Major 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 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 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 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](A1)

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

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

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.