thediagnostic breakdown was: obsessive compulsive disorder(n=11); schizoaffective disorder (n=10); personality disor-der (n=8); substance misuse (n=3); body dysmorphicdisorder (n=2); generalised anxiety disorder (n=2); post-

Table 1Socio-demographic characteristics and diagnoses of 225 inpatient admissions a.

(Mean (SD)/percentage/median (IQR))

Demographic details N=225 N=105IT

N=120NS

SexFemale 73.8% 78.1% 70.0%

Age (years) 47.9(13.2)

49.2(13.8)

46.7(12.5)

Ethnicity (self reported)British (incl English, Welshand Scottish)

89.8% 89.5% 90%

Other 10.2% 10.5% 10%Marital status

Single 30.0% 25.7% 33.9%Married or cohabiting 54.5% 61.9% 47.8%Post-marital b 15.5% 12.4% 18.3%

Health professional 26.7% 27.6% 26.0%Years in education 12.0

(11–16)12.0(11–16)

12.0(11–16)

Employment statusUnemployed 63.1% 59.0% 66.7%Employed part-time 4.1% 3.8% 4.3%Employed full-time 6.3% 9.5% 3.4%Employed (hours unspecified) 7.7% 5.7% 9.4%Retired 17.6% 20.0% 15.4%Student 1.4% 1.9% 0.9%

Clinical detailsPrimary discharge diagnosis

Unipolar depression 58.0% 72.4% 45.0%Bipolar disorder 23.7% 27.6% 20.0%Other (includes personality disorder,schizoaffective disorder, obsessivecompulsive disorder, substancemisuse, GAD, organic brain disease)

18.3% – 34.2%

Outcome of Diagnostic ReviewPrimary affective disorder diagnosis 81.8% 100% 65.8%

Primary diagnosis changed from affectivedisorder to other

15.6% – 29.2%

Admittedwith other primary diagnosis c 2.7% – 5.0%Additional diagnosis made d

No 51.1% 58.1% 45.0%Comorbid axis 1 disorder diagnosed(including substance misuse)

28.0% 24.8% 25.0%

Comorbid axis 2 disorder identified 9.3% 3.8% 14.1%Affective disorder diagnosis modified(see text)

6.7% 5.7% 7.5%

Organic factors identified 5.8% 7.6% 4.2%Admitted with other primarydiagnosis

2.7% – 5.0%

Abbreviations: IQR=Interquartile Range; SD=Standard Deviation; IT=intensive treatment study population; NS=not part of intensive treatmentstudy population.

a Demographic details are on n=216 unique cases as 9 admissions were ofpatients who had previously been admitted. Marital status data missing forn=5patients; years of educationmissing forn=22patients; employmentdatamissing for n=3 patients; diagnoses details missing on n=1 patient due toself-discharge on day of admission.

b Post-marital includes separated, divorced and widowed.c Admitted for assessment of treatment-resistant obsessive compulsive

disorder and/or psychosurgery assessment.d Numbers add up to greater than 100% as more than one additional

diagnosis in some patients.

95S.C. Wooderson et al. / Journal of Affective Disorders 131 (2011) 92–103

traumatic stress disorder (n=1); conversion disorder (n=1);dementia (n=1); and no diagnosis was made in 2 patients.

In 15 patients the type of affective disorder was modifiedas follows: in six the diagnosis was changed from bipolar to

unipolar disorder, most often because full criteria formanic orhypomanic episodes were not met; in five unipolar patientswe identified previously undiagnosed dysthymia/“doubledepression” (n=3) or atypical depression (n=2). In threepatients a diagnosis of rapid-cycling bipolar disorder failed tobe substantiated and one unipolar diagnosis was changed tobipolar.

Almost a thirdof patientshad identifiable axis-I comorbidity,whilstwe identified significantorganic factors (most commonlycognitive impairment and/or vascular/degenerative brainchanges) and axis-II comorbidity in notable proportions. Ofthe 21 patients with significant axis-II comorbidity, the primarypersonality disorder was felt to be emotionally unstable in 13,anankastic in 4, mixed/other in 3, and dependent in 1.

3.3. Illness characteristics

Patients were generally chronically unwell: the majority(74%) of unipolar patients had been in a depressive episodefor 2 years or more, while the majority of bipolar patients hadexperienced 3 or more episodes of both depression andmania/hypomania (Table 2). Over half had attempted suicideat least once.

Patients' illnesses were highly treatment-resistant: themajority had already received ECT with no sustained responseand on average over 10 separate medications had been trialled.Health professionals were also highly treatment-resistant,although slightly less so than non-health professionals. Thus,for health professionals the mean total no. of previousmedications was 9.7 (SD 6.6) and the median number ofantidepressants used was 4 (IQR 3–6). Fewer health profes-sionals (43%) had received ECT.

3.4. Assessment and treatment

154 patients received intensive inpatient therapy, includ-ingmost bipolar and unipolar patients and aminority of thosewith other primary diagnoses (Table 2).We focused the studyon those who had a primary affective disorder diagnosis andexcluded those who were not significantly depressed whenadmitted (i.e. those with a total score of b16 on the HRSD).The study flow chart is shown in Fig. 1. We present detaileddata from the study sample (n=105) in Tables 3–5. We alsopresent clinical and demographic data from the study samplein Table 1: patients in the study sample were generallyrepresentative of the population as a whole, but thoseexcluded were less likely to have a primary affective disorder(one third had another primary diagnosis) and more likely tohave axis-II comorbidity.

The treatments received by the 105 patients were asfollows.

