What should be started first, fluoxetine (selective serotonin reuptake inhibitor) or clomipramine (tricyclic antidepressant), and when?

Starting Fluoxetine or Clomipramine for Premature Ejaculation: Timing and Sequence

Fluoxetine should be started first as a daily treatment for premature ejaculation, with clomipramine reserved for on-demand use if fluoxetine is ineffective or poorly tolerated. 1

First-Line Treatment: Daily SSRI Therapy

• Daily treatment with fluoxetine 20-40 mg is recommended as a first-line pharmacological option for premature ejaculation due to its efficacy in delaying ejaculation 1
• SSRIs like fluoxetine are preferred over tricyclic antidepressants (TCAs) like clomipramine because of their better side effect profile 1
• Fluoxetine has a long half-life, making it less likely to cause discontinuation syndrome compared to other SSRIs if doses are missed 2

Second-Line/Alternative Approach: On-Demand Clomipramine

• On-demand administration of clomipramine 12.5-50 mg taken 3-6 hours before intercourse is an alternative approach if daily SSRI therapy is ineffective or not preferred 1
• Clomipramine may be used as a second-line agent after trying fluoxetine, particularly when immediate results are needed for specific sexual encounters 1, 3
• While on-demand treatment is modestly efficacious, it provides substantially less ejaculatory delay than daily treatment in most studies 1

Important Considerations for Medication Selection

Safety Considerations

• Avoid both medications in patients with a history of bipolar disorder due to risk of triggering mania 1, 2, 3
• Monitor for serotonin syndrome, especially if combining these medications or with other serotonergic drugs 1, 4, 5
• Sexual dysfunction (beyond the intended delay in ejaculation) can occur with both medications 1

Drug Interactions

• Fluoxetine inhibits CYP2D6, which metabolizes clomipramine, potentially leading to dangerously high clomipramine levels if used together 4, 5, 6
• If combination therapy is ever considered (which should be rare), extremely careful monitoring is required due to documented cases of subtoxic clomipramine levels when combined with fluoxetine 6

Timing and Dosing Recommendations

For Fluoxetine:

• Start at a low dose (10-20 mg daily) and gradually increase if needed 1, 5
• Allow 2-3 weeks to assess initial efficacy, with full effects potentially taking 4-6 weeks 5
• If effective, continue daily treatment for sustained benefit 1

For Clomipramine (if needed):

• Start with on-demand dosing of 12.5-25 mg taken 3-6 hours before intercourse 1, 3
• May increase to 50 mg as needed and tolerated 1
• Alternatively, can be used at low daily doses (12.5-50 mg) if on-demand approach is ineffective 1, 3

Common Pitfalls to Avoid

• Avoid starting both medications simultaneously, as this increases risk of serotonin syndrome and makes it difficult to determine which medication is causing side effects 1, 6
• Do not combine fluoxetine and clomipramine without careful consideration due to documented metabolic interactions that can lead to clomipramine toxicity 6
• Be aware that abrupt discontinuation of either medication can lead to withdrawal symptoms, though this is less common with fluoxetine due to its long half-life 2, 3
• Patients may be reluctant to begin treatment with antidepressants for premature ejaculation; careful explanation of the rationale is important for adherence 1