• Association between mirtazapine use and serious self-harm in people with depression: an active comparator cohort study using UK electronic health records

      Morriss, Richard K.; Butler, Debbie; Hollis, Chris P. (2022)
      Background Studies report an increased risk of self-harm or suicide in people prescribed mirtazapine compared with other antidepressants.Objectives To compare the risk of serious self-harm in people prescribed mirtazapine versus other antidepressants as second-line treatments.Design and setting Cohort study using anonymised English primary care electronic health records, hospital admission data and mortality data with study window 1 January 2005 to 30 November 2018.Participants 24 516 people diagnosed with depression, aged 18–99 years, initially prescribed a selective serotonin reuptake inhibitor (SSRI) and then prescribed mirtazapine, a different SSRI, amitriptyline or venlafaxine.Main outcome measures Hospitalisation or death due to deliberate self-harm. Age–sex standardised rates were calculated and survival analyses were performed using inverse probability of treatment weighting to account for baseline covariates.Results Standardised rates of serious self-harm ranged from 3.8/1000 person-years (amitriptyline) to 14.1/1000 person-years (mirtazapine). After weighting, the risk of serious self-harm did not differ significantly between the mirtazapine group and the SSRI or venlafaxine groups (HRs (95% CI) 1.18 (0.84 to 1.65) and 0.85 (0.51 to 1.41) respectively). The risk was significantly higher in the mirtazapine than the amitriptyline group (3.04 (1.36 to 6.79)) but was attenuated after adjusting for dose.Conclusions There was no evidence for a difference in risk between mirtazapine and SSRIs or venlafaxine after accounting for baseline characteristics. The higher risk in the mirtazapine versus the amitriptyline group might reflect residual confounding if amitriptyline is avoided in people considered at risk of self-harm.Clinical implications Addressing baseline risk factors and careful monitoring might improve outcomes for people at risk of serious self-harm.No data are available. Data used in the study were provided under licence by CPRD (www.cprd.com) and cannot be shared by the authors. All code lists and the statistical code (in the form of Stata do-files) used to prepare and analyse the data are available on Zenodo.org (https://doi.org/10.5281/zenodo.4779024).
    • BAP Position Statement: Off-label prescribing of psychotropic medication to children and adolescents

      Hollis, Chris P. (2016)
      The off-label use of medicines for children and adolescents remains a common and important issue for prescribing practice across child and adolescent psychiatry, paediatrics and primary care. This editorial focusses on psychotropic drug treatment, which plays an essential part in the comprehensive management of a range of child and adolescent psychiatric disorders. Despite a growing evidence base for drug treatment in child and adolescent psychiatric disorders, much psychotropic medication continues to be prescribed off-label (i.e. outside the limits of the marketing authorisation or product license). The reasons for and implications of off-label prescribing, including the potential clinical benefits/risks and medico-legal implications, are often poorly understood by both patients and prescribers. An important unintended consequence of the uncertainties and confusion surrounding the status of off-label prescribing for children and adolescents may be that effective drug treatments are being withheld or underused. This BAP Position Statement aims to clarify these issues, challenge some of the myths surrounding off-label prescribing for children and adolescents and offer practical guidance for prescribers. Copyright © The Author(s) 2016.
    • Consensus workshops on the development of an ADHD medication management protocol using QbTest: developing a clinical trial protocol with multidisciplinary stakeholders

      Hall, Charlotte L.; Brown, Susan S.; Martin, Jennifer L.; Brown, Nikki; Williams, Laura; Sayal, Kapil; Hollis, Chris P.; Groom, Madeleine J. (2019)
      BACKGROUNDThe study design and protocol that underpin a randomised controlled trial (RCT) are critical for the ultimate success of the trial. Although RCTs are considered the gold standard for research, there are multiple threats to their validity such as participant recruitment and retention, identifying a meaningful change, and non-adherence to the protocol. For clinical RCTs, involving patients and clinicians in protocol design provides the opportunity to develop research protocols that are meaningful to their target audience and may help overcome some of the inherent threats in conducting RCTs. However, the majority of protocols do not describe the methodology underpinning their development, limiting the amount of learned experience shared between research groups.METHODWith the purpose of reporting a collaborative approach towards developing a protocol, we present the findings from three sequential workshops that were conducted with the aim of developing a protocol to investigate the feasibility of adding a computerised test of attention, impulsivity and activity (QbTest) to medication management of children and young people with Attention deficit hyperactivity disorder (ADHD). Based on previous qualitative interviews with clinicians and families, each workshop prioritised topics for focused discussion. Information from the workshops was fed back to the participants for reflection in advance of the next workshop.RESULTSThe workshops involved 21 multi-disciplinary ADHD experts, including clinicians, patient and public involvement (PPI) members, parents of young people with ADHD and researchers. The consensus workshops addressed key research issues such as: the most relevant outcome measures/ resource drivers; methods and time points for data collection; and the clinical protocol for utilising the QbTest, including when best to use this within the medication management process. The resulting protocol details a feasibility RCT design describing these factors.CONCLUSIONProtocols which are co-developed may help overcome some of the risks associated with RCT completion (e.g. recruitment, retention, protocol adherence) and help prioritise outcomes of greater relevance to the populations under study. The methodology has potential value for researchers and organisations developing clinical guidelines, and offers insights into the valuable impact of PPI upon trial design.TRIAL REGISTRATIONClinicaltrials.gov NCT03368573, 11th December 2017 (retrospectively registered).
    • Neurological and psychiatric adverse effects of long-term methylphenidate treatment in ADHD: A map of the current evidence

