Prozac (Fluoxetine): Clinical Guide for Adults and Adolescents
Indications
Fluoxetine is FDA-approved for major depressive disorder, OCD, panic disorder, bulimia nervosa, premenstrual dysphoric disorder, and bipolar disorder (with olanzapine), and is the only antidepressant FDA-approved for pediatric depression. 1
Additional approved uses include:
- Major depressive disorder in adults and children ≥8 years 1
- Obsessive-compulsive disorder (requires higher doses: 60-80 mg daily) 1, 2
- Panic disorder 1
- Bulimia nervosa 1
- Premenstrual dysphoric disorder 1
- Bipolar depression (in combination with olanzapine) 1
Dosing Recommendations
Adults
For depression and anxiety disorders, start fluoxetine at 10 mg once daily and increase by 10-20 mg increments to an effective dose of 20 mg daily, with a maximum of 60 mg daily. 3
- Standard depression/anxiety dose: 20-40 mg once daily 4, 5
- OCD requires substantially higher doses: 60-80 mg daily for optimal efficacy 1, 2
- Maximum approved dose: 80 mg daily 3, 4
Adolescents (12-17 years)
In adolescents with depression, start at 10 mg daily and titrate slowly to 20 mg, with a maximum of 60 mg daily; only fluoxetine has FDA approval for pediatric depression. 3
- Starting dose: 10 mg once daily 3
- Effective dose: 20 mg daily 3
- Maximum dose: 60 mg daily 3
- Dosing note: Effective dosages in adolescents are generally lower than adult guidelines 3
Special Dosing Considerations
Allow 6-8 weeks for adequate trial, including at least 2 weeks at maximum tolerated dose, before concluding treatment failure. 1
For OCD specifically, use 40-60 mg daily as the optimal dose range, with evaluation not before 8 weeks to allow onset of therapeutic effects. 2
Contraindications
Fluoxetine is absolutely contraindicated with monoamine oxidase inhibitors (MAOIs); allow at least 2 weeks washout when switching between these drug classes. 3, 6
Additional contraindications and cautions:
- Concurrent use with MAOIs due to serotonin syndrome risk 3
- Caution when combining with other serotonergic agents (tramadol, triptans, other antidepressants, St. John's wort) due to increased serotonin syndrome risk 1, 6
- CYP2D6 poor metabolizers have 3.9-fold higher drug exposure at 20 mg and 11.5-fold higher exposure at 60 mg, substantially increasing toxicity risk including QT prolongation and arrhythmias 1
Critical Safety Warnings
Black Box Warning: Suicidality
All SSRIs including fluoxetine carry FDA black box warnings for treatment-emergent suicidality, particularly in adolescents and young adults under age 24, with 14 additional cases per 1000 patients treated compared to placebo. 1
- Highest risk period: First 1-2 weeks after initiation or dose changes 3, 1
- Monitoring requirement: Weekly suicidality assessments during the first month, especially after starting or adjusting doses 1
- Risk is dose-dependent: Deliberate self-harm and suicide risk increase when SSRIs are started at higher doses rather than normal starting doses 3
Behavioral Activation
Patients and families must be informed about possible behavioral activation, including switch to mania, nervousness, insomnia, or suicide-related events, which are more common in adolescents than adults. 3, 1
- Symptoms to monitor: Motor restlessness, insomnia, impulsivity, talkativeness, disinhibited behavior, aggression 1
- Management: If activation appears, temporarily reduce dose; symptoms usually resolve within days 1
- Predictive value: Nervousness or insomnia at treatment start may predict good response to fluoxetine 2
Cardiovascular Risks
Fluoxetine carries FDA warnings about QT prolongation and arrhythmias, particularly in CYP2D6 poor metabolizers or those on CYP2D6 inhibitors. 1
Common Side Effects
The most common adverse effects are nausea, anxiety, insomnia, anorexia, diarrhea, nervousness, and headache; these are dose-related and typically emerge within the first 2-4 weeks, then subside with continued treatment. 4, 5
Additional common effects:
- Gastrointestinal: Nausea, diarrhea, anorexia 4, 5
- Neuropsychiatric: Anxiety, insomnia, nervousness, headache 4, 5
- Sexual dysfunction: Decreased libido, delayed ejaculation, anorgasmia 1, 2
- Weight changes 4
Fluoxetine causes significantly fewer anticholinergic side effects than tricyclic antidepressants and does not affect cardiac conduction intervals in patients without pre-existing cardiovascular disease. 5
Drug Interactions
CYP450 Enzyme Inhibition
Fluoxetine is metabolized through CYP2D6 and is itself a potent inhibitor of CYP2D6, converting approximately 43% of normal metabolizers to poor metabolizer phenotype with chronic use. 1, 7
