Article Author:
Suma Chand
Article Editor:
Hasan Arif
10/5/2018 7:30:52 AM
PubMed Link:


Depression is a mood disorder that causes a persistent feeling of sadness and loss of interest. The American Psychiatric Association’s Diagnostic Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) classifies the depressive disorders into (i) Disruptive mood dysregulation disorder, (ii) Major depressive disorder, (iii) Persistent depressive disorder (dysthymia), (iv) Premenstrual dysphoric disorder, and (v) Depressive disorder due to another medical condition. The common feature of all the depressive disorders is the presence of sad, empty, or irritable mood, accompanied by somatic and cognitive changes that significantly affect the individual’s capacity to function.


The etiology of major depressive disorder is multi factorial with both genetic and environmental factors playing a role. First-degree relatives of depressed individuals are about 3 times as likely to develop depression as the general population; however, depression can occur in people without family histories of depression, as well.  

Some evidence suggests that genetic factors play less of a role in late-onset depression than in early-onset depression. Potential biological risk factors have been identified for depression in the elderly. Neurodegenerative diseases (especially Alzheimer's  disease and Parkinson's Disease), stroke, multiple sclerosis, seizure disorders, cancer, macular degeneration, and chronic pain have been associated with higher rates of depression. Life events and hassles operate as triggers for the development of depression. Traumatic events such as the death or loss of a loved one, lack or reduced social support, caregiver burden, financial problems, interpersonal difficulties, and conflicts are examples of stressors that can trigger depression. 


Twelve month prevalence of major depressive disorder is approximately 7%, with marked differences by age group.  The prevalence in 18 to 29 year old individuals is three fold higher than the prevalence in individuals aged 60 years or older. Females experience 1.5 to 3-fold higher rates than males beginning in early adolescence. 


The underlying pathophysiology of major depressive disorder has not been clearly defined. Current evidence points to a complex interaction between neurotransmitter availability and receptor regulation and sensitivity underlying the affective symptoms.

  • Clinical and preclinical trials suggest a disturbance in central nervous system serotonin (5-HT) activity as an important factor. Other neurotransmitters implicated include norepinephrine (NE), dopamine (DA), glutamate, and brain-derived neurotrophic factor (BDNF).[7] 
  • The role of CNS 5-HT activity in the pathophysiology of major depressive disorder is suggested by the therapeutic efficacy of selective serotonin reuptake inhibitors (SSRIs). Research findings implies a role for neuronal receptor regulation, intracellular signaling, and gene expression over time, in addition to enhanced neurotransmitter availability.
  • Seasonal affective disorder is a form of major depressive disorder that typically arises during the fall and winter and resolves during the spring and summer. Studies suggest that seasonal affective disorder is also mediated by alterations in CNS levels of 5-HT and appears to be triggered by alterations in circadian rhythm and sunlight exposure.
  • Vascular lesions may contribute to depression by disrupting the neural networks involved in emotion regulation—in particular, frontostriatal pathways that link the dorsolateral prefrontal cortex, orbitofrontal cortex, anterior cingulate, and dorsal cingulate. Other components of limbic circuitry, in particular the hippocampus and amygdala, have been implicated in depression.

History and Physical

Investigation into depressive symptoms begin with inquiries of the neurovegetative symptoms which include changes in sleeping patterns, appetite, and energy levels. Positive responses should elicit further questioning focused on evaluating for the presence of the symptoms which are diagnostic of major depression. These are the nine symptoms listed in the DSM V and five of these  must be present to make the diagnosis (one of the symptoms should be depressed mood or loss of interest or pleasure): 1. Sleep disturbance, 2. Interest/pleasure reduction, 3. Guilt feelings or thoughts of worthlessness, 4. Energy changes/fatigue, 5. Concentration/attention impairment, 6. Appetite/weight changes, 7. Psychomotor disturbances, 8. Suicidal thoughts, and 9. Depressed mood.

