Impact case study database

The results for the network meta-analyses and systematic reviews for depression, bipolar disorder and schizophrenia that Cipriani and Geddes with their collaborators developed in Oxford between 2009 and 2018 have had a significant impact on the treatment of these conditions in the NHS and overseas. The team’s 2009 Lancet publication [1] recommended sertraline as first-line treatment for depression, and in 2015 sertraline became the most commonly prescribed antidepressant in the US, with a 22.6% increase in prescriptions, the largest increase in prescribing among all antidepressants (from less than 2,100,000 to more than 2,700,000 prescriptions/year) [A]. It has also been described as the most prescribed antidepressant in Japan [B(ii)].

In China, by 2019 more than 30,000 psychiatrists had followed recommendations for treatment of bipolar disorder [C(i)] and schizophrenia [C(ii)] that were based on findings from the University of Oxford research, directly influencing the treatment of nearly a hundred million patients in China. The Vice-Chairman of the Chinese Neurology Society wrote citing [2, 3, 4], amongst others, and confirmed that the University of Oxford reviews

“... have had a great impact on clinical practice in China: they have changed the prescription patterns of psychotropic drugs in our country and have improved the clinical outcome of our patients, reducing significantly the number of hospital admissions for patient with schizophrenia and reducing the length of stay for inpatients and the number of suicides and deliberate self harm for patients with bipolar disorder.” [B(iii)]

The Professor of Medicine, of Health Research and Policy, and Director, Meta-Research Innovation Center at Stanford University, cited papers including [2,3,4,6] in summarising the influence of this body of work:

“ *This powerful work has had tremendous implications for setting the guidelines of clinical practice... it has been extremely valuable also for offering tangible information on crucial questions to tens of millions of patients worldwide.*” [B(i)]

The University of Oxford work in evidence synthesis [1, 2] allowed for the first time the evidence-based ranking, in order of effectiveness, of all most commonly prescribed pharmacological treatments for depression and bipolar disorder. By including in the analysis drugs that are in the WHO Model List of Essential Medicines, these rankings have greatly facilitated the real-world decision making between clinicians and patients in both primary and secondary care across the globe, and also in low and middle income countries. The Dean of Medical School, University of Toronto, wrote that [1] was “the single most influential paper in shaping treatment guidelines and practice” and went on to explain that, “The more recent network meta-analyses [on depression and bipolar disorder] are another game-changer, as they allow extrapolation from randomized clinical trials to real world clinical settings which are compelling for many clinicians including those outside of academic settings”. [B(iv)]

The team’s research-based recommendations have been included in official clinical guidelines in a number of countries, including:

• Canada - The Canadian Network for Mood and Anxiety Treatments (CANMAT) offers clinicians clear use recommendations for first, second, and third-line treatments, while considering the robustness of evidence and clinical relevance. The 2018 CANMAT guidelines recommend lithium as the best treatment for acute mania, bipolar depression and maintenance treatment for bipolar disorder and suicide prevention [D], based on the results from the network meta-analyses, citing papers including [3] and corroborated by letter [B(iv)].

• United Kingdom: National Institute for Health and Care Excellence (NICE) guidelines on the optimal treatment of bipolar disorder (NCG 185, first released 2014) state that the network meta-analysis [2] “... found robust evidence that several pharmacological interventions are efficacious. Furthermore, there was evidence of differential effectiveness among medications, which is a unique strength of network meta-analysis” [E, section 6.2.4]. The results were then used as the evidence base to support specific recommendations also for the cost-effectiveness analysis: “The interventions assessed in this economic analysis were determined by the availability of data reported in the network meta-analysis by Cipriani and colleagues, 2011” [E, section 6.25, p125].

• United Kingdom: The British Association for Psychopharmacology, the largest such association in Europe, issues guidelines based on the best available evidence to aid clinical decision-making and provide information for patients and carers. Its 2016 guidelines on bipolar disorder draw on the network meta-analysis [2] in the recommendations for treating mania: “The network was highly coherent, and so strongly supports the validity of the overall recommendation to use dopamine antagonist/partial agonists in mania” [F, p523].

• Australia and New Zealand: The Royal Australian and New Zealand College of Psychiatrists Mood Disorders Clinical Practice Guidelines for treating bipolar disorder first drew on Cipriani and Geddes’ work [2] in 2015, stating that, “The choice of medications is determined by the availability of medications, the required speed of onset of action and the proposed future choice of medications (Cipriani et al., 2011)” [G(i), p67]. Their update in 2020 cited [1,2,4,6] both in recommending ‘Choice’ antidepressants [G(ii), section 7.2] and those to discontinue for children and adolescents [I, box 18]. While the 2020 guidelines were in preparation, the Chair of the working group for these guidelines highlighted the role of the most recent work [4,6]:

“Presently, the 2015 guidelines are being updated and will be published in 2020, and once again Cipriani’s articles feature strongly.... In particular his most recent network meta-analyses comparing the efficacy and tolerability of antidepressants for major depression in children and adolescents and the acceptability of 21 antidepressant drugs for the acute treatment of depression in adults (2016 and 2018).” [B(v)]

The 2017 meta-analysis [5] has been used to accurately quantify, for the first time, the magnitude of the effect of antipsychotics versus placebo in the acute treatment of schizophrenia, informing guidelines in the USA and UK.

• USA: The American Psychiatric Association guidelines recommend that “ patients with schizophrenia be treated with an antipsychotic medication and monitored for effectiveness and side effects.” [H(i), Statement 4] *. * They cite [5] as one of two “high-quality meta-analyses that examined findings from RCTs of antipsychotic medications in schizophrenia” and conclude that “the strength of the research evidence is rated as high in demonstrating that the benefits of treatment with an antipsychotic medication outweigh the harms...” [H(ii) pp210-11].

• United Kingdom: The same meta-analysis [5] was used to inform the updated British Association of Psychopharmacology guidelines recommending pharmacological treatment of schizophrenia: “A meta-analysis of placebo-controlled acute treatment studies in established schizophrenia found that just over 50% of participants responded to antipsychotic treatment, compared with a figure of 30% for those receiving placebo. The respective proportions for ... ‘much improved’ were 23% and 13%”. [I, p11]

The extensive press coverage of the 2018 Cipriani et al. study [6] led to the spontaneous #MedsWorkedForMe hashtag, used to share personal stories about how antidepressants helped them manage their mental health. In just a few hours, the 5 posts in the initial thread were retweeted 335 times, liked 1,448 times, and generated 156 replies and then retweeted 730 times. This social media activity is reflected in the study having the highest ever Altmetric score of any psychiatry paper (4,543), and in the top 5% of all research outputs. The hashtag was a ‘UK Trending Topic’ in February 2018 [J(i)], and the hashtag originator went on to be interviewed by the British Medical Journal [J(ii)]. Patients sharing their positive stories were prominently featured in the extensive media coverage [K]. Example tweets in response include:

“I think seeing people you look up to publicly admitting to their depression helps you realise you’re not alone and sharing real advice on what works for them - drugs, … - is probably one of the most powerful things someone can do.”

“The stigma which surrounds taking medication for mental illness needs to end. Mental illnesses are valid illnesses. No one should ever be made to feel shamed for taking medication.”

“Mental illnesses must be the only life threatening illnesses that medication is seen as a luxury and not a need. Antidepressants aren’t ‘happy pills’; they don’t cure you, they just make it a bit easier to function. Stop stigmatising, these drugs can save lives.”