Synopsis
Verify whether treatment has truly been adequate, revisit diagnosis and barriers, use shared stepwise switching or augmentation with specialist monitoring, and build relapse prevention from residual symptoms, recurrence history and the person's priorities.
- Define the current episode, residual symptoms and function and list every psychological and medication trial with dose, duration, adherence, benefit, harm and reason for stopping.
- Reassess bipolar disorder, psychosis, trauma, substance use, neurodevelopment, personality-related needs, pain, sleep, endocrine disease and social adversity before escalation.
- Confirm that psychological treatment was accessible, formulation matched, adequately delivered and attended; referral or a few sessions is not an adequate trial.
- For medication non-response, discuss dose optimisation within licensed limits, switching within or between classes, adding psychotherapy or specialist combination and augmentation options.
- Vortioxetine is a NICE option for adults whose current major depressive episode has responded inadequately to two antidepressants.
- Lithium augmentation is level guided and requires weight, renal, thyroid and calcium baseline, interaction review, regular 12-hour serum levels and toxicity education.
- Antipsychotic augmentation requires informed off-label or indication discussion, metabolic and movement baseline, and review of cardiac, prolactin and sedation risk.
- ECT is considered for severe depression when rapid response is needed, other treatments have failed or previous benefit and informed preference support it.
- For recurrent depression, continue effective treatment and offer relapse-prevention psychological care, with scheduled review of benefits, harms and the person's wish to continue.
Key red flags
The label treatment resistant should not be applied before confirming diagnosis, bipolarity, adequate dose and duration, adherence, therapy delivery, substances, physical illness and social barriers.
Repeated antidepressant activation, mixed features or episodic reduced sleep need suggests bipolarity and makes further antidepressant escalation potentially harmful.
Psychotic features, catatonia, severe functional collapse or persistent suicide danger require specialist treatment intensity irrespective of the number of previous trials.
Lithium and antipsychotic augmentation require physical baseline, interaction review and ongoing serum, renal, thyroid, calcium, metabolic, movement or ECG monitoring as applicable.
Combining antidepressants increases adverse-effect and interaction burden and should follow specialist-informed discussion rather than being added casually in primary care.
Investigation priorities
Verify medication dose, duration, adherence and harm and psychological modality, delivery, attendance and formulation fit.
Management branches
Depression has not improved sufficiently after one or more interventions.
- Reconstruct symptoms, function and every medicine and therapy trial with dose, duration, adherence, delivery, benefit and harm.
- Reassess bipolarity, comorbidity, substances, physical causes and social or access barriers and correct remediable factors.
- Agree whether the previous trial was adequate and define the next treatment target and observable response marker.