1.1. Adults

The FDA requires that all antidepressant drugs display a black box warning describing the potential for increased suicidal thinking and behavior compared to placebo when prescribed to young adults (18 to 24 years of age) with MDD and other psychiatric disorders. In short-term clinical trials, the suicide risk was increased in young adults managed with antidepressants compared to those receiving placebo in the first few months of treatment. Suicide risk was not shown to increase in adults over 24 years of age, and patients 65 years of age and older manifested a decreased suicide risk. Patients of all ages prescribed antidepressant drugs should be closely monitored for changes in behavior, clinical worsening, or suicidality1-2.

Citalopram is FDA approved for treatment of Major Depressive Disorder (MDD), Escitalopram is FDA approved for Generalized Anxiety Disorder (GAD) and MDD. Fluoxetine is FDA approved for Bipolar I Disorder (BD), Bulimia Nervosa (BN), Obsessive Compulsive Disorder (OCD), Panic Disorder (PD), Premenstrual Dysphoric Disorder (PMDD), and MDD. Fluvoxamine is FDA approved for OCD. Paroxetine is FDA approved for Seasonal Affective Disorder (SAD), Post Traumatic Stress Disorder (PTSD), Vasomotor Symptoms associated with Menopause (VMS), GAD, MDD, OCD, PDD, and PMDD. Sertraline is FDA approved for MDD, OCD, PD, SAD, PTSD, and PMDD. Olanzapine/Fluoxetine is FDA approved for Treatment Resistant Depression (TRD) and BD1-17.

Maximum recommended daily doses for SSRI antidepressant drugs in adults, including the elderly population, are summarized in Tables 1 and 2 for both monotherapy and SSRI combination therapy, respectively. However, in all patients, the lowest effective antidepressant dose should be utilized to minimize unwanted adverse effects. Patient profiles with SSRI antidepressant dosages exceeding these recommendations will be reviewed.