3.4.1. Psychological therapyOver half (61%) of those taken on for inpatient treatment

underwent CBT following psychological assessment. Patientsreceived a median of 12 individual 60-minute sessions whilstinpatients. We also attempted to determine whether patientshad already received CBT for depression prior to admission.Of the 97 patients with sufficient such data available, almosthalf (n=45) had definitely received CBT to some extent; 17had received psychological therapy but it was not possible to

Table 2Illness characteristics of 215 a inpatients.

Characteristic Mean (SD)/median (IQR)/percentage

Unipolar (n=130) Bipolar (n=53) Other (n=41)

Age at onset of illness (years) 32.3 (15.3) 26.8 (11.2) 21.7 (10.6)Age at onset of current episode (years) 44.0 (14.4) 46.6 (11.4) 28.6 (14.1)Duration of current episode (months) 44.0 (22–86) 10.0 (1–18) 96.0 (36–261)Previous no. of manic/hypomanic episodes

0 – – –

1 – 20% –

2 – 15% –

3 or more – 65% –

Previous no. of depressive episodes0 37% 2% 38%1 24% – 19%2 17% 13% 13%3 or more 23% 85% 31%

Approximate no. of suicide attempts0 49% 48% 42%1 18% 15% 12%2 8% 13% 6%3 or more 24% 25% 39%

No. of previous antidepressant treatments 6 (4–9) 4 (3–7) 5 (2–7)No. of previous mood stabilisers (including lithium) 1 (1–3) 3 (1–4) 1 (0–2)No. of previous antipsychotics 2 (0–3) 3 (1–4) 2 (1–4)No. of previous anxiolytics/hypnotics 1 (0–2) 1 (0–3) 1 (0–2)No. of previous augmenters (excluding mood stabilisers and antipsychotics) 0 (0–1) 0 (0–2) 0 (0–1)Mean total no. of previous medications 12 (6.5) 13 (7.2) 11 (7.6)Median total no. of previous medications 11 (7–17) 11 (7–20) 9 (6–15)Past ECT 66% 69% 50%Outcome of assessment

Kept on for intensive inpatient therapy beyond assessment period 73% 76% 46%Treatment changes undertaken during 6 week assessment period only 9% 9% 7%Assessment and recommendations for local and/or outpatient treatment 9% 9% 32%Non-engagement, inappropriate admission, absconded or self discharged 9% 6% 15%

a Representing 224 inpatient admissions as n=9 patients had been previously admitted. Excluding missing data (ranges from n=3 to n=32) and excludingn=1 patient for whom there was no diagnosis due to self discharged on day of admission.

96 S.C. Wooderson et al. / Journal of Affective Disorders 131 (2011) 92–103

distinguish whether it was CBT or not; 11 had receivedtherapy that was definitely not CBT; and 24 had received nopsychological therapy.

3.4.2. Physical therapiesFewer than one in ten patients received ECT, reflecting the

high rate of prior ECT and patient preference. One patient wasreferred for psychosurgery after failing to respond tooptimized treatment.

3.4.3. Occupational therapyAll patients were given an individually optimized occu-

pational therapy plan intended to utilise the benefits ofbehavioural activation and functional rehabilitation.

3.4.4. Couple therapyAbout 30% of inpatients received at least one 60-minute

session of couple therapy during their admission. The mediannumber of sessions was 7.

3.4.5. PharmacotherapyIndividually optimized psychopharmacotherapy was insti-

gated, based on first, second and third line treatments withinthe Maudsley Prescribing Guidelines that had not already beentrialled, balanced against patient preference, likely side effects,current treatments (i.e. current treatments were optimisedbefore switching), any medical contraindications, and other

specific indications for any one particular augmentationstrategy. As listed in Table 2, patients had received numerousantidepressant medications prior to admission, but whereappropriate, switching to a class of antidepressant not yettrialled was also undertaken. Good prior treatment data wasavailable in 97/105. In terms of themost commonly prescribedaugmentation agent, almost three-quarters (72/97) of patientswere determined to have definitely previously tried lithium, orwere already taking lithium on admission. Thus, as with ECT,the population was largely already resistant to, or not willingor able to take, a treatment with one of the largest evidencebases for efficacy. Of the remaining 25 patients, 11 receivedlithium during their admission. Of the 14 patients that had notreceived a trial of lithium at discharge, other treatments werepreferred for a variety of reasons (including patient preference;response to other therapies prior to planned lithium use;medical contraindication; overdose concerns; and presence ofcomorbidities indicating other augmentation strategies).

Assessment of the adequacy of treatment trials prescribedduring the admission – using the guidance of a minimumduration of 4 weeks at a minimum dose according to theMaudsley Prescribing Guidelines – revealed that we wereable to deliver N90% of treatment trials on a minimallyadequate basis, the most common reasons for inadequacybeing: intolerance of side effects, patients responding atlower doses, and full dose titration not being completed priorto discharge. Table 3 details the treatment being received at

Total number of admissions – n=225

1 patient self discharged on day of admission prior to assessment

Diagnoses – n=224

Treatment changes undertaken during 6 week assessment period only – n=20

Assessment and recommendations for local and/or outpatient treatment – n=29

Non-engagement, inappropriate admission,absconded or self discharged – n=21

Received intensive inpatient therapy – n=154

Affective Disorder not primary diagnosis – n=19

Not significantly depressed on admission (HRSD <16) – n=22

Study population – n=113

Missing data – n=8

Data available for n=105 (93%)

Fig. 1. Study flow chart.

97S.C. Wooderson et al. / Journal of Affective Disorders 131 (2011) 92–103

the end of treatment. The large majority of unipolar patientsrequired combination psychopharmacotherapy, most oftenan antidepressant with one or more augmentation strategy.Similarly, most bipolar patients were prescribed two or threemood stabilisers and often an antipsychotic in addition. It wasalso notable that a little over half of the bipolar patientsreceived an antidepressant.

