Key Facts

TRD represents a significant clinical challenge, affecting approximately one-third of patients with depression. Systematic evaluation and a stepped-care approach are essential.

Epidemiology

Of the approximately 3.3 million adults treated for depression in the UK annually, approximately 1 million experience TRD. TRD is associated with significantly higher healthcare costs (estimated 3-6× higher than responsive depression) and poorer functional outcomes.

Aetiology

Factors contributing to poor treatment response:

• Pharmacological: Inadequate dose or duration, poor adherence, pharmacokinetic factors (CYP450 rapid metabolisers)
• Clinical: Comorbid anxiety, personality disorder, substance misuse, chronic pain, medical comorbidity
• Diagnostic: Undiagnosed bipolar disorder, ADHD, hypothyroidism, neurodegenerative disease
• Psychosocial: Ongoing adversity, social isolation, unemployment, trauma

Pathophysiology

TRD may involve:

• Glutamate system dysfunction: Basis for ketamine/esketamine treatment (NMDA receptor antagonism)
• HPA axis hyperactivity: Persistent cortisol elevation despite treatment
• Neuroinflammation: Elevated CRP and cytokines predict poor SSRI response
• Altered neuroplasticity: Impaired BDNF signalling — may explain delayed onset of antidepressant effect
• Epigenetic modifications: Stress-induced changes in gene expression affecting serotonergic/glutamatergic systems

Clinical Assessment in TRD

• Persistent depressive symptoms despite ≥2 adequate antidepressant trials
• Often significant functional impairment, social withdrawal, inability to work
• High rate of comorbid anxiety (>60%), personality disorder, substance misuse
• Increased suicide risk compared to treatment-responsive depression

Before Diagnosing TRD — Exclude

• Non-adherence: Up to 50% of patients do not take antidepressants as prescribed
• Inadequate trial: Subtherapeutic dose or insufficient duration (<6 weeks)
• Incorrect diagnosis: Bipolar depression, personality disorder, ADHD, organic cause
• Comorbid substance misuse: Alcohol and drugs can negate antidepressant effects
• Untreated medical conditions: Hypothyroidism, anaemia, chronic pain, sleep disorders

Red Flags

• Escalating suicidal ideation despite treatment optimisation
• Psychotic symptoms developing during depressive episode
• Severe self-neglect, catatonia, refusal to eat/drink — consider ECT
• Rapid cycling mood — reconsider bipolar diagnosis

Bedside

• Medication review: Confirm adequate dose, duration, and adherence for each trial
• PHQ-9: Quantify current severity and track response
• Risk assessment: Comprehensive suicide risk evaluation
• Substance use assessment: AUDIT-C, DAST-10

Bloods

• TFTs: Exclude hypothyroidism (even subclinical)
• FBC, B12, folate: Nutritional deficiencies
• Lithium level: If on lithium augmentation (target 0.4-0.8 mmol/L for augmentation)
• Renal function, calcium: Baseline for lithium
• CRP: Emerging evidence that elevated CRP predicts better response to nortriptyline vs SSRI

Special Tests

• Psychiatric review: Detailed reassessment of diagnosis, comorbidity, psychosocial factors
• Neuroimaging: Consider if organic cause suspected (e.g., space-occupying lesion)
• Pharmacogenomic testing: Emerging — CYP2D6, CYP2C19 genotyping may guide antidepressant choice (not yet routinely recommended by NICE)

Non-pharmacological

• CBT: Evidence for TRD when added to medication (CoBalT trial)
• Behavioural activation: Structured activity scheduling
• Mindfulness-based cognitive therapy (MBCT): Reduces relapse risk
• ECT: Indicated for severe TRD, psychotic depression, catatonia, life-threatening depression — bilateral typically more effective; 6-12 sessions
• Repetitive transcranial magnetic stimulation (rTMS): NICE-approved for TRD; non-invasive

Pharmacological

Switching strategies:

• Within class: SSRI → different SSRI
• Between classes: SSRI → SNRI (venlafaxine 225-375mg) or mirtazapine
• Combination: SSRI + mirtazapine ("California rocket fuel" with venlafaxine + mirtazapine)

Augmentation strategies:

• Lithium: 400-800mg OD (target 0.4-0.8 mmol/L) — strongest evidence base
• Quetiapine: 50-300mg (low-dose, off-label for augmentation)
• Aripiprazole: 2.5-10mg OD
• Triiodothyronine (T3): 20-50mcg OD — evidence primarily from STAR*D

Newer treatments:

• Esketamine nasal spray (Spravato): NICE TA854 — for TRD with SSRI/SNRI; administered under supervision, monitoring for 2 hours post-dose
• Psilocybin-assisted therapy: Under investigation; not yet approved

Referral Criteria

• Failed 2 adequate antidepressant trials — secondary care psychiatry
• Consideration for ECT — specialist unit
• Consideration for esketamine — specialist centre
• Complex comorbidity — multidisciplinary team assessment

• STAR*D trial: Cumulative remission rate ~67% after 4 treatment steps; but higher relapse rates with each subsequent step
• ECT: Response rates 50-70% in TRD; relapse rate ~50% within 6 months without continuation pharmacotherapy
• Lithium augmentation: Response rate approximately 40-50% in TRD
• Esketamine: Approximately 70% response rate in clinical trials; rapid onset (hours to days)
• Long-term: TRD associated with 2-3× higher suicide risk, longer hospital admissions, and significantly impaired quality of life
• Combination of pharmacological and psychological approaches gives the best outcomes

STAR*D Trial Summary

TRD Treatment Algorithm