Major Depressive Disorder: Etiology, Treatments, and Aspects

Major Depressive Disorder
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1 Major Depressive Disorder
Coryell (2022) stated that the diagnosis of major depressive disorder (MDD) is based on criteria by the Diagnostic and Statistical Manual of Mental Disorders-V, which describes the disorder’s symptoms. To satisfy the diagnosis, the patient must have at least five (5) of the following symptoms observed within two (2) weeks: A mainly depressed mood most of the day; Significantly reduced pleasure over previously pleasurable activities for most of the day; Lack of sleep or excessive sleep; Observed psychomotor agitation or retardation; Exhaustion or lack of energy; Feelings of unimportance or unwarranted misguided guilt; Reduced concentration; and persistent thoughts of death or suicide. One must be a loss of pleasure or interest or a depressed mood to be diagnosed with MDD.
2 Etiology of Major Depressive Disorder
Risk Factors
Eleven factors have been identified that increase the risk of having MDD. Among these, the factors with the highest associations are increased screen time with computers, television, or cellphone, daytime napping, and an inconsistent healthy diet. Different factors have also been found depending on the circumstance. For instance, in patients with genetic predisposition, consuming salty foods and screen time proved a higher risk for depression. Those who had early life trauma are at risk if they have more prolonged exposure to television (Hicklin, 2020).
Genetic and Environmental Factors
Chand et al. (2022) explained that genetic and environmental factors influence the development of MDD. However, the former affects it to a lesser extent. Genetic factors include neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease, cerebrovascular disease, seizure disorder, multiple sclerosis, cancer, chronic pain, and macular degeneration. On the other hand, environmental factors are traumatic life events that trigger a depressed mood. These include diminished social support or the complete absence of it, grief due to the loss of a loved one, financial difficulties, caregiver burden, interpersonal conflicts, and other interpersonal difficulties.
Epigenetic Factors
There is a diversity of findings regarding the genetic mechanism of depression. The reduced association is attributed to the epigenetic mechanism where the gene expression involved in stress and depressive behaviors is due to the alteration in chromatin structure. Some studies also suggest that stress and enrichment influence the activity of molecular signaling pathways in sperms, resulting in the alteration of gender-specific patterns, which play a role in the development of depression (Li et al., 2021).
Neurological and Biochemical Factors
MDD is theoretically caused by a dysfunction in monoaminergic function or the function of some neurotransmitters. Specifically, these include serotonin or 5-hydroxytryptamine (5-HT), gamma amino butyric acid (GABA), and glutamate. A reduced binding capacity of the 5-HT transporter in the midbrain and amygdala has been reported in patients with MDD. Moreover, there is also a decrease in the functioning of 5-HT receptors in the temporal, frontal, and limbic regions, with higher numbers of monoamine oxidase (Kaltenboeck & Harmer, 2018).
Consequently, GABA levels are lower in the cerebrospinal fluid (CSF) of patients with MDD. There are also lower levels of GABAergic interneurons in the occipital, prefrontal cortex, and anterior cingulate cortex of patients with depression (Kaltenboeck & Harmer, 2018).
Similarly, higher levels of glutamate in the CSF, peripheral blood, and brain have been implicated in depression. Glutamate is the primary excitatory neurotransmitter of the central nervous system, which binds to N-methyl-D-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs), both of which are inotropic glutamate receptors at the postsynaptic membrane. It then activates the signaling pathways (Li et al., 2021).
Neuroendocrine Factors
The hypothalamic-pituitary-adrenal (HPA) axis also plays a role in the development of MDD. Specifically, this involves cortisol, adrenocorticotrophic hormone (ACTH), corticotropin-releasing hormone (CRH), arginine vasopressin, and vasopressin hypersecretion. Patients with MDD have higher 24-hour blood cortisol levels, diminished inhibition of cortisol release after the administration of dexamethasone, higher waking salivary cortisol, reduced central and peripheral glucocorticoid receptors, and larger adrenal glands. Patients with MDD have also been shown to have a higher risk of incurring comorbidities such as cardiovascular diseases and diabetes mellitus, along with chronic impairments in the hippocampus. These are consistent with prolonged glucocorticoid exposure (Kaltenboeck & Harmer, 2018).
Neurotrophin Family
Patients with depression have reduced numbers of neurotrophin, which plays a role in neuroplasticity. This results in neuronal atrophy and reduced glial support. Specifically, brain-derived neurotrophic factor (BDNF) is reduced when exposed to various stresses. When its pro-domain, located presynaptically, is diminished, this results in long-term depression in the hippocampal area, resulting in symptoms of depression (Li et al., 2021).
