Dear Ms Skerrett Re: Regulation 28 Prevention of Future Deaths Report (Thomas Henry Robin Kingston) write in response to your regulation 28 report dated 7 January 2025 regarding the sad death of Thomas Henry Robin Kingston. would like to express my sincere condolences to Thomas's family_ Our patient safety leads at NICE have discussed the contents of your report and the summary information given relating to the death of Mr Kingston; while considering the relevant published NICE guidance on this topic, in this case depression _in adults: treatment and management (NG222): Given that the matters of concern relate to the side effects and safety of medication, specifically selective serotonin reuptake inhibitors (SSRIs) , we believe that the key issues raised are best addressed in the first instance by the Medicines and Healthcare products Regulatory Agency (MHRA); and note that your report has also been sent to them: Therefore, we are currently working collaboratively with the MHRA on this issue. The outcome of that work will inform any action NICE may need to take in respect of its recommendations_ Please consider this our initial reply. We will write to you again as soon as possible with further information once our work with the MHRA has concluded. Please note that given the complex nature of the MHRA work; our final response is unlikely to be submitted by the original response date required by your report hope this is an acceptable way forward and would like to assure you that will send my further reply as soon as possible.

Dear Ms Skerrett; Regulation 28 Report into the death of Thomas Henry Robin Kingston Thank you for your Regulation 28 Report relating to the death of Thomas Henry Robin_ Kingston. would like to offer my sincere condolences to Mr Kingston's family on their tragic loss In the Matters of Concern section of the report relating to Mr Kingston you ask the Medicines and Healthcare products Regulatory Agency (MHRA) whether there is adequate communication about the risks of suicide associated with the Selective Serotonin Reuptake inhibitor (SSRI) medicines and whether the current guidance to persist with SSRI medicine or switch to an alternative SSRI is appropriate when no benefit has been achieved and/ or especially when any adverse side effects are being experienced. May | start by outlining the current information with SSRI antidepressant medicines regarding the risk of suicidal behaviour The product information for all SSRI medicines contains warnings about the risk of suicidal behaviour These warnings were introduced following UK and European reviews of the evidence of such a risk which were started in_ 2003 and concluded that the risk of suicidal acts and behaviour is increased with the use of sertraline, citalopram; escitalopram, paroxetine; venlafaxine, and mirtazapine in young patients (under 25 years of age) The product information for all SSRIs warns that the risk of suicidal behaviour is considered to be greatest in the early stages of antidepressant treatment This is likely to berelated to antidepressants being effective only after a few weeks %f taking the medicine and depression itself being associated with increased risk of suicidal behaviour: an

There are no marked differences in suicidal risk between the different antidepressants within the SSRI class of medicines The product information for all SSRIs recommends that close supervision of patients and particularly those at high risk should accompany drug therapy especially in early treatment and following dose changes Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present: The current warnings in the SSRI medicines' Patient Information Leaflets (PILs) , including citalopram and sertraline _ were subject to user testing and section two contains a bold headline on Thoughts of suicide and worsening of your depression or anxiety disorder". Use of emboldened text and bullet points are used throughout the PIL to highlight key safety information and action for people who experience thoughts of self-harm. There es also advice in the PIL to inform family and friends about a diagnosis of depression or anxiety as it is recognised people with depression may not have insight into their own behaviour and in some patients leaflets this is emboldened. To supplement this information; the MHRA has informed healthcare professionals in the UK about the risk of suicidal behaviour associated with antidepressants via articles in the MHRA's bulletin Drug Safety Update in April 2008 and published guidance for prescribers on the MHRA website in December 2014 to summarise key safety messages? The British National Formulary (BNF) states, "the use of antidepressants has been linked with suicidal thoughts and behaviour; children, young adults, and patients with a history of suicidal behaviour are particularly at risk. Where necessary patients should be monitored for suicidal behaviour, self-harm, or hostility, particularly at the beginning of treatment or if the dose is changed: The information in the product information and the BNF should form the basis of a discussion between the doctor and patient when deciding on the most appropriate medicine for them: Despite all the currently available information about the risk and benefits of SSRI antidepressants designed to supplement and support the clinical conversation and monitoring 0f patients by the healthcare professionals prescribing antidepressants, the MHRA is aware that some patients and families have ongoing concerns about the effectiveness of the current warnings in the patient information leaflets. In 2022, the MHRA sought the advice of the Commission on Human Medicines (CHM) on the need to convene an Expert Working Group (EWG) to review how the risk of suicidal behaviours is communicated in the patient leaflets to establish if this can be improved or if it would be more helpful for patients to receive this information in different formats within the regulatory framework The first meeting %f the EWG was held on 4 July 2024. Round table meetings involving patient charities and families_of those bereaved by suicide will be held in March 2025. The membership and remit of the EWG can be found here Commission on Human Medicines GOV.UK: httpsIlwWW ukldrug_safety-updatelantidepressants-suicidal-thoughts-and-behaviour https JIWWW_gov_uklgovernmentlpublicationslssris-and-snris-use-and-safetvlselective Serotonin- reuptake-inhibitors-Ssris-and-serotonin-and-noradrenaline-reuptake-inhibitors snris-use-and-safety GQV.

