Medication Options for Mood Disorders
For depressive disorders, initiate treatment with a second-generation antidepressant (SSRI, SNRI, or other agent), as all demonstrate comparable efficacy with superior safety profiles compared to first-generation antidepressants. 1
First-Line Pharmacotherapy for Depression
Available Second-Generation Antidepressants
The American College of Physicians guideline establishes that the following medications show equivalent efficacy for treating major depressive disorder, dysthymia, and subsyndromal depression 1:
SSRIs (Selective Serotonin Reuptake Inhibitors):
SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors):
Other Second-Generation Agents:
Key Selection Principle
No single second-generation antidepressant demonstrates superior efficacy over others for acute-phase treatment of major depressive disorder. 1 Meta-analyses showing statistically significant differences between agents (such as escitalopram versus citalopram) revealed effect sizes too small to be clinically meaningful. 1
Special Considerations by Clinical Presentation
Depression with Anxiety Symptoms
All second-generation antidepressants show similar efficacy when depression presents with comorbid anxiety. 1 Head-to-head trials comparing fluoxetine, paroxetine, sertraline, bupropion, and venlafaxine found no significant differences in antidepressive efficacy for patients with MDD and anxiety symptoms. 1
Speed of Response
Mirtazapine demonstrates statistically significantly faster onset of action compared to citalopram, fluoxetine, paroxetine, or sertraline. 1 However, after 4 weeks of treatment, response rates equalize across agents. 1 This faster onset may be clinically relevant for patients requiring rapid symptom relief.
Bipolar Depression
For bipolar type II depression, the olanzapine-fluoxetine combination represents a first-line option with established safety. 2 This combination leverages complementary mechanisms: olanzapine's dopamine and serotonin receptor effects plus fluoxetine's selective serotonin reuptake inhibition. 2
Research demonstrates that fluoxetine monotherapy at 20 mg daily for bipolar type II major depressive episodes carries a low manic switch rate (7.3% showed hypomanic symptoms). 3 However, guideline-level evidence supports combination therapy as the preferred approach. 2
Treatment-Resistant Depression
When initial antidepressant therapy fails, switching to a different second-generation antidepressant produces remission in approximately 25% of patients. 1 The STAR*D trial demonstrated no difference in efficacy among sustained-release bupropion, sertraline, and extended-release venlafaxine when used as second-line agents. 1
Critical context: 38% of patients do not achieve treatment response during 6-12 weeks of initial treatment with second-generation antidepressants, and 54% do not achieve remission. 1 This substantial non-response rate necessitates systematic reassessment and medication adjustment.
Duration of Treatment
Continue antidepressant therapy for 4-9 months after achieving remission to reduce relapse risk. 1 For patients with two or more prior depressive episodes, even longer maintenance therapy provides benefit. 1 Meta-analysis of 31 randomized trials confirms that continuation therapy significantly reduces relapse rates. 1
Critical Safety Warnings
Suicidality Risk
All antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (ages 18-24) during initial treatment phases. 4 This risk does not extend to adults beyond age 24, and antidepressants reduce suicidality risk in adults aged 65 and older. 4
Monitor patients closely for clinical worsening, suicidality, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and mania—especially during the initial months of therapy or during dose changes. 4
Bipolar Disorder Screening
Before initiating any antidepressant, screen patients for bipolar disorder risk through detailed psychiatric history, including family history of suicide, bipolar disorder, and depression. 4 Treating a bipolar depressive episode with an antidepressant alone may precipitate a manic or mixed episode. 4
Bleeding Risk
SSRIs interfere with serotonin reuptake in platelets, increasing bleeding risk when combined with NSAIDs, aspirin, or anticoagulants. 4 Bleeding events range from ecchymoses and epistaxis to life-threatening hemorrhages. 4
Common Adverse Effects
Anxiety, nervousness, and insomnia occur in 12-16% of patients treated with fluoxetine versus 7-9% with placebo. 4 Weight loss and decreased appetite affect 11% of fluoxetine-treated patients versus 2% with placebo. 4 Hyponatremia may occur, particularly in elderly patients or those taking diuretics. 4
Practical Implementation
Prescribe the smallest quantity consistent with good management to reduce overdose risk. 4 Second-generation antidepressants demonstrate lower toxicity in overdose compared to tricyclic antidepressants. 1
Fluoxetine's long elimination half-life (2-7 days for parent drug, 4-15 days for norfluoxetine) means dose changes require several weeks to reach steady state. 4 When switching from fluoxetine to a tricyclic antidepressant or MAO inhibitor, allow adequate washout periods to prevent drug interactions or serotonin syndrome. 4
For pediatric populations, fluoxetine is the only antidepressant FDA-approved for major depression in children and adolescents aged 8 years or older. 2 Both fluoxetine and olanzapine are metabolized through cytochrome P450 2D6, requiring consideration of genetic variations affecting metabolism. 2