Cost-effectiveness of cognitive behavioural therapy and selective serotonin reuptake inhibitors for major depression in children and adolescents

Cost-effectiveness of cognitive behavioural therapy and selective serotonin reuptake inhibitors for major depression in children and adolescents
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   Cost-effectiveness of cognitive behavioural therapy and selective serotonin reuptake inhibitors for major depression in children and adolescents  Michelle M. Haby, Bruce Tonge, Lyn Littlefield, Rob Carter, Theo Vos  Objective:  To assess from a health sector perspective the incremental cost-effectiveness ofcognitive behavioural therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs) forthe treatment of major depressive disorder (MDD) in children and adolescents, compared to‘current practice’.  Method:  The health benefit is measured as a reduction in disability-adjusted life years(DALYs), based on effect size calculations from meta-analysis of randomised controlled trials.An assessment on second stage filter criteria (‘equity’; ‘strength of evidence’, ‘feasibility’ and‘acceptability to stakeholders’) is also undertaken to incorporate additional factors that impacton resource allocation decisions. Costs and benefits are tracked for the duration of a newepisode of MDD arising in eligible children (age 6–17 years) in the Australian population inthe year 2000. Simulation-modelling techniques are used to present a 95% uncertaintyinterval (UI) around the cost-effectiveness ratios.  Results:  Compared to current practice, CBT by public psychologists is the most cost-effective intervention for MDD in children and adolescents at A$9000 per DALY saved (95%UI A$3900 to A$24 000). SSRIs and CBT by other providers are less cost-effective but likelyto be less than A$50 000 per DALY saved (> 80% chance). CBT is more effective than SSRIsin children and adolescents, resulting in a greater total health benefit (DALYs saved) thancould be achieved with SSRIs. Issues that require attention for the CBT intervention includeequity concerns, ensuring an adequate workforce, funding arrangements and acceptability tovarious stakeholders.  Conclusions:  Cognitive behavioural therapy provided by a public psychologist is the mosteffective and cost-effective option for the first-line treatment of MDD in children andadolescents. However, this option is not currently accessible by all patients and will requirechange in policy to allow more widespread uptake. It will also require ‘start-up’ costs andattention to ensuring an adequate workforce.  Key words:  antidepressive agents, cognitive behaviour therapy, cost effectiveness,  Australian and New Zealand Journal of Psychiatry 2004; 38:579–591  depressive disorder, meta-analysis.   Michelle M. Haby, Senior Epidemiologist (Correspondence); Theo Vos,Senior Epidemiologist   Health Surveillance and Evaluation Section, Public Health, Departmentof Human Services, Melbourne, Victoria, Australia. Email:   Bruce Tonge, Head of School   School of Psychology Psychiatry and Psychological Medicine, MonashUniversity, Melbourne, Victoria, Australia   Lyn Littlefield, Executive Director   Australian Psychological Society, Melbourne, Victoria, Australia   Rob Carter, Deputy Director   Program Evaluation Unit, University of Melbourne, Melbourne, Vic-toria, Australia   Received 29 August 2003; revised 19 March 2004; accepted 22 March 2004.   580INTERVENTIONS FOR CHILDHOOD DEPRESSION  Major depressive disorder (MDD) affects 2.3% of Australian children and adolescents [1]. However, thecost-effectiveness of recommended treatments has notbeen assessed in this population. Clinical practice guide-lines recommend cognitive behavioural therapy (CBT)as the treatment of first choice because its efficacy issupported by evidence from randomised controlled trials(RCTs) [2,3].Pharmacological intervention is currently recom-mended as a second-line treatment [2,3]. However, amore recent review of the research literature suggeststhat selective serotonin reuptake inhibitors (SSRIs)might also be considered as a first-line treatment [4].As part of the Australian Assessing Cost-Effectiveness(ACE) – Mental Health project [5] we assessed theincremental cost-effectiveness of CBT and SSRIs forthe treatment of MDD in children and adolescents.Both treatments were assessed as first-line therapy withcurrent practice as the comparator. Selective serotoninreuptake inhibitors have also been assessed as asecond-line treatment with no further treatment as thecomparator.  