Clinical conundrum: Patient with treatment-resistant depression

GP and mental health specialist Dr Emma Nash explores the management options for a young adult male patient with recurrent depression that has not responded to three different medications and who is concerned about his drinking

A 28-year-old man with a history of depression attends for follow up. He has suffered recurrent depression since his late teens and also has a history of childhood ADHD. This latest bout has been going on for about nine months and has already proved resistant to therapeutic doses of sertraline and then citalopram. He is currently on 45mg of mirtazapine but feels there has been no improvement. He says the ongoing symptoms are making him drink more alcohol – an issue he has had problems with in the past. ‘I’m wondering if I might have bipolar, doctor?’ he asks.

1. Which alternative diagnoses should GPs consider that might explain a lack of response to antidepressant treatment? What features should the GP be alert to?

As with any other medical condition, if treatment is not effective, revisit whether the diagnosis is accurate.

This patient mentioned bipolar disorder, and it’s certainly a condition to consider. It’s not uncommon for bipolar depression to be misdiagnosed as treatment-resistant unipolar depression.¹ There are certain characteristics which should prompt further consideration of bipolar disorder as a differential in apparent treatment-resistant depression. These include:

• Antidepressant treatment causes agitation/anxiety.
• Initial response to antidepressant treatment and then relapse.
• Depressive episodes marked by hypersomnia and an increase in appetite.
• Onset of major depressive disorder before age 18.

It is important to consider bipolar disorder as evidence-based treatment options for bipolar depression are slightly different to those for depression – for example, lamotrigine can be particularly effective. Ask specifically about family history of bipolar disorder, and personal history of periods of high or irritable mood. Whilst mania is usually quite apparent in the history, hypomania needs careful questioning to detect. Enquire about episodes of persistent (lasting at least several days) mild elevation of mood, or increased irritability and increased activity, or a subjective experience of increased energy, accompanied by other characteristic symptoms such as rapid speech, rapid or racing thoughts, increased self-esteem, an increase in sexual drive or sociability, decreased need for sleep, distractibility, or impulsive or reckless behaviour. Unlike mania, the symptoms of hypomania are not severe enough to cause marked impairment in functioning.²

Depressive features can overlap with those of ADHD, for example poor concentration or psychomotor agitation.³ It is important to establish whether his ADHD is adequately controlled as part of the assessment. The fact he is using alcohol may represent under-treated ADHD, as well as a coping strategy for his symptoms. Enquire about whether he is taking any medication for his ADHD, even if there is none listed on the clinical records and consider referral for review if he is no longer under any services.

Assess whether there are other factors which are either presenting as depression or complicating its recovery. These may be biological (eg, hypothyroidism, anaemia or adrenal disorders in someone of this age), psychological (eg, childhood trauma, personality disorders, or drug/alcohol misuse) or social (eg, significant life stressors).

2. If the diagnosis does seem to be ‘pure’ clinical depression, what might be the factors blocking recovery, and where would the GP go from here?

If it does appear to be treatment-resistant depression, first consider whether the patient is taking the medication as prescribed. Barriers to concordance include dosage regimes that are more than once a day, and personal organisational challenges that mean medications run out. Using once-daily dosages and arranging repeat dispensing can be helpful. There may be people at home that can support in reminders or advise patients of strategies such as putting medication next to the toothbrush or setting alarms.

NICE guidance on further-line treatment⁴ would recommend the addition of a psychological intervention (cognitive behavioural therapy, interpersonal psychotherapy or short-term psychodynamic psychotherapy) and/or switching to a medication in a different class. He has already tried two SSRIs and mirtazapine (a tetracyclic antidepressant). Next-step options may include vortioxetine, a tricyclic such as lofepramine, an MAOI, combination therapy with a second-generation antipsychotic, lithium or lamotrigine, or consideration of physical treatments such as rTMS or ECT. Referral to secondary care for advice on this is needed.

Having explored the barriers, there may be a role for social prescribers, wellbeing coaches or care navigators in reducing any external factors which may impair recovery. Establish how much he is drinking and whether there is dependence. Brief interventions for alcohol are useful and facilitate referrals to specialist alcohol services if appropriate. Joint working protocols are increasingly commonplace now, which support both community mental health teams and drug/alcohol teams working together to support patients, rather than patients being passed between them.

3. In switching antidepressants, what is a logical progression of treatment and how rapidly should this be done? What are the principles in terms of managing each change (such as tapering) and where can GPs find reliable information about this for reference?

Due to their low risk in overdose, good tolerability, and effectiveness, SSRIs are first-line treatments. If a person’s depression has not responded at all after four weeks of antidepressant medication at a recognised therapeutic dose, then the medication can be switched.⁴ Switching within class initially is appropriate, but a further switch within class if two treatments have not been effective is unlikely to be beneficial. At this point switching to venlafaxine, mirtazapine (or adding it in) would be appropriate steps within a primary care setting.

According to the British Association for Psychopharmacology, the most effective treatments are clomipramine, venlafaxine (150mg or above), escitalopram 20mg, sertraline, amitriptyline and mirtazapine.⁵ However, the potential side effects, anticholinergic burden, risk in overdose and discontinuation symptoms also need to be considered.

A number of guidelines, including from NICE, offer advice on stopping and swapping antidepressants.^4,6 In most cases, cross-tapering is appropriate. This is important as unpleasant discontinuation symptoms can occur on reducing or stopping medication, as well as exacerbation of depressive features. The main reason for caution in swapping antidepressants is due to the risk of serotonin syndrome. Patients need to be advised that they should report symptoms of shivering, sweating, myoclonus or confusion. This is an uncommon condition, however, and usually seen where there is co-prescription of an MAOI and an SSRI⁷ – something which would not be initiated in a primary care setting.

References

1. Fogelson D, Kagan B. Bipolar spectrum disorder masquerading as treatment resistant unipolar depression. CNS Spectrums 2022;27(1):4-6
2. World Health Organization. ICD-11: Bipolar or related disorders.
3. Diler R, Daviss W, Lopez A et al. Differentiating major depressive disorder in youths with attention deficit hyperactivity disorder. J Affect Disord 2007;102:125-30
4. NICE. Depression in adults: treatment and management. Recommendations: Further-line treatment. [NG22] 2022
5. British Association for Psychopharmacology. Evidence-based guidelines for treating depressive disorders with antidepressants: A revision of the 2008 British Association for Psychopharmacology guidelines. J Psychopharmacol 2015; 29(5):459–525
6. NICE. CKS. Depression: switching antidepressants. 2025
7. NICE. CKS. Depression: selective serotonin reuptake inhibitors. 2025