Defining the clinical burden

Insomnia is more than a few sleepless nights. Diagnosis requires three components: difficulty falling asleep, difficulty staying asleep, and significant next-day consequences. Chronic insomnia is defined by these symptoms occurring at least three times a week for more than three months.

The epidemiological data is sobering. Chronic insomnia affects 5% to 10% of the adult population and is strongly associated with chronic physical illnesses involving pain or respiratory distress, as well as psychiatric disorders such as major depression.

The consequences of sleeping less than five or six hours a night are significant:

• The risk of type 2 diabetes trebles
• The risk of hypertension increases fivefold
• The risk of vascular dementia and impaired cognitive functioning more than doubles.

Furthermore, even a small reduction in sleep (less than six hours compared to seven to nine) is associated with a 13% increase in mortality risk due to accidents, stroke, cardiovascular disease and cancer.

In mental health, insomnia acts as a “multiplier” of poor outcomes. A landmark study using big data found that in patients with major depression, those with comorbid insomnia had more GP appointments, higher medication consumption, more psychiatric admissions, and increased rates of attempted suicide.

The limitations of traditional pharmacotherapy

Both benzodiazepines and the “Z-drugs” (e.g. zopiclone) are used for the short-term management of insomnia. Both classes of drug promote the actions of the inhibitory neurotransmitter gamma amino butyric acid (GABA) in the central nervous system. In effect, they “dial up” the effects of GABA. Benzodiazepines are non-selective; they affect pathways relating to sleep and also those relating to anxiety and memory. “In addition to inducing sleep, they’re anxiolytic but they also have an amnesic effect which is quite common with benzodiazepines, particularly [for] short-term memory” explains Mr Donoghue. The Z-drugs lack the anxiolytic effects and generally have shorter half-lives than benzodiazepines, making them less likely to have next day hangover effects.

A NICE appraisal concluded that there was no compelling evidence of a clinically useful advantage with Z drugs and recommended that short-acting benzodiazepines should continue to be the treatments of choice. Mr Donoghue noted that the commonly-used (short-acting) temazepam has a half life of 10-20 hours, meaning that after a 20mg night-time dose,10 mgs could still be in the body the next morning. “And here’s one of the things that pharmacists must advise patients – not ‘be careful when you’re driving’, but simply ‘do not drive’. Do not operate dangerous machinery of any kind, because even the short acting benzodiazepines have significant hangover effects” says Mr Donoghue.

Antihistamines (e.g. diphenhydramine), antidepressants and antipsychotics are also sometimes used for insomnia. Although over-the-counter antihistamines are often recommended for insomnia but they are commonly associated with side effects such as ataxia, blurred vision, constipation and dizziness. “So, diphenhydramine and drugs like promethazine are not the benign drugs that we think they are, and they do need to be used cautiously, and patients should be warned about particularly the danger involved with driving after they’ve been taking them”, he says. Antidepressants and antipsychotics should be avoided as hypnotics, he adds.

Orexin and chronic insomnia

The discovery of orexin in the late 1990s changed the understanding of the sleep-wake cycle. Orexin is an excitatory neurotransmitter that acts as the brain’s “wake signal,” released in response to daylight to kickstart alertness.

Current thinking suggests that chronic insomnia is not necessarily a lack of “sleep pressure” but rather a disorder of orexin overactivity. Essentially, the wake signal is being released inappropriately during the night. This explains why simple sleep hygiene measures often fail in chronic cases; sleep hygiene measures cannot suppress the inappropriate release of orexin.

Daridorexant: A dual orexin receptor antagonist (DORA)

Daridorexant represents a new class of treatment approved by NICE for chronic insomnia in adults. Unlike traditional hypnotics that induce sleep by “closing down” the brain, Daridorexant is a DORA that blocks the wake signal from reaching excitatory pathways. It suppresses both the wake signal (Orexin 2 receptor) and the motivation/reward signal (Orexin 1 receptor), allowing sleep to occur naturally while maintaining normal background brain activity.