Method  The incremental cost-effectiveness ratio (ICER) is calculated as thecost (A$) per disability-adjusted life year (DALY) saved. Children andadolescents eligible for the intervention are those aged 6–17 years inthe Australian population in the year 2000 who are currently seekingcare (‘consulting’) for MDD, but would have received types of careother than evidence-based medicine (EBM) under current practice(Fig. 1). All incident episodes of MDD in the year 2000 are included.For SSRIs as a second-line treatment, the eligible group is thosechildren who do not remit by the end of treatment with CBT or do notadhere to treatment with CBT (Fig. 2). Of these, we assume thatbetween 50% and 90% will actually be offered treatment with SSRIs.Health benefits are measured for the duration of the episode of MDD. Costs are measured for the duration of the intervention. Sincethe time horizon is less than one year, costs are not discounted. Theperspective is that of the health sector, including government costs(both Commonwealth and states/territories) and out-of-pocket costs forpatients and their families, that is drug and service costs.  Interventions  CBT   We model 12 ×  1 hour individual sessions of CBT plus twoparent/family sessions over 14 weeks (based on expert opinion and  Figure 1.Pathway analysis for current practice (white boxes) and for cognitive behavioural therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs) interventions (light and dark boxes, respectively). EBM, evidence-based medicine; GP, general practitioner; MDD, major depressive disorder; YLD, years lived with disability.   M.M. HABY, B. TONGE, L. LITTLEFIELD, R. CARTER, T. VOS581randomised controlled trials of CBT). A general practitioner (GP) visitfor diagnosis and referral is also included. Four different providerscenarios are costed, with only the cost of the intervention and whobears the cost (government or patient) differing between scenarios.These are: private psychologist; public psychologist; private psychi-atrist; and public psychiatrist.  SSRIs  We model 9 months of treatment with an SSRI, which includes3 months for the acute phase and 6 months for continuation treatment(based on expert opinion and clinical practice guidelines [3]). The doseper day modelled is 20 mg fluoxetine, citalopram or paroxetine, 50 or100 mg sertraline or 100 mg fluvoxamine [6,7]. Fourteen doctor visitsare included, assuming weekly visits in the first month, every twoweeks for two months, and then monthly visits (based on expertopinion). We assume the proportion of patients consulting with aGP, paediatrician or private psychiatrist is the same as currentlyhappening in those consulting (i.e. 53%, 31% and 16%, respectively[1]). Two different scenarios for the intervention are analyzed: SSRIsoffered as a first-line treatment; and SSRIs offered as a second-linetreatment.  Figure 2.Pathway analysis for selective serotonin reuptake inhibitors offered as a second-line treatment (shaded boxes). The comparator is no further treatment following treatment with cognitive behavioural therapy (CBT). YLD,  years lived with disability.  582INTERVENTIONS FOR CHILDHOOD DEPRESSION  Current practice  Current practice for the treatment of MDD was determined from the1998 National Survey of Mental Health and Wellbeing – Child andAdolescent Component (NSMHW-CA) [1] in those with MDD in theprevious 12 months (n = 88). A consult is defined as an attendance foremotional or behavioural problems during the past 6 months with afamily doctor, private paediatrician, private psychiatrist, private psy-chologist or social worker, mental health clinic, hospital emergencydepartment, hospital-based department of psychiatry, any other hos-pital based outpatient department or stayed overnight in a hospital.Of those who consulted (35%), these were further split into treat-ment with EBM (12%) or non-EBM (23%). We defined treatment withSSRIs and/or CBT as EBM. Since there is not a specific questionasking about CBT in the survey, we assumed that those who statedthey had received counselling and had made at least four visits in theprevious 6 months to a private psychiatrist, private psychologist orsocial worker, hospital psychiatry department or mental health clinic,had received CBT [1], which applies to 9% of the survey sample.Consultation with experts suggests that even these conservativeassumptions are likely to have overestimated the number of childrenactually receiving CBT. Children and adolescents who we defined asreceiving non-EBM under current practice each averaged 4.4 visits toa GP, 0.8 visits to a paediatrician, 0.1 visits to a private psychiatrist and0.2 visits to a private psychologist or social worker [1].  Assessment of benefit  Benefits are calculated by a two-stage process. The first stageinvolves the estimation of the health gain that could be attributed toeach intervention using the DALY. The second stage involves theassessment of issues that either influence the degree of confidence thatcan be placed in the cost-effectiveness ratios (such as the level of avail-able evidence), or broader issues that need to be taken into account indecision-making about resource allocation (such as equity and accept-ability to stakeholders).  Stage one: measurement of the health gain  There is no evidence in the literature that CBT or SSRIs can cause orprevent death, so only a change in the years lived with disability (YLD)component of the DALY is modelled. YLD are calculated asincidence ×  duration ×  the disability weight (DW).  