Anti-depressants, oral (other) - Index

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

  • Revision history
    • April 28, 2023
    • April 23, 2021
    • March 2019
    • March 2017
    • April 2015
    • March 2015
    • June 2013
    • July 2011
    • Sep. 2009
    • Aug. 2009
    • March 2009
    • Dec. 2003
    • Nov. 2002
    • Oct. 2002
    • Nov. 2001
    • Sept. 2001
    • Oct. 2000
    • Jan. 2000
    • Oct. 1999
    • Oct. 1998
    • Sept. 1997
    • Dec. 1996
  • Initially developed
    • Jan. 1995

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 major depressive disorder (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 suicidality. When treating elderly patients, caution is indicated when administering these medications due to risk of hyponatremia 1-43.

Nonselective serotonin reuptake inhibitor monotherapy antidepressant drugs are FDA-approved for use in MDD, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), and panic disorder (PD). Additionally, bupropion is FDA-approved for seasonal affective disorder (AD) and smoking cessation (SC), milnacipran is FDA-approved for fibromyalgia (F) management, and duloxetine is FDA-approved for neuropathic pain (NP), F, and chronic musculoskeletal pain in adults (CMP). Recently, doxepin has received FDA approval for insomnia in adults (I). Vilazodone, a selective serotonin reuptake inhibitor (SSRI) as well as a partial agonist at the 5-HT1A receptor, is FDA-approved for MDD. Levomilnacipran (Fetzima®), a serotonin and norepinephrine reuptake inhibitor (SNRI) and an enantiomer of milnacipran, has also been FDA-approved for use in treating MDD. The antidepressant agent, vortioxetine, an SSRI that also acts as an agonist at 5-HT1A receptors and an antagonist at 5-HT3 receptors, has gained FDA approval to manage MDD. Combination therapy is FDA-approved for severe depression, and moderate anxiety/agitation/depression 1-43.

Maximum recommended daily doses for antidepressant drugs in adults, including the elderly population, are summarized in Tables 1-6. Maximum recommended dosages for antidepressant combination therapy are summarized in Table 7. However, in all patients, the lowest effective antidepressant dose should be utilized to minimize unwanted adverse effects. Patient profiles with antidepressant dosages exceeding these recommendations will be reviewed.

Table 1: Adult and Elderly Maximum Recommended Antidepressant Dosages (Monotherapy) - Tricyclic Antidepressants1-18
Drug Name Available Dosage Strengths Treatment Indication Maximum Recommended Dosage
amitriptyline generics: 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg tablets MDD
  • Less than or equal to 65 years:
    • 150 mg/day
  • Greater than 65 years:
    • 150 mg/day divided into three doses
amoxapine (generics) 25 mg, 50 mg, 100 mg, 150 mg tablets MDD
  • Less than or equal to 65 years:
    • 400 mg/day*
  • Greater than 65 years:
    • 300 mg/day *
clomipramine (Anafranil®, generics) 25 mg, 50 mg 75 mg capsules OCD
  • Less than or equal to 65 years:
    • 250 mg/day
  • Greater than 65 years:
    • 250 mg/day
desipramine (generics) 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg tablets MDD
  • Less than or equal to 65 years:
    • 300 mg/day
  • Greater than 65 years:
    • 150 mg/day
doxepin (generics) 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg capsules; 10 mg/mL oral concentrate MDD
  • Less than or equal to 65 years:
    • mild to moderate illness:
      • 150 mg/day
  • Greater than 65 years:
    • mild to moderate illness:
      • 150 mg/day
     
  • Less than or equal to 65 years:
    • severe illness:
      • 300 mg/day
  • Greater than 65 years:
    • severe illness:
      • 300 mg/day
     
  • Less than or equal to 65 years:
    • mild to moderate illness:
      • 150 mg/day
  • Greater than 65 years:
    • mild to moderate illness:
      • 150 mg/day
     