Clinical evidence and safety

Two large randomised controlled trials published in The Lancet Neurology highlight several key findings for clinicians¹:

• Efficacy: At the 50mg dose, patients gained approximately one hour of extra sleep per night after three months, falling asleep 30 minutes faster and waking up for 30 minutes less.
• Daytime alertness: Critically, daridorexant showed a significant improvement in daytime alertness, with no “hangover” effects observed.
• Long-term profile: In a 12-month extension study, there was no evidence of loss of effect over time and, remarkably, no withdrawal symptoms upon discontinuation.
• Tolerability: The side effect profile is “remarkably benign,” with only fatigue occurring more frequently than placebo (affecting only 1 in 25 patients).

Responding to symptoms of insomnia

NICE recommends daridorexant as a second-line treatment following cognitive behavioural therapy for insomnia (CBTI). However, if CBTI is unavailable or the patient refuses it, daridorexant can be considered first-line.²

When patients seek help for insomnia in primary care Mr Donoghue suggests five key questions should be asked:

1. What are the sleep problems (getting to/staying asleep)?
2. Are there external factors (noise, shift work)?
3. How long has it been going on (the 3-month threshold)?
4. How often does it occur (the 3-times-a-week threshold)?
5. How do you feel the next day?

Patients who meet the criteria for chronic insomnia should either be referred to their GP or a prescribing pharmacist, who may consider prescribing daridorexant.

Regarding the cost – a common barrier to prescribing – Mr Donoghue points out that at £42 per month, the treatment costs less than half a cup of coffee per day. Given the serious consequences of chronic insomnia for people’s emotional, mental and physical well-being, this makes it a highly cost-effective intervention.

About John Donoghue

John Donoghue is the Director of Medicines in Mental Health Ltd. His work involves:

• The provision of continuing education related to the treatment of severe mental illness. His key interest is schizophrenia, but he also covers major depression and bipolar disorder. He provides medical education to psychiatrists, pharmacists, mental health nurses, psychologists and social workers.
• Pharmaco-epidemiology research. He was an early adopter of big data and has been involved in landmark studies using big data to follow outcomes in major depression.
• Consultancy He provides consultancy services, mostly to the pharmaceutical industry but also occasionally to the National Health Service.

Mr Donoghue is also a published novelist. His debut novel, The Death’s Head Chess Club was published in 2015. His new novel, Not Alive, Not Dead, was published in 2025.

References

1. Mignot E, Mayleben D, Fietze I, Leger D, Zammit G, Bassetti CLA, Pain S, Kinter DS, Roth T; investigators. Safety and efficacy of daridorexant in patients with insomnia disorder: results from two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials. Lancet Neurol. 2022 Feb;21(2):125-139. doi: 10.1016/S1474-4422(21)00436-1.
2. NICE Technology appraisal guidance (TA 922) Daridorexant for treating long-term insomnia. October 2023

The mortality gap

Individuals with schizophrenia face a 15 to 20-year reduction in life expectancy, typically dying 13 years younger than the general population (mean age of death 66 vs. 79 years in the UK). This means that “for a person with schizophrenia, on average, they won’t live long enough to qualify for the state pension”, says Mr Donoghue.

A landmark systematic review by Christoph Corell that included 4.5 million individuals with schizophrenia, underscored the severity of the problem. It revealed that overall mortality rates are nearly three times higher (risk ratio 2.9), suicide rates are ten times higher (risk ratio 9.8), and natural cause mortality rates are twice as high (risk ratio 2.2) compared to age- and sex-matched controls in the general population.

This excess mortality is multifactorial. The illness itself can impair cognitive function, making it difficult for patients to understand and engage with care, manage appointments, or adhere to treatment. Lifestyle factors contribute significantly, with high rates of obesity (affecting two-thirds of patients), smoking (twice as high), alcohol misuse (three times higher), and drug misuse (seven times higher) compared to the general population. Moreover, the historic division between mental and physical healthcare often results in fragmented care, communication gaps, and inadequate monitoring of physical health. Comorbidities such as cardiovascular disease (the most common cause of death, with mortality rates 85% higher than in the general post-myocardial infarction population), diabetes (three times higher mortality), and cerebrovascular disease (60% higher mortality) are often poorly managed.