Table 1: Oral SSRI Medications - Adult Maximum Recommended Dosages - Monotherapy3-17
Drug Name Available Dosage Strengths Treatment Indication Maximum Recommended Dosage
citalopram (Celexa®, generics) 10 mg, 20 mg, 40 mg tablets; 30 mg capsule; 10 mg/ 5 mL oral solution MDD
  • Less than or equal to 65 years:
    • 40 mg/day
  • Greater than 65 years:
    • 20 mg/day (older than 60 years)
escitalopram (Lexapro®, generics) 5 mg, 10 mg, 20 mg tablets; 5 mg/5 mL oral solution GAD, MDD
  • Less than or equal to 65 years:
    • 20 mg/day
  • Greater than 65 years:
    • 10 mg/day
fluoxetine (Prozac®, generics) 10 mg, 20 mg, 40 mg capsules; 10 mg, 20 mg, 40 mg, 60 mg tablets; 20 mg/5 mL solution  MDD, OCD
  • Less than or equal to 65 years:
    • 80 mg/day
  • Greater than 65 years:
    • 80 mg/day
    BN, PD
  • Less than or equal to 65 years:
    • 60 mg/day
  • Greater than 65 years:
    • 60 mg/day
    BD, TRD
  • Less than or equal to 65 years:
    • 75 mg/day^
  • Greater than 65 years:
    • 75 mg/day^
fluoxetine (Prozac® Weekly, generics) 90 mg delayed-release capsules MDD
  • Less than or equal to 65 years:
    • 90 mg/week
  • Greater than 65 years:
    • 90 mg/week
fluoxetine (Prozac Pulvules®) 10 mg, 20 mg, 40 mg pulvules MDD, OCD
  • Less than or equal to 65 years:
    • 80 mg/ day
  • Greater than 65 years:
    • 80 mg/ day
    BN, PD
  • Less than or equal to 65 years:
    • 60 mg/ day
  • Greater than 65 years:
    • 60 mg/ day
    BD, TRD
  • Less than or equal to 65 years:
    • 75 mg/day ^
  • Greater than 65 years:
    • 75 mg/day ^
fluoxetine (generics) 10 mg, 20 mg capsules PMDD
  • Less than or equal to 65 years:
    • 80 mg/day
  • Greater than 65 years:
    • Not applicable
fluvoxamine (generics) IR: 25 mg, 50 mg, 100 mg tablets
ER: 100 mg, 150 mg 24-hour ER capsules
OCD
  • Less than or equal to 65 years:
    • 300 mg/day*
  • Greater than 65 years:
    • 300 mg/day*
paroxetine mesylate (Pexeva®) 10 mg, 20 mg, 30 mg tablets GAD, MDD
  • Less than or equal to 65 years:
    • 50 mg/day++
  • Greater than 65 years:
    • 40 mg/day
    OCD, PD
  • Less than or equal to 65 years:
    • 60 mg/day
  • Greater than 65 years:
    • 40 mg/day
paroxetine HCl (Paxil®, generics) 10 mg, 20 mg, 30 mg, 40 mg tablets, 10 mg/ 5 mL suspension OCD, PD
  • Less than or equal to 65 years:
    • 60 mg/day++
  • Greater than 65 years:
    • 40 mg/day
    MDD, PTSD
  • Less than or equal to 65 years:
    • 50 mg/day
  • Greater than 65 years:
    • 40 mg/day
    SAD
  • Less than or equal to 65 years:
    • 60 mg/day++
  • Greater than 65 years:
    • 40 mg/day
    GAD
  • Less than or equal to 65 years:
    • 50 mg/day++
  • Greater than 65 years:
    • 40 mg/day
paroxetine HCl (Paxil CR®, generics) 12.5 mg, 25 mg, 37.5 mg 24-hour ER tablets MDD
  • Less than or equal to 65 years:
    • 62.5 mg/day
  • Greater than 65 years:
    • 50 mg/day
    PD
  • Less than or equal to 65 years:
    • 75 mg/day
  • Greater than 65 years:
    • 50 mg/day
    SAD
  • Less than or equal to 65 years:
    • 37.5 mg/day
  • Greater than 65 years:
    • 375 mg/day
    PMDD
  • Less than or equal to 65 years:
    • 25 mg/day
  • Greater than 65 years:
    • Not applicable
Paroxetine mesylate (Brisdelle®, generics) 7.5 mg capsule VMS
  • Less than or equal to 65 years:
    • 7.5 mg/day at bedtime
  • Greater than 65 years:
    • 7.5 mg/day at bedtime
sertraline (Zoloft®, generics) 25 mg, 50 mg, 100 mg tablets; 20 mg/mL oral concentrate MDD, OCD, PD, SAD, PTSD
  • Less than or equal to 65 years:
    • 200 mg/day
  • Greater than 65 years:
    • 200 mg/day +
    PMDD
  • Less than or equal to 65 years:
    • 150 mg/day
  • Greater than 65 years:
    • Not applicable

Legend:

  • BD = bipolar I disorder;
  • BN = bulimia nervosa
  • CR = controlled-release
  • ER = extended-release
  • GAD = generalized anxiety disorder
  • IR = immediate-release
  • MDD = major depressive disorder
  • OCD = obsessive-compulsive disorder
  • PD = panic disorder
  • PMDD = premenstrual dysphoric disorder
  • PTSD = posttraumatic stress disorder
  • SAD = social anxiety disorder
  • VMS = vasomotor symptoms associated with menopause
  • * Fluvoxamine IR doses greater than 100 mg daily should be administered in divided doses, if dose is unequal larger doses should be given at bedtime 
  • ++ Data do not confirm that paroxetine doses greater than 20 mg/day are more effective
  • + Lower doses may be required in elderly patients
  • ^ In combination with olanzapine
     