All patients with depression should be evaluated for suicidal risk. Any suicide risk must be given prompt attention which could include hospitalization or close and frequent monitoring.

Other areas of investigation include:

  • Past medical history and family medical history, and current medications.
  • Social history with a focus on stressors and use of drugs and alcohol.
  • History and physical examination to rule out organic causes of depression. Depressive symptoms and their severity are also evaluated with the help of questionnaires such as the Beck's Depression Inventory (BDI), Hamilton Depression Scale (Ham-D), and Zung Self Rating Depression Scale.


The diagnosis of depression is based on history and physical findings. No diagnostic laboratory tests are available to diagnose major depressive disorder. Laboratory studies are, however, useful to exclude medical illnesses that may present as major depressive disorder. These laboratory studies might include the following:

  • Complete blood cell (CBC) count
  • Thyroid-stimulating hormone (TSH)
  • Vitamin B-12
  • Rapid plasma reagin (RPR)
  • HIV test
  • Electrolytes, including calcium, phosphate, and magnesium levels
  • Blood urea nitrogen (BUN) and creatinine
  • Liver function tests (LFTs)
  • Blood alcohol level
  • Blood and urine toxicology screen
  • Arterial blood gas (ABG)
  • Dexamethasone suppression test (Cushing disease, but also positive in depression)
  • Cosyntropin (ACTH) stimulation test (Addison disease)    
  • Computed tomography (CT) scanning or magnetic resonance imaging (MRI) of the brain should be considered if organic brain syndrome or hypopituitarism is included in the differential diagnosis.

Treatment / Management

Medication alone and brief psychotherapy (cognitive-behavioral therapy, interpersonal therapy) alone can relieve depressive symptoms. Combination therapy has also been associated with significantly higher rates of improvement in depressive symptoms; increased quality of life; and better treatment compliance. There is also empirical support for the ability of CBT to prevent relapse.

Electroconvulsive therapy is useful for patients who are not responding well to medications or are suicidal.

Medications used for treatment of depression include the following:

  • Selective serotonin reuptake inhibitors (SSRIs)
  • Serotonin/norepinephrine reuptake inhibitors (SNRIs)     
  • Atypical antidepressants
  • Serotonin-Dopamine Activity Modulators (SDAMs)     
  • Tricyclic antidepressants (TCAs)      
  • Monoamine oxidase inhibitors (MAOIs)  

Selective serotonin reuptake inhibitors (SSRIs): SSRIs have the advantage of ease of dosing and low toxicity in overdose. They are also the first-line medications for late-onset depression.

SSRIs include the following: Citalopram (Celexa); Escitalopram (Lexapro); Fluoxetine (Prozac);  Fluvoxamine (Luvox); Paroxetine (Paxil) Sertraline (Zoloft); Vilazodone (Viibryd); Vortioxetine (Brintellix)    

Serotonin/norepinephrine reuptake inhibitors (SNRIs): SNRIs, which include venlafaxine (Effexor), desvenlafaxine (Pristiq), duloxetine (Cymbalta), and levomilnacipran (Fetzima) can be used as first-line agents, particularly in patients with significant fatigue or pain syndromes associated with the episode of depression. SNRIs also have an important role as second-line agents in patients who have not responded to SSRIs. 

Atypical antidepressants: Atypical antidepressants include bupropion (Wellbutrin), mirtazapine (Remeron), nefazodone, and trazodone (Desyrel). They have all been found to be effective in monotherapy in major depressive disorder and may be used in combination therapy for more difficult to treat depression.

Serotonin-Dopamine Activity Modulators (SDAMs): SDAMs include brexpiprazole (Rexulti) and aripiprazole (Abilify). SDAMs act as a partial agonist at 5-HT1A and dopamine D2 receptors at similar potency, and as an antagonist at 5-HT2A and noradrenaline alp Brexpiprazole is indicated as adjunctive therapy for major depressive disorder (MDD).

