11/3/22, 7:34 AM Major Depressive Disorder - StatPearls - NCBI Bookshelf

Major Depressive Disorder

Navneet Bains; Sara Abdijadid.
Author Information

Authors
Navneet Bains; Sara Abdijadid1.

Affiliations
1 UCLA

Last Update: June 1, 2022.

Continuing Education Activity

Major depressive disorder (MDD) has been ranked as the third cause of the burden of
disease worldwide in 2008 by WHO, which has projected that this disease will rank first
by 2030. It is diagnosed when an individual has a persistently low or depressed mood,
anhedonia or decreased interest in pleasurable activities, feelings of guilt or
worthlessness, lack of energy, poor concentration, appetite changes, psychomotor
retardation or agitation, sleep disturbances, or suicidal thoughts. This activity reviews
the evaluation and management of major depressive disorder which is one of the main
causes of disability in the world and highlights the role of the interprofessional team.

Objectives:

Identify the etiology of major depressive disorder.

Review the appropriate management of major depressive disorder.

Outline the typical presentation of a patient with major depressive disorder.

Review the importance of improving care coordination among interprofessional

team members to improve outcomes for patients affected by major depressive
disorder.

Access free multiple choice questions on this topic.

Introduction
Major depressive disorder (MDD) has been ranked as the third cause of the burden of
disease worldwide in 2008 by WHO, which has projected that this disease will rank first
by 2030.[1] It is diagnosed when an individual has a persistently low or depressed

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mood, anhedonia or decreased interest in pleasurable activities, feelings of guilt or

worthlessness, lack of energy, poor concentration, appetite changes, psychomotor
retardation or agitation, sleep disturbances, or suicidal thoughts. Per the Diagnostic and
Statistical Manual of Mental Disorders, 5th Edition (DSM-5), an individual must have
five of the above-mentioned symptoms, of which one must be a depressed mood or
anhedonia causing social or occupational impairment, to be diagnosed with MDD.
History of a manic or hypomanic episode must be ruled out to make a diagnosis of
MDD. Children and adolescents with MDD may present with irritable mood.

Per DSM-5, other types of depression falling under the category of depressive disorders
are:

Persistent depressive disorder, formerly known as dysthymia

Disruptive mood dysregulation disorder 

Premenstrual dysphoric disorder

Substance/medication-induced depressive disorder

Depressive disorder due to another medical condition

Unspecified depressive disorder

Etiology
The etiology of Major depressive disorder is believed to be multifactorial, including
biological, genetic, environmental, and psychosocial factors. MDD was earlier
considered to be mainly due to abnormalities in neurotransmitters, especially serotonin,
norepinephrine, and dopamine. This has been evidenced by the use of different
antidepressants such as selective serotonin receptor inhibitors, serotonin-norepinephrine
receptor inhibitors, dopamine-norepinephrine receptor inhibitors in the treatment of
depression. People with suicidal ideations have been found to have low levels of
serotonin metabolites. However, recent theories indicate that it is associated primarily
with more complex neuroregulatory systems and neural circuits, causing secondary
disturbances of neurotransmitter systems.

GABA, an inhibitory neurotransmitter, and glutamate and glycine, both of which are
major excitatory neurotransmitters are found to play a role in the etiology of depression
as well. Depressed patients have been found to have lower plasma, CSF, and brain
GABA levels. GABA is considered to exert its antidepressant effect by inhibiting the
ascending monoamine pathways, including mesocortical and mesolimbic systems.
Drugs that antagonize NMDA receptors have been researched to have antidepressant
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properties. Thyroid and growth hormonal abnormalities have also been implicated in the
etiology of mood disorders. Multiple adverse childhood experiences and trauma are
associated with the development of depression later in life.[2][3]

Severe early stress can result in drastic alterations in neuroendocrine and behavioral
responses, which can cause structural changes in the cerebral cortex, leading to severe
depression later in life. Structural and functional brain imaging of depressed individuals
has shown increased hyperintensities in the subcortical regions, and reduced anterior
brain metabolism on the left side, respectively. Family, adoption, and twin studies have
indicated the role of genes in the susceptibility of depression. Genetic studies show a
very high concordance rate for twins to have MDD, particularly monozygotic twins.
[4] Life events and personality traits have shown to play an important role, as well. The
learned helplessness theory has associated the occurrence of depression with the
experience of uncontrollable events. Per cognitive theory, depression occurs as a result
of cognitive distortions in persons who are susceptible to depression.