Discharge doses are detailed in Table 4. Of note is that fewtreatments were administered in sub-therapeutic doses, andthat doses at or close to the maximum were most commonlyused. Supramaximal doses were only used for tricyclics,mirtazapine, buspirone and lamotrigine; indeed, lamotriginewas rarely administered within the recommended doserange, usually because response was not seen at those dosesand because such doses gave plasma levels in the lower partof the laboratory reference range.

3.5. Treatment outcome

3.5.1. Clinician ratingsFor 3 patients in the study group post-treatment HRSD

ratings were not obtainable; for 10 of the remaining 102,LOCF was used due to the immediate pre-discharge HRSDscore being unavailable. There was a highly significantdifference between HRSD scores at admission and discharge:in thewhole group (Z=−8.08, p=b0.001); in unipolar (Z=−6.92, p=b0.001); and in bipolar subjects (Z=−4.27,p=b0.001).

Over two thirds (70/102; 69%) of patients showeda clinicalresponse on the HRSD (i.e. a 50% reduction) at some point intheir admission, and the time to achieve first response to

treatment is shown in Fig. 2. Of note is that response ratescontinue to rise up until about 40 weeks of treatment(excluding one outlier who responded at 72 weeks). Half ofthe patients (51/102; 50%) continued to sustain a full responseat the time of discharge, rates being somewhat higher inbipolar patients (Table 5). Almost three-quarters wereshowing at least a partial response to treatment at discharge(Table 5). However, 19/102 (19%) of patients were seen tohave responded to treatment during the admission (i.e.attained a 50% reduction in HRSD) but suffered a dip inmood shortly prior to discharge (i.e. were no longer sustaininga 50% reduction in HRSD at discharge), probably attributableto the pressures of the transition back home. Comparing the51 patients who sustained a full response andmaintained thisat discharge with the 19 who sustained a full response butthen dipped, those who experienced a pre-discharge dip inmood had a longer duration of current illness episode(6.4 years v 3.1 years; t=2.4, p=0.02), a higher number ofprior total medication trials (15.3 v 10.2, t=2.7, p=0.008)and prior antidepressants (7.0 v 5.1; t=2.0, p=0.05), andwere more likely to have received ECT in the past (83% v 58%,Chi2=3–7, p=0.05). Of these 19 patients, 13 were unipolarand 6 bipolar.

3.5.2. Patient global impression-improvement20 patients completed self-ratings at discharge, while 101

completed them retrospectively in a postal follow up in 2008.Patient Global Impression-Improvement ratings were avail-able for 70% of those who received intensive treatment: theratings are shown in Table 5. We determined reliability of theretrospective ratings of improvement on a 10% sample

Table 3Discharge medication following intensive inpatient therapy (n=103) a.

Class of medication Mean/percentage

Unipolar(n=76)

Bipolar(n=27) a

Antidepressants0 3 (4%) 11 (41%)1 67 (88%) 15 (55%)2 6 (8%) 1 (4%)

Augmenters (including T3; excludingmood stabilisers and antipsychotics)0 57 (75%) 26 (96%)1 18 (24%) 1 (4%)2 1 (1%) –

Antipsychotics0 44 (58%) 14 (52%)1 32 (42%) 13 (48%)2 – –

Anxiolytics0 65 (86%) 25 (93%)1 10 (13%) 2 (7%)2 1 (1%) –

Hypnotics0 45 (59%) 18 (67%)1 27 (36%) 8 (30%)2 4 (5%) 1 (3%)

L-thyroxine (T4; NB–T3 classed asan augmenter)0 65 (85%) 15 (56%)1 11 (15%) 12 (44%)

Mood stabilisers (including lithium;excluding antipsychotics)0 31 (41%) –

1 39 (51%) 7 (26%)2 6 (8%) 14 (52%)3 – 6 (22%)

Total no. of drugs at discharge(excluding anxiolytics, hypnotics, T4)1 16 (21%) 1 (4%)2 26 (34%) 5 (19%)3 23 (30%) 12 (44%)4 11 (15%) 7 (26%)5 – 2 (7%)

a Discharge medication missing on n=2 bipolar patients.

98 S.C. Wooderson et al. / Journal of Affective Disorders 131 (2011) 92–103

(n=7) who completed the PGI both at discharge andretrospectively. This showed that the mean patient rating ofillness improvement (where 1=very much worse and7=very much better) was 6.3 when rated at discharge and5.9 when rated again at follow up (paired t=−0.55, p=0.6),with no ratings being more than one point different betweenthe two test times. This suggests that the retrospective ratingswere essentially valid and reliable, though may slightlyunderestimate improvement. The retrospective PGI wasundertaken a median of 11 months after discharge.

Patients who did not complete a PGI showed similar HRSDscores (median HRSD (IQR) on admission 23 (20–30) and ondischarge 10 (7–18)) to those who did complete a PGI (HRSD22 (19–25) on admission and 13 (7–17) on discharge),suggesting that there was not a bias towards a poorerresponse to treatment in those not completing a PGI.

3.5.3. Patient satisfactionTaking all 121 replies together, 74% (100% in those

assessed contemporaneously and 68% in those assessed

retrospectively) rated their stay positively, 45% endorsing“very good” (the highest rating) and 29% “good”. Incomparison to their previous hospital experiences, 77%(100% contemporaneously and 73% retrospectively) ratedthe unit as “much better” or “better”.

3.5.4. Relative and referrer ratingsWe received completed questionnaires from 63 relatives

(chosen by the patient). 75% agreed with the statement “thedepression of your relative or friend improved while he/shewas at the ADU” and 76% “your relative or friend derivedbenefit from being on the ADU”. Only 25 replies fromreferring health professionals were received: 68% agreedwith the statement that “this person's depression improvedwhile he/she was at the ADU”.

