Antidepressants with Lowest Sexual and Insomnia Side Effects (Excluding Bupropion, Buspirone, Mirtazapine, and Trazodone)
Primary Recommendation
Among SSRIs and SNRIs, sertraline and citalopram have the lowest rates of sexual dysfunction, though they still cause significantly more sexual side effects than the excluded medications. 1
Evidence-Based Ranking of Sexual Dysfunction Risk
Lowest Risk Options (Among Remaining Antidepressants)
- Escitalopram and fluvoxamine cause the lowest rates of sexual dysfunction among SSRIs, though exact rates are not specified in guidelines 1
- Nefazodone has lower sexual dysfunction rates (28%) compared to most SSRIs, making it a reasonable alternative when the excluded medications cannot be used 2
- Sertraline causes sexual dysfunction in 14% of males and 6% of females, placing it in the moderate-low range among SSRIs 1
- Citalopram has intermediate rates of sexual dysfunction and is preferred over paroxetine or fluoxetine when an SSRI must be used 1
Medications to Avoid
- Paroxetine has the highest sexual dysfunction rate at 70.7% and should be avoided entirely when sexual function is a concern 1, 3
- Fluoxetine causes moderate-high rates of sexual dysfunction and is inferior to sertraline and citalopram 1
- Venlafaxine (SNRI) impairs sexual function and should be avoided when libido is a concern 4
Newer Antidepressants with Lower Sexual Dysfunction
- Vilazodone (SSRI + 5-HT1A partial agonist) has reduced sexual side effects compared to traditional SSRIs due to its dual mechanism, though sexual dysfunction remains a listed adverse effect in FDA labeling 5, 6
- Vortioxetine has sexual dysfunction as a common adverse effect but may have a more favorable profile than traditional SSRIs due to its multimodal mechanism 7, 6
Insomnia Considerations
- Limited evidence shows similar efficacy among fluoxetine, nefazodone, paroxetine, and sertraline for treating depression in patients with accompanying insomnia, with no clear winner for minimizing insomnia as a side effect 8
- Vilazodone lists insomnia as a common adverse effect (along with diarrhea and nausea), which resolved in 4-5 days in clinical trials 6
- Vortioxetine does not prominently list insomnia among its most common adverse effects (nausea, sexual dysfunction, constipation, vomiting) 6
Clinical Decision Algorithm
When Sexual Function is the Primary Concern:
- First choice: Escitalopram or fluvoxamine (lowest sexual dysfunction among SSRIs) 1
- Second choice: Sertraline or citalopram (intermediate sexual dysfunction rates) 1
- Third choice: Nefazodone (28% sexual dysfunction rate) 2
- Consider: Vilazodone or vortioxetine (newer agents with potentially lower sexual dysfunction) 5, 6
- Avoid: Paroxetine, fluoxetine, and all SNRIs (highest sexual dysfunction rates) 1, 4
When Both Sexual Function and Insomnia are Concerns:
- Vortioxetine may be the optimal choice as it does not prominently list insomnia among common adverse effects and has a potentially favorable sexual dysfunction profile 7, 6
- Nefazodone is a reasonable alternative with lower sexual dysfunction rates, though insomnia data is limited 8, 2
Critical Caveats
- Sexual dysfunction rates are vastly underreported in clinical trials, so actual rates are likely higher than published figures 1, 3
- All SSRIs and SNRIs carry risk of sexual dysfunction, just at varying rates—none approach the favorable profile of bupropion (8-10% rate) 1, 2
- Inquire specifically about sexual function before and during treatment, as patients rarely report these symptoms spontaneously 7
- Monitor for therapeutic response and adverse effects within 1-2 weeks of initiation, and modify treatment if no adequate response within 6-8 weeks 1
- Nefazodone carries a black box warning for hepatotoxicity, requiring liver function monitoring 6
- Vilazodone must be taken with food to ensure adequate absorption and efficacy 6