DEPRESSION: UNDERSTANDING THE PATHOPHYSIOLOGY AND TREATMENT MODALITIES

DEPRESSION: UNDERSTANDING THE PATHOPHYSIOLOGY AND TREATMENT MODALITIES

Anuradha Pannu and Abhilasha Ahlawat *

Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, Haryana, India.

ABSTRACT: Depression is accepted as a condition of misery and is treated as a disorder that includes mental and emotional disorders. Depression is a deadly disease that affects about 5% of the general population. In addition, depression is a heavy burden on patients and families. Furthermore, many epidemiological studies have shown that the occurrence of depressive disorders in the general population is increasing at an alarming rate. Depression is the most common form of emotional disorder, from a very mild condition to severe depression associated with hallucinations and delusions. In addition, altered levels of serotonin and other biogenic amines have also been shown to contribute to neuromodulatory disturbance in the etiology of depression. According to monoamine theory in depressive disorder, patients with major depression have shown biochemical symptoms which may change monoamine neurotransmitters, specifically nor-epinephrine and serotonin. Clinical data suggested that dopamine is also involved in the pathophysiology and treatment of depression.

Keywords: Depression, Monoamine Theory, Nor-Epinephrine, Serotonin, Dopamine

INTRODUCTION: Depression is commonly considered as mental disarray associated with a miserable attitude. Feelings of guilt or low self-esteem, trouble in sleep or loss of appetite, lack of energy, and difficulty concentrating can also accompany depression. Depression can be defined as mood, a condition without inspiration, a feeling of hopelessness, and an absence of physical energy. Many aspects of our life can trigger an emotional state. Any type of traumatic incident in life is considered the first sign of depression; thus depression is often considered a depressive disorder ^1-7.

Approximately 264 million patients worldwide are affected by major depressive disorder (MDD), making it the second leading cause of global morbidity ⁸. Around 8 Lac suicides are reported annually by the World Health Organization (WHO) ⁹, suggesting MDD is a major community health challenge. Depression is not an analogous disorder, but this disorder has different subtypes as well as more than one etiology. Symptoms can differentiate subtypes of depression from mild to severe with or without psychotic features ⁸.

Therefore, this disorder is commonly considered an infirming disease that disturbs a person’s daily routine like sleeping, eating, professional life, and overall health and ability to enjoy life ¹⁰. A growing experimental and clinical research has shown that functions of serotonin and noradrenaline neurotransmitters' neuronal activity in the central nervous system (CNS) are altered in patients with depression ^{11, 12}.

Brain-derived neurotrophic factor (BDNF) may also play an important role in depression ¹³. Hyperactivity of Hypothalamic–pituitary–adrenal (HPA) axis is a common finding in psychoneuroendocrinology in diagnosing major depression ¹⁴. In the mechanisms of depression, inflammatory cytokines and endogenous metabolites ¹⁵ and the gut microbiome play a critical role in depression by influencing the gut-brain axis ¹⁶. Currently, in depression, monoamine re-uptake inhibitors are the utmost frequently recommended class of antidepressants ¹⁷ though there is a big problem with these class of drugs due to a long time between the effect of the first therapeutic effect on monoamine neurotransmitter function and the reduction in the severity of clinical symptoms. Conventionally, only half of the patients experience a significant minimization in symptoms after antidepressant drug therapy. Also, about 33% of patients show resistance to the treatment due to more than one drug therapy proven inefficient ^{18, 19}. Therefore, selecting and developing new, fast-acting, and more active antidepressant therapeutic agents is necessary. Presently, there are various antidepressants exist, but the side effects of these drugs make them less efficient.

Biomarkers of Depression: Investigators continuously search for biological or diagnostic makers for the evaluation and treatment of depressed patients. Despite all these facts, no biological marker has been discovered yet. In the case of major depression, around 45-60% of patients show the symptoms of hyposecretion of cortisol or hypersecretion of cortisol, or an irregular thyroid-stimulating hormone response is found. Whenever a patient has revealed an indication of depression, it is essential to consider the possibility of medical, psychiatric, and/or drug causes ²⁰. More than 25% of patients with chronic medical disorders like diabetes mellitus, obesity, cancer, and cardiovascular diseases develop major depression during the medical condition. Moreover, the diagnosis of depression is generally not accurate in the case of aged subjects. All depression patients should be examined for physical and psychological parameters along with complete blood analysis and other biochemical parameters like liver function tests, thyroid function tests, and electrolyte determinations to diagnose any possible medical complications ²¹.