3.5.5. Functional outcomeThe Canadian Occupation Performance Measure was

administered to a subsample of 39 patients before and afterreceiving occupational therapy. The patients in this subgroupwere comparable to the total sample in terms of diagnosis,history of medication use, history of ECT use, duration ofepisode, total illness duration, and illness severity on theHRSD (data not shown). There was a mean improvement of2.6 (SD=2.1) points in perceived occupational performanceand 2.9 (SD=2.2) points in satisfaction with performance(both differences significant: t=7.5, t=8.2 respectively,both pb0.001). Scores above 2 points represent a clinicallysignificant change (Law et al., 1998): 69% met this criterionfor performance and 67% for satisfaction with performance.

3.6. Factors associated with outcome

3.6.1. Outcome and treatment receivedThere was no difference in type of treatment received

during the admission by those who were discharged as fullresponders or not. 100% both of those who responded andthosewho did not respond received occupational therapy andpharmacotherapy, while the proportions receiving psycho-logical therapy (responders 63%, non-responders 57%;Chi=0.35, p=0.56) and couple therapy (responders 29%,non-responders 43%; chi=2.1, p=0.15) did not differsignificantly. The total number of new medication trials wasalso not different (mean new medication trials totalled 6.0(SD 2.7) in non-responders and 5.4 (2.7) in responders;t=1.2, p=0.24) although non-responders received margin-ally more antidepressant trials (2.2 (1.2) trials v 1.7 (1.2) inresponders; t=2.0, p=0.05).

3.6.2. Outcome and illness characteristicsPatients who had already received ECT for the current

episode were less likely to be discharged as full respondersthan those who had not: only 35% of those who had alreadyreceived ECT were full responders at discharge compared to63% of those who had not received ECT (Chi=7.1,p=0.008). However, this was partially explained by thehigher rates of pre-discharge “dipping” in these patients(see above). Thus, when we looked at those who hadreached response criteria at some point during the admis-sion, those who had received ECT in the current episode hadsimilar response rates (63%) to those who had not (74%;

Table 4Dosing of antidepressants, mood stabilisers and augmenters at discharge following intensive inpatient therapy (n=103) a.

Unipolar (n=76) Belowminimumadequate dose

At the minimumadequate dose

Higher than minimumdose but lower thanmaximum dose

Athighestdose

Higher than maximumdose (i.e. suprahigh dose therapy)

Above minimum—

but no recognisedupper dose

AntidepressantsMAOI/RIMA (varies by drug) – 2 7 1 – –

Tricyclics (varies by drug) 1 2 3 7 7SSRIs (varies by drug) – 1 2 10 – –

Mirtazapine (30–45 mg) – – – 1 1 –

Trazodone (150–600 mg) – – 1 1 – –

Duloxetine (60–120 mg) – 3 1 10 – –

Venlafaxine (75–375 mg) – – 5 4 – –

Reboxetine 8–12 mg – 2 – 4 – –

Nefazodone (300–600 mg) – – 1 – – –

AugmentersBuspirone (15–45 mg) – 1 – 3 2 –

Buproprion (300–450 mg) – 1 – 1 – –

Pindolol (7.5–15 mg) – – – 1 – –

Pregabalin (300–600 mg) 1 – 1 – – –

T3 (20–50 μg) – 3 1 3 – –

Tryptophan (6000–9000 mg) 3 1 – – – –

Mood stabilisersCarbamazepine (min. 600 mg) 2 – – – – 1Gabapentin a – – – – – 1 a

Lamotrigine (50–200 mg) – 2 3 4 17 –

Lithium (0.4–1.0 mmol/l) – – – – – 20 b

Valproate a – – – – – 1 a,b

Bipolar (n=27) c

AntidepressantsTricyclics (varies by drug) – – 1 – 1 –

SSRIs (varies by drug) – – 1 1 – –

Trazodone (150–600 mg) 1 – – – – –

Duloxetine (60–120 mg) – 3 1 3 – –

Venlafaxine (75–375 mg) – – 2 2 – –

AugmentersT3 (20–50 μg) 1 – – – – –

Pramipexole (0.125–5 mg) – – 1 – – –

Mood stabilisersCarbamazepine (min. 600 mg) 4 1 – – – 1Lamotrigine (50–200 mg) – – 1 4 19 –

Lithium (0.4–1.0 mmol/l) – – – – – 16 b

Valproate a – – – – – 8 a,b

The recommended dosing ranges (where available) are given using the Maudsley Prescribing Guidelines (Taylor et al., 2007) as the primary source, along with theAntidepressant Treatment History Form (Sackeim, 2001) or British National Formulary (BNF_55, 2008) as secondary sources where ranges are not given in theprimary source.

a No minimum or maximum doses established for depressive disorders.b All patients were kept within the recommended laboratory range.c N=2 bipolar patients' discharge medication untraceable.

99S.C. Wooderson et al. / Journal of Affective Disorders 131 (2011) 92–103

Chi=1.3, p=0.26). Thus, a history of ECT use seemed moreclosely linked to this tendency to dip prior to discharge, oralternatively to early relapse, rather than to absolute lack ofresponse. Similar findings pertained to those who had everreceived ECT: response rates maintained at discharge weresignificantly lower (43% versus 66%; Chi=4.6, p=0.03)whereas response rates attained during admission were not(65% versus 75%; Chi=1.1, p=0.3).

