Depression has been ranked as the fourth leading contributor to disability globally. As per data provided by the World Health Organization (WHO), depression affects approximately 3.8% of the global population, constituting approximately 280 million individuals worldwide, with an annual suicide-related mortality of 700,000 people GHDx 2023). Women are 50% more affected with depression as compared to men. Approximately 27.4% have experienced symptoms associated with anxiety and depression in Pakistan. The increasing prevalence and yearly occurrence influenced by the COVID-19 have compelled us to reevaluate the significance of mental well-being. Furthermore, based on the latest data, there has been an increase of 53.2 million cases of depressive disorder worldwide, indicating a growth of 27.6% throughout this pandemic. The prevalence of depression is uniform in both developed and economically challenged nations, independent of cultural background, origin, or ethnicity. Depression has various forms which include major depressive disorder (MDD), bipolar disorder (manic depression), persistent depressive disorder (dysthymia), and seasonal affective disorder (SAD). In the present time, MDD is the leading cause of global disability, contributing to 7.5% of years lived with a disability. (YLD) worldwide, with an estimated annual cost surpassing $US 1 trillion.

The primary etiology of MDD is disturbances in neurotransmitters and neuroendocrine regulation, accompanied by a complex interaction of genetic and environmental factors. In addition to these factors, increasing attention has been directed towards understanding the pathophysiology of MDD through the relationship between oxidative stress and inflammation. Essential enzymatic antioxidants, particularly Glutathione Peroxidase (GPx) and Superoxide Dismutase (SOD), play a crucial role in moderating oxidative stress. Oxidative stress arises from an imbalance between the generation of reactive oxygen species (ROS) and the body's capacity to counteract them. Studies indicate a tendency for reduced GPx and SOD activity in individuals with MDD, leading to heightened oxidative stress.

Furthermore, the involvement of pro-inflammatory cytokines, such as Tumor Necrosis Factor-alpha (TNF) and Interleukin-6 (IL-6), in the inflammatory processes associated with depression is noteworthy. Persistent inflammation is associated with the activation of the kynurenine pathway, triggering the production of neurotoxic metabolites that may contribute to observed neurobiological changes in MDD. Elevated levels of TNF and IL-6, key immune response mediators, are observed in individuals with depression. These cytokines influence neurotransmitter metabolism, disrupt the blood-brain barrier, and activate microglia, spreading neuro-inflammation. The bidirectional interplay between oxidative stress and inflammation establishes a cyclically reinforcing paradigm, amplifying the neurobiological substrates of depression.. Moreover, deficiencies in various vitamins and minerals are significantly associated with Major Depressive Disorder (MDD), including vitamin D and E. Vitamin D and its metabolite calcitriol may act as a defense mechanism for the brain, guarding against the depletion of dopamine and serotonin whereas vitamin E has an antidepressant-like effect.

The management of major depressive disorder encompasses diverse treatment approaches, comprising pharmacological, psychotherapeutic, interventional, and lifestyle modifications, such as incorporating exercise and dietary changes. While the current antidepressants are more effective than placebos in adults with MDD, limitations of antidepressant treatment include a prolonged therapeutic time lag required for the clinical betterment of depressive symptoms and various side effects linked to their usage. These side effects frequently lead to treatment discontinuation by patients. Consequently, adjunctive treatments may play a crucial role in managing this disorder, particularly in cases of treatment resistance.

Engaging in regular exercise exerts a beneficial impact on symptoms commonly associated with depression. The consistent practice of physical activity positively influences various physiological aspects, encompassing neurotransmitter levels, neurotrophic factors, hormonal balance, immune modulation, sleep quality, and cognitive functions. This comprehensive influence collectively provides substantial evidence for the therapeutic effectiveness of exercise in alleviating depressive symptoms. Hence, the objective of the current study is to investigate the outcomes of aerobic and resistance exercises in conjunction with vitamin supplementation on individuals diagnosed with Major Depressive Disorder (MDD).

A total number of 116 participants will be recruited in the study. After the voluntarily consent, all the participants will be equally divided into four of the treatment group Group-A, B, C and D using envelop method of simple random sampling technique. In addition, a total of 116 sealed envelopes, comprises of 29 envelopes for each group will be presented to the patients. Each patient will be asked to select one envelope of their choice. Upon selection of the envelope, patients will be allocated to the respective group. Thus, each group will comprise of 29 participants Afterwards, pre-assessment will be performed for each patient on all 3 outcome measures i.e. Oxidative stress (SOD & GPX), inflammatory markers (TNF alpha & IL-6) Depression severity (PHQ-9) respectively.

Participants in Group-A will be receiving Aerobic Exercise with Vitamin E, Group-B participants will be receiving Resistance Exercise with Vitamin E, Group C: Aerobic Exercise with Vitamin D, while Group D will be receiving Resistance Exercise with Vitamin D. Whereas, all the groups will be given 48 sessions of their respective protocol, comprising of 30 minutes, 4 times/week for the duration of 12 weeks.

Participants referred to the study will undergo a thorough screening process as discussed below to determine their eligibility.

The recruitment of patients will be conducted by a psychiatrist, adhering to predefined inclusion and exclusion criteria. Patients will undergo screening and be categorized as having Major Depressive Disorder (MDD) if they exhibit at least one of the two primary criteria-depressed mood or anhedonia (the inability to experience pleasure or loss of interest)-along with four or more secondary symptoms persisting for a minimum period of 2 weeks, as per DSM-5 guidelines (American Psychiatric Association, 2013).

They will then be screened through PARQ & YOU questionnaire by physical therapist. Subsequently, the investigator will provide a comprehensive overview of the study to the patients and secure informed consent upon their agreement. Demographic information and pertinent variables, including the duration of the disease and comorbidities, will be documented before the baseline assessment. All patients will adhere to their routine pharmacological care throughout the intervention period.

An orientation session will be arranged before starting the intervention in which the physical therapists in detailed will brief the participants regarding the protocol. The intervention will last for duration of 12 weeks with a total of 48 sessions. First, the participant will perform 1 week of training as part of familiarization phase.

Inclusion Criteria:

• Diagnosed patients with mild to moderate depression, aged between 25-35 years referred by Psychiatrist with no other Psychiatric disease attending the respective unit of Creek General Hospital and Dr. Ziauddin Hospital. (Kivani M et al, 2022, Khan B et al., 2022).
• Individuals both with and without current psychoactive medication (such as antidepressants or anxiolytics) will be enrolled. (O'Sullivan et al., 2023)
• Participants willing to participate to the intervention.

Exclusion Criteria:

• Participants with diagnosed cardiovascular diseases,
• Participants with pregnant women,
• Participants with use of beta-blockers,
• Participants with a history of severe mental illnesses (mentally handicapped),
• Participants with hypertension, hyperparathyroidism,
• Participants with current significant substance or alcohol abuse, ongoing burn-out syndrome, and
• Participants with An elevated suicide risk determined by the Psychiatrist.
• Participants with Prisoners
• Participants with chronic diseases such as liver and renal diseases, mal-absorption syndrome, and other diseases that can affect the level of vitamin D.
• Patients with physical limitations that would prohibit the participation in following exercise protocol.
• Participants consuming dietary supplements two months prior to the intervention.
• Participation in regular exercise during the past 6 months (2 days/week).
• Non cooperative patients and refused to continue the intervention program.