Suicide and Risk Management: In the United States, suicide is the eighth prime reason for death, and depression was found to be the most significant causative factor at the time of death for most suicidal patients ²². Generally, people who attempt suicide are crazy, and suicide is the outcome of emotional outbursts. Aspects that raise the risk for suicide include aging due to a life partner's death, living alone, being jobless, a part of a previous psychiatric problem, any drug abuse, depression, a family history of suicide, the existence of a chronic medical problem and absence of a public support system ²³.

Although women have 2-3 times more tendency to attempt suicide, the success rate is 2-3 times more in the case of men.   Moreover, the rate of suicide is almost double in elderly people as compared to the rate in the general population ²⁴.

Occurrence of Depression Worldwide and in Indian Population: Depression is a worldwide phenomenon and contributes as a significant factor to the universal burden of disease affecting people of all communities and races worldwide. The present estimation shows that 350 million people are affected by depression. A survey conducted by World Mental Health in 17 countries revealed that 1 in 20 people reported having an episode of depression in 2011. Moreover, it is estimated in 2030 unipolar major depression can be the second prime reason for disability ²⁵.

Epidemiological studies also stated that major depression has an annual prevalence of 1- 6% globally, and over time, it is becoming more prevalent in the younger population ²⁶. In the USA, approximately 6.7% of U.S adults experience a depressive disorder.

In terms of gender, women are more susceptible compared to men to experience depression during their lifetime i.e., 70 % more women are likely to have depression than men. The incidences of depressive disorders are very common during adolescent years accompanied by comorbid substance abuse and suicidal tendencies, resulting in increased chances of death in these adolescent patients. Depressive disorders and suicide tend to have a family lineage, and the chances of depression are 1.5 to 3 times higher in first-degree relatives of patients with depression as compared to normal controls ²⁷. In India, the prevalence of serious mental disorders is about 10-20 per 1000 of the population. Depression has always been a center of attention for researchers in India. Many studies have been conducted to discover its prevalence and associated factors of depression, like psychological stress and life events responsible for stress, co-morbidities, psycho-neurobiology, treatment options available for depression, the outcome of treatment, disability, and burden linked with depression. Several studies also included pediatric and geriatric populations ²⁸.

Etiology of Depression: Depression is considered a multifactorial disorder Fig. 1 in which several factors ranging from mild to severe, combined with vulnerability, leads to a predisposition to depression.

FIG. 1: ETIOLOGY OF DEPRESSION

Genetic Factors: Genetic factors have an important role in the person's predisposition towards developing depression, specifically psychotic depression, and bipolar disorder. Any modification on the serotonin transporter gene (SLC6A4) modulates anxiety-related personality traits ²⁹ whereas it was partially replicated in subsequent studies ^{11, 23}. Moreover, further research confirmed that s-allele (s = short), which is a carrier of 5-HTTLPR-promotor polymorphism, is responsible for the improved neural activity in the amygdala to encounter negative emotional stimuli as compared to L-allele carriers.³⁰ Another gene that was found to affect emotion-related activity in the amygdala is monoamine oxidase-A (MAOA) which is responsible for the degradation of 5-HT and nor-epinephrine ³¹.

Biochemical Factors: Nerve cells communicate with each other via specific chemicals known as neurotransmitters responsible for the transfer of signals from one neuron to the next. Neurotransmitters like serotonin, GABA, glutamate, nor-epinephrine, and several others play a significant role in MDD ³². Amongst all, serotonin is most likely one of the most significant neurotransmitters in the mechanism of depression i.e. alteration in the functioning of serotonin (i.e. the density of serotonergic receptors, metabolism of serotonin as well as the reactivity of the receptors) is associated in MDD ³³. It has been observed that in depression, the activity of one or more of these neurotransmitters is reduced and affects different areas of the brain responsible for the vital function of the body like sleep, appetite, mood, and sexual activity. Decreased level of these neurotransmitters leads to reduced communication between nerve cells and explain the typical signs of depression ³⁴.

