> Table of Contents > Depression
Rachel Bramson, MD
Michael L. Brown, MD
Suzanne Shurtz, MLIS, AHIP
image BASICS
  • A primary mood disorder characterized by a sustained depressed mood and/or decreased interest in things that used to give pleasure (anhedonia), which represents a change from previous functioning.
  • Variants: (1) major depressive disorder (MDD), (2) dysthymic disorder, and (3) depressive disorder not otherwise specified (NOS). (Last two disorders have slightly different diagnostic criteria but are still treated as below.)
In United States, 6.9% of 18 years of age or older in the past year
  • 16.2% lifetime risk of having MDD
  • Patients can relapse; risk decreases with longer remission period but increases in patients with severe episodes, episodes at a younger age, and multiple episodes.
  • Predominant age
    • Low risk before early teens but highest prevalence in teens and young adults
  • Predominant gender
    • Females > males (2:1)
Complex etiology with two major models in the literature
  • Monoamine-deficiency hypothesis: symptoms related to decreased levels of norepinephrine (dullness and lethargy) and serotonin (irritability, hostility, and suicidal ideation) in multiple regions of the brain; other neurotransmitters involved include dopamine, acetylcholine, &ggr;-aminobutyric acid (GABA), glutamate
  • Stress/hypothalamic-pituitary-adrenal axis: Abnormalities in cortisol response lead to depression; elevated cortisol levels can be associated with depression, but cortisol tests are not indicated for diagnosis.
  • Other areas of research interest: inflammatory processes and abnormal circadian rhythms; impaired synthesis/metabolism of neurotransmitters
  • Environmental factors and learned behavior may affect neurotransmitters and/or have an independent influence on depression.
Multiple gene loci place a person at increased risk when faced with environmental stressor; twin studies suggest 37% concordance (1).
  • Female > male (2:1)
  • Severity of 1st episode
  • Persistent sleep disturbances
  • Presence of chronic disease(s), recent myocardial infarction (MI), cardiovascular accident (CVA)
  • Strong family history (depression, bipolar, suicide, substance abuse), spouse with depression
  • Substance abuse and dependence, domestic abuse/violence
  • Losses, stressors, unemployment
  • Single, divorced, or unhappily married
  • Bipolar disorder, cyclothymic disorder, grief reaction, anxiety disorders, somatoform disorders, schizophrenia/schizoaffective disorders
  • Medical comorbidity
  • Substance abuse
Complete physical with focus on endocrine, cardiac, neurologic, and psychiatric (affect, attention, cognition, memory); look for evidence of contributing medical or neurologic disorder
  • Psychiatric: depressed phase of bipolar disorder— inquire if prior mania, family or personal history of bipolar disorder, prior agitation or excitement with antidepressant medication. If positive, monitor carefully for mood elevation or destabilization, adjustment disorder, and bereavement.
  • Neurologic or degenerative CNS diseases, dementias
  • Medical comorbidity: adrenal disease, thyroid disorders, diabetes, metabolic abnormalities (hypercalcemia), liver/renal failure, malignancy, chronic fatigue syndrome, fibromyalgia, lupus
  • Nutritional: pernicious anemia, pellagra
  • Medications/substances: abuse, side effects, overdose, intoxication, dependence, withdrawal
  • A clinical diagnosis made by eliciting personal, family, social, and psychosocial factors
  • The Patient Health Questionnaire-9 (PHQ-9) is a brief screening test valid for diagnosis of MDD in primary care settings (3)[A].
  • Other validated standard rating scales include the following: Beck Depression Inventory, Zung, GDS 15, and so forth. Rating scales are also useful to track response to treatment over time (3)[A].
  • Rule out hypothyroidism, anemia, and metabolic disorders with TSH, CBC, and comprehensive metabolic panel (CMP)
  • Order urine drug screen if symptoms suggest intoxication.
American Psychiatric Association (APA) 2010 guidelines recommend phasic approach: acute phase (first 3 months), continuation phase (4 to 9 months), and maintenance (9 months until discontinuation) (4)[A].