Epidemiology
Major depressive disorder is a highly prevalent psychiatric disorder. It has a lifetime
prevalence of about 5 to 17 percent, with the average being 12 percent. The prevalence
rate is almost double in women than in men.[5] This difference has been considered to
be due to the hormonal differences, childbirth effects, different psychosocial stressors in
men and women, and behavioral model of learned helplessness. Though the mean age of
onset is about 40 years, recent surveys show trends of increasing incidence in younger
population due to the use of alcohol and other drugs of abuse.

MDD is more common in people without close interpersonal relationships, and who are
divorced or separated, or widowed. No difference in the prevalence of MDD has been
found among races and socioeconomic status. Individuals with MDD often have
comorbid disorders such as substance use disorders, panic disorder, social anxiety
disorder, and obsessive-compulsive disorder. The presence of these comorbid disorders
in those diagnosed with MDD increases their risk of suicide. In older adults, depression
is prevalent among those with comorbid medical illnesses.[6] Depression is found to be
more prevalent in rural areas than in urban areas. 

History and Physical

Major depressive disorder is a clinical diagnosis; it is mainly diagnosed by the clinical
history given by the patient and mental status examination. The clinical interview must
include medical history, family history, social history, and substance use history along

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with the symptomatology. Collateral information from a patient's family/friends is a very

important part of psychiatric evaluation.

A complete physical examination, including neurological examination, should be

performed. It is important to rule out any underlying medical/organic causes of a
depressive disorder. A full medical history, along with the family medical and
psychiatric history, should be assessed. Mental status examination plays an important
role in the diagnosis and evaluation of MDD. 

Evaluation
Although there is no objective testing available to diagnose depression, routine
laboratory work including complete blood account with differential, comprehensive
metabolic panel, thyroid-stimulating hormone, free T4, vitamin D, urinalysis, and
toxicology screening is done to rule out organic or medical causes of depression.

Individuals with depression often present to their primary care physicians for somatic
complaints stemming from depression, rather than seeing a mental health professional.
In almost half of the cases, patients deny having depressive feelings, and they are often
brought for treatment by the family or sent by the employer to be evaluated for social
withdrawal and decreased activity. It is very important to evaluate a patient for suicidal
or homicidal ideations at each visit.

In primary care settings, the Patient Health Questionnaire-9 (PHQ-9), which is a self-
report, standardized depression rating scale is commonly used for screening, diagnosing,
and monitoring treatment response for MDD.[7] The PHQ-9 uses 9 items corresponding
to the DSM-5 criteria for MDD and also assesses for psychosocial impairment. The
PHQ-9 scores 0 to 27, with scores of equal to or more than 10, indicate a possible MDD.

In most hospital settings, the Hamilton Rating Scale for Depression (HAM-D), which is
a clinician-administered depression rating scale is commonly used for the assessment of
depression. The original HAM-D uses 21 items about symptoms of depression, but the
scoring is based only on the first 17 items.

Other scales include the Montgomery-Asberg Depression Rating Scale (MADRS), the
Beck Depression Inventory (BDI), the Zung Self-Rating Depression Scale, the Raskin
Depression Rating Scale, and other questionnaires.

Treatment / Management
Major depressive disorder can be managed with various treatment modalities, including
pharmacological, psychotherapeutic, interventional, and lifestyle modification. The
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initial treatment of MDD includes medications or/and psychotherapy. Combination

treatment, including both medications and psychotherapy, has been found to be more
effective than either of these treatments alone.[8][9] Electroconvulsive therapy is found
to be more efficacious than any other form of treatment for severe major depression.[10]

FDA-approved medications for the treatment of MDD are as follows: All

antidepressants are equally effective but differ in side-effect profiles.

Selective serotonin reuptake inhibitors (SSRIs) include fluoxetine, sertraline,

citalopram, escitalopram, paroxetine, and fluvoxamine. They are usually the first
line of treatment and the most widely prescribed antidepressants.

Serotonin-norepinephrine reuptake inhibitors (SNRIs) include venlafaxine,

duloxetine, desvenlafaxine, levomilnacipran, and milnacipran. They are often used
for depressed patients with comorbid pain disorders.

Serotonin modulators are trazodone, vilazodone, and vortioxetine.

Atypical antidepressants include bupropion and mirtazapine. They are often

prescribed as monotherapy or as augmenting agents when patients develop sexual
side-effects due to SSRIs or SNRIs.

Tricyclic antidepressants (TCAs) are amitriptyline, imipramine, clomipramine,

doxepin, nortriptyline, and desipramine.

Monoamine oxidase inhibitors (MAOIs) available are tranylcypromine,

phenelzine, selegiline, and isocarboxazid. MAOIs and TCAs are not commonly
used due to the high incidence of side-effects and lethality in overdose.