Hormones: Hormone is a significant part of the pathogenesis of depression. Variations in hormones level may also activate depression. Hormone changes can be caused by thyroid problems, menopause, or many other conditions ³⁵.

Congenital Traits: People whose biological family members also have a history of depression are more likely to develop depression. The research is being carried out to identify the genes involved in the pathogenesis of depression ³⁶.

Life Events: Life events that affect the person's emotional status like sudden death or loss or separation from the loved one, financial issues, and high stress levels are considered some of the major triggering points for precipitation depression in some people ³⁷.

Early Childhood Trauma: Stressful or unbearable events in childhood, for example, abuse or loss of a parent, can have a permanent impact on the brain making them more prone to depression ³⁸.

Pathogenesis of Depression: Neurotransmitters are believed to play an important role in the etiology of depression ³⁹. The biogenic amine hypothesis or monoamine hypothesis came into focus as a result of numerous interpretations carried out in the early 1950 ⁴⁰.

Monoaminergic Neurotransmission: Diminished signaling of monoamines has been considered to underlie the mechanism of depressive disorders. For example, in depressive patients, the levels of monoamine metabolite were found to be reduced in the cerebrospinal fluid. Moreover, serotonin, nor-epinephrine (NE), or dopamine depletion were also responsible for pro-depressive effects ⁴¹. Monoamines are mostly presynaptically localized and neurotransmitters are removed from other cells and recycled back into the adjacent terminals. Therefore, these neurotransmitters are considered as recognized aim of several psychostimulants and antidepressant drugs which produce their mechanism via modulation of monoamines levels in the neurons. These findings are consistent with the observation that clinically effective antidepressants increased levels of monoamine concentration as well as monoaminergic signaling. It has been proved that these monoamines, especially serotonin, play an important role in the developmental mechanism and pathogenesis of depression vulnerability ^{42, 43}.

Monoamine Oxidase (MAO): MAO is the class of enzymes responsible for the metabolism of monoamines such as serotonin, nor-epinephrine and dopamine. MAO is found in almost all types of tissues. Based on the molecular coding, MAO is present in two homogenous molecular types:

MAO-A: It has a very pronounced affinity for the 5HT. It is also considered the major target for depression treatment therapy.

MAO-B: Phenylethyl amine is the main preference for MAO-B.

Monoamine oxidase enzymes act on Nor-adrenaline, dopamine, and serotonin ⁴³. Classical hypotheses for the biological origin of depression have emphasized majorly the role of NE and 5-HT. Whereas, several pieces of evidence associated biogenic amine hypothesis could not provide enough indications between the distinguished role of NE and DA in the pathogenesis of depression ⁴⁴. In the brain, DA is a precursor to epinephrine and NE, and primarily a transmitter that controls behavior ⁴⁵. Many studies in humans and animals have shown that depression and DA transmission in the central nervous system are closely linked ^{46, 47}. Moreover, the patients suffering from depression have an increased level of DA transport, making presynaptic neurons more efficient at DA re-uptake ⁴⁸.

GABA (Gamma Amino Butyric Acid) Neurotransmitter: In the brain, GABA is the most important neurotransmitter for inhibitory activity. Broadly, GABA receptors are classified into two types i.e., GABA_A and GABA_B. GABA_A receptor muscimol is an agonist; however, bicuculline, picrotoxin and SR 95531 are antagonists. GABA_A receptors have also been found to play an important role in the treatment of anxiety disorders due to their coupling to Ca⁺² channels. Whereas in rats, several antidepressants and mood stabilizers were found to produce their action by upregulation of frontal cortical GABA_B receptors not through GABA_A receptors ^{49, 50}. GABA_-B receptors are those for which baclofen is the typical agonist. GABA_B agonists are responsible for enhanced cAMP responses due to the action of noradrenaline and down-regulation of β- adrenergic in response to tricyclic antidepressants indicating the important role of GABA_B in the management of depression. The level of GABA was also reported to be decreased in CSF of depressed patients ⁵¹. In unipolar depression, GABA levels have also been reported to be decreased in plasma, which may not normalize with treatment ⁵².