  • Less than or equal to 65 years:
    • severe illness:
      • 300 mg/day
  • Greater than 65 years:
    • severe illness:
      • 300 mg/day
doxepin (Silenor®) 3 mg, 6 mg tablets I
  • Less than or equal to 65 years:
    • 6 mg/day
  • Greater than 65 years:
    • 6 mg/day
imipramine (Tofranil®, generics) generics:10 mg, 25 mg, 50 mg tablets; 75 mg 100 mg, 125 mg, 150 mg capsules
Tofranil®: 10 mg, 25 mg tablets		 MDD
  • Less than or equal to 65 years:
    • 200 mg/day
  • Greater than 65 years:
    • 100 mg/day ^
imipramine pamoate (generics) generics: 10 mg, 25 mg, 50 mg tablets; Tofranil®: 10 mg, 25 mg tablets    
nortriptyline (Pamelor®, generics) 10 mg, 25 mg, 50 mg, 75 mg capsules; 10 mg/5 mL oral solution (generic only) MDD
  • Less than or equal to 65 years:
    • 150 mg/day
  • Greater than 65 years:
    • 50 mg/day
protriptyline (generics) 5 mg, 10 mg tablets MDD
  • Less than or equal to 65 years:
    • 60 mg/day
  • Greater than 65 years:
    • 20 mg/day+
trimipramine (generics) 25 mg, 50 mg 100 mg capsules MDD
  • Less than or equal to 65 years:
    • 200 mg/day
  • Greater than 65 years:
    • 100 mg/day

Legend:

  • I = insomnia
  • MDD = major depressive disorder
  • OCD = obsessive-compulsive disorder 
  • * The maximum amoxapine dose in elderly patients and in most adults is 300 mg/day. Those patients Less than or equal to 65 years of age who have not responded adequately to a two-week trial utilizing 300 mg/day may receive a trial of 400 mg amoxapine per day.  
  • #Doxepin is also recommended for depression and anxiety associated with psychoneurosis, alcoholism, and organic disease.
  • ^ May increase to 150 mg/day, if needed; doses over 200 mg are not recommended; doses usually do not exceed 100 mg/day in geriatric patients.
  • ** When doses above 100 mg daily are administered, plasma levels of nortriptyline should be maintained in the optimum range of 50 ng/mL to 150 ng/mL.
  • + Elderly patients should usually be given lower than average protriptyline doses. Elderly patients receiving protriptyline doses greater than 20 mg daily should receive close cardiac monitoring.
Table 2: Adult and Elderly Maximum Recommended Antidepressant Dosages (Monotherapy) - Tetracyclic Antidepressants1-2, 19-20
Drug Name Available Dosage Strengths Treatment Indication Maximum Recommended Dosage
mirtazapine (Remeron®, generics) 7.5 mg, 15 mg, 30 mg, 45 mg tablets; 15 mg, 30 mg, 45 mg orally disintegrating tablets MDD
  • Less than or equal to 65 years:
    • 45 mg/day
  • Greater than 65 years:
    • 45 mg/day

Legend:

  • MDD = major depressive disorder 
Table 3: Adult and Elderly Maximum Recommended Antidepressant Dosages (Monotherapy) - Monoamine Oxidase Inhibitors 1-2, 21-25
Drug Name Available Dosage Strengths Treatment Indication Maximum Recommended Dosage 
isocarboxazid (Marplan®) 10 mg tablets MDD
  • Less than or equal to 65 years:
    • 60 mg/day
  • Greater than 65 years:
    • 60 mg/day *
phenelzine (Nardil®, generics) 15 mg tablets Depression*
  • Less than or equal to 65 years:
    • 90 mg/day
  • Greater than 65 years:
    • 90 mg/day *
selegiline (EMSAM®) transdermal patch  6 mg/ 24 hours, 9 mg/ 24 hours, 12 mg/ 24 hours transdermal patch MDD
  • Less than or equal to 65 years:
    • 12 mg/ 24 hours
  • Greater than 65 years:
    • 6 mg/24 hours
tranylcypromine (Parnate®, generics) 10 mg tablets MDD
  • Less than or equal to 65 years:
    • 60 mg/day
  • Greater than 65 years:
    • 60 mg/day*

Legend:

