Adjunctive Pharmacotherapy for Major Depressive Disorder with Anxiety Symptoms: from Monoamines to Recent Clinical Evidence

Anxiety symptoms are common in patients with major depressive disorder (MDD). The presence of anxiety symptoms can indicate greater depression severity, and is associated with a higher comorbidity burden, suicidality, lower levels of functioning, and poorer quality of life. The presence of anxiety identifies patients who are likely to experience significant burden from MDD despite standard treatment. Although clinical guidelines provide recommendations for adjunctive treatment in patients who have not responded to an antidepressant, there are currently limited recommendations specifically for patients with MDD and anxiety symptoms. Dysregulation of the monoamine system, notably noradrenaline (norepinephrine), serotonin, and dopamine signalling, has been implicated in the pathophysiology of MDD and of anxiety disorders, based mainly on preclinical, mechanistic and translational evidence. This review has two aims: (1) to explore the hypothetical role of monoamine signalling in patients with MDD with anxiety symptoms, and (2) to provide a comprehensive overview of clinical data for pharmacotherapies recommended for the first- and second-line adjunctive treatment of difficult-to-treat MDD, focusing on recent studies and analyses of patients with MDD with anxiety symptoms. Reviewed treatments included atypical antipsychotics (aripiprazole, brexpiprazole, olanzapine, quetiapine XR, risperidone, cariprazine), bupropion, ketamine/esketamine, lithium, mirtazapine/mianserin, modafinil, and triiodothyronine. Clinical data in patients with MDD with anxiety symptoms were scarce or lacking for olanzapine, risperidone, cariprazine, lithium, modafinil, and triiodothyronine. Aripiprazole, brexpiprazole, quetiapine XR, and ketamine/esketamine have been shown to improve depression and/or anxiety symptoms in patients with MDD with anxiety symptoms, although evidence is mainly short-term and derived from exploratory post hoc analyses of trials not designed to assess anxiety outcomes. Treatment decisions for patients with MDD with anxiety symptoms should be based on robust clinical data, and there is an unmet need for prospective clinical trials with anxiety-specific endpoints in this patient population.