Serotonin Transporter: 5-HT is broadly disbursed all over the nervous systems and its deficiency can precede to depression, phobias, anxiety and other psychological health disorders in humans ⁵³. Over the last few years, the 5-HT hypothesis has stimulated research into the etiology of depression. It  has been reported that depressed patients have low 5-HT levels in the brain and may exhibit altered 5-HT receptors, such as elevated 5-HT2 and reduced 5-HT1A receptors ⁵⁴. Three potential mechanisms are responsible for the impairment of 5-HT1A activity in depression: civil solitude decreasing 5-HT1 neurotransmission, 5- HT2 receptors hindering 5-HT1 neurotransmission and hypercortisolaemia hindering 5-HT1 neurotransmission ²⁷. Neuronal proteins in an adult's brain like BDNF and neurotrophin-3, are correlated with the growth and activity of 5-HT neurons ⁵⁵.

Hypothalamic Pituitary Adrenocortical (HPA) Axis System: Stress and emotional state are the key factors that stimulate the outbreak of MDD ⁵⁶. It has long been recognized that the HPA axis plays an important role in the mammalian stress response. Thus, alteration in the HPA axis in distress may detect the occurrence of depression symptoms. Stress triggers the release of corticotropin-releasing hormone (CRH) from the hypothalamus. It then stimulates the production of adrenocorticotrophic hormone (ACTH) in the pituitary, increasing glucocorticoid release from the adrenal cortex ⁵⁷. In several target tissues, glucocorticoids bind to their receptors like the HPA axis and inhibit the release of both productions of ACTH in the pituitary corticotropes and CRH in the hypothalamus. In patients with MDD, the HPA axis are excessively active under stressful situations, resulting in complications such as hypercortisolemia, reduced rhythmicity, and elated cortisol range ^{58, 59}. The stress associated with depression causes disturbances of the HPA axis and, as a result, there is increased production of cortisol and inadequate blockage of glucocorticoid receptor regulatory response ^{60, 61}. Also, high cortisol concentrations are associated with depression severity, especially when the condition of melancholic depression ^{62, 63}.

Furthermore, patients with depression could not regularize their HPA axis after the treatment; subsequently, they had a poor clinical outcome ^{64, 65}. Anyhow, prior studies have exhibited that HPA axis-regulating treatments such as glucocorticoid receptor antagonists fail to relieve the indications of depression ^{66, 67}. 2 Several factors may be responsible for the induction of stress for example, sudden or drastic changes in body temperature, abrupt decrease or increases in blood pressure, decreased food intake for a long duration, chronic illness or infection, and pain. HPA stress axis is generally considered a slower backup resistance for the stress. Moreover, the HPA stress axis also plays a vital role in the cognitive evaluation of traumatic conditions along with the modulation of behavior and endocrinal status to adapt to the stress. Moreover, the HPA axis of stress also provides the substrates for energy, supporting the sympathetic responses ⁶⁸.

In the case of experimental animal, various factors like nature of stress, duration, and mode of stress predict the pattern of HPA mal/adaptation. mRNA expression of corticotropic hormone is found to be elevated only in that stress associated with conserved HPA responses ⁶⁹. However, in maximum depressive patients shows dysfunction of HPA axis regulation whereas normalization of dysfunctional HPA axis was found to be preceded in successful antidepressant treatment of depression ^{70, 71, 72}.

Hypothalamic Pituitary Thyroid (HPT) Axis System: Numerous studies have indicated the overlapping of symptoms is linked with patients with hypothyroidism and depression. TRH receptors in the pituitary gland are stimulated by Thyrotropin-releasing hormone (TRH) is released by the hypothalamus leading to the flow of stimulating thyroid hormone (TSH) and further TSH stimulates specific receptors triiodothyronine (T3) and thyroxin (T4). These thyroid hormones are responsible for providing feedback to the hypothalamus as well as the pituitary, which further regulate the HPT axis. TRH was found to be increased in cerebral spinal fluid in depressive patients in two small studies when compared with control patients ⁷³. Moreover, one study also demonstrated exaggerated TSH responses in high normal thyroid levels in depressed patients ⁷⁴.

