INTRODUCTION:

Nowaday, more than 322 million peoples are Mentally disturbed due to mental disorder called as Depression. It is " Mood disorder ". As compare to men's depression is more common in women¹. According to the World Health Organization, depression is projected to become the second most common illness in terms of morbidity worldwide within the next ten years².

Depression is described in diagnostic literature as a mood disorder marked by a decrease in mood, lack of interest or enjoyment in activities, notable fluctuations in weight, difficulty sleeping or excessive sleeping, restlessness or slowed movements, exhaustion or lack of energy, feelings of insignificance or overwhelming guilt, trouble focusing, and thoughts of suicide and/or attempts^3,4. depression causes due to genetic and environmental conditions⁵. Interference of electrical pollutant⁶. Noise pollutants⁷. synthetically found chemicals⁸. difficulties in childhood^9,10.that are some environment causes are responsible for depressiveness.

Types of depression

Depression is classified into main two categories according to their severity first one is, Major depressive disorder which is sever than other type. Another one is Dysthymic disorder which show chronic symptoms¹¹. In 21th century, depression is classified into four parts. Like Dysthymia¹²Major depression¹³Bipolar depression¹⁴ and many other types of depression¹⁵. After that many researchers do study on advance classification of depression. According to one researcher called as " Franco Bentzi, MD, PhD) depression is classified into various descriptive several forms. It includes, Major depressive disorder¹⁶ Mixed depression^17,18. Atypical depression¹⁹. Melancholic depression²⁰. and minor depression²¹. In this review we are focusing on melancholic depression.

Melancholic Depression:

In ancient Greece, according to Hippocrates with the reference of his book name “Aphorism’s melancholy” is, long lasting sadness and dead condition²². Blood, phlegm, yellow bile and black bile are the four parts of mood was Hippocrates said in his ancient era²³. The root cause of melancholic depression is imbalancement of fourth part, black bile (it shows melancholic characteristics). Melancholic depression is differentiated form of major depressive disorder described in DSM- IV and ICD (International classification of Disease²⁴.

Historical Background of Melancholic Depression:

In An Ancient era -Hippocrates (460–379 BC) linked the melancholic state, along with other ailments such as dysentery and skin rashes, to an excess of black bile, one of the four primary humors identified by the author (blood, black bile, yellow bile, and phlegm). The author noted that these conditions were characterized clinically by a range of symptoms, most notably fear and sadness²⁵. Galen, who lived from 129 to 216 AD, adopted Hippocrates' theory of temperaments and identified four different types of temperament caused by imbalances in bodily fluids. These temperaments were melancholic, associated with an excess of black bile (known as atrabilia in Latin); optimistic, linked to an excess of blood; choleric, resulting from an excess of yellow bile; and phlegmatic, related to an excess of phlegm²⁶. Andreas Laurentius (1560–1609) penned a notable reevaluation of the interpretations associated with the concept of melancholia from the era of Galen through the sixteenth century²⁷. bright (1551–1615) wrote in his Treatise of Melancholy, believed to have influenced Burton's later work, that melancholic patients are typically sad and fearful due to feelings of distrust, doubt, diffidence, or despair²⁸. Burton (1577–1640) attempted to compile all the definitions of melancholia up to his time, likening the task to capturing a many-headed beast. Despite the challenge, Burton aimed to create a cohesive description from various authors. He noted that individuals with melancholia exhibit numerous symptoms, which he described as potentially infinite, with fear and sorrow being the most common ("Fear and sorrow are the true characters and inseparable companions of most melancholy"). In addition to fear and sorrow, symptoms may include ideas of persecution poisoning and jealousy burton observed that these patients could be intense in their thoughts and not very friendly in speech. However, he emphasized that these ideas were not universal but rather confined within specific limits, as "they are of profound judgement in some things, although in others, non recte judicant inquieti"²⁹. William Cullen (1710–1790) introduced the term "partial insanity" to describe monothematic delusions in melancholia, contrasting it with "universal insanity," which he associated with mania. Nevertheless, Cullen acknowledged the challenge of distinguishing between the two conditions, stating that "the boundaries between universal and partial insanity cannot always be drawn with accuracy"³⁰. Esquirol's work on "monomania" was a crucial development during the transition from the eighteenth to the nineteenth century³¹. During the late 1800s, the classification system developed by Kraepelin distinguished between affective disorders (such as Manic-Depressive Illness and melancholia) and Dementia Praecox. Kraepelin placed greater emphasis on affective symptoms in the former, while focusing on thought and cognitive changes in the latter. As a result, the concept of melancholia as a disorder primarily characterized by abnormal beliefs limited to certain objects was gradually disregarded in favor of a disease primarily marked by affective symptoms, particularly depressive ones. At the start of the twentieth century, the term melancholia was slowly replaced by the term depression, which carried a physiological implication, appearing in medical literature as "mental depression"³².