  • Acute phase
    • Full evaluation, including risk to self and others, with selection of appropriate treatment setting (hospitalization for those at risk of harm to self or others, or so incapacitated as to be unable to take care of themselves and/or who have no support system to assist with treatment)
    • Goal should be symptom remission, with intervention based on clinical picture, including patient's preference, availability of services
    • For mild to moderate depression, psychotherapies (individual, interpersonal, or cognitive-behavioral therapy [CBT]) and/or medication are recommended.
    • For refractory/severe depression, medication is indicated.
    • For patients not responding to medication alone, CBT should be initiated.
    • Continue to increase dosage q3-4wk until symptoms in remission. Full medication effect is complete in 4 to 6 weeks. Augmentation with 2nd medication may be necessary.
    • See within 2 to 4 weeks of starting medication and q2wk until improvement, then monthly to monitor medication changes.
    • ≥6 visits recommended for monitoring (younger patients; those at high suicide risk, see within 1st week, and follow frequently)
  • Continuation/maintenance phase
    • Regular visits to monitor for signs of relapse, q3-6mo if stable; depression rating scales should be used.
    • Once remission achieved, dosage should be continued for at least 6 to 9 months to reduce relapse; CBT is also effective in reducing relapse (visits typically q2wk).
    • If/when drug discontinuation is considered, medications should be tapered gradually (weeks to months).
  • Refer immediately for active suicidal ideations, psychosis, severe agitation, severe self-neglect, and significant risk of self-harm.
  • Refer to psychiatry for failed response to medication trials, suspected bipolar disorder, more persistent suicidal thoughts, and self-neglect.

  • Effectiveness of medications is comparable between/within classes; selection should be based on provider familiarity and patient characteristics/preferences (5)[A].
  • Selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) are effective, but TCAs are second line due to side effects and lethality in overdose. Tolerability is much poorer than newer antidepressants.
  • First-line SSRIs* (starting dose; usual dose)
    • Fluoxetine (Prozac): 20 mg/day; 20 to 60 mg/day
    • Sertraline (Zoloft): 50 mg/day; 50 to 200 mg/day
    • Paroxetine (Paxil): 10 mg/day; 20 to 50 mg/day
    • Paroxetine CR (Paxil CR): 12.5 mg/day; 25 to 62.5 mg/day
    • Citalopram (Celexa): 20 mg/day; 20 to 40 mg/day (higher doses not advised; EKG monitoring for doses >40 mg/day due to increased risk of QTc prolongation)
    • Escitalopram (Lexapro): 10 mg/day; 10 to 20 mg/day
    • Precautions: abrupt discontinuation may result in withdrawal symptoms (i.e., dizziness, nausea, headache, paresthesia)
    • Fluoxetine, paroxetine may raise serum levels of other drugs; escitalopram, sertraline have minimal to no drug interactions.
    • Common side effects: sexual dysfunction (20%), nausea, GI upset, dizziness, insomnia, headache; typically resolve in the 1st week
    • Less common side effects: drowsiness, weight gain, emotional blunting, dry mouth
    • *Lower starting doses for elderly, adolescents, those with comorbid conditions, panic disorder, significant anxiety, or hepatic conditions
  • Others (starting dose; usual dose)
    • Venlafaxine (Effexor, Effexor XR): 37.5 mg/day; 300 mg/day
    • Bupropion XL (Wellbutrin XL): 150 mg/day; 300 to 450 mg/day (precautions: powers seizure threshold at doses >450 mg/day)
    • Duloxetine (Cymbalta): 30 mg/day; 60 to 120 mg/day
    • Desvenlafaxine (Pristiq): 50 to 100 mg/day
    • Vilazodone: start 10 mg/day; usual target 40 mg/day
    • Vortioxetine: start 5 mg/day; target dose 20 mg/day
    • Levomilnacipran: start 20 mg/day; target dose 40 to 120 mg/day
Second Line
  • TCAs (starting dose; usual dose)
    • Amitriptyline (Elavil): 25 to 50 mg/day; 100 to 300 mg/day
    • Nortriptyline (Pamelor): 25 mg/day; 50 to 150 mg/day
    • Doxepin (Sinequan): 25 to 50 mg/day; 100 to 300 mg/day
    • Imipramine (Tofranil, Tofranil-PM): 25 to 50 mg/day; 100 to 300 mg/day
    • Desipramine (Norpramin): 25 to 50 mg/day; 100 to 300 mg/day
    • Precautions: advanced age, glaucoma, benign prostate hyperplasia, hyperthyroidism, cardiovascular disease, liver disease, monamine oxidase inhibitor (MAOI) treatment, potential for fatal overdose, arrhythmia, worsening glycemic control; *SSRIs recommended for patients with diabetes (4)[A]
    • Common side effects: dry mouth, blurred vision, constipation, urinary retention, tachycardia, confusion/delirium; elderly particularly susceptible
  • &agr;2-Antagonists (sedating) (starting dose; usual dose)
    • Mirtazapine (Remeron): 15 mg/day; 15 to 45 mg/day
  • Atypical antipsychotics
    • Adjunctive treatment: aripiprazole or quetiapine
    • Treatment-resistant depression (TRD): olanzapine
    • Significant side effects: dyslipidemia, hypertriglyceridemia, glucose dysregulation, diabetes mellitus, hyperprolactinemia, tardive dyskinesia, neuroleptic malignant syndrome, QTc prolongation (6)[A]
    • Recommended for depression with psychotic features; consult with psychiatry and consider carefully before starting (4)[A].