BDNF (Brain-Derived Neurotrophic Factor): In the postmortem samples obtained from patients with a mental disorder, it has been found that the level of brain BDNF was reduced, and during the treatment of depression, BDNF level reached the normal range ^{75, 76}. BDNF is present in blood, and it gets accumulates in platelets. The BDNF gene has a complicated genetic organization with seven upstream exons and one coding exon that is responsible for the multiple splice variants controlled by different promoters. In the human BDNF gene, various polymorphisms are available i.e., val66met polymorphism in which valine changes to methionine in the BDNF peptide ⁷⁷. These studies have concluded that loss of function due to mutations in BDNF may be responsible for depression through dysregulation of an individual’s HPA system. Mutations in BDNF are responsible for reduced hippocampal volume, fear of learning, anxiety and a lack of response to chronic depression treatment ⁷⁸.

Human Growth Hormone: The release and storage of growth hormone (GH) occur in the anterior pituitary gland. Growth hormone release is under the regulation of two hormones Growth hormone releasing factors (GHRF) and somatostatin (growth hormone inhibiting factor) which is secreted by the hypothalamus and these two hormones modulate the release of human growth hormone from the pituitary. The neurotransmitters i.e., noradrenaline, serotonin, and dopamine have a major role in mood regulation and affect GH release. In depression, the level of somatostatin is decreased in CSF ⁷⁹.

Inflammatory Cytokines: In depressed patients, the level of pro-inflammatory cytokines like chemokines and cellular adhesion molecules was found to be elevated. Moreover, administration of the cytokine, interferon–α resulted in the development of depression in approximately 50% of patients. Moreover, pro-inflammatory cytokines were found to have interaction and positive correlation with several pathophysiological factors which describe depression, like neuroendocrine function, synaptic plasticity, and behavior. Based on the role and involvement of these proinflammatory cytokines and their signaling pathway, a new approach can be designed by targeting these proinflammatory markers in the treatment of depression ⁸⁰.

Oxidative Stress: Stress and oxidative stress are linked positively. Due to stress, the oxidative damage of cells is increased, leading to the generation of malonialdehyde (MDA). In stressed mice, the level of MDA was found to be in more concentration as compared to normal mice ⁸¹.

Treatment for Depression: It has been more than 40 years since tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs) were launched. These drugs have been found to be very harmful in managing depression. The side effects of these drugs lead to the development of selective serotonin re-uptake inhibitors (SSRIs) and selective noradrenaline re-uptake inhibitors (SNRIs). It is reliable in use ⁸².

Tricyclic Antidepressants: In the late 1950s, for the treatment of depression and associated disorders, imipramine was found to be effective. As a result of this discovery, several chemical analogs of imipramine were synthesized and evaluated for antidepressant activity. Collectively these compounds were called TCAs. However presently for the treatment of depression, TCAs are not considered first-line drugs. These drugs were found to be associated with significant side effects as well as life-threatening adverse effects. Moreover, in the case of TCAs uses in depression, there is a requirement for continuous monitoring of the blood level of the drug to avoid toxicity ⁸³.

TCAs are categorized into different categories like tertiary or secondary amines. Desipramine, nortriptyline, and protriptyline are secondary amines whereas imipramine, amitriptyline, trimipramine, and doxepin are tertiary amines. Clomipramine is also considered a member of this tricyclic family due to its comparable pharmacological action and efficacy in the treatment of depressants. Maprotiline and amoxapine are heterocyclic antidepressant agents, they are not members of this tricyclic family but because of their similar pharmacological action to the tricyclic amines, these drugs are included along with TCAs class of antidepressant. In the second generation of antidepressants, duloxetine was found to have a significant risk for the development of hepatotoxicity. In the category of TCAs, clomipramine and amitriptyline were also found to have higher incidences of hepatotoxicity than SSRIs. Pharmacovigilance studies conducted in Europe also revealed comparable results indicating the highest risk of hepatotoxicity with agomelatine ⁸⁴.

