This will be a single center, prospective, open label, quasi-experimental pre-post intervention trial in major depressive disorder (MDD) patients with insomnia.

The main objectives are i. to assess efficacy of mirtazapine in reducing depression and insomnia symptom severity in major depressive disorder (MDD) patients with insomnia.

ii. to evaluate side effects of mirtazapine.

Following enrollment and baseline assessment patients will be prescribed mirtazapine at 15-30 mg/day. Depending on the response, doses will be adjusted after two weeks and might be titrated up to 45 mg/day.

Each patient will be monitored for 42 days and assessment will be carried out on Day 0, Day 14, Day 28 and Day 42 of the trial.

Background: Mirtazapine is an atypical antidepressant acts by increasing noradrenergic and serotonergic neurotransmission. It inhibits presynaptic adrenergic alpha-2 receptor along with inhibition of postsynaptic serotonergic 5-HT2 and 5-HT3 receptors and histamine (H1) receptor (Jilani et al., 2022). It was approved by FDA in 1996 for treating moderate and severe depression; but it also has sedative, antiemetic, anxiolytic, and appetite stimulant effects and for these prescribed in many other psychiatric disorders (Nutt, 2002). Because of its efficacy, safety and tolerability, it is one of the drugs recommended by NICE to consider as first-choice in treating depression (Middleton et al., 2005).

A depressive episode is characterized by a period of depressed mood or diminished interest in activities occurring most of the day, nearly every day during a period lasting at least two weeks accompanied by other symptoms such as difficulty concentrating, feelings of worthlessness or excessive or inappropriate guilt, hopelessness, recurrent thoughts of death or suicide, changes in appetite or sleep, psychomotor agitation or retardation, and reduced energy or fatigue. There have never been any prior manic, hypomanic, or mixed episodes, which would indicate the presence of a bipolar disorder (ICD-11, 2019).

Around 6.7% of adult population in Bangladesh suffers from depressive disorders (NIMH, 2019). However, no interventional study has yet been carried out to see efficacy of different antidepressants in this population. As one of the frequently observed features of depression is insomnia, mirtazapine could be a good choice in these cases. This study intends to assess the efficacy of mirtazapine in major depressive disorder when the patients also present with insomnia.

General objective To assess the efficacy of mirtazapine in reducing depression with insomnia symptoms in patients with major depressive disorder (MDD) with insomnia.

Specific objectives

1. To assess the efficacy of mirtazapine in reducing depressive symptoms in patients with MDD with insomnia.
2. To assess the efficacy of mirtazapine in reducing insomnia symptoms in patients with MDD with insomnia.
3. To compare the quality of life in patients with MDD before and after introducing mirtazapine.
4. To assess the side-effects experienced by trial patients.

Methods: This will be a single center, prospective, open label, quasi-experimental pre-post intervention trial in MDD patients with insomnia. The study will be conducted at National Institute of Mental Health (NIMH), Bangladesh over a period of 8 months. A total of 135 MDD patients with insomnia who fulfill the selection criteria will be conveniently selected for the study. Following enrollment and baseline assessment patients will be prescribed mirtazapine at 15-30 mg/day. Depending on the response, doses will be adjusted after two weeks and might be titrated up to 45 mg/day.

Each patient will be monitored for 42 days and assessment will be carried out on Day 0, Day 14, Day 28 and Day 42 of the trial. A semi-structured clinical information questionnaire, Hamilton Depression Rating Scale (HDRS), Insomnia Severity Index (ISI), Antidepressant Side-Effect Checklist (ASEC), World Health Organization Quality of Life (WHOQOL-BREF) will be used by research psychiatrists during assessment.

The whole study will be on accordance with Helsinki Declaration and prior to commencement, ethical approval will be taken from IRB and Bangladesh Medical Research Council (BMRC). The protocol will also be registered with the International Clinical Trials Registry Platform (ICTRP).

Potential significance: The findings will generate information on efficacy of mirtazapine in reducing depressive and insomnia symptom severity in MDD patients with insomnia and regarding side effects of mirtazapine in Bangladeshi adult population.

Funding: This study is conceptualized and sponsored by Bangladesh Association of Psychiatrists (BAP) with scientific support and research grant from Sun Pharmaceutical Bangladesh Ltd.

Inclusion Criteria:

1. Age 18-60 years.
2. Diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) for MDD.
3. A ≥20 total score on the 17-item Hamilton depression rating scale (HDRS).
4. A ≥15 total score on the 7-item Insomnia Severity Index (ISI).
5. Considered to require antidepressant treatment based on the judgment of the consulting psychiatrist.
6. For women - willing to abstain from conception or willing to use modern method of contraception (she or her partner) during trial period.

Exclusion Criteria:

1. History of use of mirtazapine in the last 3 months period.
2. Pregnant or breastfeeding mother.
3. At significant risk for suicide.
4. Diagnosed with a primary condition including dementia as well as bipolar, obsessive-compulsive, or eating disorders, schizophrenia, or alcohol or substance dependence except for tobacco dependence.
5. Experiencing any medical conditions judged to render the patient ineligible to participate in the study.