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Wiles N, Thomas L, Abel A, et al. Clinical effectiveness and cost-effectiveness of cognitive behavioural therapy as an adjunct to pharmacotherapy for treatment-resistant depression in primary care: the CoBalT randomised controlled trial. Southampton (UK): NIHR Journals Library; 2014 May. (Health Technology Assessment, No. 18.31.)

Cover of Clinical effectiveness and cost-effectiveness of cognitive behavioural therapy as an adjunct to pharmacotherapy for treatment-resistant depression in primary care: the CoBalT randomised controlled trial

Clinical effectiveness and cost-effectiveness of cognitive behavioural therapy as an adjunct to pharmacotherapy for treatment-resistant depression in primary care: the CoBalT randomised controlled trial.

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Chapter 8The prevalence of treatment-resistant depression in primary care


Depression is a disabling condition and the third most common reason for consulting a GP in the UK.124 As outlined earlier (see Chapter 1 ), antidepressants are the first-line treatment for moderate and severe depression in primary care, and there has been a steady rise in antidepressant prescribing in recent years, in the UK and elsewhere.24 However, not all patients respond adequately to antidepressants and there is concern about the impact on both patients and society for those whose symptoms do not respond to such treatment. Much of the cost and disability associated with depression is accounted for by treatment resistance.125,126 Yet, there are few estimates of the prevalence of TRD.

The large US STAR*D study found that more than half of all patients recruited through primary care and psychiatric clinics did not achieve remission after first-line antidepressant treatment, and one-third did not experience remission after four courses of acute treatment.127 A multicentre European study (Group for the Study of Resistant Depression) found that 50.7% of depressed patients recruited from specialist referral centres were considered treatment resistant after two consecutive courses of treatment with antidepressants.128 Although there is no single accepted definition of what constitutes ‘treatment resistance’,129 these data suggest that non-response to medication following antidepressant treatment is a substantial problem. However, it is unclear whether or not these data would generalise to UK primary care.

Accurate estimates of non-response to antidepressant treatment are important to determine whether or not there is unmet need, particularly given the high prevalence of depression among patients presenting to primary care. The CoBalT study provides an opportunity to estimate the prevalence of TRD among those prescribed antidepressants for at least 6 weeks in UK primary care.


This was a secondary analysis of data collected during the initial screening stage of the CoBalT study (filter 1 and filter 2), which is described in full earlier (see Chapter 2 , Filter 1: Search of general practitioner records to identify patients being treated for depression). Brief details are outlined below.

Identification of participants

A search of computerised records was conducted at each of the 73 collaborating GP practices, to identify patients aged 18–75 years who were currently receiving antidepressants and who had received repeated prescriptions for antidepressants [at an adequate dose for depression (see Appendix 1 ) during the previous 4 months]. GPs excluded individuals with bipolar disorder, psychosis or major alcohol or substance use problems, as well as those who were unable to complete the study questionnaires or for whom the study was regarded as inappropriate. Patients who were currently receiving CBT or other psychotherapy (or who had undertaken CBT in the last 3 years) were also excluded. The remaining patients were mailed an invitation letter and brief information sheet about the study and asked to respond, indicating whether or not they were willing to be contacted by the research team. Anonymised data on age and gender of those patients who were mailed an invitation to participate but who did not respond were collected in order to assess the generalisability of the study findings.


Patients who agreed to participate were mailed a short screening questionnaire. This questionnaire included a self-report measure of depressive symptoms – the BDI-II46 – and asked for details of their current antidepressant medication, including the duration of their current treatment and their adherence to antidepressants. The latter was assessed using a modified version of the Morisky scale48,49 (see Chapter 2 , Inclusion criteria). The questionnaire also collected data on sociodemographic variables (age, gender, marital status, educational qualifications, employment status, housing situation and financial situation).

Defining treatment resistance

Given the lack of consensus in the definition of TRD, we proposed an inclusive definition, directly relevant to UK primary care.13 Treatment resistance was defined as those patients who scored ≥ 14 on the BDI-II and who had been taking antidepressant medication at an adequate dose for at least 6 weeks.

Data set

As well as recruiting participants via a search of electronic records, GPs were able to refer patients directly to the research team. However, for the purpose of the present analysis, such individuals (n = 37) were excluded. In addition, for those individuals who were rescreened to ascertain eligibility for the trial, data from only their first postal questionnaire were used. Thus, the estimates of prevalence are based on questionnaire data obtained from one search of patient records from all participating practices.

Statistical analysis

All analyses were conducted in Stata 11.2. The prevalence of TRD was estimated with 95% CI, adjusting for clustering by GP practice. The impact of non-response (to the initial study invitation and screening questionnaire) on estimates of prevalence was assessed using probability weights (inverse of the non-response rate for each GP practice), such that data from practices with higher response rates were given more weight. Weighted estimates of prevalence were calculated using the survey commands in Stata (svy commands). Technical limitations meant that it was not possible to adjust the latter estimates for clustering by GP practice; however, preliminary analyses showed that there was little evidence of clustering by GP practice.

