What is the evidence-base/position in guidelines?

A summary of the place of ECT in current UK guidelines is provided in Table 1. As can be seen, guidance indicates that there are a range of specific situations where ECT is safe and effective, suggesting that ECT should be a common part of everyday psychiatric practice. However, ECT prescription rates, particularly in the UK, show that its use has fallen in the past 50 years and that it is used much less frequently than its evidence base would predict. This is unlikely to be primarily due to a reduction in indications for ECT, which are still wide-ranging and broadly similar to those described by Pippard & Ellam (Reference Pippard and Ellam1981), where 83% of ECT was used for a primary diagnosis of depression.

TABLE 1

Current indications for electroconvulsive therapy (ECT) in UK guidelines

What is the evidence ECT is underused?

The chequered history of ECT is well-documented and it has proved one of the most controversial treatments in the whole of medicine. Following the first description of the technology by Cerletti and Bini in 1938, ECT became widely used and misused. Data quantifying levels of ECT use in the decades following its introduction are patchy and poor quality in most countries. Nevertheless, the trend in decreasing ECT use over the latter decades of the 20th century is clear in the UK. An indication of the extent of decline is provided in a study in selected South London teaching hospitals (Lambe Reference Lambe, Mask and Trimikas2014) which found that 35% of psychiatric in-patients received ECT in 1956 before widespread availability of effective pharmacotherapies, compared with 2.2% in 1991, despite large reductions in bed availability.

A survey in 1980–1981 (Pippard Reference Pippard and Ellam1981) documented 380–400 places providing ECT across Britain and approximately 7800 courses of ECT occurring over a 3-month period, equivalent to over 30 000 courses per year. Data collection via the Department of Health/National Health Service in the UK documents clearly, despite some methodological issues (e.g. whether individual ECT treatments, courses or patients were recorded, variable clinic response rates, which parts of the UK are included), a consistent decline in ECT use, particularly from the 1980s onwards. For example, Bickerton et al (Reference Bickerton, Worrall and Chaplin2009) found that in England the number of individual ECT treatment sessions (i.e. not ECT courses) in a 3-month period fell from 34 485 in 1985 to 16 482 in 1999 and then to 6782 in 2006. This last cohort represented 1276 patients undergoing ECT in a 3-month period, which would extrapolate to around 5000 patients undergoing the treatment in England in the whole of 2006.

The establishment in 2003 of the ECT Accreditation Service (ECTAS; www.rcpsych.ac.uk/improving-care/ccqi/quality-networks-accreditation/ectas) has substantially improved ECT data reporting in the UK, particularly since the introduction of a regular national survey (excluding Scotland, which has its own arrangements) in 2012. The most recent ECTAS survey (Electroconvulsive Therapy Accreditation Service 2023) covers the calendar year of 2021 and received data from 85 of the UK’s 93 registered ECT clinics (excludes Scotland). In this period there were 1989 acute courses, 62 continuation courses and 107 maintenance courses (total of 2158 courses), representing a further significant drop from the 2006 data in Bickerton et al’s study.

Why has ECT use fallen in the UK?

There are a range of interacting factors linked to the decline in usage of ECT, which can be summarised as (a) stigma/attitudinal factors, (b) concerns regarding effectiveness, (c) concerns about side-effects, (d) complex regulations/de-emphasis in guidelines and (e) subsequent reduced availability of and familiarity with the treatment.

Negative attitudes towards ECT have been reported among patients, the general public and health professionals, including psychiatrists (Maughan Reference Maughan and Molodynski2016). It is likely that this has been fuelled by poor standards of historic practice, which include crude, unmodified and poorly monitored stimulation paradigms across inadequately selected patients, as well as outright abuse of ECT by authoritarian regimes, for example in Nazi Germany and the Soviet Union. Negative perceptions of ECT have been maintained by media portrayal (especially Miloš Forman’s 1975 film One Flew Over the Cuckoo’s Nest) and critical psychiatry literature. Even in high-quality UK newspapers, recent potentially stigmatising accounts are not hard to find (Oppenheim Reference Oppenheim2022).

Although ECT has built a reliable evidence base in acute treatment of depressive episodes, studies have shown that up to 85% of patients relapse if an ECT course is followed by placebo antidepressant medication (Sackheim Reference Sackheim2017). This risk can be partly mitigated by pharmacotherapy and psychological treatment (Sackheim Reference Sackheim2017). This may be a contributing factor limiting use by psychiatrists. The introduction of effective antidepressant drugs from the 1960s onwards is also associated with falling rates of ECT usage.

ECT has historically been associated with burdensome side-effects, particularly cognitive, and indeed these have been prominent in critical media portrayals of the treatment. These are likely to still colour perception among patients and professionals despite major technical advances, such as use of general anaesthesia, muscle relaxants, threshold titration, electroencephalogram (EEG) monitoring, ultrabrief stimulation and unilateral electrode placement, which have improved the safety and tolerability of ECT.

