Treatment of Major Depressive Disorder

Definition and Diagnosis

Major Depressive Disorder (MDD) is characterized by a minimum of 2 weeks of symptoms, including at least one core symptom (depressed mood or anhedonia) and a total of five or more symptoms, affecting normal functioning, as defined by the American College of Physicians 1, 2
Useful tools for assessing MDD symptoms include the Patient Health Questionnaire-9 (PHQ-9), Hamilton Depression Rating Scale (HAM-D), and Hospital Anxiety and Depression Scale (HADS), with the HAM-D scores ranging from mild (7-17) to severe (≥25) depression 2
Diagnosis involves direct interviews with patients and families/caregivers, assessment of functional impairment, and screening for comorbid conditions (anxiety, substance use disorders), along with safety assessment for suicidal ideation 2, 3

The American College of Physicians recommends assessing patient status, therapeutic response, and adverse effects within 1-2 weeks of initiating sertraline therapy, with close monitoring for emergence of agitation, irritability, or unusual changes in behavior, especially during the first 1-2 months of treatment 4
Regular follow-up is essential as the risk for suicide attempts is greater during the first 1-2 months of treatment, and full therapeutic effect may take 6-8 weeks to achieve 4
The American Academy of Pediatrics recommends assessment of side effects, medication adherence, and initial response, as well as suicide risk monitoring, especially during the first few weeks of treatment 5

Recommended medications for elderly patients include:

Medication	Initial Dose	Maximum Dose
Sertraline (Zoloft)	25-50 mg daily	200 mg daily
Citalopram (Celexa)	10 mg daily	20 mg daily (maximum in elderly due to QT prolongation risk)
Escitalopram (Lexapro)	10 mg daily	20 mg daily

The American College of Physicians recommends starting escitalopram at 10 mg daily for most adults with depression, with close monitoring within 1-2 weeks of initiation, and full therapeutic effect may take 6-8 weeks 4
If inadequate response after 6-8 weeks, dose may be increased in 50 mg increments at intervals of not less than 1 week, up to a maximum of 200 mg daily, with consideration of treatment modification if no adequate response within 6-8 weeks 4

Common adverse effects of sertraline include mild effects such as constipation, diarrhea, dizziness, headache, insomnia, nausea, somnolence, and major effects such as sexual dysfunction, with bupropion associated with lower rates of sexual adverse events 4
Bupropion (Wellbutrin) has a lower rate of sexual adverse events and promotes weight loss, according to the American Gastroenterological Association and the American Diabetes Association 9, 10
For a first episode of depression, continue treatment for 4-9 months after achieving a satisfactory response, and for patients who have had 2 or more episodes of depression, longer duration therapy is beneficial 4
The American Academy of Pediatrics recommends tapering escitalopram slowly to avoid withdrawal effects upon discontinuation 5
The American Geriatrics Society recommends gradual tapering of tricyclic antidepressants (TCAs) to avoid autonomic rebound symptoms, and suggests monitoring for cognitive changes, falls risk, and orthostatic hypotension during tapering 11

Interpersonal therapy is particularly effective for depression, focusing on identifying interpersonal problem areas, improving interpersonal problem-solving skills, and modifying communication patterns, with involvement of parents/caregivers in therapy sessions during specific phases of treatment, especially for younger patients 5
Psychosocial interventions, such as Cognitive Behavioral Therapy (CBT), Family-Focused Therapy (FFT), and Interpersonal and Social Rhythm Therapy (IPSRT), are recommended as adjunctive treatments to medication for depression, with the strongest evidence base for reducing relapse rates and improving functional outcomes, as supported by the American Academy of Child and Adolescent Psychiatry 12
Combination therapy, consisting of an SSRI plus CBT, may provide additional benefits for moderate to severe MDD, although it shows no significant difference in response or remission compared to SSRI monotherapy, as supported by the American College of Physicians, with a moderate strength of evidence 1

Options for treatment modification include increasing the dose, augmentation with another agent, switching to another antidepressant, or adding other therapeutic modalities, with consideration of the potential benefits and risks of each option 4
For mild depression, clinicians should consider a period of active support and monitoring before starting evidence-based treatments, including psychoeducation, supportive counseling, and regular monitoring of depressive symptoms and suicidality, as recommended by the American Academy of Pediatrics and the American College of Physicians 5, 13
Active support and monitoring is recommended as the initial approach for mild depression, with the goal of facilitating patient self-management strategies and improving outcomes 5
Escitalopram is contraindicated with MAOIs, and caution should be exercised when using other serotonergic drugs, NSAIDs, and anticoagulants 5
CYP2D6 and CYP2C19 genetic variations can affect metabolism of antidepressants, with fluoxetine and paroxetine being primarily metabolized through CYP2D6, which is subject to genetic variation and inhibition, as supported by the American Academy of Child and Adolescent Psychiatry 14

50-60% of individuals with depression will have comorbid anxiety disorders, highlighting the importance of assessment for comorbid conditions 2
The American College of Physicians strongly recommends that primary care clinicians work with administration to organize clinical settings that reflect best practices in integrated and/or collaborative care models, which have been shown to be more effective in improving outcomes 5, 13
When mild depression persists despite initial interventions or worsens to moderate/severe depression, consultation with mental health specialists should be considered, as recommended by the American Academy of Pediatrics 5