Selective Serotonin Reuptake Inhibitors: For the treatment of major depression in 1987, fluoxetine was approved by the FDA. Fluoxetine is a selective serotonin re-uptake inhibitor (SSRIs). The other drugs in this class include citalopram sertraline, fluvoxamine, and paroxetine. SSRIs were found to be safer, and the tolerability of antidepressants increased significantly with the beginning of the SSRIs. These agents were found to be safer and devoid of cardiac side effects.

Moreover, these agents did not have any affinity toward cholinergic, β-adrenergic, or histamine receptors. These agents were found to be safe and tolerable in elderly patients and in cardiac patients ⁸⁵. The SSRIs are highly selective for the uptake of serotonin at the nerve terminals of synapse. This activity provides ample support to the hypothesis of the re-uptake of monoamines at the nerve terminals and reveals the mechanism of action of these drugs. These agents produce their therapeutic action by modulating serotonin neurotransmission in the brain ⁸⁶.

The increased 5- HT levels further activate 5-HT1A autoreceptors and decrease neuronal firing. Whereas, desensitization of 5-HT1A autoreceptors increases serotonin release, terminal 5-HT1B autoreceptors also become desensitized. These receptors are responsible for the inhibition of the release of serotonin. All these events result from inhibiting serotonin re-uptake in the nerve terminal, which ultimately potentiates serotonin neurotransmission at central synaptic sites. The time-lapse in the development of these synaptic events is responsible for the delayed response of therapeutic activity of antidepressant drugs while treating depression ⁸⁷. Patients who have adverse reactions to one of the SSRI drugs may be identified, and it will be helpful to replace another drug from that class. SSRIs are more reliable than MAOIs and TCAs, have hardly any side effects, and reduce the affinity for acetylcholine and amine receptors, making overdose deaths less likely ⁸⁸. Nevertheless, various side effects, such as nausea, insomnia, and sexual dysfunction, are caused by SSRIs ⁸⁹.

Monoamine Oxidase Inhibitors: Monoamine oxidase (MAO) is a mitochondrial enzyme and is widely distributed throughout the body but with high concentrations found in gastrointestinal, hepatic, and neuronal tissues. The enzyme plays an important role in the metabolism and oxidative deamination of several endogenous and exogenous monoamines and neurotransmitters. Moreover, monoamine oxidase is also responsible for detoxifying endogenous and exogenous amines. Two molecular forms of monoamine oxidase exist in the human body commonly called type A and type B and the substrates and inhibitors are also selective for this isozyme.

Neurotransmitter amines, like nor-epinephrine and 5HT, are specifically substrate to be metabolized by MAO-A in the brain, whereas dopamine is the preferential substrate to be catabolized by MAO-B. Iproniazid, which has anti-tubercular activity, was also found to exhibit mood-elevating properties in clinical trials in patients of tuberculosis with depression. Due to toxicity associated with monoamine oxidase inhibitors in treating depression, the use of drugs is limited. Hepatotoxicity is found to be associated with the administration of isocarboxazid or phenelzine. These hydrazine compounds have significant potential to damage the hepatic parenchymal cells, especially in patients who are slow acetylators of hydrazine compounds ⁹⁰. Today MAOIs are rarely prescribed or are the last antidepressants used because of drug-induced hypertensive crisis and potentially fatal food and drug interactions ⁸⁸.

Reversible Inhibitors of MAO-A: The selective, reversible inhibitors of MAO-A (RIMAs) were synthesized in the 1980s in worldwide labs (RIMAs) ⁹¹. This theory was tested in numerous clinical trials by using tyramine challenges in patients ^{92, 93}. Currently, moclobemide is the only RIMA that is available for clinical use. Another RIMA is methylene blue ^{94, 95} which has several pharmacological actions like nitric oxidase synthase (NOS) and guanylate cyclase inhibition ⁹⁶.