  • MDD = major depressive disorder
  • ▪ Use MAOIs cautiously in elderly patients due to a greater risk of morbidity if hypertensive crisis develops.
  • * Phenelzine has been found to be effective in depressed patients clinically characterized as "atypical,” “nonendogenous,” or “neurotic.”
  • ^ Indicated for MDD in patients who have not responded adequately to other antidepressants.
Table 4: Adult and Elderly Maximum Recommended Antidepressant Dosages (Monotherapy) – Serotonin and Norepinephrine Reuptake Inhibitors 1-2, 26-32
Drug Name Available Dosage Strengths Treatment Indication Maximum Recommended Dosage
desvenlafaxine (Pristiq®, generics) 25 mg, 50 mg 100 mg 24-hour ER tablets MDD
  • Less than or equal to 65 years:
    • 400 mg/day^
  • Greater than 65 years:
    • 400 mg/day^
duloxetine (Cymbalta®, Drizalma Sprinkle®, generics) 30 mg, 60 mg delayed-release capsules
Generic only: 20, 40 mg		 CMP, F, NP
  • Less than or equal to 65 years:
    • 60 mg/day
  • Greater than 65 years:
    • 60 mg/day
    GAD, MDD
  • Less than or equal to 65 years:
    • 120 mg/day #
  • Greater than 65 years:    
    • 120 mg/day #
levomilnacipran (Fetzima®) 20 mg, 40 mg 80 mg, 120 mg 24-hour ER capsules MDD
  • Less than or equal to 65 years:
    • 120 mg/day
  • Greater than 65 years:
    • 120 mg/day
milnacipran (Savella®)12.5 mg, 25 mg, 50 mg 100 mg tablets 12.5 mg, 25 mg, 50 mg 100 mg tablets F
  • Less than or equal to 65 years:
    • 200 mg/day
  • Greater than 65 years:
    • 200 mg/day
venlafaxine (generics) 25 mg, 37.5 mg, 50 mg, 75 mg, 100 mg IR tablets MDD
  • Less than or equal to 65 years:
    • 375 mg/day ~
  • Greater than 65 years:
    • 375 mg/day ~
venlafaxine (Effexor XR®, generics) 37.5 mg, 75 mg, 150 mg 24-hour ER capsules  
  • Less than or equal to 65 years:
    • 225 mg/day
  • Greater than 65 years:
    • 225 mg/day
    SAD
  • Less than or equal to 65 years:
    • 75 mg/day
  • Greater than 65 years:
    • 75 mg/day
venlafaxine (generics) 37.5 mg, 75 mg, 150 mg, 225 mg 24-hour ER tablets MDD
  • Less than or equal to 65 years:
    • 225 mg/day
  • Greater than 65 years:
    • 225 mg/day
    SAD
  • Less than or equal to 65 years:
    • 75 mg/day
  • Greater than 65 years:
    • 75 mg/day

Legend:

  • CMP = chronic musculoskeletal pain
  • F = fibromyalgia
  • GAD = generalized anxiety disorder
  • MDD = major depressive disorder
  • NP = neuropathic pain
  • PD = panic disorder
  • SAD = social anxiety disorder
  • ^ In studies, desvenlafaxine doses up to 400 mg per day were no more effective than 50 mg daily doses and were associated with increased adverse events.
  • # Duloxetine doses of 120 mg, while effective, are no more effective than 60 mg daily doses.
  • ~ The maximum recommended venlafaxine dose is 225 mg/day for moderately depressed outpatients. Dosages Greater than 225 mg/day in moderately depressed outpatients do not demonstrate additional efficacy. However, more severely depressed inpatients may respond to venlafaxine dosages up to 375 mg/day.
Table 5: Adult and Elderly Maximum Recommended Antidepressant Dosages (Monotherapy) – Selective Serotonin Reuptake Inhibitors (SSRIs)/5-HT1A Receptor Agonists and SSRIs/5-HT1A Receptor Agonists/5-HT3 Receptor Antagonists 1-2, 33-34
Drug Name Available Dosage Strengths Treatment Indication Maximum Recommended Dosage
vilazodone (Viibryd®) 10 mg, 20 mg, 40 mg tablets MDD
  • Less than or equal to 65 years:
    • 40 mg/day
  • Greater than  65 years:
    • 40 mg/day
vortioxetine (Trintellix®) 5 mg, 10 mg, 20 mg tablets MDD
  • Less than or equal to 65 years:
    • 20 mg/day
  • Greater than  65 years:    
    • 20 mg/day

Legend:

  • MDD = major depressive disorder 

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Table 6: Adult and Elderly Maximum Recommended Antidepressant Dosages (Monotherapy) – Miscellaneous Agents1-2, 35-40
Drug Name Available Dosage Strengths Treatment Indication Maximum Recommended Dosage
bupropion (generics)  75 mg, 100 mg IR tablets MDD
  • Less than or equal to 65 years:
    • 450 mg/day
  • Greater than 65 years:
    • 450 mg/day
bupropion (Forfivo XL®, Wellbutrin XL®, generics) Wellbutrin XL®, generics: 150 mg, 300 mg 24-hour ER tablets
Forfivo XL®, generics:
450 mg 24-hour-ER tablets		 MDD
  • Less than or equal to 65 years:
    • 450 mg/day
  • Greater than 65 years:
    • 450 mg/day
bupropion (Wellbutrin SR®, generics) 100 mg, 150 mg, 200 mg 12-hour ER tablets MDD
  • Less than or equal to 65 years:
    • 400 mg/day
  • Greater than 65 years:
    • 400 mg/day
bupropion (Aplenzin®) 174 mg, 348 mg, 522 mg 24-hour ER tablets MDD
  • Less than or equal to 65 years:
    • 522 mg/day
  • Greater than 65 years:
    • 522 mg/day
    AD
  • Less than or equal to 65 years:
    • 348 mg/day
  • Greater than 65 years:
    • 348 mg/day
bupropion (Wellbutrin XL®, generics) Wellbutrin XL®, generics: 150 mg, 300 mg 24-hour ER tablets AD
  • Less than or equal to 65 years:
    • 300 mg/day
  • Greater than 65 years:
    • 300 mg/day
bupropion (generics) 150 mg 12-hour ER tablets SC
  • Less than or equal to 65 years:
    • 300 mg/day
  • Greater than 65 years:
    • 300 mg/day
nefazodone (generics) 50 mg, 100 mg, 150 mg, 200 mg, 250 mg tablets MDD
  • Less than or equal to 65 years:
    • 600 mg/day
  • Greater than 65 years:
    • 600 mg/day
trazodone (generics) 50 mg, 100 mg, 150 mg, 300 mg IR tablets MDD
  • Less than or equal to 65 years:
    • outpatients:
      • 400 mg/day
  • Greater than 65 years:
    • outpatients:
      • 400 mg/day

Legend:

  • AD = seasonal affective disorder
  • MDD = major depressive disorder
  • SC = smoking cessation
Table 7: Adult Maximum Recommended Antidepressant Dosages (Combination Therapy) 1-2, 41-42
Treatment Indication Drug Name  Available Dosage Strengths Maximum Recommended Dosage
severe depression chlordiazepoxide/ amitriptyline (generics) 5 mg/ 12.5 mg, 10 mg/25 mg tablets 60 mg/150 mg/day * 
anxiety/agitation/depression perphenazine/ amitriptyline (generics) 2 mg/10 mg, 4 mg/10 mg, 2 mg/25 mg, 4 mg/25 mg, 4 mg/50 mg tablets 16 mg/200 mg/day

Legend:

  • * Lower chlordiazepoxide/amitriptyline dosages and close monitoring are recommended in elderly patients due to greater risks for impaired cognitive/motor function.

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.

Maximum recommended doses for non-SSRI antidepressants approved for use as monotherapy in pediatric patients are summarized in Tables 8-10. 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 8-11. Dosages exceeding these recommendations will be reviewed.

Table 8: Pediatric Maximum Recommended Antidepressant Drug Dosages (Monotherapy) - Tricyclic Antidepressants1-2, 3-4, 6-9, 12-18, 44
Drug Name Available Dosage Strengths Treatment Indication Literature Based Maximum Dosage FDA Approved Maximum Recommended Dosage
amitriptyline (generics) generics: 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg tablets MDD Reviewed but not included/ recommended
  • Greater than 12 years of age: 50 mg daily divided into three doses^  
clomipramine (Anafranil®, generics) 25 mg, 50 mg 75 mg capsules OCD Age 10-17 years: 3 mg/kg/day or 200 mg/ day, whichever is less
  • Greater than or equal to 10 years of age:
    • 3 mg/kg/day or 200 mg/day, whichever is less
desipramine (Norpramin®, generics) generics: 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg tablets
Norpramin®: 10 mg, 25 mg tablets		 aa Reviewed but not included/ recommended
  • adolescents:  
    • 150 mg/day
imipramine (Tofranil®, generics) generics:10 mg, 25 mg, 50 mg tablets; Tofranil®: 10 mg, 25 mg, 50 mg tablets MDD Reviewed but not included/ recommended
  • adolescents:
    • 100 mg/day
    nocturnal enuresis  
  • 6-11 years of age:
    • 2.5 mg/kg/day up to 50 mg/day
  • Greater than or equal to 12 years of age:
    • 2.5 mg/kg/day up to 75 mg/day
nortriptyline (Pamelor®, generics) 10 mg, 25 mg, 50 mg, 75 mg capsules; 10 mg/5 mL oral solution (generic only) MDD Reviewed but not included/ recommended
  • adolescents:
    • 50 mg/day
protriptyline 5 mg, 10 mg tablets MDD Reviewed but not included/ recommended
  • adolescents:  
    • 30 mg/day*
trimipramine (generics) 25 mg, 50 mg 100 mg capsules MDD Reviewed but not included/recommended
  • adolescents:  
    • 100 mg/day