Longer duration of episode was also a poor prognosticindicator for a full response at discharge: non-responders hadlonger current illness durations than responders (5.6 (5.6)versus 3.1 (4.2) years, t=2.6, p=0.01). Again, however, thisdid not hold for response attained during the admission (4.8(4.9) versus 3.7 (5.1) years, t=0.98, p=0.33), and likelyrelated at least partly to the higher tendency for thesepatients to dip (see above). The same applied to prior

treatment resistance: those attaining a response duringadmission had the same number of total prior treatmenttrials (responders 11.6 (6.9), non-responders 11.6 (5.3),t=0.05, p=0.96) whereas at discharge, non-respondershad a higher number of prior treatment trials (13.0 (6.8)versus 10.2 (5.9), t=2.1, p=0.04).

The number of previous suicide attempts was higher inthose who were non-responders at discharge (1.8 (1.7)versus 1.1 (1.4), t=2.3, p=0.02). Response rates at dischargewere higher in those with no prior attempts (61%) and 1 priorattempt (62%) than those with 2 attempts (46%) or 3 or moreattempts (32%).

There was no difference in response rates at dischargebetween those determined definitely to have previouslyreceived CBT or not (prior CBT response rate 51%, no priorCBT response rate 54%, Chi=0.71, p=0.40).

Table 5Patient severity scores at the beginning and end of treatment in depressedpatients receiving intensive inpatient treatment.

HRSD21 Unipolar(n=76)

Bipolar(n=29)

Overall(n=105)

Median (IQR) HRSD21

admission score22.5(19.0–27.0)

22.0(18.0–27.5)

22.0(19.0–27.0)

Median (IQR) HRSD21

discharge score a12.0(8.0–19.0)

10.5(3.3–15.8)

11.5(7.0–17.0)

Remission 42% 50% 44%Response 45% 61% 50%Partial response 24% 11% 21%At least partial response 70% 71% 71%

Patient Global Improvement (self-rated)Overall rating “much improved”or “very much improved”:contemporaneous (n=12) – – 75%Retrospective (n=62) – – 53%Total (n=74) – – 57%

Overall rating “slightly improved”:contemporaneous (n=12) – – 25%Retrospective (n=62) – – 24%Total (n=74) – – 24%

a Discharge scores missing on n=3 patients.

100 S.C. Wooderson et al. / Journal of Affective Disorders 131 (2011) 92–103

3.6.3. Effect of comorbidityWithin the study group, the presence of comorbidity

(defined as having an additional diagnosis either on axis 1 oraxis 2; n=31) did not affect the response rates on discharge(53% of those with and 48% of those without comorbidity metcriteria for full response at discharge; Chi2=0.17, p=0.68) orthe HRSD on discharge (median HRSD in those withcomorbidity 11.0 compared to 12.5 in those withoutcomorbidity; z=−0.56, p=0.58). Similarly, the presence

0%

10%

20%

30%

40%

50%

60%

70%

80%

0 4 8 12 16 20 24 28 32 3

Cum

ulat

ive

perc

enta

ge r

espo

nse

Time to first response (50%Patients with primary affective disorder re

Weeks

Legend

The number of weeks taken to first reach criteria for clinicaHamilton Depression Rating Scale or a score of ≤10) in 102diagnosis receiving intensive multidisciplinary inpatient tre

Fig. 2. Time to 50% reduction in HRS

of identifiable organic factors in the aetiology of the affectivedisorder (n=8 in the study sample) was not associated witha poorer outcome in terms of median discharge HRSD (12.5 inthose with and 11.5 in those without; z=−0.24, p=0.82) orresponse rates (50% in both groups).

4. Discussion

These data indicate that an intensive period of multimodalinpatient treatment can be effective in previously highlytreatment-refractory depression.We found that 69% of highlytreatment-resistant patients showed a clinical response totherapy during admission, 50% sustained a response ondischarge, while reports from patients, relatives and referrersgave improvement rates of between 53% and 76%. There wasclinically significant functional improvement in 69% of thesubset assessed.

Putting this study into the context of prior studies isdifficult because there are few prior studies and thoseavailable studied less treatment-resistant patients; further-more, TRD is excluded frommost antidepressant clinical trials(Dodd et al., 2005). Kennedy and Paykel (2004) assessed 203patients with TRD treated on an inpatient unit (mean 14.7inpatient and 17.9 day patient weeks). On a global ratingscale, 27% improvedmarkedly; 59% improvedmoderately; 7%improved minimally and 7% were unchanged. The authorssuggested that long admissions, gradual discharge, psycho-therapy, family work and high-dose continuation medicationcontributed to sustained remission over discharge. We reportcomparable and perhaps more favourable outcomes usingmore specific outcome measures and with a shorter overallperiod of treatment (though comparable duration of inpa-tient stay).

6 40 44 48 52 56 60 64 68 72

reduction in HRSD-21)ceiving intensive inpatient therapy (n=102)

of admission

l response (defined as a 50% reduction in 21-item patients with a primary affective disorderatment.

D-21 scores from admission.

101S.C. Wooderson et al. / Journal of Affective Disorders 131 (2011) 92–103

Outpatient studies in TRD have shown variable rates ofresponse depending on the degree of treatment resistance. Ofnote are the results from the sequentially treated patients inSTAR*D: response rates reduced with each sequential trial,just 7–14% responding to a fourth trial after three prior failedtrials (McGrath et al., 2006). In comparison, our patientsaveraged ten or more previous trials. It seems that moreseverely refractory patients may do less well with outpatienttherapy than inpatient therapy, though there are no directcomparisons and this is a question suitable for further study.

