Background :

Depression and Anxiety are linked to COVID (Coronavirus Disease)-19 long-term impact through several mechanisms. The possible way is the alteration of neurotransmitter regulation from the interaction of severe acute respiratory syndrome -Coronavirus-2 (SARS-COV2) with Angiotensin-Converting Enzyme 2 (ACE2) receptor, and Dopa Decarboxylase (DDC), an enzyme that associated with the production of dopamine, serotonin, and other neurotransmitters. However, some arguments exist that depression and anxiety occur naturally due to external stressors, as the impact of public health measures, and not associated with physiological changes due to viral infection.

Objective:

1. This study aims to identify whether the patient discharged after COVID 19 treatment has significant changes in serotonin and dopamine level which might induce depression and anxiety internally and,
2. To distinguish external etiologies that might induce depression and anxiety such as social isolation and stress due to public health restriction.

Method:

A prospective longitudinal study of people with the interest exposure is COVID 19 and the primary outcome is Depression, Anxiety, and Neurotransmitter level

Hypothesis:

People with a previous infection of COVID 19 have a significant difference in neurotransmitter level over time and compared to non exposed group and a higher prevalence of anxiety and depression.

Method :

Prospective Longitudinal study for 6 months. with both exposed and unexposed group

Target population :

A cohort of the population in multiple centers (3 centers)

Sample Size Calculation with Longitudinal study formula:

1. Effect Size: 0.15
2. Type I error: 0.05
3. Power of Study: 80%
4. Number of Group: 2
5. Repeated measurement: 3 times
6. Correlation among Repeated Measures: 0.5
7. Nonsphericity Correction: 1
8. Initial Sample size: 75

Adjusted by clustering effect:

1. Intraclass Correlation Coefficient = 0.05
2. Number of people per cluster = 25
3. Design Effect= 1 + 0.05(25-1) = 2.2
4. Total sample size = 75 x 2.2 = 165 participants

Procedure:

1. Participants will be assessed for eligibility
2. Screening for Depression, Anxiety, and Stress using Depression Anxiety Stress Scale (DASS) Questionnaire. Health-Related Quality of Life (QoL) and Pittsburgh Sleep Quality Index (PSQI)
3. Sample Collection and assessment of QoL, DASS, PSQI on the first day
4. Sample Collection and assessment of QoL, DASS, PSQI on day 60
5. Sample Collection and assessment of QoL, DASS, PSQI on day 120

Variables

1. Case Definition: Realtime Polymerase Chain Reaction (RT-PCR) and Cycle Threshold Value (CT)
2. Degree of COVID 19 Symptom-based on World Health Organization Criteria (Asymptomatic, Mild, Moderate, Severe, Critical)
3. Sociodemographic Variables (Age, Gender, Education, Income, Marital Status)
4. Sleep Quality using Pittsburgh Sleep Quality Index (PSQI)
5. Treatment of COVID: Antiviral, Antibiotic, Interleukin-6 Antagonist, Steroid, Plasma Convalescent, Ventilator, Human Intravenous Immunoglobulin, anticoagulant
6. Chronic Disease including Diabetes Mellitus, Hypertension, Chronic Kidney Disease
7. Medication that affects neurotransmitter level taken prior to recruitment.
8. History of Smoking classified by Brinkmann Index.
9. Body Mass Index
10. Complete Blood Count
11. Vaccination history

Outcome

1. Dopamine Serum
2. Serotonin Serum
3. Prevalence of Anxiety, and Depression according to Diagnostic and Statistical Manual of Mental disorders (DSM) 5

Statistical analysis Basic Analysis: Intention to Treat analysis

1. Linear Mixed Model for Neurotransmitter
2. Generalized Estimating Equation for Prevalence of Anxiety and Depression
3. Sensitivity analysis will be conducted, concerning the lost-to-follow up
4. A subgroup analysis will be conducted, particularly the participants with specific comorbidities

Inclusion Criteria:

1. Age minimum 18 years old
2. For exposed group should be confirmed with RT-PCR
3. Not being diagnosed by depression or anxiety prior to recruitment

Exclusion Criteria:

1. The unexposed participants will be excluded from the unexposed group if contracted with the virus within the 6-month observation.
2. Patient falls into critical condition and it is unlikely to attend at least one follow-up measurement
3. Patient refuses to continue observation

Three clusters will be appointed as the study center. The level of the cluster is at the municipality level where participants will be recruited consecutively

Protocol, Statistical Analysis Plan and De-identified data will be shared accordingly