Major Depressive Disorder


The exact cause of major depressive disorders is not well understood (1). However, it is likely multifactorial (1). It is suggested the genetic predisposition, psychological stressors and biologic pathophysiology contribute to MDD, but there is no accepted unifying theory that explains these factors adequately (1). The symptoms that are noted by the patients with MDD they consistently reflect changes in the brain monoamine neurotransmitters, which include norepinephrine, serotonin, and dopamine (1).


This is a quite common condition in which the lifetime and 12 month prevalence estimates are 16.2% and 6.6% respectively (1). Women are at an increased risk of depression from the period of early adolescence until their mid-50s, with a lifetime rate is about 1.7 to 2.7 times greater than for men (1,3). MDD can begin at any age, but the adults 18 to 29 years of age experience the highest rates of major depression during the given year (1). MDD patients may also suffer from comorbid psychiatric disorders, such as anxiety disorders and substance use disorders (1). Approximately 8 to 18% of patients that have major depression will have at least one first degree relative with a history of depression, compared with 5.6% of first degree relatives without depression (1). First degree relatives of patients that have depression are 1.5 to 3 times more likely to have depression compared to normal controls (1,2,3). Additional risk factors include mental illness such as anxiety disorders, social anxiety, panic disorder, substance abuse, and dependence (1,2,3). Life events such as personal loss, trauma, and stress play a role as well (1,2). Physical illnesses such as diabetes, cancer, migraine and stroke are also contributing factors (1). Medications that are associated with depression include drugs of abuse (such as alcohol, narcotics, phenytoin,), cancer chemotherapy (tamoxifen), steroids and hormones (glucocorticoid), cardiac drugs (beta blockers, clonidine, and methyldopa) (1). High users of the medical system, psychosocial adversity and psychiatric conditions are also risk factors for depression as well (1,3).

Biogenic Amine Hypothesis

In the early 1950s, the cause of depression was linked to decreased brain levels of neurotransmitters such as NE, 5-HT, and DA (1,2). This was because the antihypertensive drug reserpine depleted neuronal storage granules of NE, 5-HT, and DA, and provided clinically significant depression in about 15% and more of the patients (1,2). Though, the blockage of the monoamines through the reuptake process occurs immediately upon administration of an antidepressant, the clinical effects are generally not observed until after 4 weeks of dosing (1,2). This may be due to a result of cascade events from receptor occupancy to gene transcription (1,2). The discrepancy between monoamine reuptake blockade (immediate) and improvement in the depressive symptoms (delayed therapeutic response) led scientists to focus on the adaptive changes of antidepressants (1,2).

In the mid 1970s, it is acknowledged that the chronic, but not acute administration of AD to animals lead to the desensitization of the NE-stimulated cyclic adenosine monophosphate synthesis (1,2). The downregulation of b adrenergic receptors also will accommodate this desensitization majority of the time (1,2). Studies have demonstrated that the desensitization or the downregulation of NE receptors corresponds to a clinically relevant time course for the antidepressant effects (1,2). Further studies have demonstrated that the desensitization of the presynpatic 5-HT1A autoreceptors following chronic administration of antidepressants (1,2). Basically, the change in the receptor sensitivity may be an explanation of the delayed onset of the response of the antidepressant drugs in the therapeutic outcomes (1,2).

Dysregulation Hypothesis

Dysregulation hypothesis emphasizes that effective antidepressant treatments will efficiently restore regulation to dysregulated neurotransmitter systems (1,2). This suggests that depression is related to the abnormal functioning of neurotransmitter receptors (1,2).

Serotonin/Noradrenalin Hypothesis

There is no single neurotransmitter theory that is adequate enough to describe depression (1,2). This link hypothesis says that both the 5-HT and NE systems are involved in an antidepressant response (1,2). This is based on the postsynaptic alteration theory of depression that emphasizes the importance of B-adrenergic receptor downregulation for achieving an antidepressant effect (1,2).

Role of Dopamine in Depression

There is a large body of evidence that suggest DA transmission is decreased in depression (1,2). Agents that increase dopaminergic transmission are effective antidepressants (1,2). Some studies have suggested that the increase DA transmission in the mesolimbic pathway is partly accountable for the MOA of antidepressant medications (1,2).

Biologic Markers

45-60% of patients with MDD have a neuroendocrine abnormality, including the hypersecretion of cortisol, lack of cortisol suppression after dexamethasone administration (a positive dexamethasone suppression test; measures hypothalamic pituitary adrenal axis overactivity; dexamethasone administration suppresses adrenal corticosteroid production in normal subjects for 24 hours) or an abnormal or diminished thyroid stimulating hormone response to the administration of thyrotropin releasing hormone (1,2). Sleep studies have found that patients with MDD have abnormalities that increase with age, such as the occurence of REM being earlier in sleep (1,2). There is also a decrease in the number of minutes that are in the slow wave sleep stages (3 and 4) and also increased number of awakenings during sleep and early morning awakening (1,2).