Legend:

  • MDD = major depressive disorder
  • OCD = obsessive-compulsive disorder
  • ^ In general, lower dosages are recommended for these patients. Ten milligrams 3 times daily with 20 mg at bedtime may be satisfactory in adolescent and elderly patients who do not tolerate higher dosages.
  • # imipramine pamoate is not approved for pediatric use
  • * Adolescents should usually be given lower than average protriptyline doses
Table 9: Pediatric Maximum Recommended Antidepressant Drug Dosages (Monotherapy)– Monoamine Oxidase Inhibitors1-2, 21, 24, 44
Drug Name Available Dosage Strengths Treatment Indication Literature Based Maximum Dosage FDA Approved Maximum Recommended Dosage
isocarboxazid (Marplan®) 10 mg tablets MDD Not reviewed
  • Greater than or equal to 16 years of age:  
    • 60 mg/day
selegiline (EMSAM®) transdermal patch 6 mg/ 24 hours, 9 mg/ 24 hours, 12 mg/ 24 hours transdermal patch MDD Age ≥ 12 years: 12 mg per 24 hours Not approved for pediatric use

Legend:

  • MDD = major depressive disorder
Table 10: Pediatric Maximum Recommended Antidepressant Drug Dosages (Monotherapy) – Serotonin and Norepinephrine Reuptake Inhibitors1-2, 26-28, 44
  Drug Name Available Dosage Strengths Treatment Indication Literature Based Maximum Dosage FDA Approved Maximum Recommended Dosage
  desvenlafaxine (Pristiq®, generics) 25 mg, 50 mg 100 mg 24-hour ER tablets Major depressive disorder Age 7-17 years: 50 mg/day Not approved for pediatric use
  duloxetine (Cymbalta®, generics) 20 mg, 30 mg, 40 mg 60 mg delayed-release capsules General anxiety disorder Age 7-17 years: 120 mg/day
  • 7-17 years of age:  
    • 120 mg/day
      Fibromyalgia  
  • 13 years of age:
    • 60 mg/ day
Table 11: Pediatric Maximum Recommended Antidepressant Drug Dosages (Monotherapy) - Tetracyclic Antidepressants 1-2, 19-20, 44
Drug Name Available Dosage Strengths Treatment Indication Literature Based Maximum Dosage FDA Approved Maximum Recommended Dosage
mirtazapine (Remeron®, generics) 7.5 mg, 15 mg, 30 mg, 45 mg tablets; 15 mg, 30 mg, 45 mg orally disintegrating tablets Major depressive disorder Age greater than or equal to 3 years: 45 mg/day Not approved for pediatric use

1.3. Renal Impairment

Many antidepressants do not require significant dosage modifications in renal impairment. However, dosage guidelines for select non-SSRI antidepressants in renal impairment are available. Tables 12-15 summarizes dosage modifications and/or restrictions for specific non-SSRI antidepressant medications.

