01Purpose and principlesWhat the treatment does and how it fits into care.
Treatment resistance is a prompt to investigate, not a fixed identity. Reconstruct the current episode and every intervention. For medicines, record indication, preparation, dose, duration at therapeutic dose, missed doses, interactions, benefit, adverse effects and withdrawal. For therapy, record modality, formulation, number and frequency of sessions, practitioner competence, engagement, homework or behavioural exposure and access barriers. Determine whether improvement was absent, partial or lost after an initial response and whether function changed differently from symptom scores.
Reopen diagnosis and mechanism. Ask again about hypomania, mania, mixed activation, psychosis, trauma, anxiety, obsessive symptoms, eating disorder, ADHD or autism, substance use and personality-related needs. Review thyroid and other physical causes, pain, sleep apnoea, reproductive context and medicines. Examine housing, debt, domestic abuse, discrimination, isolation and inaccessible care. Non-adherence may reflect adverse effects, cost, shame, executive difficulty or disagreement and should be understood rather than moralised.
Agree the next step from prior evidence and preference. NICE options include increasing dose within licensed limits when tolerated, switching antidepressant, combining medication with psychological therapy or changing psychological approach. Switching may require direct change, cross-taper, taper then washout or specialist supervision depending on pharmacology; MAOIs and fluoxetine create particular interaction timing concerns. Combining antidepressants, lithium or antipsychotic augmentation increases risk and generally warrants specialist input and a defined monitoring and stopping plan.
Vortioxetine is recommended by NICE technology appraisal as an option after no or inadequate response to two antidepressants in the current episode. Lithium augmentation is guided by serum concentration and clinical response and requires renal, thyroid, calcium, weight and interaction assessment. Antipsychotic augmentation may cause metabolic, cardiovascular, movement and prolactin harms. ECT is an option for selected severe depression requiring rapid response, after other treatments fail or when previous effective experience and current informed preference support it.
Recurrent depression needs relapse prevention. Identify residual symptoms, number and severity of episodes, recent recurrence, consequences, ongoing stress and prior rapid relapse after stopping. Continue the antidepressant dose that achieved remission unless there is a reason to reduce, and consider relapse-prevention CBT or mindfulness-based cognitive therapy according to preference and availability. Review at least periodically for mood, function, adherence, adverse effects, physical monitoring and desire to continue, avoiding indefinite automatic repeats.
Key points
- 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.
02Indications, selection and cautionsWho may benefit, who needs urgent treatment and important alternatives.
The apparent failure reflects incorrect diagnosis, inadequate dose or duration, missed treatment, inaccessible therapy, interaction, substance use or an untreated maintaining factor.
Some symptoms or functions improve while clinically important residual features persist, informing optimisation or combination rather than assuming complete failure.
Several adequately delivered evidence-based treatments fail despite diagnostic review, adherence and barrier correction, supporting specialist resistance care.
Repeated or severe episodes, residual symptoms, recent recurrence, major consequences or rapid previous relapse favour structured maintenance and psychological prevention.
Renal, thyroid, cardiac, metabolic, neurological or interaction factors make lithium or antipsychotic augmentation unsafe without specialist monitoring.
03Assessment before treatmentTests and checks that guide safe selection.
Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.
- 01
Treatment adequacy inventoryFirst step - Why
- Verify medication dose, duration, adherence and harm and psychological modality, delivery, attendance and formulation fit.
- Interpretation and limitations
- A referral, subtherapeutic exposure or intolerable early stop is not equivalent to an adequate failed trial; document limitations before labelling resistance.
- 02
Diagnostic and maintaining-factor review - Why
- Reassess bipolarity, psychosis, comorbidity, substances, physical illness, sleep, pain and social adversity.
- Interpretation and limitations
- A newly identified mechanism may require a different treatment pathway rather than another antidepressant with the same assumptions.
- 03
Augmentation baseline - Why
- Assess weight, renal, thyroid, calcium, metabolic, cardiovascular, movement and interaction risks for the proposed strategy.
- Interpretation and limitations
- Select tests by medicine. Abnormalities may require correction, alternative treatment or closer specialist monitoring.
- 04
Lithium serum monitoring - Why
- Guide augmentation exposure and detect accumulation after initiation, dose change, illness or interacting medicine.
- Interpretation and limitations
- Use a 12-hour level and current NICE and local targets; toxicity can occur with dehydration or renal change even near a previous stable result.
- 05
Relapse-risk formulation - Why
- Identify episode pattern, residual symptoms, triggers, consequences, supports and previous discontinuation outcomes.