Table 2: Oral SSRI Medications - Adult Maximum Recommended Dosages – Combination Therapy1-2, 17
Treatment Indication Drug Name Available Dosage Strengths Maximum Recommended Dosage 
BD, TRD olanzapine/ fluoxetine (Symbyax®, generics) 3 mg/ 25 mg, 6 mg/ 25 mg, 12 mg/25 mg, 6 mg/ 50 mg, 12 mg/ 50 mg capsules
  • Less than or equal to 65 years
    • 18 mg/ 75 mg per day
  • Greater than 65 years:
    • 18 mg/ 75 mg per day

Legend:

  • BD = bipolar I disorder
  • TRD = treatment-resistant depression

1.2. Pediatrics

The FDA requires that all antidepressant drugs display a black box warning describing the potential for increased suicidal thinking and behavior when prescribed to children and adolescents with MDD and other psychiatric disorders. In short-term clinical trials, the suicide risk occurred twice as frequently with antidepressant-treated children/adolescents compared to those receiving placebo (4% vs. 2%, respectively) in the first few months of treatment. Pediatric patients prescribed antidepressant drugs should be closely monitored for changes in behavior.

Citalopram and paroxetine are not FDA-approved for use in pediatric patients as safety and effectiveness in this age group have not been well established. The olanzapine/fluoxetine combination is FDA-approved in pediatric patients.

Maximum pediatric recommended doses for SSRI antidepressants approved for use as monotherapy and combination therapy are summarized in Tables 3 and 4, respectively. An additional column reflecting literature-based dosing included in the Texas Health and Human Services Psychotropic Medication Utilization Parameters for Children and Youth in Texas Public Behavioral Health (6th Version) is included in Tables 3 and 4. Dosages exceeding these recommendations will be reviewed.

Table 3: Recommended SSRI Antidepressant Drug Dosages for Pediatric Patients – Monotherapy 1-18
Drug Name Available Dosage Strengths Treatment Indication Literature Based Maximum Dosage FDA Approved Maximum Recommended Dosage
citalopram (Celexa®) 10 mg, 20 mg, 40 mg tablets; 30 mg capsule; 10 mg/ 5 mL oral solution  
  • Greater than or equal to 6 years of age:
    • 40 mg/ day
  • Not FDA approved for children & adolescents
escitalopram (Lexapro®, generics) 5 mg, 10 mg, 20 mg tablets; 5 mg/5 mL oral solution MDD
  • 6-11 years of age:
    • 20 mg/ day
  • Greater than or equal to 12 years of age:
    • 30 mg/day
  • 12 to 17 years of age:
    • 20 mg/day
fluoxetine (Prozac®, generics) 10 mg, 20 mg, 40 mg capsules; 10 mg, 20 mg, 60 mg tablets; 20 mg/5 mL solution MDD
  • Greater than or equal to 6 years of age: 60 mg/ day
  • 8 to 17 years of age: 20 mg/day
    OCD
  • Greater than or equal to 6 years of age: 60 mg/ day
  • 7 to 17 years of age:
    • lower weight children:
      • 30 mg/day
    • higher weight children:
      • 60 mg/day
fluoxetine (Prozac Pulvules®) 10 mg, 20 mg, 40 mg pulvules BD  
  • 10 to 17 years of age: 50 mg/ day^
    MDD
  • 8 to 18 years of age: 20 mg/day
  • 8 to 18 years: 20 mg/day
    OCD
  • 7 to 17 years of age: 60 mg/day
  • 7 to 17 years: 60 mg/day
fluvoxamine (generics) IR: 25 mg, 50 mg, 100 mg tablets OCD
  • Age 8-11 years:
    • 200 mg/day
  • Age 12-17 years:
    • 300 mg/day
  • 8-11 years of age:
    • 200 mg/day#
  • 12 to 17 years of age:
    • 300 mg/day#
Fluvoxamine controlled release (Luvox CR®, generics) CR: 100 mg, 150 mg OCD
  • Age 8-11 years:
    • 200 mg/day
  • Age 12-17 years:
    • 300 mg/day
  • 8-11 years of age:
    • 200 mg/day
  • 12 to 17 years of age:
    • 300 mg/day
sertraline (Zoloft®, generics) 25 mg, 50 mg, 100 mg tablets; 20 mg/mL oral concentrate OCD Age greater than or equal to 6 years: 200 mg/day 6 to 17 years of age: 200 mg/day