Descriptive data on the type of antidepressant medication taken by those fulfilling our definition of TRD are reported, including the number on combined (defined as two different antidepressant medications at an adequate dose) or augmented antidepressant treatment (with a non-antidepressant medication). Sociodemographic characteristics were compared for the TRD group, with those who were not adhering to medication and with those who had minimal depressive symptoms. Comparisons of age and gender were also made between those who did and did not participate in the study.


Response to study invitation and questionnaire completion

A total of 10,629 patients who were mailed an invitation letter, of whom 4552 (43%) responded (Figure 6). Of these, 64% agreed to being sent a questionnaire by the research team, and subsequently, most (n = 2439, 84%) returned a completed questionnaire (see Figure 6 ).

FIGURE 6. Flow chart of the recruitment process and number of participants with data for estimating the prevalence of TRD.


Flow chart of the recruitment process and number of participants with data for estimating the prevalence of TRD.

Of those who returned a questionnaire, we had complete data on dose and duration of antidepressant treatment and depressive symptoms from 2317 participants (95%). Of these, 8.8% were not taking an adequate dose of medication or had been taking their medication for < 6 weeks and were excluded from further analyses. This gave a sample of 2129 patients (see Figure 6 ) for whom to estimate the prevalence of TRD.

Data on age and gender were available for most of those who were mailed an invitation and were compared for participants and non-participants (those who did not respond to the invitation, n = 6077; and those who responded but who declined to participate, n = 1643). There were no differences in age between those who returned a completed questionnaire (participants) and those who did not (Table 68). However, women were more likely to participate than men (see Table 68 ).



Comparison of age and gender for participants and non-participants of the CoBalT study

Prevalence of treatment-resistant depression

Among the 2129 patients who had been prescribed an adequate dose of antidepressant medication for at least 6 weeks, 1635 (77%, 95% CI 75% to 79%) had a BDI-II score of ≥ 14. Overall, 55% met our definition of TRD (Table 69). Twenty-two per cent had a BDI-II score of ≥ 14 but had not adhered to medication, and 23% had minimal symptoms of depression (BDI-II score of < 14) (see Table 69 ). Of those with minimal symptoms, the majority [n = 401; 81% (95% CI 78% to 84%)] had adhered to their medication.



Prevalence of TRD

Given the non-response to the study invitation and subsequently to the postal questionnaire, we examined the impact on estimates of prevalence. The response rate (for the study invitation and screening questionnaire) varied between 8% and 50% for the 73 practices. Response rate was negatively correlated with prevalence of TRD (Figure 7) and positively correlated with prevalence of minimal depressive symptoms (BDI-II score of < 14) (Table 70) for the 73 practices. However, estimates of prevalence weighted for non-response differed little from the figures reported above [weighted prevalence of TRD: 54.7% (95% CI 52.2% to 57.2%); non-adherers: 21.6% (95% CI 19.5% to 23.7%); minimal symptoms: 23.7% (95% CI 21.4% to 26.0%)].

FIGURE 7. Prevalence of TRD against response to the postal screening questionnaire for each of the 73 GP practices [weighted according to number of responses (the size of the dot in the graph represents the number of responses per practice: the larger the dot, the greater the number of responses)].


Prevalence of TRD against response to the postal screening questionnaire for each of the 73 GP practices [weighted according to number of responses (the size of the dot in the graph represents the number of responses per practice: the larger the dot, (more...)



Correlation between invitation/questionnaire response rate, and prevalence of TRD, non-adherers and those with minimal symptoms for the 73 general practices

Antidepressant medication

Among those with TRD, SSRIs were the most common type of antidepressants taken (79%) (Table 71). The two most common medications were citalopram and fluoxetine. Together they accounted for 67% of all antidepressants prescribed, in line with prescribing figures for England for 2011.5 Most patients were taking one antidepressant (monotherapy), with < 2% of those with TRD receiving combined treatment. Augmented antidepressant treatment was very rare (see Table 71 ). A further 57 patients were taking a second antidepressant medication but at a dose below our definition of ‘adequate’.



Prescribed antidepressant medication among patients with TRD

Characteristics of patients with treatment-resistant depression

Sociodemographic and clinical variables were compared for those with TRD, for those who had significant depressive symptoms but who had not adhered to their medication (not adherent) and for those with minimal symptoms (Table 72). Differences were evident for a number of variables but tended to reflect differences between those with minimal symptoms compared with the other two groups. For example, those with minimal symptoms were more likely to be married, working (full/part time) and were less likely to be living in rented accommodation or experiencing financial difficulty than the other two groups (see Table 72 ). Almost 70% of patients had been taking their current antidepressant for > 12 months. This was a consistent finding among the three groups of patients described: those with TRD (67.2%); those non-adherent to their antidepressants (67.2%); and those with minimal symptoms (71.9%) (see Table 72 ).



