What is a SARI (Serotonin Antagonist and Reuptake Inhibitor) category of antidepressant?

SARI (Serotonin Antagonist and Reuptake Inhibitor) Antidepressants

SARI antidepressants are a class of medications that work by both blocking serotonin receptors (particularly 5-HT2A and 5-HT2C) and inhibiting serotonin reuptake, with trazodone and nefazodone being the primary examples in this category. 1, 2

Mechanism of Action

• SARIs have a dual mechanism of action that distinguishes them from other antidepressant classes:
  • They antagonize (block) specific serotonin receptors, particularly 5-HT2A and 5-HT2C 1
  • They inhibit the serotonin transporter (SERT), preventing serotonin reuptake, though this effect is typically weaker than with SSRIs 2
  • They may also have effects on other receptors, including alpha-adrenergic and histamine receptors 1

Examples of SARI Medications

• Trazodone is the most commonly prescribed SARI antidepressant and is available in Poland and many other countries 1
• Nefazodone is another SARI, though its use has been limited due to concerns about hepatotoxicity 3

Clinical Use and Efficacy

• SARIs have not been adequately studied compared to more established antidepressant classes such as SSRIs and SNRIs 4
• Current clinical guidelines do not include SARIs among first-line recommendations for anxiety disorders due to limited evidence 4
• Japanese guidelines for social anxiety disorder specifically note that SARIs "have not been adequately studied and are thus not included in the guideline with or without recommendations" 4

Advantages of SARIs

• The unique pharmacodynamic profile of SARIs may help avoid certain side effects common with SSRIs:
  • Lower incidence of sexual dysfunction 2
  • Less likely to cause insomnia (may actually improve sleep due to sedative properties) 2
  • Minimal weight gain compared to some other antidepressants 2
• Trazodone's sedative properties make it particularly useful for depression with comorbid insomnia 1, 2

Side Effects and Safety Considerations

• Common side effects of SARIs include:
  • Somnolence/sedation (most common) 1, 2
  • Dizziness and headache 2
  • Dry mouth (xerostomia) 1, 2
  • Gastrointestinal disturbances 1
• Specific safety concerns:
  • Nefazodone carries a boxed warning for hepatotoxicity with cases of life-threatening liver failure reported 3
  • Orthostatic hypotension may occur, especially in elderly patients or those with cardiovascular disease 2
  • QT interval prolongation and cardiac arrhythmias have been reported (though rare) 2
  • Priapism is a rare but serious potential side effect 2

Comparison to Other Antidepressant Classes

• Unlike SSRIs, which primarily work by inhibiting serotonin reuptake, SARIs have additional receptor antagonist properties 5, 6
• Unlike SNRIs, which affect both serotonin and norepinephrine reuptake, SARIs primarily target serotonin systems but through dual mechanisms 6, 7
• SARIs are distinct from NaSSAs (Noradrenergic and Specific Serotonergic Antidepressants) like mirtazapine, which increase both noradrenergic and specific serotonergic transmission 7

Clinical Positioning

• Trazodone is often used at lower doses (50-100mg) for insomnia, even when the primary diagnosis is not depression 2
• For major depressive disorder, trazodone is typically dosed at 150-300 mg/day 2
• SARIs may be particularly useful for patients who experience insomnia, anxiety, or sexual dysfunction with SSRIs 1, 2
• Current evidence supports SSRIs and SNRIs as first-line pharmacological treatments for anxiety disorders and depression, with SARIs as alternative options 4