Statistical methods for automated drug susceptibility testing: Bayesian minimum inhibitory concentration prediction from growth curves

Determination of the minimum inhibitory concentration (MIC) of a drug that prevents microbial growth is an important step for managing patients with infections. In this paper we present a novel probabilistic approach that accurately estimates MICs based on a panel of multiple curves reflecting features of bacterial growth. We develop a probabilistic model for determining whether a given dilution of an antimicrobial agent is the MIC given features of the growth curves over time. Because of the potentially large collection of features, we utilize Bayesian model selection to narrow the collection of predictors to the most important variables. In addition to point estimates of MICs, we are able to provide posterior probabilities that each dilution is the MIC based on the observed growth curves. The methods are easily automated and have been incorporated into the Becton--Dickinson PHOENIX automated susceptibility system that rapidly and accurately classifies the resistance of a large number of microorganisms in clinical samples. Over seventy-five studies to date have shown this new method provides improved estimation of MICs over existing approaches.Comment: Published in at http://dx.doi.org/10.1214/08-AOAS217 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

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

Background: Cognitive behavioural therapy (CBT) is an effective treatment for people whose depression has not responded to antidepressants. However, the long-term outcome is unknown. In a long-term follow-up of the CoBalT trial, we examined the clinical and cost-effectiveness of cognitive behavioural therapy as an adjunct to usual care that included medication over 3–5 years in primary care patients with treatment-resistant depression. Methods: CoBalT was a randomised controlled trial done across 73 general practices in three UK centres. CoBalT recruited patients aged 18–75 years who had adhered to antidepressants for at least 6 weeks and had substantial depressive symptoms (Beck Depression Inventory [BDI-II] score ≥14 and met ICD-10 depression criteria). Participants were randomly assigned using a computer generated code, to receive either usual care or CBT in addition to usual care. Patients eligible for the long-term follow-up were those who had not withdrawn by the 12 month follow-up and had given their consent to being re-contacted. Those willing to participate were asked to return the postal questionnaire to the research team. One postal reminder was sent and non-responders were contacted by telephone to complete a brief questionnaire. Data were also collected from general practitioner notes. Follow-up took place at a variable interval after randomisation (3–5 years). The primary outcome was self-report of depressive symptoms assessed by BDI-II score (range 0–63), analysed by intention to treat. Cost-utility analysis compared health and social care costs with quality-adjusted life-years (QALYs). This study is registered with isrctn.com, number ISRCTN38231611. Findings: Between Nov 4, 2008, and Sept 30, 2010, 469 eligible participants were randomised into the CoBalT study. Of these, 248 individuals completed a long-term follow-up questionnaire and provided data for the primary outcome (136 in the intervention group vs 112 in the usual care group). At follow-up (median 45·5 months [IQR 42·5–51·1]), the intervention group had a mean BDI-II score of 19·2 (SD 13·8) compared with a mean BDI-II score of 23·4 (SD 13·2) for the usual care group (repeated measures analysis over the 46 months: difference in means −4·7 [95% CI −6·4 to −3·0, p<0·001]). Follow-up was, on average, 40 months after therapy ended. The average annual cost of trial CBT per participant was £343 (SD 129). The incremental cost-effectiveness ratio was £5374 per QALY gain. This represented a 92% probability of being cost effective at the National Institute for Health and Care Excellence QALY threshold of £20 000. Interpretation: CBT as an adjunct to usual care that includes antidepressants is clinically effective and cost effective over the long-term for individuals whose depression has not responded to pharmacotherapy. In view of this robust evidence of long-term effectiveness and the fact that the intervention represented good value-for-money, clinicians should discuss referral for CBT with all those for whom antidepressants are not effective

An expert consensus on the most effective components of cognitive behavioural therapy for adults with depression:a modified Delphi study