5-HT and NE Reuptake Inhibitors: Even though TCAs are very efficient in the treatment of major types of depression, their practice in the management of depression has decreased because of the accessibility of similarly active therapeutic options and greater safety, efficacy and tolerability. TCAs produce their mechanism of action by potentiating the action of nor-epinephrine and serotonin by hindering the re-uptake at the neural site. However, the potency and selectivity of Venlafaxine, a structurally novel antidepressant, is an effective inhibitor of 5-HT and NE re-uptake and a weak inhibitor of dopamine re-uptake. Venlafaxine has almost no affinity for muscarinic, histaminergic and α1-adrenergic receptors ⁹⁷. Both maprotiline and amoxapine are inhibitors of NE re-uptake, with fewer effects on 5-HT re-uptake. As compared to imipramine or amitriptyline the risk of seizures is higher in maprotiline ⁹⁸.

NE and 5-HT Selective Antidepressants: The newly discovered antidepressant agent mirtazapine produces its mechanism by affecting 5HT and NE level CNS. Moreover, it is also devoid of cholinergic and cardiovascular effects. Mirtazapine has an exceptional mechanism of action and enhances noradrenergic and 5-HT_1A–mediated serotonergic neurotransmission which is responsible for the antidepressant activity of mirtazapine ⁸³. Moreover, mirtazapine does not, inhibits NE re-uptake and α₂-heteroreceptors in serotonergic nerve terminals leading to an increase in the concentration of neurotransmitters ⁹⁹. The use of mirtazapine for acute and chronic duration leads to weight gain ¹⁰⁰. SARIs have correlative potency and a minimal rate of induced sexual dysfunction correlated to other classes of antidepressants for the management of MD ⁸.

CONCLUSION: Disorders of the central nervous system are highly prevalent, accounting for approximately 15% of the global burden of diseases. Among these, 8–12% are affected by depression at least once in their life. Moreover, the prevalence distribution is drastically changed if epidemiological factors like age and sex are focussed. While disorders of the central nervous system pose a greater burden on the quality of life than any other single disease, psychotherapy still is not lacking a place in terms of research and funding. Various factors like lack of consensus surrounding classification, diagnosis, and treatment are some of the major factors responsible for the incomplete understanding of the mechanism and course of mental health disorders. Specifically, in mood disorders, the incomplete understanding of the nature and cause of disease makes mood disorders a tough challenge for the pharmacotherapy of mood disorders.

These mood disorders are the category that comprises the single largest burden in mental health. Major depressive disorder (MDD), is the most prevalent mood disorder of complex and heterogeneous illness, where 60% of patients experience resistance to treatment that prolongs and worsens episodes. Major depression is an ordinary which sometimes can be fatal also, 25% of psychiatric disorders in the general population worldwide are responsible for disability worldwide.

It is a highly prevalent and disabling condition associated with significant morbidity and mortality. A lot of evidence suggests a positive correlation between chronic stress and the development of depression. Despite advancements in Pharmacotherapy, psychiatry still depends majorly on 19th-Century diagnostic categories, and this criterion is based on the assemblage of symptoms rather than biological markers. Moreover, the treatment of these disorders was carried out with drugs discovered serendipitously several decades ago. Although depression has generally been explained with monoamine theory, it is far more multifactorial, and therapies that address the disease’s pathway have not been developed.

Several studies have shown that oxidative stress may play an essential role in the pathophysiology of neuropsychiatric disorders. The mechanism of the development of depression and the involvement of stress has been widely investigated in animals for decades. For example, animal models established with maternal deprivation and chronic unpredictable stress exposure are commonly used models which depict the early life stress experience and adulthood of humans, respectively.

ACKNOWLEDGEMENTS: Nil

Funding: No funding has been received from any funding agency.

CONFLICTS OF INTEREST: There is no conflict of interest.

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     How to cite this article:

     Pannu A and Ahlawat A: Depression: understanding the pathophysiology and treatment modalities. Int J Pharm Sci & Res 2023; 14(4): 1611-21. doi: 10.13040/IJPSR.0975-8232.14(4).1611-21.

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