Legend:

  • BD = bipolar I disorder
  • IR = immediate-release
  • MDD = major depressive disorder
  • OCD = obsessive-compulsive disorder
  • # Fluvoxamine IR doses > 50 mg daily should be administered in divided doses, if the two doses are unequal the larger dose should be given at bedtime
  • ^ In combination with olanzapine
Table 4: Recommended SSRI Antidepressant Drug Dosages for Pediatric Patients – Combination Therapy1-2, 17-18
Treatment Indication Drug Name Available Dosage Strengths Literature Based Maximum Dosage FDA Approved Maximum Recommended Dosage
BD olanzapine/ fluoxetine (Symbyax®, generics) 3 mg/ 25 mg, 6 mg/ 25 mg, 12 mg/25 mg, 6 mg/ 50 mg, 12 mg/ 50 mg capsules Age 10-17 years: 12 mg olanzapine/50 mg fluoxetine once daily 10 to 17 years of age: 12 mg/50 mg per day

Legend:

  • BD = bipolar I disorder

1.3. Renal Impairment

Many antidepressants do not require significant dosage modifications in renal impairment. However, dosage guidelines for select SSRIs in renal impairment are available. Table 5 summarizes dosage modifications and/or restrictions for specific SSRI antidepressant medications.

Table 5: Select SSRI Antidepressant Dosage Modifications in Renal Impairment1-5, 12-13
Drug Name  Dosage in Renal Impairment
Citalopram
  • Severe renal impairment (creatinine clearance less than 20 mL/min):
    • use cautiously, as specific dosage guidelines not available
Escitalopram
  • Severe renal impairment (creatinine clearance less than 20 mL/min):
    • use cautiously, as specific dosage guidelines not available
Paroxetine (Paxil®, Pexeva®, Paxil CR®)
  • Serum levels, AUC increase as renal function declines; therefore, maximum doses when creatinine clearance less than 30 mL/min are:
    • IR: 40 mg/day
    • CR: 50 mg/day

Legend:

  • CR = controlled-release
  • IR = immediate-release

2. Duration of Therapy

There is no basis for limiting antidepressant therapy duration when used to manage MDD, OCD, GAD, PTSD, or PD as these disorders can all be characterized as chronic conditions.

Clinical trials have documented fluoxetine efficacy in BN management for up to 52 weeks. Fluoxetine has demonstrated efficacy in PMDD for up to 6 months when administered continuously and up to 3 months when administered intermittently. Paroxetine and sertraline have demonstrated efficacy in PMDD for up to 6 months and 12 months, respectively, in clinical trials. Patients should be assessed periodically to determine need for continued treatment. However, the potential exists for PMDD symptoms to worsen with advancing age until patients reach menopause. Patients responding to fluoxetine, paroxetine, or sertraline therapy for PMDD may benefit from chronic administration.

Paroxetine treatment for VMS exceeding 24 weeks has not been evaluated in clinical trials. Additionally, paroxetine dosages used to manage VMS are not FDA-approved to manage psychiatric conditions, as the dose contained in Brisdelle® is lower than the recommended doses used to manage psychiatric disorders. Patients requiring paroxetine for psychiatric disorders should discontinue Brisdelle® and initiate therapy with a paroxetine formulation FDA-approved for psychiatric use.

3. Duplicative Therapy

The concurrent use of two SSRI antidepressant medications with the same spectrum of activity may not be justified and will be reviewed.

