To investigate the effectiveness of combining mirtazapine with serotonin-noradrenaline reuptake inhibitor (SNRI) or selective serotonin reuptake inhibitor (SSRI) antidepressants for treatment resistant depression in primary care.

Introduction

Depression is among the top five contributors to the global burden of disease, and by 2030 is predicted to be the leading cause of disability in high income countries.1 People with depression in the United Kingdom are usually managed in primary care, and antidepressants are often the first line treatment. The number of prescriptions for antidepressants has risen dramatically in recent years in the National Health Service, increasing by 6.8% (3.9 million items) during 2014-15 (total 61 million items).2 Many patients, however, do not respond to treatment. The STAR*D study (Sequenced Treatment Alternatives to Relieve Depression) found that half of those treated failed to experience at least a 50% reduction in depressive symptoms after 12-14 weeks of treatment with a single antidepressant.3 A substantial proportion of those who take antidepressants in an adequate dose and for an adequate period do not experience a clinically meaningful improvement in depressive symptoms.3

The National Institute for Health and Care Excellence advises general practitioners to reconsider treatment if patients show no response after 4-6 weeks of antidepressant use.4 Limited evidence is currently available to guide doctors in the management of patients who meet the ICD-10 (international classification of diseases, 10th revision) criteria for depression after taking a serotonin-noradrenaline reuptake inhibitor (SNRI) or selective serotonin reuptake inhibitor (SSRI) at an adequate dose for a minimum of six weeks.5 Several drug strategies have been proposed, including increasing the dose, switching antidepressants, combining two antidepressants, and augmenting the antidepressant with another psychotropic drug, such as lithium or an antipsychotic.6 A systematic review of antidepressant combinations for those who did not respond to monotherapy found that the small number of trials and methodological drawbacks of those trials precluded definitive conclusions about effectiveness, and some of the combinations carry a substantial risk of adverse effects and are not considered appropriate for initiation in primary care.7 There is a pharmacological rationale for adding a second antidepressant with a different and complementary mode of action to SSRIs or SNRIs. Mirtazapine, a noradrenaline (α2 adrenoreceptor) and serotonin (5 hydroxtryptamine receptors 2 and 3) antagonist, has the potential for an additive and perhaps synergistic action with SSRIs and SNRIs and could enhance clinical response compared with monotherapy with SSRIs or SNRIs. Four trials have been carried out of this combination against SSRI and SNRI monotherapy in participants who are treatment resistant and in those without treatment failure, with mixed results.891011

We determined the effectiveness of adding mirtazapine to an SSRI or SNRI in reducing depressive symptoms and improving quality of life at 12 weeks (primary follow-up) and at 24 and 52 weeks compared with adding placebo for patients in primary care who still experience depression after an adequate course of treatment.