      Hall, Charlotte L.; Groom, Madeleine J.; Kochhar, Puja; Roberts, Samantha; Sayal, Kapil; Xia, Jun; Hollis, Chris P.; Liddle, Elizabeth B. (2019)
      Methylphenidate (MPH), the most common medication for children with Attention Deficit/Hyperactivity Disorder (ADHD) in many countries, is often prescribed for long periods of time. Any long-term psychotropic treatment in childhood raises concerns about possible adverse neurological and psychiatric outcomes. We aimed to map current evidence regarding neurological and psychiatric outcomes, adverse or beneficial, of long-term MPH (> 1 year) treatment in ADHD. We coded studies using a "traffic light" system: Green: safe/favours MPH; Amber: warrants caution; Red: not safe/not well-tolerated. Un-categorisable study findings were coded as "Unclear". Although some evidence suggests an elevated risk of psychosis and tics, case reports describe remission on discontinuation. Several studies suggest that long-term MPH may reduce depression and suicide in ADHD. Evidence suggests caution in specific groups including pre-school children, those with tics, and adolescents at risk for substance misuse. We identified a need for more studies that make use of large longitudinal databases, focus on specific neuropsychiatric outcomes, and compare outcomes from long-term MPH treatment with outcomes following shorter or no pharmacological intervention.
    • Optimising medication management in children and young people with ADHD using a computerised test (QbTest): a feasibility randomised controlled trial

      Williams, Laura; Hall, Charlotte L.; Brown, Susan S.; Guo, Boliang; James, Marilyn; Brown, Nikki; Sayal, Kapil; Hollis, Chris P.; Groom, Madeleine J. (2021)
      BACKGROUNDMedication for attention deficit hyperactivity disorder (ADHD) should be closely monitored to ensure optimisation. There is growing interest in using computerised assessments of ADHD symptoms to support medication monitoring. The aim of this study was to assess the feasibility and acceptability of a randomised controlled trial (RCT) to evaluate the efficacy of one such computerised assessment, the Quantified Behavior (Qb) Test, as part of medication management for ADHD.METHODSThis feasibility multi-site RCT conducted in child and adolescent mental health and community paediatric settings recruited participants aged 6-15 years diagnosed with ADHD starting stimulant medication. Participants were randomised into one of two arms: experimental (QbTest protocol) where participants completed a QbTest at baseline and two follow-up QbTests on medication (2-4 weeks and 8-10 weeks later) and control where participants received treatment as usual, including at least two follow-up consultations. Measures of parent, teacher, and clinician-rated symptoms and global functioning were completed at each time point. Clinicians recorded treatment decision-making and health economic measures were obtained. Data were analysed using multi-level modelling and participants (children and parents) and clinicians were interviewed about their experiences, resulting data were thematically analysed.RESULTSForty-four children and young people were randomised. Completion of study outcome measures by care-givers and teachers ranged from 52 to 78% at baseline to 47-65% at follow-up. Participants reported the questionnaires to be useful to complete. SNAP-IV inattention scores showed greater reduction in the intervention than the control group (- 5.85, 95% CI - 10.33, - 1.36,). Engagement with the intervention ranged from 100% at baseline, to 78% follow-up 1 and 57% follow-up 2. However, only 37% of QbTests were conducted in the correct time period. Interview data highlighted that the objectivity of the QbTest was appreciated by clinicians and parents. Clinicians commented that the additional time and resources required meant that it is not feasible to use QbTest for all cases.CONCLUSIONThe trial design and protocol appear to be feasible and acceptable but could be improved by modifying QbTest time periods and the method of data collection. With these changes, the protocol may be appropriate for a full trial. Adding QbTest may improve symptom outcome as measured by SNAP-IV.TRIAL REGISTRATIONClinicalTrials.gov, NCT03368573 , prospectively registered, 11th December 2017, and ISRCTN, ISRCTN69461593 , retrospectively registered, 10th April 2018.
    • Secondary care specialist visits made by children and young people prescribed antidepressants in primary care: a descriptive study using the QResearch database

