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Background: Stopping long-term (>12 months) antidepressant use can be difficult due to unpleasant withdrawal symptoms. Many people do not recognise withdrawal symptoms or understand how to minimise them while safely discontinuing antidepressants. To address the gaps, the authors developed the 'Redressing long-term antidepressant use' (RELEASE) resources, comprising a medicines information brochure, a decision aid, and drug- specific hyperbolic tapering protocols. Aim: To explore patients' acceptability of the RELEASE resources to optimise their use and impact. Design and setting: A think-aloud interview study among adults with lived experience of long-term antidepressant use conducted in south-east Queensland, Australia, between November 2021 and June 2022. Method: Participants were purposively sampled from general practices and interviewed face-to-face or via videoconferencing. Participants verbalised their thoughts, impressions, and feelings while engaging with each resource. Interviews were analysed using a deductive coding framework, including codes related to acceptability and optimisation. Interviews were analysed in a series of four tranches, with iterative modifications made to resources after each tranche. Results: Participants (n = 14) reported the resources to be relevant, informative, motivational, and usable. Participants' comments informed modifications, including changes to wording, content order, and layout. Several participants expressed frustration that they had not had these resources earlier, with one reporting the information could have been 'life changing'. Many commented on the need for these resources to be widely available to both patients and doctors. Conclusion: The RELEASE resources were found to be acceptable, useful, and potentially life changing. The effectiveness of these consumer-informed resources in supporting safe cessation of long-term antidepressants is currently being tested in general practice. [ABSTRACT FROM AUTHOR]

Background: Public Health England recently called for the establishment of services to help people to safely stop prescribed drugs associated with dependence and withdrawal, including benzodiazepines, z-drugs, antidepressants, gabapentinoids and opioids. NICE identified a lack of knowledge about the best model for such service delivery. Therefore, we performed a global survey of existing deprescribing services to identify common practices and inform service development. Methods: We identified existing deprescribing services and interviewed key personnel in these services using an interview co-produced with researchers with lived experience of withdrawal. We summarised the common practices of the services and analysed the interviews using a rapid form of qualitative framework analysis. Results: Thirteen deprescribing services were included (8 UK, 5 from other countries). The common practices in the services were: gradual tapering of medications often over more than a year, and reductions made in a broadly hyperbolic manner (smaller reductions as total dose became lower). Reductions were individualised so that withdrawal symptoms remained tolerable, with the patient leading this decision-making in most services. Support and reassurance were provided throughout the process, sometimes by means of telephone support lines. Psychosocial support for the management of underlying conditions (e.g. CBT, counselling) were provided by the service or through referral. Lived experience was often embedded in services through founders, hiring criteria, peer support and sources of information to guide tapering. Conclusion: We found many common practices across existing deprescribing services around the world. We suggest that these ingredients are included in commissioning guidance of future services and suggest directions for further research to clarify best practice. [ABSTRACT FROM AUTHOR]

Adaptation of the brain to the presence of a drug predicts withdrawal on cessation. The outcome of adaptation is often referred to as 'physical dependence' in pharmacology, as distinct from addiction, although these terms have unfortunately become conflated in some diagnostic guides. Physical dependence to antidepressants may occur in some patients, consistent with the fact that some patients experience withdrawal effects from these medications. It is thought that longer duration of use, higher dose and specific antidepressants affect the risk of antidepressant withdrawal effects as they might cause greater adaptation of the brain. We searched PubMed for relevant systematic reviews and other relevant analyses to summarise existing data on determinants of antidepressant withdrawal incidence, severity and duration. Overall, data were limited. From survey data, increased duration of use was associated with an increased incidence and severity of withdrawal effects, consistent with some evidence from data provided by drug manufacturers. Duration of use may be related to duration of withdrawal effects but data are heterogenous and sparse. Serotonin and noradrenaline reuptake inhibitors and paroxetine are associated with higher risks than other antidepressants, though data for some antidepressants are lacking. Higher doses of antidepressant has some weak association with an increased risk of withdrawal, with some ceiling effects, perhaps reflecting receptor occupancy relationships. Past experience of withdrawal effects is known to predict future risk. Based on these data, we outline a preliminary rubric for determining the risk of withdrawal symptoms for a particular patient, which may have relevance for determining tapering rates. Given the limited scope of the current research, future research should aim to clarify prediction of antidepressant withdrawal risk, especially by examining the risk of withdrawal in long-term users of medication, as well as the severity and duration of effects, to improve the preliminary tool for predictive purposes. Further research into the precise adaptations in long-term antidepressant use may improve the ability to predict withdrawal effects for a particular patient. [ABSTRACT FROM AUTHOR]