Designing new approaches to delivering cognitive behavioural therapy (CBT) requires an understanding of the key components. This study aimed to establish an expert consensus on the effective components of CBT for depressed adults. An international panel of 120 CBT experts was invited to participate in a modified Delphi study. Thirty-two experts participated in round 1; 21 also provided data in round 2. In round 1, experts rated the effectiveness of 35 content and process components. A priori rules identified components carried forward to round 2, in which experts re-rated items and final consensus items were identified. Consensus was achieved for nine content components (ensuring understanding; developing and maintaining a good therapeutic alliance; explaining the rationale for CBT; eliciting feedback; identifying and challenging avoidant behaviour; activity monitoring; undertaking an initial assessment; relapse prevention methods; homework assignments); and three process components (ensuring therapist competence; scheduling sessions flexibly; scheduling sessions for 45–60 mins). Five of the twelve components identified were generic therapeutic competences rather than specific CBT items. There was less agreement about the effectiveness of cognitive components of CBT. This is an important first step in the development of novel approaches to delivering CBT that may increase access to treatment for patients

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

Background: Only one-third of patients with depression respond fully to treatment with antidepressant medication. However, there is little robust evidence to guide the management of those whose symptoms are 'treatment resistant'.<p></p> Objective: The CoBalT trial examined the clinical effectiveness and cost-effectiveness of cognitive behavioural therapy (CBT) as an adjunct to usual care (including pharmacotherapy) for primary care patients with treatment-resistant depression (TRD) compared with usual care alone.<p></p> Design: Pragmatic, multicentre individually randomised controlled trial with follow-up at 3, 6, 9 and 12 months. A subset took part in a qualitative study investigating views and experiences of CBT, reasons for completing/not completing therapy, and usual care for TRD.<p></p> Setting: General practices in Bristol, Exeter and Glasgow, and surrounding areas.<p></p> Participants: Patients aged 18-75 years who had TRD [on antidepressants for 6 weeks, had adhered to medication, Beck Depression Inventory, 2nd version (BDI-II) score of 14 and fulfilled the International Classification of Diseases and Related Health Problems, Tenth edition criteria for depression]. Individuals were excluded who (1) had bipolar disorder/psychosis or major alcohol/substance abuse problems; (2) were unable to complete the questionnaires; or (3) were pregnant, as were those currently receiving CBT/other psychotherapy/secondary care for depression, or who had received CBT in the past 3 years.<p></p> Interventions: Participants were randomised, using a computer-generated code, to usual care or CBT (12-18 sessions) in addition to usual care.<p></p> Main outcome measures: The primary outcome was 'response', defined as 50% reduction in depressive symptoms (BDI-II score) at 6 months compared with baseline. Secondary outcomes included BDI-II score as a continuous variable, remission of symptoms (BDI-II score of < 10), quality of life, anxiety and antidepressant use at 6 and 12 months. Data on health and social care use, personal costs, and time off work were collected at 6 and 12 months. Costs from these three perspectives were reported using a cost-consequence analysis. A cost-utility analysis compared health and social care costs with quality adjusted life-years.<p></p> Results: A total of 469 patients were randomised (intervention: n = 234; usual care: n = 235), with 422 participants (90%) and 396 (84%) followed up at 6 and 12 months. Ninety-five participants (46.1%) in the intervention group met criteria for 'response' at 6 months compared with 46 (21.6%) in the usual-care group {odds ratio [OR] 3.26 [95% confidence interval (CI) 2.10 to 5.06], p < 0.001}. In repeated measures analyses using data from 6 and 12 months, the OR for 'response' was 2.89 (95% CI 2.03 to 4.10, p < 0.001) and for a secondary 'remission' outcome (BDI-II score of < 10) 2.74 (95% CI 1.82 to 4.13, p < 0.001). The mean cost of CBT per participant was £910, the incremental health and social care cost £850, the incremental QALY gain 0.057 and incremental cost-effectiveness ratio £14,911. Forty participants were interviewed. Patients described CBT as challenging but helping them to manage their depression; listed social, emotional and practical reasons for not completing treatment; and described usual care as mainly taking medication.<p></p> Conclusions: Among patients who have not responded to antidepressants, augmenting usual care with CBT is effective in reducing depressive symptoms, and these effects, including outcomes reflecting remission, are maintained over 12 months. The intervention was cost-effective based on the National Institute for Health and Care Excellence threshold. Patients may experience CBT as difficult but effective. Further research should evaluate long-term effectiveness, as this would have major implications for the recommended treatment of depression.<p></p&gt

Are multiple physical symptoms a poor prognostic factor or just a marker of depression severity?:Secondary analysis of the GenPod trial