- Interpretation and limitations
- Use the formulation to choose continuation, psychological prevention and review intensity rather than applying a fixed duration to everyone.
04Treatment approachPreparation, options, escalation and aftercare.
01Verify resistanceAudit diagnosis and treatment exposureFirst stepDepression has not improved sufficiently after one or more interventions.+
- 1Reconstruct symptoms, function and every medicine and therapy trial with dose, duration, adherence, delivery, benefit and harm.
- 2Reassess bipolarity, comorbidity, substances, physical causes and social or access barriers and correct remediable factors.
- 3Agree whether the previous trial was adequate and define the next treatment target and observable response marker.
02Escalate treatmentSwitch, combine or augment deliberatelyEscalationAn adequate intervention has failed or produced only insufficient response.+
- 1Discuss optimisation, switching, psychological change or combination, incorporating previous benefit, adverse effects and patient preference.
- 2Use specialist input for antidepressant combinations, lithium, antipsychotic augmentation, MAOI strategies or ECT and complete required baseline assessment.
- 3Set dose or exposure, monitoring, response timeframe and stopping criteria and review suicide risk and function during the transition.
03Prevent recurrenceMaintain recovery with planned reviewThe person is in remission but has factors indicating substantial relapse risk.+
- 1Identify residual symptoms, episode pattern, prior relapse, consequences, stressors, warning signs and protective routines.
- 2Discuss continuation of effective medication and relapse-prevention CBT or mindfulness-based cognitive therapy, including burdens and withdrawal concerns.
- 3Schedule reviews of mood, function, harm and preference and maintain a personalised plan for early symptoms and rapid access.
05Regimens, contraindications and interactionsTreatment details and the circumstances that modify them.
Vortioxetine
Use 10 mg orally once daily in adults under 65, adjusting between 5 and 20 mg daily by response; start 5 mg once daily from age 65.Review nausea, bleeding, hyponatraemia, mania and serotonergic interactions; MAOI combinations are contraindicated and switching requires current product-specific washout guidance.
Lithium augmentation
Initiate and adjust under specialist-informed care to a 12-hour serum level usually at least 0.4 mmol/L and not above 1.0 mmol/L, using lower ranges when clinically appropriate.Check renal, thyroid, calcium, weight, pregnancy and ECG indications; explain toxicity, hydration and interactions with NSAIDs, ACE inhibitors, ARBs and diuretics and use formulation-consistent prescribing.
06Complications, monitoring and follow-upAdverse effects, response and longer-term review.
- Review symptom domains and concrete function after each optimisation, switch or augmentation at an agreed interval, including suicide and activation assessment.
- For lithium, check a 12-hour level one week after initiation and dose change and weekly until stable, then at the guideline interval with more frequent testing for risk factors.
- Monitor renal, thyroid, calcium, weight and adverse effects during lithium and metabolic, movement, prolactin, cardiovascular and ECG factors during antipsychotic augmentation.
- Review maintenance treatment at least every six months for mood, function, adverse effects, adherence, relapse factors and the person's wish to continue.
- Update early-warning and crisis plans after each relapse, identifying whether the intervention failed, was inaccessible or was started too late.
07Special situationsVariants, exceptions and circumstances that change the usual approach.
Failure has a mechanism
No response can reflect diagnosis, pharmacology, delivery, access or maintaining adversity, and each mechanism points toward a different next step.
Partial benefit is evidence
Improvement in sleep or initiation can indicate useful mechanism even when mood remains low, supporting targeted optimisation or complementary therapy.
Augmentation adds burden
Potential benefit must be weighed against blood tests, metabolic effects, interactions, pregnancy implications and complexity that may reduce adherence.
Residual symptoms predict
Persistent insomnia, avoidance, hopelessness or cognitive difficulty after remission can precede relapse and are active prevention targets.
Maintenance is a decision
Long-term medication should be reviewed with current benefit, harm and preference rather than repeated indefinitely because it once worked.
08Common pitfallsFrequent interpretation and management errors.
- 01
Labelling resistance after a low dose, short duration or inaccessible therapy.
- 02
Adding another antidepressant without repeating bipolar and interaction assessment.
- 03
Combining medicines without specialist monitoring, a response target and stopping plan.
- 04
Using lithium without renal, thyroid, calcium, interaction and serum-level safeguards.
- 05
Treating adverse effects or non-adherence as patient failure instead of clinical information.
- 06
Stopping effective relapse-prevention treatment abruptly after remission.
- 07
Focusing on score remission while residual functional and suicide risks remain.