Another notable outcome is the rediagnosis of 15% ofpatients with another primary disorder. Almost 9% werediagnosed with a personality disorder, although not everypatient underwent a full SCID-II assessment. This was due tothe relatively conservative approach we took to diagnosingpersonality disorder in the context of chronic affectivedisorder because of the potential for overdiagnosis whenrelying on this approach alone. Only when the history frompatient, relative or case notes suggested a lifelong set ofpersonality traits which persisted in the absence of mooddisorder did we diagnose a personality disorder. A significantproportion of the remaining patients exhibited currentmaladaptive personality traits as would be commonlyobserved in such a population. In relation to the 15% whodid have a primary disorder other than an affective disorder,where appropriate thesewere also treated in the unit. Clearly,this group of patients was not the focus of this report, and inany case the numbers treated were small (n=19) and thevariety of other diagnoses was too heterogeneous for muchmeaningful conclusion. However, it was notable that outcomein these patientswas less favourable in terms of a reduction indepressive symptoms (mean HRSD on admission was 19.7(SD 7.0) and on discharge was 18.4 (7.2)). Nevertheless, thisreinforces the oft-repeated advice to reconsider the diagnosisin depressed patients failing to respond to treatment.

In terms of factors predicting outcome, it was notable thatcomorbidity was not a poor prognostic factor, and norwas thepresence or organic factors, though only a small number withorganic aetiology were treated. We would argue that theability to target comorbidity alongside affective symptomswithin an intensive therapy setting is likely to be importanthere given evidence that such factors can be poor prognosticfactors in other settings (Fava et al., 1997). Similarly, clinicalexperience suggests that those with organic factors implicat-ed in the aetiology may need more aggressive and longertherapy in order to obtain response.

Finally, although many patients did respond to treatment,almost one-in-three showed no meaningful improvement bythe time of discharge. This likely reflects the chronicity andintractability of some affective disorders, although it could bethat benefits in some patients are not apparent until afterdischarge, a hypothesis that would require a longer termfollow up.

4.1. Limitations

There are obvious limitations to these data that limit over-interpretation of the results. First, this was an observationalstudy, without any untreated control group. However, theprognosis for the study groupwas established to be poor priorto admission given the extremely high degree of prior

treatment resistance, the chronicity of the illness, and theprior literature noting a poor outcome in TRD even withtreatment (Fekadu et al., 2009b). Thus, we feel it unlikely thatthe observed treatment effects are due to any naturaltendency for patients' illnesses to have recovered. Second,clinician ratings were not blinded, opening the possibility ofobserver bias. However, the high degree of concordancebetween the HRSD outcomes and the patient's own ratings onthe PGI, as well as relative and referrer ratings, suggest thatthe improvements were genuine and not due to over-optimistic clinician ratings. Third, PGI reports were notavailable for all patients, and it is possible that a morenegative assessment of outcome is associated with a lowerlikelihood of returning the assessment thus potentiallybiasing the results slightly. In order to check for this, wecompared those who completed a PGI with those who didnot, and found no statistically significant differences in termsof severity of illness at admission and symptom burden ondischarge using the HRSD scale. Fourth, generalisability of thefindings is limited by the highly specialised nature of the unitand the selection of patients that are admitted to such a unit.To some extent this reflects the wide variety of patientstermed “TRD”: there is a continuum of severity of suchpatients (Fekadu et al., 2009c) and multimodal inpatienttherapy is unlikely to be relevant to patients with milderillness. However, for themoderate to severe patients includedin this study, we believe that the findings are relevant. Manypatients with TRDwho are either treated in the community orin conventional hospital setting with shorter duration of stayeither fail to respond to such short treatments, or relapse soonthereafter (Fekadu et al., 2009b). The patients included in thepresent study were referred because of a failure to respond toother methods of treatment available, and thus the informa-tion is relevant to clinicians currentlymanaging such patients.It suggests that, at least in the short term, intensive inpatienttreatment can be effective and is an option (if available) forsuch patients. Fifth, our main focus was on depressivesymptoms, and we only assessed functional outcome in asubset. The measure we chose – the COPM – is a patientfocused and individualised measure, but its reliability andgeneralisability in depressive populations is not fully known.Finally, the purpose of the study was not to compareindividual treatments or combinations, and it was notdesigned nor powered to compare the relative efficacy ofthe interventions used. Nevertheless, the study does demon-strate that the range of available treatments delivered in asystematic manner and usually in combination can beeffective inmany patientswith previously treatment resistantillnesses.

One factor missing from this report is the longer termoutcome, an important consideration given that depression isa frequently recurrent disorder: we plan to assess this in afuture study.

4.2. Strengths

A strength of this study is the use of standardised outcomemeasures, thorough diagnostic procedures (using a widevariety of sources, though we must acknowledge that not allpatients underwent a formal structured interview) and asystematic treatment approach. Although we are unable to

102 S.C. Wooderson et al. / Journal of Affective Disorders 131 (2011) 92–103

disentangle the active ingredients of the treatment package,we feel it is most likely the combination of therapeuticapproaches that is important. We also feel that delivery ofsuch a package by a cohesive team experienced in treatingaffective disorders is likely to be important. We must alsoacknowledge that other aspects of the milieu, includingimproved compliance with medication, occupational andpsychological therapy approaches, represent a likely compo-nent of the effectiveness of treatment. It is also worthhighlighting that change was not rapid in the study group,and that admissions of months rather than weeks are neededfor meaningful improvements.

