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Therapeutics update: Depression

Therapeutics update: Depression

Dr Peter Bagshaw reviews the latest thinking in depression management, offers practical advice to busy GPs and looks at what’s on the horizon

NICE guidelines on depression in adults were updated in June 2022.1 Highlights include:

  • Always ask people with depression directly about suicidal ideation and intent. Arrange help appropriate to the level of need and advise them to seek further help if the situation deteriorates. If a person with depression presents immediate risk to themselves or others, refer urgently to specialist mental health services.
  • Review treatment if people develop marked or prolonged agitation. The guidelines give no specific advice, but fluoxetine can worsen agitation. Paroxetine, mirtazapine and tricyclics are more sedative. I rarely use tricyclics because of safety and overdose concerns. NICE says lofepramine has the best safety profile.
  • Review treatment efficacy after two to four weeks, or after one week if the person is under 25 years old or at risk of suicide. NICE advises monitoring treatment concordance, unwanted effects of treatment and suicidal ideation, particularly in the early weeks. Ensure patients have written information.
  • Patients often ask if antidepressants are addictive. They do not give rise to classic addictive behaviour such as seeking to increase the dose, but we need to warn about withdrawal side-effects. Explain that it is necessary to reduce the dose in stages, but that most people stop antidepressants successfully. Explain withdrawal symptoms usually appear within a few days of reducing or stopping, and go away within two weeks, but can last longer and can be severe, particularly if the medication is stopped suddenly. Paroxetine and venlafaxine are more likely to cause withdrawal symptoms. Antidepressants can make both bipolar disease and suicidal ideation worse.
  • Some GPs and psychiatrists use combinations of antidepressants. However, there is little information about the safety of these drugs in combination, and combining drugs is not covered by NICE.  
  • NICE gives guidance on which antidepressant should be used in older people.2 Sertraline is the least toxic in this group, with mirtazapine if sedation is required.

What’s old?

The serotonin theory
A review published in July 2022 stated: ‘The main areas of serotonin research provide no consistent evidence of an association between serotonin and depression’.3 

The review included reports of emotional blunting in around half of patients taking SSRIsand the growing suspicion that, rather than being a ‘magic bullet’ that corrects an underlying cause of depression, our current alphabet soup of MAOIs, TCAs, SSRIs, SNRIs NASSAs and SARIs provide only a sticking plaster solution, an ‘emotional analgesic’.  

We now have guidance that drug therapy should not be used for mild to moderate depression, and we should explain potential side-effects and withdrawal risk when we do.

The questions about antidepressant efficacy may further increase the popularity of non-drug therapies such as cognitive behavioural therapy (CBT). 

Newer drugs are moving away from the serotonin model.

What’s new?

Digital therapies
Earlier this year NICE published a list of approved digital providers for Improving Access to Psychological Therapies (IAPT) providers (now rebranded as NHS talking therapies).5 

NICE has also approved the use of nine digital tools for treating depression and anxiety in adults to speed up access to NHS services. These include apps or websites that use CBT techniques with the support of an NHS talking therapies clinician or psychological wellbeing practitioner. Three tools are for people with depression and six for anxiety.

The guidance rates the cost-effectiveness of non-drug options. Some now believe that expecting drug treatment to cure mental health problems may be as unhelpful as putting people with chronic pain onto ever stronger analgesics. One of the drivers for investigating novel therapies in treatment resistant disease is that they do not seem to cause the increased risk of suicide in depression, particularly in bipolar disease, associated with current drug therapies.

Brexanolone, which raises brain levels of the neurotransmitter gamma aminobutyric acid (GABA), has been approved by the FDA for use specifically in post-partum depression. 

Esketamine, a chemical cousin of ketamine, has been approved by the FDA for use in treatment-resistant depression. To many of us, ketamine is viewed as a powerful anaesthetic associated with abuse and serious side-effects such as ketamine bladder. But studies say ‘the overall tolerability of intranasally administered esketamine in trials is good’ and it is ‘effective in decreasing the severity of short-term depressive symptoms’,6 and particularly useful in patients at risk of suicide, where standard antidepressants can increase the risk initially.

Other drugs we might associate more with illegal use such as mescaline (peyote cactus), psilocybin (magic mushrooms), LSD and MDMA (ecstasy) are also being researched. The European Medicines Agency has approved psilocybin in a study of treatment-resistant depression.7

Vagal nerve stimulation
Vagal nerve stimulation has been ‘found beneficial in improving quality of life and suicidality among unipolar treatment-resistant disease (TRD) patients and depression among bipolar TRD patients’,8 while for repetitive transcranial stimulation (rTMS) NICE comments that ‘the evidence for depression shows no major safety concerns. The evidence on its efficacy in the short term is adequate’.1

Depression is hugely debilitating and distressing to our patients. With paradigm shifts in thinking (such as its link with inflammation, the gut-brain axis or insulin resistance) an already challenging condition looks set to become more complex. 

Resisting the urge to reach for a prescription, remembering NICE guidelines, and being open to new, often counterintuitive, approaches are key to doing our best for our patients who have depression.


  1. NICE. Depression in adults: treatment and management. NG222. June 2022. Link
  2. Mental Health in Older People: a practice primer. Link
  3. Moncrieff J. et al, The serotonin theory of depression: a systematic umbrella review of the evidence Mol Psychiatry 2022 Link
  4. Cronquist C The Motivation and Energy Inventory (MEI): Analysis of the clinically relevant response threshold in patients with major depressive disorder and emotional blunting using data from the COMPLETE study Journal of Affective Disorders 2023 323. Link
  5. NHS Talking Therapies. Link
  6. Vasiliu O. Esketamine for treatment‑resistant depression: A review of clinical evidence (Review) Experimental and Therapeutic Medicine, Jan 2023. Link
  7. Nutt, D. Psychedelic drugs—a new era in psychiatry? Dialogues in Clinical Neuroscience, 21:2, 139-147 2019. Link
  8. Lojine, Y. Vagal nerve stimulation: an update on a novel treatment for treatment resistant depression. Journal of the Neurological Sciences vol 434 Mar 2022. Link


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