YLD for the current practice comparator   To estimate the number of incident cases in the year 2000 weassumed that the prevalence rates calculated from the 1998 NSMHW-CA [1] still apply in 2000 and that incidence can be derived from prev-alence by using the formula: 1-year incidence = 1-year prevalence/ (1 + average duration). This 1-year incidence figure (1.5%) is appliedto Australian population figures for 6–17 year-olds in June 2000(Australian Bureau of Statistics, Time series spreadsheet 3201.0) togive 48 552 incident episodes of MDD.The average duration of an episode of MDD was calculated usingthe spread of durations found in the Oregon Adolescent DepressionProject [8]. While the average duration of an episode of MDD is26.7 weeks there is a difference in the average duration of an episodebetween those consulting and those not consulting for their MDD. Weassume that there is a lag from onset of MDD to treatment of 4 weeks(range 2–6 weeks) so that children with episodes of 4 weeks or lesswould remit before getting to treatment (25.5%). Conversely, all chil-dren treated would have durations greater than the lag. Thus, we derivean average duration of 20.8 weeks in those children not consulting and34.8 weeks in those consulting.The disability weights (DW) used are based on the Dutch weightingsystem [9]. These are 0.14 for mild, 0.35 for moderate and 0.76 forsevere MDD. Composite DWs were calculated separately for thosewho: did not consult; consulted and received EBM; and consulted andreceived non-EBM under current practice, based on the spread of severities in the Australian population. We extrapolated this severityinformation from the young adults (18–34 years) in the adult NationalSurvey of Mental Health and Wellbeing [10] because the numbers withdepression in the NSMHW-CA [1] were too small to obtain reliableestimates of the spread of severity of depression. We used the MentalComponent Score of the SF-12 [11], which has a mean populationvalue of 50 and a standard deviation of 10. We classified cases into:severe (> 2.5 SD below mean, i.e. < 25); moderate (> 1.5–2.5 SDbelow mean, i.e. 25–34.9); and mild (> 0.5–1.5 SD below mean,i.e. 35–44.9). The proportion of cases in each severity category ismultiplied by the appropriate DW for the category to get a weightedaverage DW for those in each group. The resulting DWs are: ‘didnot consult’ = 0.270; ‘received EBM’ = 0.397; and ‘received non-EBM’ = 0.417.  YLD for the comparator for SSRIs as a second-line treatment   To derive the average duration of an episode of MDD before becom-ing eligible for treatment with SSRIs under this scenario we assumedan average of 2 weeks treatment with CBT before being treated withSSRIs for those who do not adhere to CBT and 14 weeks of CBT forthose who adhere but do not remit. This is in addition to the 4-week lagto treatment with CBT. This gives an average duration of 41.4 weeks inthose not adhering to treatment with CBT and 74.0 weeks in those notremitting by the end of treatment with CBT. We assumed no healthbenefit from the prior treatment with CBT, so used a disability weightof 0.417 at baseline, consistent with the modelling of SSRIs as a first-line treatment.   Determining the reduction in YLD with treatment   The reduction in severity, and hence YLD, was modelled using theeffect size and both the ‘conversion factor method’ and the ‘surveyseverity method’ [5] to translate the effect size into a reduction in theDW. For the ‘conversion factor method’ we multiplied the effect sizeby the DW conversion factor. This conversion factor is an averagechange in the DALY disability weights for the equivalent of a standarddeviation change in severity for the particular mental disorder [12]. Forthe ‘survey severity method’ the effect size is applied directly to theMental Component Score, which was used to determine the averageDW at baseline. The severity of respondents is then reclassified and anew average DW calculated. The difference in average DW is thechange attributed to treatment [5].   M.M. HABY, B. TONGE, L. LITTLEFIELD, R. CARTER, T. VOS583The effect size was calculated from a meta-analysis of the relevantRCTs. Although the interventions do impact on the duration of theepisode of MDD, we assumed that the effect size captures the effectsof both the reduced severity and duration. Reductions in the DW wereonly applied to the time from the commencement of the intervention.For cases not adherent to treatment no reduction in DW has beenmodelled (although they do incur costs of the treatment provided).   