The considerations of the EWG are anticipated to complete in 2025. We will communicate to healtfare professionals, patient groups and relevant voluntary organisations any updates on how the risk of suicidal behaviours associated with antidepressants is presented in the antidepressant PILs following the conclusions of the EWG and subsequent CHM advice Secondly in your letter you also ask about the guidance around the use of SSRIs, particularly if no benerit has been seen or adverse reactions have been repoced (Clinical guidance issued by the National Institute for Health and Care Excellence (NICE) Cloai= Guideline NG222) on depression in adults recommends that if a person with depressionis started on antidepressants and is considered to be an increased suicide risk or is between 18 and 25 years (because of the potential increased prevalence of suicidal thoughts in the early stages of antidepressant treatment for this group) they should be reviewed afteoiore Z week of starting antidepressants or after increasing the dose and after this as often as needed, but no later than four weeks after the appointment at which the antidepressant was started. Clinical Guideline 90 advises prescribers to follow a stepped-care model in which to organise the provision of services and supports patients, carers and practitioners in identifving and accessing the most effective interventions; the least intrusive and most effective intervention is provided first: More details of this stepped-care model can be found at https IwWWnice org Uklquidancelcg9O/resourcesldepression-in-adults-recognition-and: management-pdf-975742636741 NICE guidelines advise healthcare professionals that if a person's depression has had nase limited response to treatment with antidepressant medication alone_and no obvious cause found and resolved, to discuss further treatment options with the person and make a can be shared decision on how to proceed based on their clinicai need and preferences Finally I should add that your report of Mr Kingston's adverse reaction to SSRIoedicines has been added to the Yellow Card database (reference number ADR 34440796) which is the UKs system for collecting and monitoring information on suspected Adverse Drug Reactions. Shouldvouhaveany further questions, please do not hesitate to contact my office

Dear Ms Skerrett Regulation 28 Report to Prevent Future Deaths touching on the death of Thomas Henry Robin Kingston Thank you for sharing a copy of your report touching on the tragic death of Thomas Henry Robin Kingston am responding on behalf of the Royal College of General Practitioners as Honorary Secretary to Council. Firstly , can convey our sincere condolences to the family and friends of Thomas_ You asked me to specifically comment on two matters of concern: Whether there is adequate communication of the risks of suicide associated with the selective serotonin reuptake inhibitor (SSRI) medications , and Whether the current guidance to persist with SSRI medication or switch to an alternative SSRI medication is appropriate when no benefit has been achieved andl or especially when any adverse side effects are being experienced: General comments The GP Curriculum includes within its Clinical topic guides a section on Mental Health mentioning a role of the GP to specifically communicate effectively, professionally, and sensitively with patients, relatives and carers, recognising potential difficulties in communicating with people with mental health conditions and the importance of generating and maintaining rapport There is a recognition to assess risk to make the patients safety a priority and offer patients relatives and carers advice and support regarding prevention, prescribing monitoring, and self-management of both mental and physical multimorbidity: The curriculum recognises the emerging issue of suicide prevention in mental health care. Royal College of General Practitioners 30 Euston Square; London; NW1 2FB Tel: 020 3188 7400 info@rcgp org uk rcgp org uk Patron: HRH The Duke of Edinburgh (1972-2021) Registered Charity Number 223106