In modern mental health practice, ECT operates under specific safeguards (e.g. requirements for independent second opinions for detained patients who cannot consent) and standards of practice (e.g. the ECTAS scheme). Although these are, of course, important for quality assurance, this may contribute to a perception of ECT being a risky treatment. It is arguable that some treatment guidelines have not given sufficiently robust recommendations for ECT based on its evidence base.

As rates of ECT prescription fall, clinics administering it close and younger psychiatrists become less familiar with the treatment, potentially leading to a further circular decline in ECT use.

What can be done to ensure more evidence-based use?

For ECT use to increase to levels expected if it was prescribed according to current UK guidelines, several things need to happen. Clinicians and patients need to be aware of up to date evidence of effectiveness and reassured about side-effects, and negative attitudinal barriers need to be challenged. The treatment should be easily accessible and, although overseen by effective clinical governance, not subject to excessive regulation or bureaucratic operational procedures.

There is therefore a need for high-quality information about ECT to be available to clinicians and patients. It is important to provide information about the safety of ECT, for example research showing it is not associated with an increased rate of serious medical events (Kaster Reference Kaster, Vigod and Gomes2021). Cognitive side-effects are now much reduced following improvements in technique, and if they do occur, they are likely to be transient (Sackheim Reference Sackheim2017). This is particularly important as evidence builds of relatively low remission rates with conventional antidepressant medications in patients who do not respond to the first couple of agents tried. Further research is needed to establish the most effective pharmacological treatment strategies following successful acute use of ECT, although lithium may have an important role for some patients (Lambrichts Reference Lambrichts, Detraux and Vansteelandt2021).

The Royal College of Psychiatrists and similar institutions in other countries have a central role in promoting evidence-based use of ECT. This includes challenging inaccurate or stigmatising portrayals of ECT and ensuring that the voices of patients and carers who have had recent direct experience of the treatment are heard. Surveys indicate significantly more positive attitudes towards ECT among people who receive it (Maughan Reference Maughan and Molodynski2016). To combat inaccurate perceptions among the workforce, exposure to ECT prescription and usage should be a central part of the training of psychiatrists and other mental health professionals. Academics and clinicians with expertise in neurostimulatory therapies need to be adequately represented in working groups responsible for producing guidelines to ensure ECT receives appropriate emphasis in treatment algorithms. Bodies such as ECTAS have an important function in striking a balance between effective governance of ECT without excessive bureaucratisation.

A final suggestion, recognising the major difference between the current practice of ECT and the original description by Cerletti and Bini, is to rename the treatment. In a public survey in Bangalore, India, Andrade & Thyagarajan (Reference Andrade and Thyagarajan2007) found that the term ‘electrostimulatory therapy’, for example, had significantly higher levels of acceptability than ‘electroconvulsive therapy’.

What is evidence-base/position in guidelines?

In a first episode of psychosis, the British Association for Psychopharmacology (BAP) (Barnes Reference Barnes, Drake and Paton2020) recommends that clozapine should be considered after there has been an adequate trial of two antipsychotics as well as family therapy and cognitive–behavioural therapy (CBT) for psychosis (where available). This is anticipated as being achieved within 3 years of initiating treatment.

The BAP guideline also recommends that clozapine is used first line in treatment-resistant schizophrenia as soon as the above pharmacological criteria have been met (provided that substance use and limited adherence have been ruled out as contributing factors). The trial should last a minimum of 3–6 months (during which time adverse effects should be proactively managed) before other options such as augmentation are considered.

The Scottish national clinical guideline on management of schizophrenia (Scottish Intercollegiate Guidelines Network 2013) states that clozapine should be offered to people with treatment-resistant schizophrenia, for example where their illness has not responded to two antipsychotics (including a second-generation antipsychotic), after reviewing diagnosis and accessing for any comorbidity. The dose should then be optimised, and augmentation with options such as a second-generation antipsychotic or lamotrigine should be considered only if there has been an inadequate response to clozapine monotherapy. It advises that high-dose antipsychotic medication should be used only after other trials, including clozapine, have failed.

In its clinical guideline for prevention and management of schizophrenia, NICE (2014) provides similar recommendations. It advises that clozapine is offered as soon as the following steps have been completed:

• two consecutive antipsychotics (one of which should be second generation) have been trialled without success, at an adequate dose, for an adequate duration

• a check of adherence to the antipsychotics

• review of diagnosis

• offer of CBT and family intervention (where appropriate)

• consideration of other contributors to illness, such as substance use, other prescribed medicines and any physical illness.

Augmentation through the use of two antipsychotics is recommended only after clozapine has been used at an optimised dose.

These guidelines stem from a compelling evidence base in favour of using clozapine as gold standard treatment for resistant schizophrenia; for example, it is effective in 41% of people with treatment-resistant schizophrenia, whereas olanzapine at up to 25 mg per day is effective in only 5% (Conley Reference Conley, Tammiga and Kelly1999) (see also Kane Reference Kane, Honigfeld and Singer1988).

There is good reason to avoid delaying initiation. A 2017 study (Yoshimura Reference Yoshimura, Yada and So2017) found that if clozapine is started within 2.8 years of onset of psychosis, response rates are around 82%, as opposed to 31% in those where treatment is delayed beyond this.