Tricyclic antidepressants (TCAS): TCAs include the following: Amitriptyline (Elavil); Clomipramine (Anafranil); Desipramine (Norpramin); Doxepin (Sinequan); Imipramine (Tofranil); Nortriptyline (Pamelor); Protriptyline (Vivactil); Trimipramine (Surmontil). TCAs have a long record of efficacy in the treatment of depression. They are used less commonly because of their side-effect profile and their considerable toxicity in overdose.

Monoamine oxidase inhibitors (MAOIs): MAOIs include isocarboxazid (Marplan), phenelzine (Nardil), selegiline (Emsam), and tranylcypromine (Parnate). These agents are widely effective in a broad range of affective and anxiety disorders. Because of the risk of hypertensive crisis, patients on these medications must follow a low-tyramine diet. Other adverse effects can include insomnia, anxiety, orthostasis, weight gain, and sexual dysfunction. 

Electroconvulsive Therapy (ECT):

ECT is a highly effective treatment for depression. Onset of action may be more rapid than that of drug treatments, with benefit often seen within 1 week of commencing treatment. A course of ECT (usually up to 12 sessions) is the treatment of choice for patients who do not respond to drug therapy, are psychotic, or are suicidal or dangerous to themselves. Thus, the indications for the use of ECT include the following:     

  • Need for a rapid antidepressant response  Failure of drug therapies     
  • History of good response to ECT     
  • Patient preference     
  • High risk of suicide
  • High risk of medical morbidity and mortality

Although advances in brief anesthesia and neuromuscular paralysis have improved the safety and tolerability of ECT, this modality poses numerous risks, including those associated with general anesthesia, postictal confusion, and, more rarely, short-term memory difficulties.  


Cognitive Behavior Therapy and Interpersonal Therapy are evidence based psychotherapies that have been found to be effective in the treatment of depression.

Cognitive-behavioral therapy (CBT):

CBT is a structured, and didactic form of therapy that focuses on helping individuals identify and modify maladaptive thinking and behavior patterns (16 to 20 sessions). It is based on the premise that patients who are depressed exhibit the “cognitive triad” of depression, which includes a negative view of themselves, the world, and the future. Patients with depression also exhibit cognitive distortions that help to maintain their negative beliefs. CBT for depression typically includes behavioral strategies (i.e., activity scheduling), as well as cognitive restructuring for the purpose of changing negative automatic thoughts and addressing maladaptive schemas.

There is evidence supporting the use of CBT with individuals of all ages. It is also  considered to be efficacious for the prevention of relapse. It is particularly valuable for elderly patients, who may be more prone to problems or side effects with medications.  

Mindfulness based cognitive therapy (MBCT) was designed to reduce relapse among individuals who have been successfully treated for an episode of recurrent major depressive disorder. The primary treatment component is mindfulness training. MBCT specifically focuses on ruminative thought processes as being a risk factor for relapse. Research indicates that MBCT is effective in reducing risk of relapse in patients with recurrent depression, especially in those with the most severe residual symptoms. Interpersonal therapy (IPT)

Interpersonal Therapy (IPT):

Interpersonal therapy (IPT) is a time-limited (typically 16 sessions) treatment for major depressive disorder. IPT draws from attachment theory and emphas the role of interpersonal relationships, focusing on current interpersonal difficulties. Specific areas of emphasis include grief, interpersonal disputes, role transitions, and interpersonal deficits.

Pearls and Other Issues

Education plays an important role in the successful treatment of major depressive disorder. This would include education of the family as well as the patient. Lack of accurate information and misperceptions of the illness as a personal weakness or failing leads to painful stigmatization and avoidance of the diagnosis by many of those affected.  Patients should be aware of the rationale behind the choice of treatment, potential adverse effects, and expected results. The involvement of the patient in the treatment plan can enhance medication compliance and referral for psychotherapy. Engaging family members can be a critical component of a treatment plan. Family members are helpful informants, can ensure medication compliance, be a big source of social support and can encourage patients to change behaviors that perpetuate depression (e.g., inactivity).