4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions. The following drug-drug interactions summarized in Table 6 are considered clinically relevant for SSRI antidepressants. Only those drug-drug interactions identified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed.

Table 6: Major Drug-Drug Interactions for SSRI Antidepressant Drugs
Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level #
fluoxetine ergot derivatives increased risk of ergotism due to fluoxetine inhibition of CYP3A4-mediated ergot metabolism avoid concurrent use moderate (CP)
SSRIs anticoagulants co-administration may increase bleeding risk due to impaired platelet aggregation most likely resulting from platelet serotonin depletion patients should be monitored for signs/symptoms of bleeding (including INR) if combined therapy necessary major (DrugReax) 3-moderate (CP)
SSRIs drugs with serotonergic properties (e.g., antipsychotics, tramadol, triptans) or dopamine antagonist properties (e.g., phenothiazines, metoclopramide) combined use may increase risk of serotonin syndrome or neuroleptic malignant syndrome (NMS) cautiously administer concurrently and closely observe for signs/symptoms of serotonin syndrome or NMS, especially with treatment initiation or dosage increases moderate(CP)
SSRIs MAOIs increased risk of serotonin syndrome (e.g., mental status changes, hyperpyrexia, autonomic instability, neuromuscular symptoms, seizures and/or gastrointestinal symptoms, restless, shivering, hypertonia, tremor) due to serotonin metabolism inhibition by monoamine oxidase allow 14 days after MAOI discontinuation before initiating other antidepressant therapy; wait 5 weeks after discontinuing fluoxetine before initiating MAOIs contraindicated (CP)
SSRIs tramadol increased risk of serotonin syndrome and seizures due to increased nervous system serotonin concentrations (additive effects on serotonin, SSRI inhibition of CYP2D6-mediated tramadol metabolism) as well as potential reduced seizure threshold with SNRIs, SSRIs avoid concurrent use moderate (CP)
SSRIs pimozide increased risk of pimozide toxicity including cardiotoxicity (QT prolongation) due to elevated plasma concentrations or additive effects on QT interval avoid concurrent use contraindicated (DrugReax) 1-severe (CP)
SSRIs select phenothiazines (mesoridazine, thioridazine) increased risk of somnolence, bradycardia and serious cardiotoxicity (QT prolongation, torsades de pointes) due to potential additive effects on QT interval prolongation; increased thioridazine serum concentrations/ decreased thioridazine elimination and potential for serious cardiac arrhythmias due to CYP2D6 inhibition by duloxetine, fluoxetine, or paroxetine avoid concurrent use; if adjunctive use necessary, monitor for increased pharmacologic/toxic effects; adjust dose as necessary contraindicated (CP)
Citalopram, Escitalopram Chlorpromazine Increased risk of QT prolongation and torsade’s de pointes. SSRIs may increase serum concentration of chlorpromazine leading to phenothiazine related reactions. Increased risk for serotonin syndrome. Avoid concurrent use. If adjunctive use is necessary, ECG monitoring is recommended. Monitor for increased pharmacologic/toxic effects; adjust dose as necessary Major (CP)
SSRI Chlorpromazine Increased risk of QT prolongation and torsade’s de pointes. SSRIs may increase serum concentration of chlorpromazine leading to phenothiazine related reactions. Increased risk for serotonin syndrome. Should be avoided if possible. If adjunctive use is necessary, ECG monitoring is recommended. Monitor for increased pharmacologic/toxic effects; adjust dose as necessary Major (CP)

Legend:

  • MAOI = monoamine oxidase inhibitor
  • SNRI = serotonin-norepinephrine reuptake inhibitor
  • SSRI= selective serotonin reuptake inhibitor
  • # CP = Clinical Pharmacology