SUMMARY: We now recognise that withdrawal symptoms from antidepressants are common, and can be severe and long-lasting in some people. Many withdrawal symptoms overlap with symptoms of anxiety or depression, making it difficult to distinguish withdrawal from relapse. We describe how their onset soon after dose reduction, the association of psychological with physical symptoms, their prompt response to reinstatement, and their typical 'wave' pattern of onset, peak and resolution can help distinguish withdrawal symptoms from relapse. We also examine evidence that suggests that antidepressant withdrawal symptoms are misdiagnosed as relapse in discontinuation studies aimed at demonstrating the ability of antidepressants to prevent future relapse (relapse prevention properties). In these discontinuation studies people have their antidepressants stopped abruptly, or rapidly, making withdrawal symptoms very likely, and little effort is made to measure withdrawal symptoms or distinguish them from relapse. We conclude that there is currently no robust evidence for the relapse prevention properties of antidepressants, and current guidance might need to be re-evaluated. [ABSTRACT FROM AUTHOR]

Esketamine has been licensed for 'treatment-resistant depression' in the USA, UK and Europe. Licensing trials did not establish efficacy: two trials were negative, one showed a statistically significant but clinically uncertain effect, and a flawed discontinuation trial was included, against Food and Drug Administration precedent. Safety signals - deaths, including suicides, and bladder damage - were minimised. [ABSTRACT FROM AUTHOR]

In the acute treatment phase, 13 of 136 patients in the escitalopram arm reported suicidal ideation, compared with 2 of 137 in the placebo arm. B To the Editor: b Recently, Strawn et al. ([4]) reported on a clinical trial about escitalopram for the treatment of generalized anxiety disorder among children and adolescents. Relative to treatment with placebo, 8% more patients treated with escitalopram developed suicidal ideation (1.5% placebo vs. 9.5% escitalopram) but only 6.2% more patients achieved clinical response (33.3% vs. 39.5%) and 1.5% fewer achieved remission (17.7% vs. 18.8%). [Extracted from the article]

Palmer I et al i ' I s i article aiming to translate recent change in NICE guidance to GPs is timely and useful.[1] Some GPs may have a negative response to the article and understandably, given how big a shift the updated NICE guidance on stopping antidepressants represents from previous guidance. 2022;37:143-157 3 Horowitz MA, Taylor D. Distinguishing relapse from antidepressant withdrawal: clinical practice and antidepressant discontinuation studies. [Extracted from the article]

Public Health England has recommended that services be put in place to support people who choose to withdraw from antidepressants because of a current gap. This study aims to explore the views of members of online withdrawal peer-support groups about existing healthcare and what additional support is needed. The administrators of 15 online support groups for people stopping antidepressants were asked to advertise an online survey to their members. The survey, which was online from May 2021 to April 2022, was completed by 1276 people from 49 countries. 71% of respondents found their doctors' advice unhelpful (57% 'very unhelpful') regarding stopping an antidepressant; the main reasons being 'Recommended a reduction rate that was too quick for me', 'Not familiar enough with withdrawal symptoms to advise me' and 'Suggested stopping antidepressants would not cause withdrawal symptoms'. One in three did not seek advice from their prescriber when deciding whether to withdraw, with the main reasons being 'I felt they would not be supportive' (58%) and 'I felt that they didn't have the expertise to help me' (51%). The most common prescriber responses to those who did seek advice was 'Suggested a quick withdrawal schedule' (56%) and 'Not supportive and offered no guidance' (27%). The most common discontinuation periods recommended by doctors were one month (23%) and two weeks (19%). A range of potential professional services were rated 'very useful', most frequently: 'Access to smaller doses (e.g. tapering strips, liquid, smaller dose tablets) to ensure gradual reduction' (88%) and 'A health professional providing a personalised, flexible reduction plan' (79%). This was a convenience sample, which may have been biased towards people who took longer to withdraw, and experienced more withdrawal symptoms, than antidepressant users in general. Black and ethnic minority people, and people without access to the internet, were underrepresented. Most participants reported their prescribers were unable to help them safely stop antidepressants, compelling them to turn to online peer-support groups instead. Our findings indicate, in keeping with previous studies, that clinicians require upskilling in safe tapering of antidepressants, and that patients need specialised services to help them stop safely. [ABSTRACT FROM AUTHOR]

