Intended for healthcare professionals


Treatment resistant depression: what are the options?

BMJ 2018; 363 doi: (Published 18 December 2018) Cite this as: BMJ 2018;363:k5354
  1. Greta McLachlan
  1. The BMJ

Some patients with treatment resistant depression have tried up to 12 antidepressants and waited 10 years before they are seen at specialist centres, a recent press briefing heard. The figures fall far short of targets set out in draft guidance from the National Institute for Health and Care Excellence, which says that all patients who have not responded to two antidepressants should be referred to specialists.1

NICE’s definition would mean that 2.7 million people in the UK have treatment resistant depression (between 10% and 30% of people with depression), an unmanageable number for the NHS’s psychiatric services.

Allan Young, honorary consultant at Maudsley and Bethlem Hospitals in south London, told the briefing that though GPs were good at identifying and treating depression, “TRD [treatment resistant depression] is a subgroup—and there isn’t the capacity in secondary mental health teams to deal with this.”

So what are GPs supposed to do? The answer it seems is, first, know the options and, second, know when to refer.

Second line options

After trying selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors, GPs could try the multimodal serotonin stimulator vortioxetine, said Young. If symptoms persist after an adequate dose and trial of this, patients should be reassessed for diagnosis, adherence, and other comorbidities, he said.

Adding in psychotherapies such as cognitive behavioural therapy is the next option. If this is unsuccessful, adding an atypical antipsychotic, such as lithium, quetiapine, or aripiprazole, has been shown to be beneficial.2

The thyroid hormone liothyronine (T3) is another effective adjunct second line treatment with few side effects.2 Although its price has risen 6000% over the past 10 years, from £4.46 for 28 pills in 2006 to £258 in 2017, it is still useful, said specialists.

Tony Cleare, professor of psychopharmacology and affective disorders at the Institute of Psychiatry, Psychology and Neuroscience at King’s College London, said that if GPs don’t think they are adequately trained to prescribe these drugs they should refer patients to specialist centres. And any patients about whom GPs have concerns or GPs believe are not coping with their depression should also see a specialist, said Young.

“GPs used to ask me, ‘Who should we refer?’ You should refer people that you think need referring. It sounds a bit daft, but it’s the old gatekeeper model: if you refer everyone willy-nilly then the whole system will break down,” he said.

On the horizon

James Rucker, honorary consultant at the Maudsley and Bethlem Hospitals, says that there have been relatively few medical advances in depression treatment since fluoxetine (Prozac) hit the scene in the late 1980s.

“As the pharmaceutical pipeline has run dry, people have looked to history for inspiration,” he said, pointing to investigations by his team at King’s College London into psilocybin.3

In the 1960s psilocybin was marketed as a medicine by Sandoz (now Novartis) as a “catalyst” for people with treatment resistant depression. In a systematic review of clinical trials Rucker has shown that approximately 80% of patients who were given psilocybin showed clinical improvement.4 This did not mean “we are saying psilocybin is ‘safe,’” he said, or that it was an effective drug for treatment resistant depression, “but we are trying to work out if it is.”

In 1970 psilocybin was made a schedule 1 drug in the UK, making it nearly impossible to use in clinical trials. The evidence that placed psilocybin into schedule 1 was “flimsy,” said Rucker, and public opinion on the drug is now shifting, making it possible for him to study psilocybin in the same way as all potential new medicines.


It’s a situation similar to that of ketamine, although ketamine is still used routinely in hospitals and “field” settings such as conflict or disaster zones.

A 1996 randomised controlled trial showed that ketamine had an almost immediate effect on treatment resistant depression. Patients’ symptoms improved within an hour, and the effects lasted for up to seven days. These results have been replicated numerous times, and ketamine is now being used to treat treatment resistant depression in specialist centres. It is delivered as an intravenous infusion, taking about an hour to administer.

The drug company Janssen is trying to develop an intranasal ketamine spray, which would make the process of administration much quicker and cheaper.

James Stone, of the Institute of Psychiatry, Psychology and Neuroscience, told the briefing: “[Our] Oxford clinic is overrun with people wanting ketamine treatment as their depression is so bad.”

Ketamine spray could be available in the United States as early as next year, he said, and enter the European market two or three years later.

However, neither ketamine nasal spray nor psilocybin would be take home drugs. They would still need to be administered in controlled environments, much like methadone is now, agreed the specialists.


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