Shared Decision making 10 years ago, the RCGP recognised that GPs were leading the way in shared decision making and called for more guidance on shared_decision making: The College has pioneered the development of a Person-Centred Care toolkit which includes support for shared decision making and in 2023 RCGP Scotland's joint chair Chris Williams Commenting on the prescription of antidepressants by GPs, RCGP Scotland Joint Chair Dr Chris Williams said: "Depressive illness affects many adults and causes a huge burden of disease worldwide "When prescribed appropriately , evidence shows that antidepressants can be an effective treatment for many patients suffering from mental health conditions such as depression and anxiety. As with any medication, GPs carefully consider the benefits and risks when prescribing antidepressants, the various factors relevant to the individual patient, alongside new clinical guidance as it is published: "Shared decision-making is an evidence-based health communication framework that is commonly used in general practice_ A person with mild to moderate depression may have more than one treatment option, including where medication might be used on its own or in combination. "GPs are highly trained to have frank ad sensitive conversations with our patients, and this includes any potential side effects which may occur from taking antidepressants Once prescription has been made, follow-up appointments and ongoing medication reviews can assist GPs to assess whether patient's symptoms have improved, any side effects they may have experienced as well as if additional support is needed. "Improved access to alternatives to anti-depressant medication, such as talking therapies and CBT, may be beneficial, but resourcing and access issues persist for these treatments. Improved access to these treatment pathways through further resourcing may be beneficial for patients The Royal College of Psychiatrists published a Position statement in 2019 on antidepressants and depression They mentioned the importance of shared decision making: 'To ensure informed consent and shared decision-making; the use of antidepressants should always be underpinned by a discussion with the patient; and familylcarer (as appropriate) , about the potential level of benefits and harms; including withdrawal, and concordance about initiation and continuation. Greater emphasis is also required on regularly reviewing antidepressant use (supported by adequate resourcing and better use of technology) to monitor how well the treatment is working and any side effects as well as to ensure that long-term use remains clinically indicated' _ also raised the issue of risk of suicide when using antidepressants looking at the current evidence at that time_ The Royal College of Psychiatrists have also published comprehensive information for patients on how to stop antidepressants which is as important as starting them_ Specific comments In answer to the two specific questions: They

Is there adequate communication of the risks of suicide with SSRI medication? There can always be more effective communication of risk and in General Practice weuse personalised care approach with an emphasis on the domain of shared decision making: Shared decision making is a process where effective communication between the GP and the patient reaches decision based on a shared understanding of the risks and benefits of different treatment options_ Shared_decision_aids_have_been_produced_to_help_patients_in_managing depression This shared decision aid (SDA) is not specific to particular medication such as SSRIs and does not highlight suicide risk An SDA for SSRIs which balances the benefits and risks for patients would be an effective basis for discussion between the GP and their patient before starting treatment: Is current guidance to persist with SSRI medication or switch to an alternative SSRI medication appropriate when no benefit has been achieved andl or especially when any adverse side effects are being experienced? There are specific guidelines for Depression produced_by NICE and most GPs shall follow NICE CKS (Clinical Knowledge Summaries). The guidance specifically covers the consideration of antidepressant drug treatment (using shared decision making to agree an appropriate treatment plan): The guidance includes advising 'that symptoms of anxiety, agitation, hopelessness; or suicidal ideas may increase when starting treatment; and advise when to seek urgent review'. Advice is also given regarding review and switching_antidepressant_medication: This does mention considering switch to a drug that the person has previously found helpful or prefers. In this case it is not clear whether there was a previous preference for a particular SSRI. It is however usual to switch to a different class if there has not been a benefit or side effects and there are recommendations in the guidance on how to switch drugs safely between classes due to interactions and different bioavailability. It is also important to be clear on the indication for an SSRI and use of diagnostic criteria for both anxiety as well as depression, as the conditions can be separate or mixed and this can guide various treatment options_ The RCGP also has a Mental Healhtoolkitwhich provides evidence-based guidelines for medical and psychological treatments for both depression and anxiety. trust that this reply is helpful and if you have any questions, please do not hesitate to contact me. Our sincere condolences are with Thomas' family_