Meta-analysis  Trials of CBT and SSRIs were identified from published meta-analyses, searches of the Cochrane Controlled Trials Register andMedline, from reference lists in included trials, review articles, booksand clinical practice guidelines and from authors of published trials. Tobe included, trial participants had to be less than 18 years and havediagnosed depression (MDD or dysthymia). For CBT seven studiesfitted the inclusion criteria [13–19]. However, the study by Reed [14]could not be included in the calculation of the effect size for CBT dueto lack of continuous outcome measures. For SSRIs four RCTs fittedthe inclusion criteria [20–23].The effect size (standardized mean difference) was calculated usingHedges’ g and the random effects method of DerSimonian and Laird[24]. We first calculated an effect size for each study by averagingacross the relevant outcome measures within the study. All continuousoutcome measures related to depression (including anxiety and mood)and health-related quality of life were included. Clinician, parent andchild/adolescent reported measures were included. Some outcomemeasures that were considered to be relevant could not be includedbecause data were not presented in a way that could be incorporatedinto the calculation of the effect size (e.g. data presented in figuresonly). For the study by Simeon et al  . [20] no data were presented in thepaper but it was stated that there were no significant differencesbetween the treatment and control groups. Thus, an effect size of zerowas assumed. The weighted mean effect size for CBT is 0.41 (95%CI = 0.15–0.67) and for SSRIs is 0.29 (95% CI = 0.11–0.46). Someunexplained heterogeneity was present in the effect size for CBT(Q = 12.04, df = 7, p = 0.099) but not for SSRIs (Q = 0.90, df = 3,p = 0.8).   Adherence  It was assumed that the completion rate of the treatment group in theRCTs reflects the best possible adherence with treatment. No longitu-dinal studies measuring adherence to CBT or SSRIs were available forMDD in children and adolescents so a minimum adherence rate of 50%was used in the uncertainty analysis (Table 1). This was done to betterreflect what could be expected under routine health service conditionswhere results may vary due to the motivation of clinicians and patients,the availability of skilled clinicians and the capacity to vary the inter-vention to suit the needs of the patient.  Stage two: the second stage filter criteria  The first stage of measuring benefit described above is characterizedby a reliance on data sets and the application of quantitative methodsbased on health economics and epidemiology. The second stage incor-porates, explicitly, broader aspects where decisions rest heavily on judgement and notions of ‘due process’. The filters chosen for theACE–MH study were ‘strength of evidence’, ‘equity’, ‘feasibility’ and‘acceptability to stakeholders’ [5].  Assessment of costs  Pathway analysis was used to identify the component activities of theinterventions and their current practice comparator (Figs 1 and 2).Resource usage (i.e. dosage, number of visits, etc.) for the componentactivities was estimated from the published literature and supplementedby expert advice. Unit costs and data sources are shown in Table 2.Costs that would have been incurred under current practice are sub-tracted from the intervention (and non-adherence) costs to obtain theincremental cost.Children and adolescents who don’t adhere to treatment with CBTor SSRIs incur some costs but no health benefit. However, there are nodata available on their care-seeking behaviour. Thus, it is assumed thatthe cost of non-adherence is (on average) the same as the cost of non-EBM. However, for SSRIs as a second-line treatment, we assume thatthese patients behave differently from the average patient receivingnon-EBM. Thus, for those not adherent to SSRIs as a second-linetreatment, we model the cost of filling one or two scripts of the SSRIand 1–3 doctor visits (in addition to the GP visit for referral to apaediatrician or psychiatrist).  Uncertainty analysis  Simulation-modelling techniques were used to allow the presenta-tion of an uncertainty range around the health benefits, costs and ICERs(Table 1). @RISK software [25] was used to conduct Monte Carlosimulations, which allow multiple recalculations of a spreadsheet, eachtime choosing a value from the specified distribution for each inputvariable (shown in Table 1). We used 2000 iterations for each of thetwo methods for translating the effect size into a change in the DW(i.e. the ‘conversion factor method’ and the ‘survey severity method’).Thus, the final results are based on the 2000 + 2000 iterations. Medianvalues were calculated because results are not normally distributed. Theranges presented can be interpreted as the range within which the trueresult lies with 95% certainty.Uncertainty analyses are used to address issues of uncertainty in theresults due to sampling error (e.g. in the meta-analyses) and the needto make assumptions due to the lack of evidence for some parameters(e.g. the lag to treatment).In addition to the uncertainty range, the @RISK analysis can alsoshow which model parameters contribute most to the uncertainty in theresults. We list the input variables that contribute to overall uncertaintyaround the cost-effectiveness ratios with a regression coefficient of   ±  0.30 or greater.  Results  Cognitive behavioural therapy by public psychologists (or othereffective providers at a similar salary level) is the most cost-effectiveintervention for child and adolescent depression at A$9000 per DALYsaved (95% UI A$3900 – A$24 000) and is also the second mostaffordable first-line treatment option for the government at anincremental cost of A$3.7 million (95% UI A$1.9 – A$6.7 million)
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