Major Depressive Disorder
Navneet Bains; Sara Abdijadid.
Author Information and Affiliations
Last Update: April 10, 2023.
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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.
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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 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
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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 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.
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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.
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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 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.
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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.
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Treatment / Management
Major depressive disorder can be managed with various treatment modalities, including
pharmacological, psychotherapeutic, interventional, and lifestyle modification. The 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
• 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
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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
• Malignancies
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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.
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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.
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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.
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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 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]