Signs and Symptoms:

Melancholic depression do not cause only mood alteration or sadness but it also show some physical symptoms.

A) Physical Symptoms (Psychomotor Sign):

· Alterations in speech patterns, such as variations in volume, pauses during conversation, or modifications in tone.

· Lack of eye contact or maintaining a fixed gaze while engaging in verbal communication.

· Reduced speed of movement in the head, limbs, or torso

· Psychomotor disruption.

· Adopting a slouched posture during interactions.

· Frequent touching of the face or body³³.

B) Other Than Physical Symptoms:

· The enjoyment you once derived from activities in your life has ceased.

· You are unable to react positively to pleasurable experiences.

· You are experiencing sleep issues, such as difficulty falling and staying asleep or waking up prematurely.

· There is a noticeable decrease in your appetite or weight.

· You are facing challenges with concentration or memory.

· You feel empty or unresponsive emotionally.

· You are burdened by excessive guilt.

· Feelings of hopelessness have taken hold of you.

· lack of pleasure, premature awakening, and daily fluctuations.

· You are plagued by thoughts of suicide^33,34.

Today the sever melancholic show some following signs of depression:

Deep sorrow, lack of pleasure, diminished emotional intensity, physical symptoms (sleeplessness, loss of appetite, mood fluctuations throughout the day), a pattern related to seasons, slowed movement, and the existence of delusions and/or hallucinations³⁵. Patients diagnosed with melancholic depression commonly face symptoms such as difficulty sleeping and waking up prematurely in the morning³⁶.

Factors Affecting on Melancholia Depression:

There are various socio-demographic and clinical factors that can help differentiate between melancholic and non-melancholic depression. Socio-demographic factors include age, gender, employment status, marital status, education, and ethnicity. On the other hand, clinical factors encompass the duration of illness, number of depressive episodes, age of onset, length of episodes, and any medical or psychiatric co-morbidities Depression^37,38_.

Age:

Symptoms of melancholic depression typically occur in the later stages of life.

Genetics:

This form of depression often has a hereditary component, with a history of mood disorders or suicide in your family tree.

Seasonal factors:

Melancholic depression symptoms may intensify during periods of reduced sunlight, shorter days, or colder weather.

Postpartum changes:

Individuals who experience postpartum depression, which occurs shortly after childbirth, may also exhibit symptoms of melancholic depression³⁹.

Etiology and Pathogenesis:

etiology of any disease known as scientific study of cause of disease. In ancient era the main route cause of melancholia is ambulancemen of black bile humour. Melancholic depression can be attributed to the activation of the hypothalamic-pituitary-adrenal (HPA) axis, as well as various inflammatory and metabolic mediators. Individuals experiencing melancholic depression often exhibit elevated levels of cortisol^40,41. The etiology and pathogenesis of melancholic depressive disorders are predominantly attributed to biological factors, which may have a hereditary component. Biological underpinnings of the disorder encompass dysfunctions in the HPA axis and sleep architecture of individuals^42,43. Neuroimaging studies using MRI have revealed abnormalities in the connectivity between various brain regions, particularly the insula and frontal-parietal cortex, in patients with melancholic depression^44,45. Variances in biological markers have been observed between individuals with melancholic depression and other forms of depression^46,47. While stressful circumstances can sometimes precipitate episodes of melancholic depression, they are considered contributory rather than causative factors. Additionally, individuals exhibiting psychotic symptoms are believed to be more vulnerable to developing this disorder^48,49. Physicians frequently overlook symptoms of melancholic depression in elderly patients, mistaking them for manifestations of dementia. It is important to recognize that major depressive disorder, whether melancholic or not, is a distinct condition that can coexist with or manifest concurrently with dementia in the elderly^50,51.

Pathophysiology:

Pathophysiology of melancholic depression meaning physical and functional changes or mechanism that occur during melancholia. Excessive functioning of the HPA axis, marked by high levels of cortisol, adrenal gland enlargement, and disruptions in negative feedback, is the most frequently reported biological irregularity in melancholic depression^52,53.