Immunologic Factors
An increase in immunologic biomarkers has been associated with the development of MDD. These inflammatory markers include C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-a), and interleukin-6 (IL-6). Using immune-modulating drugs as treatment can also induce depressive symptoms by increasing the levels of tryptophan-metabolizing enzyme (indoleamine 2,3-dioxygenase), reducing the number of 5-HT precursors, tryptophan, and a higher availability of potentially neurotoxic metabolite, quinolinic acid (Kaltenboeck & Harmer, 2018).
Evidence revealed that infection and autoimmune diseases are highly associated with depression. The peripheral and central immune systems play a role in its pathophysiology, resulting in a neuroimmune response. For instance, IL-6 and IL-1 β can enter the blood-brain barrier and ultimately affect supporting cells such as astrocytes, stromal cells, and neurons. Aside from these, other cytokines can enter the blood-brain barrier through a carrier such as the monocytes. These cytokines and chemokines enter the brain’s circulation and bind to the surface receptors of astrocytes and endothelial cells of the blood-brain barrier to cause a negative effect. Furthermore, these may affect neuroplasticity by binding directly to neurons and promoting depression-like behavior. To a lesser extent, the immune system can also induce depression by transmitting peripheral signals of danger to the central nervous system, such as stress, trauma, infection, or inflammation (Li et al., 2021).
An imbalance in the microglial function is also implicated in depression. There are two types of microglia, M1, and M2, which have pro-inflammatory and anti-inflammatory effects, respectively. Excessive activity of M1 increases pro-inflammatory markers in the central nervous system, resulting in depressive-like behaviors (Li et al., 2021).
Anatomic Factors
Structural and functional abnormalities of the brain have been implicated in the development of MDD. Specifically, the limbic-cortico-striato-pallido-thalamic pathway involves the anterior cingulate cortex, orbitofrontal cortex, basal ganglia, hippocampus, parahippocampus, and amygdala. A reduction in grey matter in the anterior cingulate cortex, orbitofrontal cortex, basal ganglia, and hippocampus due to neuronal and glial cell death has been implicated in MDD. Conversely, damage in the white matter regions may be due to ischemia that interjects in the projection of signals in the frontal cortex areas that are significant in mood regulation. This phenomenon is predominant in late-onset depression (Kaltenboeck & Harmer, 2018).
Microbiome-Gut-Brain Axis
Alterations in the gastrointestinal microbiota are linked to depressive-like behaviors, as seen in eating disorders and diseases such as irritable bowel syndrome (IBS). In one experiment where a fecal transplant in patients with depression was done to a rodent, the latter exhibited depressive behaviors. Hypothetically, this may be due to the interaction of the gastrointestinal system with the central nervous system via the HPA axis, autonomic, neuroendocrine, and neuroimmune systems. The gut microbiota can alter the levels of neurotransmitters, including 5-HT, norepinephrine, GABA, dopamine, and glutamate. Furthermore, these can induce the production of peripheral inflammatory cytokines.
3 Treatment – Psychopharmacological Intervention
There is no single “most effective” psychopharmacologic intervention for major depressive disorder (MDD), as treatment depends on individual patient characteristics and response. There are instances wherein an intervention works for some but does not work for others. However, numerous evidence-based research studies show several medications to be effective in treating MDD.
The most commonly used medications for MDD are SSRIs, such as paroxetine, fluoxetine, and sertraline. These medications increase serotonin levels, a neurotransmitter associated with mood regulation, in the brain (Murphy et al., 2021). Other antidepressant drugs such as tricyclic antidepressants, monoamine oxidase inhibitors, and atypical antidepressants like bupropion and mirtazapine have also been effective in treating MDD (Fornaro et al., 2021; Sanches et al., 2021).
Controversies in psychopharmacology may influence the pharmacologic treatment of MDD. One issue is the potential for antidepressant medications to cause adverse side effects. These side effects can include weight gain, sexual dysfunction, and increased risk of suicide in younger patients (Moncrieff, 2020). Another controversy is "off-label" prescribing, where medications are used for conditions other than those specifically approved (Urits et al., 2019). It can be an issue when using psychotropic medications on children and adolescents, who may be more vulnerable to their effects.
Furthermore, there is an ongoing debate about the role of antidepressants in treating MDD versus non-pharmacological interventions like cognitive behavioral therapy (CBT) or electroconvulsive therapy (ECT). According to some studies, these non-pharmacological interventions may be as effective as, if not more effective, antidepressant medications. Additionally, there is an ongoing debate about the long-term effects of antidepressant medications and the potential for withdrawal symptoms when discontinuing the medication (Moncrieff, 2020).
In summary, evidence-based research supports using various psychopharmacologic interventions for treating MDD, with SSRIs being the most commonly prescribed medication class. However, controversies in psychopharmacology, such as side effects, off-label prescribing, and questions about long-term effectivene...