5. References

  1. IBM Micromedex DRUGDEX (electronic version). IBM Watson health, Greenwood Village, Colorado, USA. Available at: www-micromedexsolutions-com.libproxy.uthscsa.edu/ (cited: January 18th, 2023)
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2021. Available at: http://clinicalpharmacologyip.com.ezproxy.lib.utexas.edu/. Accessed January 18, 2023.
  3. Citalopram [Package Insert]. Morristown. NJ: Almatica Pharma LLC.https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2f815b0c-6da7-cb61-e89c-7de628092d0d&audience=consumer. February 2022.
  4. Citalopram capsules [Package Insert]. Morristown. NJ: Almatica Pharma LLC. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2f815b0c-6da7-cb61-e89c-7de628092d0d. February 2022.
  5. Escitalopram [Package Insert]. East Windsor. NJ: Aurobindo Pharma Limited. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=d5fbc8ce-bd41-4bd0-b413-0dea97e596c3&type=display. October 2021.
  6. Prozac [Package Insert]. Indianapolis, IN: Dista Products Company. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2f815b0c-6da7-cb61-e89c-7de628092d0d&audience=consumer. February 2022.
  7. Prozac [Package Insert]. Bachupally, India: Dr. Reddys’ Laboratory Limited. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=887fc670-db67-4cfe-967b-46b38375dae5&type=display. June 2021.
  8. Prozac [Package Insert]. Bachupally, India: Dr. Reddys’ Laboratory Limited. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=887fc670-db67-4cfe-967b-46b38375dae5&type=display. June 2021.
  9. Fluoxetine [Package Insert]. Indrad, India: Torrent Pharmaceuticals Limited. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=dcebc7cf-6f95-4f7a-a22b-c7d2e0f04d74&type=display. November 2022.
  10. Fluvoxamine Maleate Extended Release [Package Insert]. Princeton, NJ: Bion Pharma Inc. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=9924422b-7c90-42bf-a680-ffd92063d5f0&type=display. October 2020.
  11. Pexeva [Package Insert]. Roswell, GA: Sebela Pharmaceutics  Inc. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=50fe88bd-f0dd-5fad-e054-00144ff8d46c&type=display. July 5, 2022. 
  12. Paxil CR [Package Insert]. Toronto, ON: Apotex Inc. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=483bd97f-c4d0-4e23-aaa8-6334f4471e0c&type=display. December 6, 2022. 
  13. Paxil [Package Insert]. Toronto, ON: Apotex Inc. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=584ace29-6e40-432f-950f-ab7e98653d32&audience=professional. December 6, 2022. 
  14. Brisdelle [Package Insert]. Roswell, GA: Sebela Pharmaceutics  Inc. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=50361fc8-8fba-1c45-e054-00144ff88e88&type=display. June 16, 2022.
  15. Fluvoxamine Maleate [Package Insert]. Toronto, ON: Apotex Inc. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6Eeb14df-6fcf-a737-5359-5744eb4accea&audience=consumer. November 2021.
  16. Sertraline [Package Insert]. Morristown, NJ: Almatica Pharma LLC. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=8c8bcba9-eaeb-aa44-f9ea-b580de55a439&type=display. October 4, 2021. 
  17. Symbyax [Package Insert]. Indianapolis, IN: Lilly USA LLC. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=6b28c424-0b7e-4b75-b090-f116b113554e&type=display. December 23, 2021.
  18. Texas Health and Human Services. Psychotropic medication utilization parameters for children and youth in Texas public behavioral health (6 version), June 2019. Available at: https://hhs.texas.gov/sites/default/files/documents/doing-business-with-hhs/provider-portal/facilities-regulation/psychiatric/psychotropic-medication-utilization-parameters.pdf. Accessed January 18, 2023.
  19. National Institutes of Health. (n.d.). DailyMed. U.S. National Library of Medicine. Retrieved January 18, 2023, from https://dailymed.nlm.nih.gov/dailymed/index.cfm 
  20. DRUGS@FDA: FDA-approved drugs. FDA. (n.d.). Retrieved January 18, 2023, from https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm