Supporting treatment resistant depression.

Welcome to Priory Bitesize, our new monthly e-bulletin in which a mental health expert will discuss dealing with certain conditions to support your patient discussions.  

This month, Dr Judith Mohring, Consultant Psychiatrist at the Priory Wellbeing Centre Fenchurch Street in London, talks about treatment resistant depression and how it can be addressed.

Treatment resistant depression (TRD) is generally defined as failure to respond to two antidepressant trials of adequate dose and duration. Around 30% of those who receive adequate treatment achieve remission, a further 20% respond but do not reach remission while 50% do not respond at all.

These 50% of patients have a condition which is harder to treat effectively and requires a more strategic, holistic and pharmacologically complex approach.

In this article I describe a range of next steps that can be taken by GPs which are suitable in a primary care setting.

Step 1 - Provide adequate treatment

An adequate trial of treatment with an antidepressant is 6-8 weeks. 

  • Start with an SSRI unless there’s a good reason not to.
  • Take time to explain the treatment rationale, duration and side effects as a good therapeutic alliance predicts response to medication.
  • If there is no response after around 4 weeks, increase the dose if tolerable or switch to an alternative antidepressant.
  • If there is inadequate response after 6-8 weeks switch to an alternative antidepressant. Ensure the patient is compliant with medication.

Step 2 - Don’t delay changing treatments

Duration of untreated depression and poor response predicts poorer outcome so don’t delay in making changes to treatment. By 12-16 weeks you should know whether the patient has treatment resistant depression.

Step 3 - Review the diagnosis

After two failed trials review the diagnosis and do a thorough assessment of the patient.

  • Check for co-morbid substance misuse, personality disorder, chronic pain, underlying anxiety or a history of hypomania.
  • Patients with bipolar 2 respond poorly to antidepressants and may merit a trial of quetiapine 300mg.
  • In patients with underlying anxiety, consider augmenting antidepressants with low dose pregabalin.

Step 4 - Offer holistic interventions

There is a whole range of evidence based lifestyle advice which can make a big difference.

  • Reducing alcohol
  • Ensuring adequate sleep
  • Taking some exercise and increasing social support

Behavioural activation is a highly effective therapy which focuses simply on activity scheduling and changing context during the day and week. Using a diary and setting goals which gently challenge each week mimics its approach.

Step 5 - Augment with psychotherapy

Patients may avoid psychotherapy or it may be hard to access. Anyone with treatment resistant depression should be offered cognitive behavioural therapy as part of their treatment package.

Bibliotherapy is an easy way to approach the ideas used in therapy and prepares people for their treatment, whilst also having an effect in its own right. I recommend Mind over Mood (Greenberger and Padesky) as a simple guide.

Mindfulness is another evidence based treatment which can be accessed and learned from Apps downloaded to your phone.

Step 6 - Be aware of pharmacological evidence and individual variability

There is good evidence now supporting a range of approaches to TRD. The ‘Star D’ trial is well known. It found few significant differences between a range of approaches, remission rates were low for individual treatments but the majority of patients eventually responded.

I explain to patients that treating depression is ‘horses for courses’ because we have a great deal of serotonin receptor heterogeneity so individual responses to medication acting at these receptors varies greatly.

Step 7 - Have an algorithm

Pharmacological options essentially consist of switching, augmenting treatment or increasing doses. One study showed better response (even when being treated by an expert) when a treatment algorithm was used. So develop an algorithm for treating the patient based on these 3 options:

A – Switching

  • There’s some evidence of differences in efficacy between antidepressants but the effect size is small.
  • Clomipramine, venlafaxine and escitalopram have all shown benefit over another antidepressant in more than 1 RCT. So switching to one of these is worth considering.
  • The patient’s response to past treatment (and their first degree relative’s response to antidepressants) can predict future response.
  • If they’ve responded to serotonin receptor blockade before, consider clomipramine or escitalopram. If they’ve responded to noradrenaline receptor blockade, consider reboxetine.
  • If in doubt try venlafaxine, mirtazapine or duloxetine which have dual actions.
  • Escitalopram and agomelatine are useful where tolerability is an issue.

B - Dose increases

  • Increase if tolerated to the maximum BNF dose where response is poor.
  • Specialists may use above BNF doses with a normal ECG and U+Es, subject to written rationale and patient consent.
  • Maximum licensed doses are not developed from an evidence base but from drug licenses.

C - Augmentation

  • SSRI + Buproprion 150-300mg daily. Buproprion is not licensed for depression in the UK but this is well tolerated and supported by STAR D.
  • Antidepressant + antipsychotic- quetiapine 300mg is licensed for this indication.
  • Antidepressant + Lithium- well established, recommended by NICE, monitoring and side effects in the long term are an issue. Aim for levels 0.4.-0.8- requires specialist referral.
  • Add tri-iodothyronine 20-50mcg/day- requires specialist referral
  • Venlafaxine and mirtazapine- recommended by NICE, widely used, theoretical risk of serotonin syndrome.

Step 8 - Remain hopeful

Therapeutic nihilism is unhelpful for both doctor and patient so try to remain hopeful. A supportive relationship with the GP is in itself useful. Resolving chronic depression may require resolution of a psychosocial problem, outside of medical control so don’t take poor treatment response personally.

Step 9 - Refer if stuck

As a psychiatrist I see patients who are antidepressant naïve, and those whose GPs have tried a broad range of treatments. There is no merit in struggling on alone with a hard to treat patient and I regularly refer to colleagues for second opinions. So refer early if stuck for advice on specialist prescribing.

Step 10 - Be mindful of risk

Treatment resistant depression carries with it increased suicide risk. Be aware of this when prescribing toxic drugs like SSRIs and lithium. Consider early referral to secondary care, use of the crisis team and close monitoring of risk and response to treatment in patients at higher risk of suicide.

Dr Judith Mohring is a Consultant Psychiatrist at the Priory Wellbeing Centre, Fenchurch Street,London.  Click here for her full biography.   

To visit our dedicated GP section on the website, click here.  If you would like to make a referral call: 0800 090 1354,  to send an email click here, or alternatively use our secure online referral form.

Reference and further reading

NICE guideline CG90 depression in adults

The Maudsley Prescribing Guidelines in Psychiatry

British Association for Psychopharmacology- consensus guidelines for treating depression with antidepressants.