Table 12: Select non-SSRI Antidepressant Dosage Modifications in Renal Impairment – Tetracyclic Antidepressants1-2, 19-20
Drug Name Dosage in Renal Impairment 
Mirtazapine Initiate with the lowest dosage and titrate slowly as renal clearance reduced by approximately 30% in moderate (Creatinine clearance 11-39 ml/min) and 50% in severe (Creatinine clearance less than 10 ml/min) renal impairment
Table 13: Select non-SSRI Antidepressant Dosage Modifications in Renal Impairment – Monoamine Oxidase Inhibitors1-2, 21-23, 25
Drug Name Dosage in Renal Impairment 
Isocarboxazid Contraindicated in severe renal impairment; use cautiously in moderate renal impairment due to potential accumulation of active metabolites
Phenelzine Contraindicated for use in severe renal impairment
Table 14: Select non-SSRI Antidepressant Dosage Modifications in Renal Impairment – Serotonin and Norepinephrine Reuptake Inhibitors 1-2, 26-32
Drug Name Dosage in Renal Impairment 
Desvenlafaxine
  • Moderate renal impairment (CrCl 30-50 ml/min):
    • 50 mg/day
  • Severe renal impairment (CrCl less than 30 ml/min), ESRD:
    • 25 mg once daily or 50 mg every other day
Duloxetine
  • Mild to moderate renal impairment: start with lower dose, titrate gradually
  • Severe renal impairment (GFR less than 30 ml/min)
  • ESRD: avoid use
Levomilnacipran
  • Moderate renal impairment (CrCl 30-59 ml/min):
    • 80 mg/day
  • Severe renal impairment (CrCl 15-29 ml/min):
    • 40 mg/day
  • ESRD:
    • not recommended
Milnacipran
  • Moderate renal impairment (CrCl 30-49 ml/min): use cautiously
  • Severe renal impairment (CrCl 5-29 ml/min): reduce dose by 50% to 25 mg twice daily or -50 mg once daily (based on response and tolerability)
  • ESRD: not recommended
Venlafaxine
  • Mild to moderate renal impairment (CrCl 30-89 ml/min):
    • IR:  reduce total daily dose by 25%
    • ER:  reduce total daily dose by 25% to 50%
  • Severe renal impairment (CrCl less than 30 ml/min) and hemodialysis:
    • reduce total daily dose by 50%
  • Adjust doses based on response and tolerability due to variability in renal clearance

Legend:

  • CrCl = creatinine clearance
  • ESRD = end-stage renal disease
  • ER = extended-release
  • IR = immediate-release 
Table 15: Select non-SSRI Antidepressant Dosage Modifications in Renal Impairment – Other Miscellaneous Agents1-2, 35-38, 40
Drug Name Dosage in Renal Impairment
Bupropion Administer cautiously in renal impairment due to potential for accumulation and risk for adverse events (e.g., seizures); consider reduced dosage/dosage frequency Forfivo™ XL: not recommended in renal impairment as no lower dose available
Trazodone Use cautiously in patients with renal impairment 

Legend:

  • CrCl = creatinine clearance

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. NP, CMP, and F are considered chronic conditions and may be used for the duration of the condition.

While clinical trials have not evaluated vilazodone use in MDD beyond 52 weeks, it is accepted that vilazodone therapy may exceed 52 weeks, as acute episodes of MDD require extended (several months or longer) drug therapy. Patients should be periodically assessed for continued need for vilazodone treatment33.

Duloxetine treatment duration in diabetic NP lasting greater than 6 months has not been evaluated in clinical trials. Additionally, duloxetine efficacy in CMP beyond 13 weeks has not been established in clinical trials.

Duloxetine use lasting greater than 12 months as F therapy has not been evaluated in clinical trials. Recent clinical trials have evaluated milnacipran use for up to one year in F with sustained results in pain management. F patients should be routinely evaluated for treatment effectiveness, with milnacipran therapy tapered and discontinued if positive treatment outcomes are no longer present.

3. Duplicative Therapy

The concurrent use of two antidepressant medications with the same spectrum of activity may not be justified. The concomitant use of two cyclic antidepressants, two MAOIs or two SNRIs will be reviewed.

