Evidence Supporting Minimum Effective Dose Trials Before Declaring Antidepressant Failure
The 2022 Molecular Psychiatry consensus guideline establishes that an antidepressant must be administered at the minimum licensed (approved) dose for at least four weeks before it can be considered a treatment failure. 1
Rationale for the Four-Week Minimum Duration
The evidence base for this recommendation comes from multiple converging sources:
Initial response timing differs from stable remission: While some studies demonstrate that two weeks can be sufficient to observe an initial response, a stable response or remission typically requires four weeks of treatment at therapeutic doses. 1
Complete remission may require longer: Approximately half of patients who ultimately remit on citalopram in the STAR*D trial achieved remission between weeks 6 and 14, not within the first four weeks. 1 This finding underscores that four weeks represents the minimum adequate trial duration, not the optimal endpoint for all patients.
Premature discontinuation should not count as failure: The guideline explicitly states (with 96% consensus) that discontinuation before completing four weeks, without clear evidence of lack of response, should not be considered treatment failure—particularly because it is difficult to retrospectively distinguish between non-response and intolerance. 1
Why Minimum Licensed Dose Is the Standard
The consensus recommendation (74% agreement) specifies that "adequate dose" means the minimal effective dosage—that is, the minimal approved dosage—not higher doses. 1
This recommendation is supported by several key findings:
Most meta-analyses show no benefit for dose escalation: The majority of studies and meta-analyses have found no benefit for antidepressant dose escalation versus staying on the minimum licensed dose, with dose increases associated with increased side effects and higher discontinuation rates. 1
SSRI dose-response curves are flat: A 2018 meta-analysis of nine randomized controlled trials involving 1,273 patients found a statistically nonsignificant effect size of 0.053 (95% CI, -0.143 to 0.248) favoring dose increase over dose continuation for SSRIs after initial treatment failure. 2 This provides evidence against increasing SSRI doses (with the possible exception of citalopram) in adults with major depression and antidepressant treatment failure.
Flat dose-response is an SSRI class phenomenon: Multiple fixed-dose clinical trials demonstrate that SSRIs exhibit flat dose-response curves, meaning higher doses do not produce meaningfully better outcomes. 3, 4
Parallel Evidence from Schizophrenia Treatment Guidelines
The 2017 American Journal of Psychiatry consensus guidelines for treatment-resistant schizophrenia provide a useful parallel framework, recommending that each antipsychotic trial last at least 6 weeks at therapeutic dose (minimum 12 weeks total for two trials) before declaring treatment resistance. 1 This longer duration reflects the different pharmacology of antipsychotics, but the principle remains consistent: adequate dose and duration must be confirmed before concluding treatment failure.
Common Pitfalls to Avoid
Premature switching before four weeks: Switching medications before allowing four weeks at the minimum licensed dose leads to missed opportunities for response and creates false impressions of treatment resistance. 1
Assuming higher doses are better: For SSRIs specifically, increasing beyond the minimum licensed dose rarely improves efficacy but does increase side effects and discontinuation rates. 1, 2
Relying on patient recall alone: Assessment of prior treatment adequacy should be based on clinical documentation and standardized instruments, not solely on subjective recollection. 1
Ignoring the distinction between non-response and intolerance: If a patient discontinues treatment before four weeks due to side effects rather than clear lack of efficacy, this should not be counted as a failed adequate trial for defining treatment-resistant depression. 1
Defining Treatment-Resistant Depression
The consensus definition requires failure of at least two adequate trials (minimum licensed dose for at least four weeks each) with medications of different mechanisms of action before a patient meets criteria for treatment-resistant depression. 1 This framework ensures that patients receive genuine therapeutic trials before being labeled as treatment-resistant and potentially exposed to more aggressive interventions.
FDA Labeling Supports Delayed Full Effect
The FDA-approved fluoxetine label explicitly states: "As with other drugs effective in the treatment of major depressive disorder, the full effect may be delayed until 4 weeks of treatment or longer." 5 This regulatory language reinforces that four weeks represents the minimum timeframe for assessing antidepressant efficacy, not an arbitrary research convention.
When to Consider Dose Escalation
While the minimum licensed dose for four weeks is the standard for declaring treatment failure, partial response (25-50% improvement) at four weeks may warrant dose escalation for an additional four weeks before switching or augmenting. 6 However, this applies primarily to individual patient optimization rather than the definition of adequate trial for treatment-resistant depression.