Antipsychotics: benefits and risks

While antipsychotics are the cornerstone of schizophrenia treatment, their cardio-metabolic side effects, including weight gain, obesity and type 2 diabetes, are a concern. It is important to recognise that the risks of these effects vary widely by individual drug, and a false dichotomy between first- and second-generation agents is misleading. For instance, “weight gain and BMI change with haloperidol (first-generation) is no different from placebo but the same is true of aripiprazole, cariprazine and lurasidone, all of which are second generation agents”, says Mr Donoghue.  In contrast, “olanzapine is associated with significant weight gain and increased risk for type 2 diabetes but so is chlorpromazine”, he continued. Individual drug profiles must guide clinical decisions.

Despite these considerations, the evidence for efficacy is unequivocal: regular antipsychotic use significantly reduces mortality risk.

Evidence for second-generation LAIs

The Corell review strongly supports the role of SGA LAIs as key mitigating factors for premature mortality. These agents offer profound benefits including an overall mortality reduction of 61% and a 57% reduction in suicide mortality. For first-episode (incident) patients, second-generation LAIs are associated with an 85% reduction in all-cause mortality. In contrast, first-generation oral antipsychotics are associated with a doubling of suicide mortality rates in first-episode patients. “For this reason alone, first generation antipsychotics should be contraindicated in first episodes of schizophrenia”, says Mr Donoghue.

The superior outcome with second-generation LAIs is attributed to enhanced long-term mental stability and significantly improved treatment adherence. Furthermore, psychosis is a neurotoxic process, causing irreversible brain volume loss with each episode; preventing relapse is therefore paramount. LAIs dramatically reduce relapse risk with a ‘number needed to treat’ (NNT) of 4 at one year). In addition, SGAs are more effective at preventing relapse and possess neuroprotective properties, unlike some first-generation drugs which may actually be neurotoxic.

Clozapine

For treatment-resistant schizophrenia, clozapine is indispensable. Despite its challenging side effect profile (including agranulocytosis, myocarditis, and crucially, constipation, which is the most common cause of clozapine-related death), it delivers a remarkable 60% reduction in overall mortality and an 80% reduction in suicide mortality in this difficult-to-treat population. Its effectiveness is linked to significant improvements in quality of life and extremely high adherence rates, even with its side effects. Healthcare professionals must understand that “for patients with treatment-resistant schizophrenia, clozapine literally is a matter of life or death”, emphasises Mr Donoghue, and they should counter any ill-informed negative press comment.

Revision of NICE guidance

The current NICE guideline (CG 178, 2014) for schizophrenia, recommends oral antipsychotics with no preference for first or second-generation. As such, it is outdated and no longer fit for purpose given the compelling new evidence, explains Mr Donoghue.

He suggests that an updated, evidence-based approach should involve:

• A presumption that first-line treatment for all patients will be a second-generation LAI, unless clinically contraindicated.
• Immediate consideration of clozapine if a patient fails two second-generation oral treatments, accelerating access to this vital therapy.
• Integrated, holistic physical health monitoring within mental health services, adequately resourced to manage the complex needs of this population, rather than relying solely on overwhelmed primary care.

Implementing these changes is not merely a clinical imperative but an economic one. The average cost of a single hospital admission for a psychotic relapse is £47,000. Investing in effective, long-term treatments like LAIs, which prevent relapses, leads to substantial overall cost savings for healthcare systems.

The evidence demands a paradigm shift in the management of schizophrenia. By prioritising second-generation LAIs, judiciously utilising clozapine, and ensuring comprehensive physical health monitoring within specialised mental health services, it should be possible to reduce significantly premature mortality and improve the lives of those affected by this complex illness.

A career in mental health pharmacy?

Mr Donoghue recommends a career in mental health for pharmacists. “I have thoroughly enjoyed working in mental health. I find the work interesting, challenging, involving and rewarding. Pharmacists are welcomed as members of an extensive multidisciplinary team – and that’s true in both acute and community settings. …. I wouldn’t work in any other specialty”, he says.