      Butler, Debbie; Hollis, Chris P.; Morriss, Richard K. (2020)
      BACKGROUNDAntidepressants may be used to manage a number of conditions in children and young people including depression, anxiety, and obsessive-compulsive disorder. UK guidelines for the treatment of depression in children and young people recommend that antidepressants should only be initiated following assessment and diagnosis by a child and adolescent psychiatrist. The aim of this study was to summarise visits to mental health specialists and indications recorded around the time of antidepressant initiation in children and young people in UK primary care.METHODSThe study used linked English primary care electronic health records and Hospital Episode Statistics secondary care data. The study included 5-17-year-olds first prescribed antidepressants between January 2006 and December 2017. Records of visits to paediatric or psychiatric specialists and potential indications (from a pre-specified list) were extracted. Events were counted if recorded less than 12 months before or 6 months after the first antidepressant prescription. Results were stratified by first antidepressant type (all, selective serotonin reuptake inhibitors (SSRIs), tricyclic and related antidepressants) and by age group (5-11 years, 12-17 years).RESULTSIn total, 33,031 5-17-year-olds were included. Of these, 12,149 (37%) had a record of visiting a paediatrician or a psychiatric specialist in the specified time window. The majority of recorded visits (7154, 22%) were to paediatricians. Of those prescribed SSRIs, 5463/22,130 (25%) had a record of visiting a child and adolescent psychiatrist. Overall, 17,972 (54%) patients had a record of at least one of the pre-specified indications. Depression was the most frequently recorded indication (12,501, 38%), followed by anxiety (4155, 13%).CONCLUSIONSThe results suggest many children and young people are being prescribed antidepressants without the recommended involvement of a relevant specialist. These findings may justify both greater training for GPs in child and adolescent mental health and greater access to specialist care and non-pharmacological treatments. Further research is needed to explore factors that influence how and why GPs prescribe antidepressants to children and young people and the real-world practice barriers to adherence to clinical guidelines.
    • Study protocol for a randomised controlled trial of CBT vs antipsychotics vs both in 14-18 year-olds: Managing Adolescent first episode Psychosis: A feasibility study (MAPS)

      Hollis, Chris P. (2019)
      BACKGROUND: Adolescent-onset psychosis is associated with more severe symptoms and poorer outcomes than adult-onset psychosis. The National Institute for Clinical Excellence (NICE) recommend that adolescents with first episode psychosis (FEP) should be offered a combination of antipsychotic medication (APs), cognitive behavioural therapy (CBT) and family intervention (FI). The evidence for APs in treating psychosis is limited in adolescents compared to adults. Nevertheless, it indicates that APs can reduce overall symptoms in adolescents but may cause more severe side effects, including cardiovascular and metabolic effects, than in adults. CBT and FI can improve outcomes in adults, but there are no studies of psychological interventions (PI) in patients under 18 years old. Given this limited evidence base, NICE made a specific research recommendation for determining the clinical and cost effectiveness of APs versus PI versus both treatments for adolescent FEP. METHODS/DESIGN: The current study aimed to establish the feasibility and acceptability of conducting such a trial by recruiting 14-18-year-olds with a first episode of psychosis into a feasibility prospective randomised open blinded evaluation (PROBE) design, three-arm, randomised controlled trial of APs alone versus PI alone versus a combination of both treatments. We aimed to recruit 90 participants from Early Intervention and Child and Adolescent Mental Health Teams in seven UK sites. APs were prescribed by participants' usual psychiatrists. PI comprised standardised cognitive behavioural therapy and family intervention sessions. DISCUSSION: This is the first study to compare APs to PI in an adolescent population with FEP. Recruitment finished on 31 October 2018. The study faced difficulties with recruitment across most sites due to factors including clinician and service-user treatment preferences. TRIAL REGISTRATION: Current controlled trial with ISRCTN, ISRCTN80567433 . Registered on 27 February 2017.