Treatment-resistant depression: what it means and what options exist

There is no single universal definition, but in the NICE appraisal of esketamine nasal spray the target group is adults with moderate to severe depression that has not responded to at least 2 different antidepressants in the current episode. The label describes a situation, not a person: it means the first approaches have not been enough, and that the next steps are specialist-led.

The NHS reminds readers that you may respond to 1 antidepressant but not to another, that you may need to try 2 or more treatments before you find one that works, and that different types of antidepressant work about as well as each other on average though side effects vary. Needing several attempts is therefore common, and it is not a sign of personal failure.

NICE guideline NG222 stresses assessing the whole person: past response to treatments, other mental or physical conditions, any history of mood elevation (which could mean the depression is part of bipolar disorder), lifestyle, stressful life events, alcohol and drug use, debt, employment and loneliness. These are the kinds of factors a clinician reviews before deciding that earlier treatment has not worked.

The NHS says symptoms should start to improve within 4 weeks of starting an antidepressant, that if it is working you continue at the same dose for at least 4 to 6 months after symptoms ease, and that you should see a GP or specialist nurse every week or 2 for at least 4 weeks after starting. Missed doses, stopping early because of side effects, other health conditions, alcohol and other medicines are all worth discussing, because they can affect how well treatment works.

• Was each medicine taken at an adequate dose for long enough?

• Has bipolar disorder been considered if there have been periods of unusually elevated mood?

• Are physical conditions or other medicines contributing?

• Has talking therapy been offered alongside medicine?

• Are alcohol, drugs, trauma, isolation or money worries driving the low mood?

The NHS describes several talking therapies for depression: cognitive behavioural therapy (usually 8 to 16 sessions), interpersonal therapy (8 to 16 sessions), behavioural activation (12 to 16 sessions), individual problem-solving (6 to 12 sessions), psychodynamic psychotherapy, counselling and behavioural couples therapy. A combination of an antidepressant and CBT usually works better than either alone, and you can refer yourself to NHS talking therapies without a GP referral.

Waiting times for talking therapies can be several weeks or months, and the NHS says a GP can advise what to do if your condition gets worse while waiting. Exercise, sleep, social contact and structured activity are not substitutes for specialist treatment, but they support it.

Beyond trying a different antidepressant, NICE NG222 describes augmentation, adding a second medicine. Its guidance on lithium augmentation sets out safety monitoring: weight, kidney and thyroid function and calcium levels are assessed before starting and monitored at least every 6 months, blood lithium levels are checked regularly, women of reproductive age need a discussion about risks, and lithium prescribing is managed under shared care with the specialist. NICE also says to stop lithium only in specialist services or with their advice.

NG222 notes that using antipsychotics to treat depression was, in June 2022, an off-label use for some antipsychotics, and sets out checks before starting them (pulse, blood pressure, weight, blood glucose or HbA1c and lipids), regular monitoring afterwards, and shared care arrangements. These are specialist decisions with real trade-offs between benefit and side effects, and should be explained to you in detail.

Esketamine nasal spray was assessed by NICE for treatment-resistant depression, and its guidance (TA854, published December 2022) does not recommend it for adults whose depression has not responded to at least 2 different antidepressants in the current episode. NICE said the long-term benefit is uncertain because the trials were short, and that people already receiving it on the NHS can continue until they and their clinician decide to stop. Always check the latest NICE position with your specialist, as guidance can be updated.

NG222 advises that every person having treatment for depression has their treatment reviewed between 2 and 4 weeks after starting, with monitoring for side effects and suicidal thoughts, particularly in the early weeks, and that clinicians always ask directly about suicidal thoughts. It advises that a person at risk of suicide should not have depression treatment withheld, that the amount of medicine supplied may be limited, and that support may be increased with more frequent contact.

If you take antidepressants, do not stop suddenly. The NHS says antidepressants are not addictive but you may get withdrawal symptoms if you stop suddenly or miss a dose, and NG222 says withdrawal should be slow and agreed with the prescriber and may take weeks or months. Contact a GP straight away if hopelessness or suicidal thoughts start or get worse after starting treatment.

If you are in immediate danger, or have taken an overdose, call 999 or go to A&E. If you are having thoughts of ending your life but are not in immediate danger, NHS 111 can direct you to urgent mental health help, and Samaritans can be called free on 116 123. Tell someone you trust, and avoid being alone if you feel unsafe.

Seek same-day help from your GP or a crisis team if you notice that low mood is rapidly worsening, that you are not eating or drinking, that you are hearing voices or having unusual beliefs, or that you cannot look after yourself or dependants.

On the NHS the usual path is GP, NHS talking therapies, and then a community mental health team or psychiatrist for severe or persistent depression, where the options in the previous sections are considered and monitored. NICE describes regular liaison between specialist and non-specialist healthcare professionals.

Some people choose a private psychiatrist for a second opinion or faster review of medicine options. The key questions to ask are whether the diagnosis, including bipolar disorder, has been reconsidered, how long each medicine would be tried, what monitoring is planned, who will prescribe and how your GP will be involved under shared care. Be cautious of any provider promising a guaranteed outcome or marketing prescription medicines directly.