Criteria for Diagnosis

Patients who are depressed should have a complete physical examination, mental status examination, and a complete blood count differential, thyroid function tests, electrolyte determinations, and a complete medication review to rule out any causes due to medical conditions of drugs (1,4). The basis for diagnosis of a Major Depressive Episode requires presentation of at least 5 depressive symptoms for a minimum period of 2 weeks (1,4). This includes: depressed mood, markedly diminished interest or pleasure in usual activities, increased or decrease in appetite or weight, increase or decrease in amount of sleep, increase or decrease in psychomotor activity, fatigue or loss of energy, feelings of worthlessness or guilt, diminished ability to think, concentration or make decisions, recurrent thoughts of death, suicidal ideation, or suicide attempt (1,4). These symptoms must have been present daily for at least 2 weeks and must be a change of the previous level of functioning for the patient (1,4).

Major depressive disorder (MDD) — A major depressive syndrome or episode manifests with five or more of the following symptoms, present most of the day nearly every day for a minimum of two consecutive weeks. (2) At least one symptom is either depressed mood or loss of interest or pleasure. (2) • Depressed mood (2) • Loss of interest or pleasure in most or all activities (2) • Insomnia or hypersomnia (sleep disturbances generally present as frequent early morning awakening with difficulty returning to sleep (1)) • Change in appetite or weight (some patients lose 0.9 kg (2 lb) or more per week without dieting (1)) • Psychomotor retardation or agitation (2) • Low energy (2) • Poor concentration (2) • Thoughts of worthlessness or guilt (2) • Recurrent thoughts about death or suicide (2)

Conceptually these symptoms may be grouped as disturbances in: • Emotions (depressed mood, loss of interests, auditory hallucinations saying the patient is a bad person) (2) • Ideation (worthlessness or guilt, death or suicide) (2) • Neurovegetative or somatic symptoms (sleep, appetite or weight, energy, psychomotor, concentration) (2) • Some patients exhibit gastrointestinal complaints, others cardiovascular complaints, especially palpitations. (1) (2)

Dysthymic disorder — Dysthymic disorder is marked by depressed mood for at least two years. (1) Depression is present for most of the day, for more days than not. The depressed mood is accompanied by two or more of the following symptoms: (1) • Decreased or increased appetite (1) • Insomnia or hypersomnia (1) • Low energy (1) • Poor self esteem (1) • Poor concentration (1) • Hopelessness (1)

Thus, symptoms are not as numerous as in major depression. (1) Symptom free periods during the course of dysthymia can occur, but may not exceed two months during the two year (or longer) timeframe. (1) A major depressive episode may not occur during the first two years of dysthymic disorder. (1)

HAM-D: Designed to measure the severity of depressive symptoms in patients with primary depressive illness, but has since been used to assess depressive symptoms in other groups. (3) Hamilton published recommendations for rating each item in 1967; the most commonly used version is the 17-item. (3) Is also useful for monitoring changes in depressive symptoms during treatment and in comparing the efficacy of various interventions. It is not used as a diagnostic tool. (3) Validity can be a problem in patient populations having concurrent somatic illnesses. (3) There is some consensus for interpretation of the total scores: very severe, >23; severe, 19–22; moderate, 14–18; mild, 8–13; and no depression, 0-7. (3) KC has a total score > 23 (~28), so KC is classified as having very severe depression

Clinical Presentation

Major depressive episodes are due to persistent, diminished ability to experience pleasure (1,4). There is a loss of interest and pleasure in the usual activities, which may include hobbies and work (1,4). Patients will appear sad and are often pessimistic and believe that nothing will help them feel better (1,4). If the patient has feelings of worthlessness or inappropriate guilt, this can be used to identify patients who are at risk of suicide (1,4). Anxiety is present in almost 90% of depressed patients (1,4). Guilt feelings are often unrealistic and can also become delusional (1,4). It is common for a patient to believe that they deserve punishment and their illness is punishment (1,4). MDD with psychotic disorders can hear voices that may refer to the patient as a bad person and encourage suicide (1,4). Irritability and feelings of emptiness are also present (1,4). Physical symptoms include chronic fatigue, which decreases the ability of the patient to perform routine tasks (1,4). This is usually worse during the morning and will not improve with rest (1,4). Pain and headache are common as well (1,4). There are also sleep disturbances, in which the patient has frequent early morning awakening and difficulty returning to sleep (2). They could also have difficulty falling asleep and frequent nighttimes awakening (2). Appetite irregularities that may include decreased appetite and hence weight loss can occur (2). 2 lbs per week without dieting can be lost (2). The opposite can occur, patients that are in the ambulatory setting may overeat, and gain weight even if they do not enjoy eating (2). There are also reports of loss of sexual interest and decreased libido (1,4). Cognitive functions include a decreased ability to concentrated, slower speed of thinking and a poor memory for short term recent events (1,4). The patients may be confused and indecisive (1,4). Psychomotor disturbances can include noticeably slowed or retarded physical movements, thought process and speech (1,4). There could also be psychomotor agitation, which manifests as purposeless, restless motion (pacing, wringing of hands, or outbursts of shouting) (1,4).