The pharmacotherapy requires specific comment. Al-though monotherapy is often felt to be a worthy treatmentgoal, it is becoming accepted that many bipolar patientsrequire two or more mood stabilising medications foroptimum control. Three-quarters of our bipolar patientswere receiving three or more such medications, reinforcingthe need for multiple medications in severely affected bipolarpatients. Similarly, over three-quarters of our unipolarpatients were taking two or moremedications for depression.It is notable that while dosing was used in the upper end ofthe recommended ranges, it was relatively uncommon to usesupramaximal dosing. The main exceptions were tricyclics,where there is an established therapeutic strategy using highdosing (Taylor et al., 2007), particularly where fast metabolicrates are suspected (and plasma monitoring can aid in this),and lamotrigine, which is emerging as an effective augmen-tation strategy (Taylor et al., 2007) and which seems welltolerated in higher doses. It might be considered that the useof lamotrigine was rather more frequent than might beexplained by the position of lamotrigine augmentation forunipolar depression within the Maudsley Prescribing Guide-lines. However, for a proportion of patients this was due tothe presence of subclinical bipolar symptoms; such symptomsare a recognised cause of treatment resistance (Sharma et al.,2005; Smith et al., 2009), but patients retain a diagnosis ofunipolar depression under current classification symptoms. Itwas also due to the exercise of patient choice, the use of otheraugmentation strategies previously (either prior to or duringadmission), and to the treatment having been already startedprior to admission. The use of antidepressants in bipolardisorder is a controversial issue given concern regardingcycle acceleration and the induction of mood instability(Fountoulakis et al., 2008); pragmatically many bipolarpatients seem to require them and can take them withoutsuch issues arising, and around half of our sample was dis-charged taking an antidepressant.

In summary, the outcomes reported demonstrate thatspecialist, multidisciplinary inpatient treatment can beeffective for patients with the most disabling and intractabledepressive disorders. However, there are few such highlyspecialised treatment services presently available. The modelof integrated, multimodal therapy delivery may also beapplicable to less specialist inpatient units in deciding howbest to organise treatment for this common patient popula-tion, and may also be applicable on an outpatient basis: bothsuggestions would require evaluation. Given the expense ofan adequate treatment duration in a specialist service, we alsosuggest that further research that may help identify whichpatients are most likely to respond to this treatment will also

be desirable; recent work suggests that certain biologicalvariables may be so predictive (Juruena et al., 2009) whileemerging methods using biomarkers (e.g. pharmacogenetics(Rasmussen-Torvik and McAlpine, 2007)) hold potential forthe clarification of second-step interventions (Rush et al.,2008).

Role of funding sourceThis research was supported by the NIHR Biomedical Research Centre at

the South London and Maudsley NHS Foundation Trust and the Institute ofPsychiatry (King's College London); the NIHR had no further role in the studydesign; in the collection, analysis and interpretation of data; in the writing ofthe report; and in the decision to submit the paper for publication.

Conflict of interestDr Cleare has received honoraria for consulting and/or speaking from Eli

Lilly, UCB Pharma, Merck, Organon, Pfizer and Cyberonics, and unrestrictedresearch grant support from Glaxo SmithKline, between 2001 and 2010. DrJuruena has received honoraria for consulting and/or speaking from GlaxoSmithKline, Lundbeck, Eli Lilly, Organon, Sanofi-Synthélabo, Astra-Zeneca,Pfizer andWyeth, and unrestricted research grant support from Novartis. Allother authors declare that they have no conflicts of interest.

Acknowledgement

We would like to thank all members of the NationalAffective Disorders Unit team for their efforts in this work andfor their contribution to the clinical service. Dr Cleare ispartially funded by the National Institute of Health Biomed-ical Research Centre at the South London and Maudsley NHSFoundation Trust and the Institute of Psychiatry, King'sCollege London.

References

Ay-Woan, P., Sarah, C.P., Lyinn, C., Tsyr-Jang, C., Ping-Chuan, H., 2006. Qualityof life in depression: predictive models. Qual. Life Res. 15, 39–48.

Berlim, M.T., Turecki, G., 2007. What is the meaning of treatment resistant/refractory major depression (TRD)? A systematic review of currentrandomized trials. Eur. Neuropsychopharmacol. 17, 696–707.

BNF_55 (2008) British National Formulary. 55th ed. British MedicalAssociation and Royal Pharmaceutical Society of Great Britain, London,UK.

Dodd, S., Horgan, D., Malhi, G.S., Berk, M., 2005. To combine or not tocombine? A literature review of antidepressant combination therapy. J.Affect. Disord. 89, 1–11.

Dunner, D.L., Rush, A.J., Russell, J.M., Burke, M., Woodard, S., Wingard, P.,Allen, J., 2006. Prospective, long-term, multicenter study of thenaturalistic outcomes of patients with treatment-resistant depression.J. Clin. Psychiatry 67, 688–695.

Fava, M., 2003. Diagnosis and definition of treatment-resistant depression.Biol. Psychiatry 53, 649–659.

Fava, M., Uebelacker, L.A., Alpert, J.E., Nierenberg, A.A., Pava, J.A., Rosenbaum,J.F., 1997. Major depressive subtypes and treatment response. Biol.Psychiatry 42, 568–576.

Fekadu, A., Wooderson, S.C., Markopoulou, K., Cleare, A.J., 2009a. TheMaudsley StagingMethod for treatment-resistant depression: predictionof longer-term outcome and persistence of symptoms. J. Clin. Psychiatry70, 952–957.

Fekadu, A., Wooderson, S.C., Markopoulo, K., Donaldson, C., Papadopoulos, A.,Cleare, A.J., 2009b. What happens to patients with treatment-resistantdepression? A systematic review of medium to long term outcomestudies. J. Affect. Disord. 116, 4–11.

Fekadu, A., Wooderson, S., Donaldson, C., Markopoulo, K., Masterson, B.,Poon, L., Cleare, A.J., 2009c. A multidimensional tool to quantifytreatment resistance in depression. The Maudsley Staging MethodJournal of Clinical Psychiatry 70, 177–184.

Fountoulakis, K.N., Grunze, H., Panagiotidis, P., Kaprinis, G., 2008. Treatmentof bipolar depression: an update. J. Affect. Disord. 109, 21–34.