Other medications include mood-stabilizers, antipsychotics which may be

added to enhance antidepressant effects.

Psychotherapy 

Cognitive-behavioral therapy

Interpersonal therapy 

Electroconvulsive Therapy (ECT)

Acute suicidality 

Severe depression during pregnancy 

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Refusal to eat/drink

Catatonia

Severe psychosis

Transcranial Magnetic Stimulation (TMS)

FDA-approved for treatment-resistant/refractory depression; for patients who have

failed at least one medication trial

Vagus Nerve Stimulation (VNS)

FDA-approved as a long-term adjunctive treatment for treatment-resistant

depression; for patients who have failed at least 4 medication trials

Esketamine

Nasal spray to be used in conjunction with an oral antidepressant in treatment-

resistant depression; for patients who have failed other antidepressant medications

Differential Diagnosis
While evaluating for MDD, it is important to rule out depressive disorder due to another
medical condition, substance/medication-induced depressive disorder, dysthymia,
cyclothymia, bereavement, adjustment disorder with depressed mood, bipolar disorder,
schizoaffective disorder, schizophrenia, anxiety disorders, and eating disorders for the
appropriate management. Depressive symptoms can be secondary to the following
causes:

Neurological causes such as cerebrovascular accident, multiple sclerosis, subdural

hematoma, epilepsy, Parkinson disease, Alzheimer disease 

Endocrinopathies such as diabetes, thyroid disorders, adrenal disorders

Metabolic disturbances such as hypercalcemia, hyponatremia

Medications/substances of abuse: steroids, antihypertensives, anticonvulsants,

antibiotics, sedatives, hypnotics, alcohol, stimulant withdrawal

Nutritional deficiencies such as vitamin D, B12, B6 deficiency, iron or folate

deficiency

Infectious diseases such as HIV and syphilis

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Malignancies

Prognosis
Untreated depressive episodes in major depressive disorder can last from 6 to 12
months. About two-thirds of the individuals with MDD contemplate suicide, and about
10 to 15 percent commit suicide. MDD is a chronic, recurrent illness; the recurrence rate
is about 50% after the first episode, 70% after the second episode, and 90% after the
third episode. About 5 to 10 percent of the patients with MDD eventually develop
bipolar disorder.[11] The prognosis of MDD is good in patients with mild episodes, the
absence of psychotic symptoms, better treatment compliance, a strong support system,
and good premorbid functioning. The prognosis is poor in the presence of a comorbid
psychiatric disorder, personality disorder, multiple hospitalizations, and advanced age of
onset.

Complications
MDD is one of the leading causes of disability worldwide. It not only causes a severe
functional impairment but also adversely affects the interpersonal relationships, thus
lowering the quality of life. Individuals with MDD are at a high risk of developing
comorbid anxiety disorders and substance use disorders, which further increases their
risk of suicide. Depression can aggravate medical comorbidities such as diabetes,
hypertension, chronic obstructive pulmonary disease, and coronary artery disease.
Depressed individuals are at high risk of developing self-destructive behavior as a
coping mechanism. MDD is often very debilitating if left untreated.

Deterrence and Patient Education

Patient education has a profound impact on the overall outcome of major depressive
disorder. Since MDD is one of the most common psychiatric disorders causing disability
worldwide and people in different parts of the world are hesitant to discuss and seek
treatment for depression due to the stigma associated with mental illness, educating
patients is very crucial for their better understanding of the mental illness and better
compliance with the mental health treatment. Family education also plays an important
role in the successful treatment of MDD.

Enhancing Healthcare Team Outcomes

An interdisciplinary approach is essential for the effective and successful treatment of
MDD. Primary care physicians and psychiatrists, along with nurses, therapists, social
workers, and case managers, form an integral part of these collaborated services. In the
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majority of cases, PCPs are the first providers to whom individuals with MDD present
mostly with somatic complaints. Depression screening in primary care settings is very
imperative. The regular screening of the patients using depression rating scales such as
PHQ-9 can be very helpful in the early diagnosis and intervention, thus improving the
overall outcome of MDD. Psychoeducation plays a significant role in improving patient
compliance and medication adherence. Recent evidence also supports that lifestyle
modification, including moderate exercises, can help to improve mild-to-moderate
depression. Suicide screening at each psychiatric visit can be helpful to lower suicide
incidence. Since patients with MDD are at increased risk of suicide, close monitoring,
and follow up by mental health workers becomes necessary to ensure safety and
compliance with mental health treatment. The involvement of families can further add to
a better outcome of the overall mental health treatment. Meta-analyses of randomized
trials have shown that depression outcomes are superior when using collaborative care
as compared with usual care.[12]

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