Suicidal Management

All patients that have a diagnosis for MDD should be assessed for suicidal thoughts (1,3). Factors that increase the risk of suicide include suicidal plans/attempts, male gender, single or living alone, inpatient status, having feelings of hopelessness, alcohol/substance abuse, having a general medication condition, more work hours missed during the past week and difficulties with relationships (1).


The symptoms of a MD episode can occur over days to weeks (4). The mild depressive and anxiety symptoms may last for weeks of months prior to the onset of the full syndrome (4). If untreated, the major depressive episodes will typically last 6 months or more (4). There is a small percentage of patients that may experience chronic episodes that can last for 2 years (4). 2/3 will have recovery fully from major depressive episodes and return to usual mood and full functioning (4). The other 1/3 will experience partial remission and may continue to experience detrimental effects (4).

The course varies from patient to patient and some patients may experience only one major depressive episode, but most patients that have MDD will experience multiple episodes (4). Some patients experience isolated episodes that are separated by many years, others will have clusters of episodes and some patients may have more frequent episodes when they age (4). The pattern varies among patients (4). The pattern is useful in determining the likelihood of developing subsequent episodes, such that by the time the patient reaches a third major depressive episode, there is a 90% chance of a fourth one (4). MDD has a high mortality rate because 15% of the patients will ultimately commit suicide (4).

Types of Depression

Melancholic Depression: Features melancholic signs such as non-reactive mood, anhedonia, weight loss, psychomotor retardation or agitation, guilt, morning worsening of mood, early morning awakening and excessive or inappropriate guilt (1,4). Dysthymic disorder: This is a depressed mood for at least two years in duration (1,4). The depression is present for most of the day, for more days than not and is accompanied by two or more of the following symptoms: decreased or increased appetite, insomnia or hypersomina, low energy, poor self esteem, poor concentration, or hopelessness (1,4). The patient will never have been symptom free for >2 consecutive months and there is no MDE present in the first 2 years. No evidence of mania and cyclothymia will exist (1,4). Psychotic Depression: This is depression with psychotic features such as hallucinations or delusions (1,4). Atypical Depression: This is depression with typical features that include reactive mood, over-sleeping, over-eating, leaden paralysis, interpersonal rejection sensitivity (1,4).

Postpartum Depression

The onset of a depressive episode is within 4 weeks of postpartum (1,4). ==Chronic Depression== Two or more years with the full criteria for major depressive episode (1,4). ==Catatonic depression== This includes catatonic features that include catalepsy (waxy flexibility), catatonic excitement, negativism or mutism, mannerisms or stereotypes, echolalia or echopraxia (1,4). Seasonal affective disorder: There is a regular onset and remission of depressive episodes during a particular season (1,4). This is usually fall or winter (1,4).


  1. DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, editors. Pharmacotherapy: a pathophysiologic approach. 7th ed. Toronto: McGraw-Hill; 2007. p. 1123
  2. Chisholm-Burns MA, Wells BG, Schwinghammer TL, Malone PM, Kolesar JM, Rotschafer JC, Dipiro JT. Pharmacotherapy: Principles and Practice. McGraw-Hill: 2008. p. 569.
  3. Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). Jama 2003;289(23):3095.
  4. Cepoiu M, McCusker J, Cole Mg, et al. Recognition of depression by non-psychiatric physicians –a systematic literature review and meta-anaylsis. J Gen Intern Med 2008;23(1):25.
  5. Zisook S, Lesser I, Stewart JW, et al. Effect of age at onset on the course of major depressive disorder. Am J Psychiatry 2007;164:1539.


This information is presented for informational purposes only and is not meant to be a substitute for advice provided by qualified health care professionals. You should contact your qualified health care provider if you have or suspect any health problems. This article is not intended to provide medical advice for its readers

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