Greden, J.F., 2001. The burden of disease for treatment-resistant depression.J. Clin. Psychiatry 62 (Suppl 16), 26–31.

103S.C. Wooderson et al. / Journal of Affective Disorders 131 (2011) 92–103

Greenberg, P.E., Stiglin, L.E., Finkelstein, S.N., Berndt, E.R., 1993. The economicburden of depression in 1990. J. Clin. Psychiatry 54, 405–418.

Guy, W., 1976. Clinical global impressions. In: Guy, W. (Ed.), ECDEUAssessment Manual for Psychopharmacology (Revised). National Insti-tute of Mental Health, Rockville (Md), pp. 217–221.

Hamilton, M., 1960. A rating scale for depression. J. Neurol. Neurosurg.Psychiatry 23, 56–62.

http://www.ids-qids.org/index2.html#table3.Juruena, M.F., Pariante, C.M., Papadopoulos, A.S., Poon, L., Lightman, S., Cleare,

A.J., 2009. Prednisolone suppression test in depression: prospectivestudy of the role of HPA axis dysfunction in treatment resistance. TheBritish Journal of Psychiatry 194, 342–349.

Kennedy, N., Paykel, E.S., 2004. Treatment and response in refractorydepression: results from a specialist affective disorders service. J. Affect.Disord. 81, 49–53.

Ker, S., Anderson, I., 2006. Service innovations: developing a specialised(tertiary) service for the treatment of affective disorders. Psychiatr. Bull.30, 103–105.

Law, M., Baptiste, S., Carswell, A., McColl, M., Polatajko, H., Pollock, N. (Eds.),1998. Canadian Occupational Performance Measure. CAOT Pub. ACE,Ottawa, Ontario.

Malhi, G.S., Parker, G.B., Crawford, J., Wilhelm, K., Mitchell, P.B., 2005.Treatment-resistant depression: resistant to definition? Acta Psychiatr.Scand. 112, 302–309.

Mcgrath, P.J., Stewart, J.W., Fava, M., Trivedi, M.H., Wisniewski, S.R.,Nierenberg, A.A., Thase, M.E., Davis, L., Biggs, M.M., Shores-Wilson, K.,Luther, J.F., Niederehe, G., Warden, D., Rush, A.J., 2006. Tranylcypromineversus venlafaxine plus mirtazapine following three failed antidepres-sant medication trials for depression: a STAR*D report. Am. J. Psychiatry163, 1531–1541 quiz 1666.

Nierenberg, A.A., Fava, M., Trivedi, M.H., Wisniewski, S.R., Thase, M.E.,Mcgrath, P.J., Alpert, J.E., Warden, D., Luther, J.F., Niederehe, G., Lebowitz,B., Shores-Wilson, K., Rush, A.J., 2006. A comparison of lithium and T(3)augmentation following two failed medication treatments for depres-sion: a STAR*D report. Am. J. Psychiatry 163, 1519–1530 quiz 1665.

Rasmussen-Torvik, L.J., McAlpine, D.D., 2007. Genetic screening for SSRI drugresponse among those withmajor depression: great promise and unseenperils. Depress. Anxiety 24, 350–357.

Rush, A.J., Trivedi, M.H., Wisniewski, S.R., Nierenberg, A.A., Stewart, J.W.,Warden, D., Niederehe, G., Thase, M.E., Lavori, P.W., Lebowitz, B.D.,McGrath, P.J., Rosenbaum, J.F., Sackeim, H.A., Kupfer, D.J., Luther, J., Fava,M., 2006. Acute and longer-term outcomes in depressed outpatientsrequiring one or several treatment steps: a STAR*D report. Am. J.Psychiatry 163, 1905–1917.

Rush, A.J., Wisniewski, S.R., Warden, D., Luther, J.F., Davis, L.L., Fava, M.,Nierenberg, A.A., Trivedi, M.H., 2008. Selecting among second-step antide-pressant medication monotherapies: predictive value of clinical, demo-graphic, or first-step treatment features. Arch. Gen. Psychiatry 65, 870–880.

Sackeim, H.A., 2001. The definition and meaning of treatment-resistantdepression. J. Clin. Psychiatry 62 (Suppl 16), 10–17.

Sackeim, H.A., Prudic, J., Devanand, D.P., Decina, P., Kerr, B., Malitz, S., 1990.The impact of medication resistance and continuation pharmacotherapyon relapse following response to electroconvulsive therapy in majordepression. J. Clin. Psychopharmacol. 10, 96–104.

Scott, J., Dickey, B., 2003. Global burden of depression: the intersection ofculture and medicine. Br. J. Psychiatry 183, 92–94.

Sharma, V., Khan, M., Smith, A., 2005. A closer look at treatment resistantdepression: is it due to a bipolar diathesis? J. Affect. Disord. 84, 251–257.

Smith, D.J., Forty, L., Russell, E., et al., 2009. Subthreshold manic symptoms inrecurrent major depressive disorder are a marker for poor outcome. ActaPsychiatr. Scand. 119, 325–329.

SPSS, 2001. SPSS for Windows, release 13.0, standard version. SPSS Inc., Chicago.Taylor, D., Paton, C., Kerwin, R. (Eds.), 2007. The Maudsley Prescribing

Guidelines. Informa Healthcare, UK, London.Thomas, C.M., Morris, S., 2003. Cost of depression among adults in England in

2000. Br. J. Psychiatry 183, 514–519.WHO (Ed.) (2001) World Health Organization. World health report 2001:

mental health: new understanding, new hope., Geneva.Williams, J.B., 1988. A structured interview guide for the Hamilton

Depression Rating Scale. Arch. Gen. Psychiatry 45, 742–747.