Fig. Pathophysiology of melancholic disorder:

Treatment:

Medication of melancholic depression is based on herbal remedies as well as synthetic basement. As compare to herbal synthetic medication show maximum effect. Certain research indicates that melancholic depression demonstrates a lesser improvement with hospitalization, placebo, and psychotherapy^54,55. while showing a more favorable response to electroconvulsive therapy (ECT) and tricyclic antidepressants (TCA) compared to non-melancholic depression.^56,57. Over the course of the 20th and 21st centuries, numerous diagnostic frameworks for melancholic depression have emerged, distinct from the melancholic specifiers outlined in DSM-III, DSM-IIIR. DSM IV^58,59. American Psychiatric Association, Washington, DC), and DSM-5⁶⁰in order to delineate a specific diagnostic category for melancholic depression distinct from other forms of depression⁶¹. The potential significance of melancholia in forecasting the effectiveness of antidepressant treatment has also been proposed. Initial research indicated that individuals with melancholic characteristics exhibited a more favorable response to tricyclic antidepressants (TCAs) compared to a placebo, while displaying a less favorable response to a placebo in comparison to patients without melancholic features in outpatient studies⁶². Certain research has indicated that individuals exhibiting melancholic symptoms, especially in their later years, may exhibit a poorer response to SSRIs compared to TCAs⁶³. Combination of more than two medicines is most suitable and effective in melancholic depression⁶⁴.

Antidepressants Class:

Physicians frequently recommend tricyclic antidepressants (TCAs) for melancholic depression, although they may also opt for alternative antidepressants and medications. The TCAs consist of the following medications. (Table-1).

Electroconvulsive Therapy:

If tricyclic antidepressants doesn't work then we use this therapy. This is the method in which ECT Send electrical signals to patients’ brain and alternate the chemical balance^,65. ECT is typically used when other treatments, including medication and psychotherapy, haven’t worked.ECT is also used for people who require a rapid treatment response because of the severity of their condition, such as being at risk for suicide. ECT’s effectiveness in treating severe mental illnesses is recognized by the American Psychiatric Association, the American Medical Association, the National Institute of Mental Health, and similar organizations in Canada, Great Britain and many other countries. ECT is very effective for the treatment of episodes of serious mental illness, but it does not prevent a return of the illness in the future. Consequently, most people treated with ECT need to continue with some type of maintenance treatment. This typically means medication and or psychotherapy or, in some circumstances, ongoing ECT treatments.

Table No.1: Tricyclic antidepressant’s

Drug	Mechanism of action	Side effect
Amitriptyline	amitriptyline inhibits the membrane pump mechanism responsible for the re-uptake of transmitter amines, such as norepinephrine and serotonin, thereby increasing their concentration at the synaptic clefts of the brain Label,	Constipation, feeling dizzy, Feeling sleepy or tired, Difficulty peeing, Headache, dry mouth.
Amoxapine	It exhibits antagonistic activity on dopamine (D2) receptors.	Nausea, drowsiness, weakness or tiredness, nightmares, dry mouth, skin more sensitive to sunlight than usual, changes in appetite or weight, constipation,
Desipramine	It works by increasing the amounts of certain natural substances in the brain that are needed for mental balance.	Nausea, drowsiness, weakness or tiredness, nightmares, dry mouth, skin more sensitive to sunlight than usual.
Doxepin	increasing the concentration of the neurotransmitter's serotonin (5-HT) and norepinephrine (NE) in the brain.	Dizziness, Xerostomia, Heartburn, Allergic reaction.
Imipramine	Imipramine works by inhibit in the neuronal reuptake of the neurotransmitter’s norepinephrine and serotonin.	Weakness or tiredness, excitement or anxiety, nightmares, dry mouth, skin more sensitive to sunlight than usual.
Nortriptyline	nortriptyline inhibits the reuptake of serotonin and norepinephrine by the presynaptic neuronal membrane.	Feeling dizzy, dry mouth, feeling sleepy, difficulty peeing, headaches.
Protriptyline	Protriptyline acts by decreasing the reuptake of norepinephrine and serotonin (5-HT).	Abdominal or stomach pain, agitation or irritability, burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings, change in urination, chest pain or discomfort, clay-colored stools. cold sweats.
Trimipramine-	Trimipramine acts by decreasing the reuptake of norepinephrine and serotonin (5-HT).	Agitation, black, tarry stools, bleeding or bruising, blood in the urine or stools. burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings.

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Received on 03.05.2024 Revised on 07.11.2024

Accepted on 10.03.2025 Published on 14.05.2025

Available online from May 16, 2025

Res.J. Pharmacology and Pharmacodynamics.2025;17(2):89-94.

DOI: 10.52711/2321-5836.2025.00014

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