AbstractBackgroundUsing data from the GenPod trial this study investigates: (i) if depressed individuals with multiple physical symptoms have a poorer response to antidepressants before and after adjustment for baseline Beck Depression Inventory II (BDI-II); and (ii) if reboxetine is more effective than citalopram in depression with multiple physical symptoms.MethodsLinear regression models were used to estimate differences in mean BDI-II score at 6 and 12 weeks.ResultsBefore adjusting for baseline BDI-II, the difference in mean BDI-II score between no and multiple physical symptoms was 4.5 (95% CI 1.87, 7.14) at 6 weeks, 4.51 (95% CI 1.60, 7.42) at 12 weeks. After adjustment for baseline BDI-II, there was no evidence of a difference in outcome according to physical symptoms with a difference in mean BDI-II of 2.17 (95% CI −0.39, 4.73) at 6 weeks and 2.43 (95% CI −0.46, 5.32) at 12 weeks. There was no evidence that reboxetine was more effective than citalopram in those with multiple physical symptoms at 6 (P=0.18) or 12 weeks (P=0.24).LimitationsDifferential non-adherence between treatment arms has the potential to bias estimates of treatment efficacy.ConclusionMultiple physical symptoms predict response to antidepressants, but not after adjustment for baseline depression severity. Physical symptoms could be a marker of severe depression rather than an independent prognostic factor and depression should be considered in patients with multiple physical symptoms. Treatment with reboxetine conferred no advantage over citalopram in those with physical symptoms, and it is less well tolerated

Materials used to support cognitive behavioural therapy for depression:a survey of therapists’ clinical practice and views

Use of supporting materials in cognitive behavioural therapy (CBT) is widely advocated, and homework increases effectiveness. The study aimed to identify materials most frequently used by CBT therapists to support CBT for depression, and those perceived clinically most effective. Questionnaires were sent to 3665 accredited CBT therapists asking about their use of resources commonly described in CBT manuals, and their views on effectiveness. Of 3665 approached by post/email, 994 (27%) responded. Another 33 completed the questionnaire via the study website. 818/1027 (80%) of respondents were accredited practitioners who deliver one-to-one therapy. Symptom measures, lists of problems/goals, activity schedules, behavioural activation diaries/plans, and case formulation worksheets were used “frequently” or “very frequently” by over 85% of respondents. Sleep diaries and computerised CBT were used least. Most resources were used within and between sessions. Activity schedules, behavioural activation diaries/plans, case formulation worksheets, thought records, and resources to support the identification of conditional beliefs were regarded as most effective. Symptom measures, sleep diaries, and computerised/online materials were considered only moderately effective. Therapists use a wide range of materials to support individual CBT. For delivering CBT, technology-enabled approaches should incorporate a range of materials to enable therapists to tailor treatment effectively

Combining mirtazapine with SSRIs or SNRIs for treatment-resistant depression: The MIR RCT

