Anti-depressants, selective serotonin reuptake inhibitors

Medications listed in the tables and non-FDA approved indications included in these retrospective criteria are not indicative of Texas Vendor Drug Program formulary coverage.

  • Initially developed
    • March 2017
  • Revision history
    • April 23, 2021; March 2019

1.1. Adults

The FDA requires that all antidepressant drugs display a black box warning describing the potential for increased suicidal thinking and behavior 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. Young adult patients prescribed antidepressant drugs should be closely monitored for changes in behavior.

Selective serotonin reuptake inhibitor (SSRI) antidepressant drugs are FDA-approved for use in major depressive disorder (MDD), obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder (PD), premenstrual dysphoric disorder (PMDD), and posttraumatic stress disorder (PTSD). Recently, paroxetine has been approved to manage moderate to severe vasomotor symptoms associated with menopause (VMS). Combination therapy is FDA-approved for bipolar I disorder (BD) and treatment-resistant depression (TRD).

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 - Monotherapy

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

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

Treatment Indication Drug Name Available Dosage Strengths Literature Based Maximum Dosage FDA Approved Maximum Recommended Dosage
  citalopram (Celexa®) 10 mg, 20 mg, 40 mg tablets; 10 mg/ 5 mL oral solution ≥6 years of age: 40 mg/ day Not FDA approved for children & adolescents
MDD escitalopram (Lexapro®, generics) 5 mg, 10 mg, 20 mg tablets; 5 mg/5 mL oral solution
  • 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
MDD fluoxetine (Prozac®, generics) 10 mg, 20 mg, 40 mg capsules; 10 mg, 20 mg, 40 mg, 60 mg tablets; 20 mg/5 mL solution 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
BD fluoxetine (Prozac Pulvules®) 10 mg, 20 mg, 40 mg pulvules   10 to 17 years of age: 50 mg/ day^
OCD fluvoxamine (generics) IR: 25 mg, 50 mg, 100 mg tablets
  • 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#
OCD Fluvoxamine controlled release (Luvox CR®, generics) CR: 100 mg, 150 mg
  • 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
OCD sertraline (Zoloft®, generics) 25 mg, 50 mg, 100 mg tablets; 20 mg/mL oral concentrate 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 greater than 50 mg daily should be administered in divided doses
  • ^ In combination with olanzapine

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 Impairment

Drug Name  Dosage in Renal Impairment
Citalopram Severe renal impairment (creatinine clearance less than 20 mL/min): use cautiously, as potential exists for active metabolites to accumulate with associated adverse effects
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 contraindicated (DrugReax) major (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 major (DrugReax) 2-major (CP)
SSRIs MAOIs increased risk of serotonin syndrome (e.g., mental status changes, hyperpyrexia, 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 (DrugReax) 1-severe (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 major (DrugReax) 2-major (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 (DrugReax) 1-severe (CP)

Legend:

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

5. References

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