Depression and migraine are among the most prevalent conditions in the general population, and many research shows they are closely related. Migraine is one of the most common debilitating diseases, affecting over one billion people worldwide. Migraine is frequently comorbid with psychiatric conditions such as anxiety disorders and major depression, with a negative impact on quality of life (QoL) and disability.

The knowledge of the pathophysiology of migraine involves changes in physiological processes, functional connectivity, and structural changes of the central nervous system (CNS) in patients with underlying genetic susceptibility. Upregulation of vasoactive and pro-inflammatory mediators such as calcitonin gene-related peptide (CGRP) and cytokines have been found in the trigeminal ganglia and the plasma, cerebrospinal fluid, saliva, and tears of these patients.

Various classes of antidepressants - like Selective Serotonin Reuptake Inhibitors (SSRI), Selective Serotonin and Norepinephrine Inhibitors (SNRI), and Tricyclic Antidepressants (TCAs) - were investigated but in a low number of studies and with inconsistent results.

Vortioxetine (VO) is a novel multimodal serotonergic antidepressant, approved in the last decade for the treatment of major depression. VO inhibits 5-HT transporter (SERT), like commonly used antidepressants, but different from them, it directly modulates the activity of 5-HT receptors. Vortioxetine also modifies the release of glutamate and gamma amino butyric acid (GABA), implicated in migraine pathogenesis. Recent experimental and clinical studies have shown that VO exerts antidepressant and pro-cognitive activities and is also effective in modulating pain hypersensitivity and could be effective in treating chronic pain syndromes.

Inclusion Criteria:

• The patient is aged >18 years old
• The patient has a diagnosis of depression, according to DSM-5, and in treatment with Vortioxetine (for no more than a week).
• Patients with depression and anxiety symptoms will also be included in the study
• The patient had a score of the HAM-D >18 (moderate to severe)
• The patient has a diagnosis of episodic migraine with and without aura according to ICHD-3 criteria confirmed at the Screening Visit with a history of migraine onset of at least one year before the Screening Visit
• No concomitant other treatment for depression
• The patient has had an onset of migraine at <50 years of age
• All participating patients will provide written informed consent
• No concomitant preventive treatment for migraine with TCAs, other antidepressants, anti-CGRP monoclonal antibodies (mAbs) or gepants. The patient is not eligible for treatment with anti-CGRP mAbs
• Stable treatment for migraine for at least two months without prevision to change it in the next two12 weeks

Exclusion Criteria:

• The patient has confounding and clinically significant pain syndromes (for example, chronic low back pain and fibromyalgia)
• The patient has a history or diagnosis of chronic tension-type headache, hypnic headache, cluster headache, hemicrania continua, new daily persistent headache, or unusual migraine subtypes such as hemiplegic migraine (sporadic and familial), or migraine with brainstem aura
• Patients with a lifetime history of psychosis, bipolar mania
• Patients with cognitive impairment are excluded (MoCA <26)

Patients with diagnosis of depression, according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), and concomitant episodic migraine with or without aura, fulfilling the criteria of ICHD-3.