  • Significant potential interactions
    • TCAs: amphetamines, barbiturates, clonidine, epinephrine, ethanol, norepinephrine
    • ALL ANTIDEPRESSANTS: allow 14-day washout period before starting MAOIs
    • MAOIs: not recommended in primary care. Significant drug and food interactions limit use.
Pregnancy Considerations
SSRIs: Fluoxetine, sertraline, and bupropion considered safe in pregnancy (paroxetine, Category D; other SSRIs, Category C).
  • Electroconvulsive therapy (ECT) for refractory cases
  • Repetitive transcranial magnetic stimulation (rTMS) may be helpful for TRD (6)[A].
Used in mild depression but not regulated by FDA nor recommended by APA
  • Hypericum perforatum (St. John's wort): multiple drug interactions; not safe in pregnancy
  • Data do not support S-adenosyl methionine (SAM-e) or acupuncture.
Admission Criteria/Initial Stabilization
Inpatient care is indicated for severe depression, patients at risk of suicide/homicide, and for comorbid conditions.
Discharge Criteria
Depressive symptoms abating, no longer suicidal, appropriate outpatient follow-up in place
  • Depression is a common medical illness, not a character defect.
  • Emphasize the need for long-term treatment and follow-up, which includes lifestyle changes.
  • Exercise, good sleep hygiene, good nutrition, and decreased use of tobacco and alcohol are recommended. The optimal regimen is one the patient prefers and will adhere to.
  • 70% show significant improvement
  • Of patients with a single depressive episode, 50% will relapse over their lifetime.
1. Flint J, Kendler KS. The genetics of major depression. Neuron. 2014;81(3):484-503.
2. Mitchell AJ, Bird V, Rizzo M, et al. Diagnostic validity and added value of the Geriatric Depression Scale for depression in primary care: a meta-analysis of GDS30 and GDS15. J Affect Disord. 2010;125(1-3):10-17.
3. Deneke DE, Schultz H, Fluent TE. Screening for depression in the primary care population. Prim Care. 2014;41(2):399-420.
4. American Psychiatric Association. Practice guidelines for the treatment of patients with major depressive disorder. http://www.psychiatryonline.com/pracGuide/pracGuideTopic_7.aspx. Accessed 2015.
5. Arroll B, Elley CR, Fishman T, et al. Antidepressants versus placebo for depression in primary care. Cochrane Database Syst Rev. 2009;(3):CD007954.
6. McIntyre RS, Filteau MJ, Martin L, et al. Treatment-resistant depression: definitions, review of the evidence, and algorithmic approach. J Affect Disord. 2014;156:1-7.
Additional Reading
  • American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013.
  • Patient Health Questionnaire (PHQ) Screeners: http://www.phqscreeners.com/overview.aspx?Screener=03_GAD-7
See Also
Algorithms: Depressed Mood Associated with Medical Illness; Depressive Episode, Major
  • F32.9 Major depressive disorder, single episode, unspecified
  • F33.9 Major depressive disorder, recurrent, unspecified
  • F34.1 Dysthymic disorder
Clinical Pearls
  • Therapeutic alliance is important to treatment success.
  • Given the high recurrence rates, long-term treatment is often necessary.