Characteristics of patients with TRD compared with those not adhering to medication and those with minimal symptoms



More than three-quarters of primary care patients taking antidepressants for at least 6 weeks had significant residual depressive symptoms. Fifty-five per cent of patients who had taken an adequate dose of antidepressant medication for at least 6 weeks were classified as having TRD, clearly showing that inadequate response to antidepressant medication is an important problem in UK primary care.

Most of these patients (70%) reported having taken their current medication for > 12 months. This finding highlights the chronic nature of depression among many of those treated in primary care, and gives rise to concern about the systematic reassessment and treatment of those on long-term antidepressant therapy.

The frequency of the different types of antidepressant taken by those with TRD, in the main, reflected national prescribing data for England.5 Amitriptyline was frequently prescribed at low doses that were not regarded as an effective therapeutic dose for depression, which accounted for the lower ranking of this medication among those with TRD in our sample. Venlafaxine was slightly more frequently used compared with national prescribing data,5 suggesting that GPs may have initially prescribed an SSRI in line with NICE recommendations for the treatment of depression, and switched to venlafaxine as an alternative because of a lack of response.

Strengths and limitations

We used data from the recruitment phase of the CoBalT RCT based in UK primary care. The large number of practices covering urban, rural and semi-rural settings across the three centres (Bristol, Exeter and Glasgow) has enabled us to estimate a figure for the prevalence of TRD in UK primary care with a high degree of precision.

Unlike other studies such as STAR*D,127 we distinguished between non-response and non-adherence to medication in defining our treatment-resistant group. Non-adherence to medication is known to be common in depressed patients130 but is difficult to measure. Other studies have relied upon clinician report to gather this information,128 but we know that patients find it difficult to be honest with health professionals about whether they are taking their medication as prescribed.131 We relied upon a self-report measure of medication use,48 which has been validated against electronic monitoring bottles.49

There are a number of limitations to our study. Only 43% of those invited to participate responded to the letter from the GP, with 54% subsequently returning a completed postal questionnaire. Our estimates of prevalence may be biased by this non-response. However, there was no difference in estimates of prevalence that were or were not weighted for non-response by practice, suggesting that our estimates were robust.

Our data are cross-sectional and we acknowledge that individuals may have experienced a change in their depressive symptoms between the initial prescription and the time that the questionnaire was completed. A longitudinal study of patients newly starting an antidepressant could help make finer distinctions in terms of defining treatment responders, partial responders and non-responders. Furthermore, although the BDI-II measures severity of depressive symptoms, it is not a diagnostic instrument. Nonetheless, those with TRD had a mean BDI-II score of 29.1, which is indicative of severe depression.

As highlighted earlier, there are many definitions of treatment resistance. The definition of TRD used in the CoBalT study is pragmatic and directly relevant to UK primary care, given the uncertainty about what treatments to recommend to those who do not respond after 4–6 weeks of antidepressant medication.13

Comparisons with other studies

Reports suggest that the management of TRD is an area that has been poorly investigated, with few robust data to guide treatment.14,132,133 Although non-response to antidepressants is frequently cited as a key issue in the management of patients with depression, few studies have quantified the magnitude of this problem and, prior to this study, no evidence has existed for UK primary care. Estimates of the prevalence of TRD range from 30%127 to 50%.128 Our estimate of 55% is at the upper end of this range. It is difficult to compare the estimates of prevalence between studies directly because of differing definitions of treatment resistance, including whether or not diagnostic criteria have been applied to identify those with depression.128 Nonetheless, our data clearly demonstrate that TRD represents a significant burden for patients and primary care clinicians in the UK.

Clinical implications and directions for future research

Based on our data, the scale of inadequate response to antidepressants in UK primary care is worrying, particularly in the context of the continued increase in prescribing. Little is known about the treatment received by patients with depression after an antidepressant has been prescribed. It is not clear what constitutes usual care. Although the Quality Outcomes Framework has incentivised primary care clinicians to record the severity of depressive symptoms at the start of treatment (DEP6) and again within 12 weeks (DEP7), no incentives are in place with respect to longer-term management.134 A large number of patients may receive long-term antidepressants without being adequately assessed for treatment response. Our data suggest that the NICE guidelines13 for sequencing treatments after initial inadequate response are not widely followed, as there is very little evidence in our sample of combining or augmenting antidepressant treatments.

Given the lack of motivation that is common among depressed patients, it has been suggested that a more proactive clinician-led approach to the management of this patient population could be of benefit.135 We would urge repeated monitoring of symptoms, together with recording of medication adherence, at regular reviews. Such an approach may help identify those patients whose symptoms have not responded to medication at an earlier stage when it might be possible to intervene to prevent chronicity and to improve patient outcome.

Copyright © Queen’s Printer and Controller of HMSO 2014. This work was produced by Wiles et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

Included under terms of UK Non-commercial Government License.

Bookshelf ID: NBK261988


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