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If partial response or failure to respond - options for combining antidepressants in depression

Last reviewed dd mmm yyyy. Last edited dd mmm yyyy

Authoring team

Summary points are derived from the full guideline (1).

If a person with depression develops side effects early in antidepressant treatment, provide appropriate information and consider one of the following strategies:

  • monitor symptoms closely where side effects are mild and acceptable to the person or
  • stop the antidepressant or change to a different antidepressant if the person prefers or
  • in discussion with the person, consider short-term concomitant treatment with a benzodiazepine if anxiety, agitation and/or insomnia are problematic (except in people with chronic symptoms of anxiety); this should usually be for no longer than 2 weeks in order to prevent the development of dependence

If failure to respond or partial response to first antidepressant prescribed:

  • if improvement is not occurring on the first antidepressant after 2-4 weeks, check that the drug has been taken as prescribed

  • if response is absent or minimal after 3-4 weeks of treatment with a therapeutic dose of an antidepressant, increase support and consider:
    • increasing the dose in line with the summary of product characteristics (SPC) if there are no significant side effects or
    • switching to another antidepressant if there are side effects or if the person prefers

  • if there is some improvement by 4 weeks, continue treatment for another 2-4 weeks. Consider switching antidepressants if:
    • response is still not adequate or
    • there are side effects or
    • the person prefers to change drug

If inadequate response to antidepressant treatment

  • sequencing treatments after an inadequate response
    • switching and combining antidepressants  
      • when reviewing treatment after an inadequate response to initial pharmacological interventions:
        • check adherence to, and side effects from, initial treatment
        • increase the frequency of appointments
        • be aware that using a single antidepressant is usually associated with a lower side-effect burden
        • consider reintroducing treatments that have been inadequately delivered or adhered to, including increasing the dose or switching antidepressants

      • when switching antidepressants, consider:
        • initially, a different SSRI or a better tolerated newer-generation antidepressant
        • subsequently, an antidepressant of a different class that may be less well tolerated (such as venlafaxine, a TCA or an MAOI)

      • do not switch to, or start, dosulepin

      • normally switch within 1 week for drugs with a short half-life. Consider interactions and exercise caution when switching:
        • from fluoxetine to other antidepressants
        • from fluoxetine or paroxetine to a TCA, because both of these drugs inhibit the metabolism of TCAs; a lower starting dose of the TCA will be required, particularly if switching from fluoxetine because of its long half-life
        • to a new serotonergic antidepressant or MAOI - because of the risk of serotonin syndrome
        • from a non-reversible MAOI: a 2-week washout period is required (do not routinely prescribe other antidepressants during this period)

      • do not normally combine antidepressants in primary care without consulting a consultant psychiatrist

      • combining and augmenting antidepressants
        • if a person is informed about and prepared to tolerate the increased side-effect burden, consider augmenting an antidepressant with:
          • lithium
            • when prescribing lithium:
              • monitor renal and thyroid function before treatment and every 6 months during treatment (more often if there is evidence of renal impairment)
              • consider ECG monitoring in people at high risk of cardiovascular disease
              • monitor serum lithium levels 1 week after treatment starts and every dose change, and then every 3 months

          • an antipsychotic such as aripiprazole*, olanzapine*, quetiapine* or risperidone*
            • drug names are marked with an asterisk if they do not have UK marketing authorisation for the indication in question at the time of publication (April 2018)
            • when prescribing an antipsychotic, monitor weight, lipid and glucose levels, and side effects (for example, extrapyramidal side effects and prolactin-related side effects with risperidone)

          • another antidepressant, such as mianserin or mirtazapine

        • do not routinely augment an antidepressant with:
          • a benzodiazepine for more than 2 weeks as there is a risk of dependence
          • augmentation of an antidepressant with buspirone*, carbamazepine*, lamotrigine* or valproate* as there is insufficient evidence for their use
          • augmentation of an antidepressant with pindolol* or thyroid hormones* as there is inconsistent evidence of effectiveness

Combining psychological and drug treatment

  • if a person's depression has not responded to either pharmacological or psychological interventions, consider combining antidepressants with CBT.


  • If a person's depression has not responded to various augmentation and combination treatments, consider referral to a specialist practitioner or service

NICE (2) noted in 2007 guideline that:

  • if switching from one antidepressant to another, prescribers should be aware of the need for gradual and modest incremental increases of dose, of interactions between antidepressants and the risk of serotonin syndrome when combinations of serotonergic antidepressants are prescribed. Features include confusion, delirium, shivering, sweating, changes in blood pressure and myoclonus
    • before prescribing mirtazapine, practitioners should take into account its propensity to cause sedation and weight gain
    • before prescribing moclobemide, practitioners should take into account the need to wash out previously prescribed antidepressants
    • before prescribing reboxetine, practitioners should take into account the relative lack of data on side effects. Patients taking reboxetine should be monitored carefully
    • before prescribing tricyclic antidepressants, practitioners should take into account their poorer tolerability compared with other equally effective antidepressants, the increased risk of cardiotoxicity and their toxicity in overdose
      • if a tricyclic is chosen as an antidepressant, lofepramine is a reasonable choice because of its relative lack of cardiotoxicity
      • patients who start on low-dose tricyclic antidepressants and who have a clear clinical response may be maintained on that dose with careful monitoring
      • if a patient has been started on low-dose tricyclic antidepressants should be carefully monitored for side effects and efficacy, and the dose gradually increased if there is lack of efficacy and no major side effects
    • with respect to venlafaxine:
      • practitioners should take into account the increased likelihood of patients stopping treatment because of side effects, and its higher cost, compared with equally effective SSRIs
      • practitioners should ensure pre-existing hypertension is controlled in line with the current NICE guideline on hypertension.Venlafaxine should not be prescribed for patients with uncontrolled hypertension
      • for patients prescribed venlafaxine, blood pressure should be checked on initiation and regularly during treatment, particularly during dosage titration. For patients who experience a sustained increase in blood pressure, the dose should be reduced or discontinuation considered
      • practitioners should monitor patients prescribed venlafaxine for the signs and symptoms of cardiac dysfunction, particularly in those with known cardiovascular disease, and take appropriate action as necessary
      • when prescribing antidepressants (particularly fluoxetine, fluvoxamine, paroxetine, tricyclic antidepressants, or venlafaxine), practitioners should be aware of clinically significant interactions with concomitant drugs. They should consider consulting appendix 1 of the 'British National Formulary'
      • venlafaxine should only be prescribed at high dose (300 mg/day or more) under the supervision or advice of a specialist mental health medical practitioner
      • venlafaxine and tricyclic antidepressants (with the exception of lofepramine) should not be prescribed for patients with a:
        • high risk of serious cardiac arrhythmias
        • recent myocardial infarction

In elderly patients then consider continuing treatment for up to 9 weeks before changing (3).


When switching antidepressants then follow recommended precautions to avoid adverse reactions. Non-reversible monoamine oxidase inhibitors (MAOIs), such as phenelzine, should normally be prescribed only by specialist mental health professionals (1).

Dosulepin should not be prescribed (1).

For more detailed guidance then consult full guideline (1)


  1. NICE (April 2018). Depression
  2. NICE (April 2007). Management of depression in primary and secondary care
  3. Anderson IM et al (2000). Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 1993 British Association for Psychopharmacology guidelines. J Psychopharmacol, 14, 3-20.

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