Fluoxetine strongly inhibits CYP2D6 and can cause dangerous interactions with tamoxifen, codeine, tramadol, and other CYP2D6 substrates. 1
- Clinically significant interactions: Tamoxifen (reduced efficacy), codeine/tramadol (reduced analgesic effect), other drugs metabolized by CYP2D6 1, 7
- Auto-inhibition effect: Higher fluoxetine doses create auto-inhibition that further elevates drug levels 1
Serotonergic Drug Combinations
Combining fluoxetine with other serotonergic agents increases risk of serotonin syndrome, characterized by mental status changes, neuromuscular hyperactivity, and autonomic hyperactivity. 6
Pharmacokinetics
Fluoxetine has a very long elimination half-life of 1-3 days after single dose and 4 days after long-term administration; its active metabolite norfluoxetine has a half-life of 7 days after chronic use. 4
Key pharmacokinetic properties:
- Bioavailability: Approximately 72% 4
- Time to peak: 4-8 hours 4
- Protein binding: 94% 4
- Active metabolite: Norfluoxetine (also inhibits serotonin reuptake) 4
- Advantage of long half-life: Essentially precludes withdrawal phenomenon and provides buffer if doses are occasionally missed 1, 7
Treatment Duration
Continue fluoxetine for 4-9 months after satisfactory response for first-episode major depression; longer duration (≥1 year) is recommended for patients with recurrent episodes. 1
For OCD, maintenance therapy should continue for at least 12-24 months after remission, with longer durations frequently needed due to high relapse risk. 1
Monitoring Requirements
Initial Phase (First 1-2 Months)
Contact (in-person or telephone) should occur after treatment initiation to review understanding, adherence, current status, and access to educational materials about depression. 3
Monitor for treatment-emergent suicidality closely during the first 1-2 weeks after starting or adjusting doses, especially in patients ≤24 years. 1
Ongoing Monitoring
Assess treatment response at 4 weeks and 8 weeks using standardized symptom rating scales; evaluate adherence, side effects, and patient satisfaction. 1
If little improvement after 8 weeks despite good adherence, adjust the regimen by switching to a different SSRI or SNRI, or adding psychological intervention. 1
Discontinuation
Fluoxetine should be slowly tapered when discontinued to minimize risk of withdrawal effects, though it has the lowest risk of discontinuation syndrome among SSRIs due to its long half-life. 3, 1
- Withdrawal symptoms: Dizziness, nausea, sensory disturbances 1
- Tapering advantage: Long half-life provides natural taper effect 1
Special Populations
Pediatric Considerations
Fluoxetine is the only antidepressant FDA-approved for pediatric depression and should be the first-line medication choice in this population. 3, 1
Behavioral activation and suicidality monitoring are especially critical in adolescents, who experience these effects more frequently than adults. 1
Geriatric Patients
Geriatric patients respond as well to fluoxetine as to tricyclic antidepressants like doxepin, with a superior safety profile. 5
CYP2D6 Poor Metabolizers
Consider genetic testing for CYP2D6 and CYP2C19 to guide dosing, as poor metabolizers have dramatically increased drug exposure and toxicity risk. 1
Combination with Psychotherapy
Combination treatment with cognitive-behavioral therapy (CBT) or interpersonal therapy (IPT-A) plus fluoxetine is superior to either alone for anxiety disorders and should be offered preferentially when available. 3, 1
The American College of Physicians recommends CBT or interpersonal therapy as first-line treatment for comorbid anxiety and depression, with fluoxetine as the preferred pharmacologic option when psychotherapy is unavailable, not preferred, or symptoms are severe. 1
Common Pitfalls to Avoid
Do not discontinue fluoxetine prematurely; approximately 38% of patients do not achieve response during the initial 6-8 weeks, and full therapeutic effects may take up to 12 weeks. 1
Do not start fluoxetine at higher than recommended doses, as this increases risk of deliberate self-harm and suicide-related events. 3
Do not combine fluoxetine with MAOIs or use caution with other serotonergic agents due to serotonin syndrome risk. 3, 6
Do not use fluoxetine as first-line in patients with marked agitation, as it is classified as "activating" and may worsen agitation; consider sertraline instead. 1
Do not prescribe fluoxetine to patients taking tamoxifen, as CYP2D6 inhibition reduces tamoxifen efficacy. 1