• Most of 708 users of antidepressants describe the prescriber of their drugs as uninformed about withdrawal symptoms. • Prescribers were also described as unable to provide effective support to withdraw from antidepressants. • Recommendations included individualised, gradual withdrawal plans, with small doses, liquids or tapering strips. • Psychotherapy, withdrawal support groups, patient-led services, nutrition advice and 24-hour crisis support also suggested. • Professional bodies should urgently disseminate evidence-based withdrawal information to GPs and Psychiatrists. Approximately half of the tens of millions of people currently taking antidepressants will experience withdrawal symptoms when they try to reduce or come off them. Nearly half of these describe their symptoms as severe in surveys. Many prescribing doctors seem ill-informed and unprepared to provide effective discontinuation advice and support, often misdiagnosing withdrawal as a relapse of depression or anxiety. 708 members of online support groups for people on antidepressants, from 31 countries, completed a sentence in an online survey: 'A public health service to help people come off antidepressants should include................'. Two independent researchers categorised their responses into themes, and then reached consensus via discussion. Seven themes emerged: 'Prescriber Role', 'Information', 'Other Supports/Services', 'Strong Negative Feelings re Doctors/Services etc.', Informed Consent When Prescribed', 'Drug Companies' and: 'Public Health Campaign'. The most frequently mentioned requirements of the Prescriber Role were that prescribers be properly informed, provide small doses/liquid/tapering strips, develop a withdrawal plan and believe patients about their withdrawal experiences. The most frequently recommended other services were psychotherapy/counselling, support groups, patient led/informed services, nutrition advice, 24-hour crisis support and 'holistic/lifestyle' approaches. Many respondents were angry about how uninformed their doctors were and how they had been treated. [ABSTRACT FROM AUTHOR]

Background: The increasingly recognized role of inflammation in the pathogenesis and prognosis of depression has led to a renewed focus on the immunomodulatory properties of compounds with antidepressant action. Studies have, so far, explored such properties in human blood samples and in animal models. Methods: Here we used the more relevant model of human hippocampal progenitor cells exposed to an inflammatory milieu, induced by treatment with IL-1β. This increased the levels of a series of cytokines and chemokines produced by the cells, including a dose- and time-dependent increase of IL-6. We investigated the immunomodulatory properties of four monoaminergic antidepressants (venlafaxine, sertraline, moclobemide, and agomelatine) and two omega-3 polyunsaturated fatty acids (n-3 PUFAs; eicosapentanoic acid [EPA] and docosahexanoic acid [DHA]). Results: We found that venlafaxine and EPA were anti-inflammatory: venlafaxine decreased IL-6, with a trend for decreases of IL-8 and IP-10, while EPA decreased the levels of IL-6, IL-15, IL-1RA, and IP-10. These effects were associated with a corresponding decrease in NF-kB activity. Unexpectedly, sertraline and DHA had pro-inflammatory effects, with sertraline increasing IFN-α and IL-6 and DHA increasing IL-15, IL-1RA, IFN-α, and IL-6, though these changes were also associated with a decrease in NF-kB activity, suggesting distinct modes of action. Agomelatine and moclobemide had no effect on IL-6 secretion. Conclusions: These observations indicate that monoaminergic antidepressants and n-3 PUFAs have distinctive effects on immune processes in human neural cells. Further characterization of these actions may enable more effective personalization of treatment based on the inflammatory status of patients. [ABSTRACT FROM AUTHOR]

Both increased inflammation and reduced neurogenesis have been associated with the pathophysiology of major depression. We have previously described how interleukin-1 (IL-1) β, a pro-inflammatory cytokine increased in depressed patients, decreases neurogenesis in human hippocampal progenitor cells. Here, using the same human in vitro model, we show how omega-3 (ω-3) polyunsaturated fatty acids and conventional antidepressants reverse this reduction in neurogenesis, while differentially affecting the kynurenine pathway. We allowed neural cells to proliferate for 3 days and further differentiate for 7 days in the presence of IL-1β (10 ng/ml) and either the selective serotonin reuptake inhibitor sertraline (1 µM), the serotonin and norepinephrine reuptake inhibitor venlafaxine (1 µM), or the ω-3 fatty acids eicosapentaenoic acid (EPA, 10 µM) or docosahexaenoic acid (DHA, 10 µM). Co-incubation with each of these compounds reversed the IL-1β-induced reduction in neurogenesis (DCX- and MAP2-positive neurons), indicative of a protective effect. Moreover, EPA and DHA also reversed the IL-1β-induced increase in kynurenine, as well as mRNA levels of indolamine-2,3-dioxygenase (IDO); while DHA and sertraline reverted the IL-1β-induced increase in quinolinic acid and mRNA levels of kynurenine 3-monooxygenase (KMO). Our results show common effects of monoaminergic antidepressants and ω-3 fatty acids on the reduction of neurogenesis caused by IL-1β, but acting through both common and different kynurenine pathway-related mechanisms. Further characterization of their individual properties will be of benefit towards improving a future personalized medicine approach. [ABSTRACT FROM AUTHOR]