Background: Depression is usually managed in primary care and antidepressants are often the first-line treatment, but only half of those treated respond to a single antidepressant. Objectives: To investigate whether or not combining mirtazapine with serotonin–noradrenaline reuptake inhibitor (SNRI) or selective serotonin reuptake inhibitor (SSRI) antidepressants results in better patient outcomes and more efficient NHS care than SNRI or SSRI therapy alone in treatment-resistant depression (TRD). Design: The MIR trial was a two-parallel-group, multicentre, pragmatic, placebo-controlled randomized trial with allocation at the level of the individual. Setting: Participants were recruited from primary care in Bristol, Exeter, Hull/York and Manchester/Keele. Participants: Eligible participants were aged ≥ 18 years; were taking a SSRI or a SNRI antidepressant for at least 6 weeks at an adequate dose; scored ≥ 14 points on the Beck Depression Inventory-II (BDI-II); were adherent to medication; and met the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, criteria for depression. Interventions: Participants were randomised using a computer-generated code to either oral mirtazapine or a matched placebo, starting at a dose of 15 mg daily for 2 weeks and increasing to 30 mg daily for up to 12 months, in addition to their usual antidepressant. Participants, their general practitioners (GPs) and the research team were blind to the allocation. Main outcome measures: The primary outcome was depression symptoms at 12 weeks post randomization compared with baseline, measured as a continuous variable using the BDI-II. Secondary outcomes (at 12, 24 and 52 weeks) included response, remission of depression, change in anxiety symptoms, adverse events (AEs), quality of life, adherence to medication, health and social care use and cost-effectiveness. Outcomes were analysed on an intention-to-treat basis. A qualitative study explored patients’ views and experiences of managing depression and GPs’ views on prescribing a second antidepressant. Results: There were 480 patients randomised to the trial (mirtazapine and usual care, n = 241; placebo and usual care, n = 239), of whom 431 patients (89.8%) were followed up at 12 weeks. BDI-II scores at 12 weeks were lower in the mirtazapine group than the placebo group after adjustment for baseline BDI-II score and minimisation and stratification variables [difference –1.83 points, 95% confidence interval (CI) –3.92 to 0.27 points; p = 0.087]. This was smaller than the minimum clinically important difference and the CI included the null. The difference became smaller at subsequent time points (24 weeks: –0.85 points, 95% CI –3.12 to 1.43 points; 12 months: 0.17 points, 95% CI –2.13 to 2.46 points). More participants in the mirtazapine group withdrew from the trial medication, citing mild AEs (46 vs. 9 participants). Conclusions: This study did not find convincing evidence of a clinically important benefit for mirtazapine in addition to a SSRI or a SNRI antidepressant over placebo in primary care patients with TRD. There was no evidence that the addition of mirtazapine was a cost-effective use of NHS resources. GPs and patients were concerned about adding an additional antidepressant. Limitations: Voluntary unblinding for participants after the primary outcome at 12 weeks made interpretation of longer-term outcomes more difficult. Future work: Treatment-resistant depression remains an area of important, unmet need, with limited evidence of effective treatments. Promising interventions include augmentation with atypical antipsychotics and treatment using transcranial magnetic stimulation

Integrated therapist and online CBT for depression in primary care (INTERACT): study protocol for a multi-centre randomised controlled trial

BACKGROUND: Cognitive behavioural therapy (CBT) is an effective treatment for depression. Self-directed online CBT interventions have made CBT more accessible at a lower cost. However, adherence is often poor and, in the absence of therapist support, effects are modest and short-term. Delivering CBT online using instant messaging is clinically and cost-effective; however, most existing platforms are limited to instant messaging sessions, without the support of between-session "homework" activities. The INTERACT intervention integrates online CBT materials and 'high-intensity' therapist-led CBT, delivered remotely in real-time. The INTERACT trial will evaluate this novel integration in terms of clinical and cost-effectiveness, and acceptability to therapists and clients. METHODS: Pragmatic, two parallel-group multi-centre individually randomised controlled trial, with 434 patients recruited from primary care practices in Bristol, London and York. Participants with depression will be identified via General Practitioner record searches and direct referrals. INCLUSION CRITERIA: aged ≥ 18 years; score ≥ 14 on Beck Depression Inventory (BDI-II); meeting International Classification of Diseases (ICD-10) criteria for depression. EXCLUSION CRITERIA: alcohol or substance dependency in the past year; bipolar disorder; schizophrenia; psychosis; dementia; currently under psychiatric care for depression (including those referred but not yet seen); cannot complete questionnaires unaided or requires an interpreter; currently receiving CBT/other psychotherapy; received high-intensity CBT in the past four years; participating in another intervention trial; unwilling/unable to receive CBT via computer/laptop/smartphone. Eligible participants will be randomised to integrated CBT or usual care. Integrated CBT utilises the standard Beckian intervention for depression and comprises nine live therapist-led sessions, with (up to) a further three if clinically appropriate. The first session is 60-90 min via videocall, with subsequent 50-min sessions delivered online, using instant messaging. Participants allocated integrated CBT can access integrated online CBT resources (worksheets/information sheets/videos) within and between sessions. Outcome assessments at 3-, 6-, 9- and 12-month post-randomisation. The primary outcome is the Beck Depression Inventory (BDI-II) score at 6 months (as a continuous variable). A nested qualitative study and health economic evaluation will be conducted. DISCUSSION: If clinically and cost-effective, this model of integrated CBT could be introduced into existing psychological services, increasing access to, and equity of, CBT provision. TRIAL REGISTRATION: ISRCTN, ISRCTN13112900. Registered on 11/11/2020. Currently recruiting participants. Trial registration data are presented in Table 1