Combining antidepressants

All B-Z use can lead to long-term regular use, sometimes lasting for years.¹⁰⁷ This is contrary to good practice guidance^36,37 and the terms of their licence^31,69 therefore, consider reviewing appropriateness where:

• B-Z are initiated to treat anxiety or insomnia prior to starting antidepressant therapy, or to treat agitation, anxiety or insomnia symptoms associated with starting an SSRI.^20,36 B-Z only demonstrate marginal benefits for short-term relief of insomnia and some anxiety disorders.
• B-Z are initiated to treat avoidable adverse drug effects caused by higher SSRIs doses (e.g. insomnia, agitation),^39,40,42 or for signs and symptoms of poorly controlled depression, anxiety or back pain.
• B-Z use is known to worsen depressive symptoms, cause cognitive dysfunction and other avoidable adverse effects, and reduce the efficacy of some psychological therapies.^107-110 This should be considered one of the priority groups for review.
• Long-term B-Z have been prescribed, to review and gradually withdraw using an agreed structured and planned reduction schedule. A small minority of individuals may require longer-term B-Z treatment with regular review to optimise care and minimise street B-Z use, see the Benzodiazepine and Z-drugs Quality Prescribing Guidance for more detail.
• Included in this guide is a suite of National Therapeutic Indicators allowing identification of variation in prescribing at NHS board or GP practice level with accompanying case finding STU searches to allow identification of individuals at risk of harm from within general practice. For example, those on antidepressant medication in combination with other psychotropic medication.

Combining antidepressants for depression is not recommended. Non-specialist psychiatry prescribers should not initiate such combinations, unless on the advice of specialist services.

• Consultant psychiatrists may initiate combined therapy for their regular patient(s), e.g. for treatment of treatment resistant depression. The quality of evidence supporting combination antidepressant treatment is poor. For example, SSRIs or serotonin and noradrenaline re-uptake inhibitors (SNRIs) plus mirtazapine (30-45mg) demonstrate marginal benefits in observational studies to no difference in randomised placebo-controlled studies.^20,111,112
• Antidepressant augmentation with an antipsychotic or lithium therapy (as per guidance from the Directorate of the Chief Medical Officer)  can be more effective; providing clearer benefits, but these are not without risks and the requirement of extra monitoring which is often lacking.^20,114,115 Monitoring for antipsychotic therapy may include regular cardiometabolic risk assessment, including HbA1c, lipids, weight, blood pressure and lifestyle advice.¹¹⁶

Low dose mirtazapine added to SSRI/SNRIs therapy

• This combination to reduce antidepressant induced sexual dysfunction is supported by limited evidence of efficacy.^117,118 Clinicians should assess the efficacy of such strategies and record this as the mirtazapine indication where appropriate. 
• This combination has also been used for short-term sedating antihistamine effects (also seen with trazodone). In part, these additional antidepressants are possibly being used to treat SSRI/SNRI induced insomnia, agitation etc., and as an alternative to B-Z. However, this combination is of questionable benefit, and it may be more appropriate to reduce the dose of the SSRI/SNRI to minimise potential adverse effects and drug-related harms, rather than adding additional psychotropics, especially as tolerance can develop quickly to mirtazapine and trazodone sedating effects.^84,119 This avoids the prescribing cascade.

Specialists should be conscious of their prescribing actions potentially influencing prescribing habits in general practitioners.⁵ Specialists should consider providing clear rationale and therapeutic goals, alongside withdrawal strategies when initiating psychotropic combinations as outlined above.

Neuropathic pain plus depression/anxiety

• At times prescribers switch from a TCA and an effective antidepressant (for depression for example) to a TCA or duloxetine to treat both pain and mood. In these cases the TCA or duloxetine may only be effective for one condition, and not the other, or individuals may not tolerate higher doses of TCAs or duloxetine which can be more effective for treating depression.^20,39,53,54 For non-neuropathic pain prescribers should also consider avoiding concomitant antidepressant and tramadol use, due to the risk of serotonin syndrome.⁹⁴
• Two antidepressants (e.g. TCA for neuropathic pain and an antidepressant for depression such as a SSRI) may be appropriate to reduce symptoms (not two TCAs). However, use should be reviewed regularly, considering interactions, adverse and synergistic effects, e.g. sedating effects, TCA dose related QTc prolongation (greater risk of prolongation with higher doses).⁹⁶