There are additional benefits that come with using clozapine. There is plenty of evidence of its anti-suicidal properties, it is the most effective oral antipsychotic for reducing risk of relapse requiring psychiatric admission (Tihonan Reference Tihonan, Mittendorfer-Rutz and Majak2017) and it is associated with reduced use of drugs and alcohol once someone is taking it.

What is the evidence it is underused and why might this be?

Only around one-third of people eligible to use clozapine in the UK are prescribed it. This is substantially lower than in other parts of Europe (Whiskey Reference Whiskey, Barnard and Oloyede2021). It is likely that, at least in part, this is related to reluctance to prescribe, with surveys showing clinicians lack confidence in doing so (Tungaraza Reference Tungaraza and Farooq2015). Additionally, the media may have served to increase patients’ concerns, for example in January 2024, The Times ran an article about clozapine with the headline ‘Britain’s most dangerous prescription drug – linked to 400 deaths per year’, which prompted a counter-response letter from Lade Smith, the President of the Royal College of Psychiatrists. Public and clinician concerns are often a mismatch with the experience of patients who find they feel better on clozapine and want to stay on it (Taylor Reference Taylor, Shapland and Laverick2000).

The risk of dangerous, potentially fatal side-effects is a major consideration with clozapine, and is one of the reasons it is not a first-line antipsychotic. Severe complications include myocarditis, cardiomyopathy and gastrointestinal obstruction. In the UK, clozapine requires careful blood monitoring because of the risk of adverse effects on white blood cells. Neutropenia occurs in about 3% of patients and agranulocytosis in 0.4% (Li et al Reference Li, Zhong and Lu2020). This monitoring is resource-intensive, whereas NHS mental health services are comparatively underfunded, and requires significant long-term commitment from the patient. Furthermore, if a patient stops clozapine for more than 48 h, careful re-titration with short-term increase in mental health service input is required.

Drug interactions are another safety concern. Clozapine can adversely interact with other drugs, which could put off prescribers when they are treating patients who may be experiencing physical as well as mental illness (for example, care is needed when prescribing antibiotics; clozapine with trimethoprim is contraindicated; and the risk of QT prolongation increases with clarithromycin).

Psychiatrists may decide against prescribing clozapine in favour of a depot antipsychotic because of a patient’s history of poor adherence to other medicines, yet adherence to clozapine is typically very good, even for those where this was an issue before starting it (Brodeur Reference Brodeur, Courteau and Vanasse2022).

Changes in the amount of tobacco smoked must be carefully assessed in people taking clozapine, with dose adjustments by as much as 70% if someone gives up smoking, owing to the risk of clozapine toxicity from reduced metabolism. Dose adjustments also need to be made if someone starts smoking more, to minimise the risk of recurrence of psychosis through suboptimal clozapine levels caused by increased metabolism. This necessitates monitoring and making dose adjustments based on the patient’s smoking habits not just in the community – as in-patient units are increasingly smoke-free, this should be considered during the start and end of admissions too. However, this challenge is not exclusive to clozapine – it also applies to other antipsychotics, such as olanzapine.

A newer issue for people taking clozapine, and their healthcare teams, is the impact of COVID-19 infection. Bacterial and viral infections have been reported to increase plasma levels of clozapine, and clozapine use is thought to be associated with an increased risk of COVID-19 and pneumonia (Govind Reference Govind, Fonseca de Freitas and Pritchard2021), which might be another reason for reluctance to prescribe clozapine.

What can be done to ensure more evidence-based use?

As with ECT, educating prescribers about clozapine could improve their confidence in prescribing it as soon as a patient with schizophrenia has had insufficient response to two consecutive antipsychotics at adequate dose for an adequate duration. If clinicians and patients know the advantages of clozapine over other antipsychotics and if clinicians know how to monitor and address problems as they arise, it is likely to increase prescribing to bring clozapine use more in line with national guidelines.

As experts in balancing evidence, risks and benefits, psychiatrists and pharmacists could play a part in challenging the publication of misinformation or one-sided information in the media, to help the public be better informed.

The UK could also look to other countries and new perspectives to consider changes in how we license and use clozapine. A study in Finland looked at long-term risk of agranulocytosis and suggested that benefits of relaxing long-term neutrophil monitoring could outweigh the risks, as the likelihood of developing neutropenia decreases steeply over time (Rubio Reference Rubio, Kane and Tanskanen2024), and following review of Australian data, there has even been a call to stop monitoring altogether after 2 years (Northwood Reference Northwood, Myles and Clark2024). If the UK swapped to the USA’s less stringent neutrophil monitoring criteria (allowing a lower neutrophil count before stopping treatment, and no white cell count and platelet monitoring) there would be a significant reduction in the number of people having to stop clozapine for haematological reasons (Oloyede Reference Oloyede, Whiskey and Casetta2022).

What is the evidence-base/position in guidelines?

We will examine national clinical guidelines for four specific conditions with a strong evidence base for use of lithium.