The concurrent use of three or more antidepressants is not justified. Therefore, the adjunctive use of three or more antidepressants, including MAOIs, SNRIs, SSRIs, cyclic antidepressants, trazodone, bupropion, and nefazodone, 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 16 are considered clinically relevant for 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 16: Major Drug-Drug Interactions for Non-SSRI Antidepressant Drugs1-43
Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level #
bupropion systemic corticosteroids concurrent administration may increase seizure risk as both agents lower seizure threshold reduce initial doses and titrate doses upward slowly; monitor closely for seizure activity Moderate (CP)
cyclic antidepressants, SNRIs, bupropion, levomilnacipran, milnacipran, nefazodone, trazodone, vilazodone, vortioxetine monoamine oxidase inhibitors (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 (CP)
MAOIs select CNS stimulants (amphetamines, atomoxetine, methylphenidate, and derivatives) increased risk of hypertensive crisis due to additive effects on catecholamine neurotransmitters     avoid concurrent use; allow two weeks between discontinuing MAOIs and initiating CNS stimulant  contraindicated (CP)
MAOIs cyclobenzaprine increased risk of hyperpyretic crisis, seizures, and death potentially due to additive adrenergic activity avoid concurrent use; allow two weeks between discontinuing MAOIs and initiating cyclobenzaprine therapy contraindicated (CP)
MAOIs morphine increased risk of hypotension and enhanced CNS/respiratory depression as MAOIs amplify morphine pharmacologic effects avoid concurrent use; allow two weeks between discontinuing morphine and initiating MAOI therapy contraindicated (CP)
MAOIs sympathomimetics increased risk of hypertensive crisis as MAOIs increase norepinephrine availability at neuronal storage sites as well as enhance adrenergic effects avoid concurrent use; allow two weeks between discontinuing sympathomimetics and initiating MAOI therapy contraindicated (CP)
nefazodone (NZD) carbamazepine reduced NZD serum levels/antidepressant effects and increased carbamazepine (CBZ) serum levels and potential for toxicity due to induced CYP3A4-mediated NZD metabolism and inhibited CYP3A4-mediated CBZ metabolism avoid concurrent use contraindicated (CP)
NZD pimozide enhanced pimozide pharmacologic effects and potential for cardiovascular toxicity due to NZD-mediated CYP3A4 inhibition avoid concurrent use contraindicated (CP)
SNRIs, vilazodone, vortioxetine 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 moderate (CP)
SNRIs, vortioxetine, vilazodone antiplatelet agents adjunctive 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 if combined therapy necessary moderate (CP)
SNRIs drugs with serotonergic properties (e.g., antipsychotics, dextromethorphan, 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 contraindicated (CP)
Vilazodone
Vortioxetine		 drugs with serotonergic properties (e.g., antipsychotics, dextromethorphan, tramadol, triptans) or dopamine antagonist properties (e.g., phenothiazines, metoclopramide) combined use may increase risk of serotonin syndrome or neuroleptic malignant syndrome (NMS). Platelet aggregation may be impaired due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication cautiously administer concurrently and closely observe for signs/symptoms of serotonin syndrome or NMS, especially with treatment initiation or dosage increases Moderate (CP)
SNRIs, vortioxetine 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)
TCAs 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 (CP)
TCAs, duloxetine select phenothiazines (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)
vilazodone CYP3A4 inducers combined administration may result in reduced vilazodone serum levels and decreased pharmacologic effects, as vilazodone is primarily metabolized by CYP3A4 monitor for decreased pharmacologic effects and adjust doses as necessary moderate (CP)
vilazodone CYP3A4 inhibitors adjunctive administration may result in increased vilazodone serum levels and enhanced pharmacologic/adverse effects, as vilazodone is primarily metabolized by CYP3A4 monitor for increased pharmacologic/adverse effects; reduce vilazodone dose to 20 mg daily when prescribed concurrently with strong (e.g., ketoconazole) CYP3A4 inhibitors; reduce vilazodone dose to 20 mg daily when co-administered with moderate (e.g., erythromycin) CYP3A4 inhibitors and intolerable adverse effects are present major (CP)
vortioxetine strong CYP2D6 inducers combined administration may result in reduced vortioxetine serum levels and decreased pharmacologic effects, as vortioxetine is primarily metabolized by CYP2D6 as well as QTC prolongation with concurrent use of Thioridazine monitor for decreased pharmacologic effects; increase the vortioxetine dose (by no more than 3x the recommended dose) if strong CYP2D6 inducer administered concurrently for more than 14 days; reduce vortioxetine dose to original dose within 14 days of CYP2D6 inducer discontinuation major (CP)
vortioxetine strong CYP2D6 inhibitors adjunctive administration may result in increased vortioxetine serum levels and enhanced pharmacologic/adverse effects, as vortioxetine is primarily metabolized by CYP2D6 Reduce vortioxetine dose by 50% when administered concurrently with strong CYP2D6 inhibitor; reduce vortioxetine dose to original dose when CYP2D6 inhibitor discontinued major (CP)
Amitripityline/Perphenazine cisapride increased risk of QT prolongation and increased risk for arrythmia avoid concurrent use Contraindicated (CP)

Legend:

  • #CP = Clinical Pharmacology
  • CNS = central nervous system
  • SNRIs = serotonin and norepinephrine reuptake inhibitors
  • TCAs = tricyclic antidepressants

5. References

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