What is the role of Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) in treating irritability?

Role of SNRIs in Treating Irritability

SNRIs can be considered for treating irritability associated with anxiety disorders, particularly in patients aged 6-18 years with social anxiety, generalized anxiety, separation anxiety, or panic disorder, as they have demonstrated efficacy in improving anxiety symptoms which may manifest as irritability. 1

Mechanism of Action and Available Medications

• SNRIs inhibit the presynaptic reuptake of both norepinephrine and serotonin in the brain, affecting stress responses including alertness, arousal, attentiveness, and vigilance which are modulated by noradrenergic neurons 1
• Currently available SNRIs in the United States include:
  • Venlafaxine (Effexor®)
  • Desvenlafaxine
  • Duloxetine (Cymbalta®)
  • Levomilnacipran 1
• Duloxetine is the only SNRI with FDA indication for treating anxiety disorders (specifically generalized anxiety disorder) in children and adolescents 7 years and older 1

Efficacy in Anxiety-Related Irritability

• High-quality evidence shows SNRIs improve primary anxiety symptoms based on clinician reports, which often include irritability as a manifestation 1
• In clinical trials involving 911 patients (63.4% male, mean age 12.4 years), SNRIs demonstrated superiority over placebo in treating anxiety symptoms 1
• SNRIs have shown efficacy in treating various anxiety disorders that commonly present with irritability:
  • Social anxiety disorder
  • Generalized anxiety disorder
  • Separation anxiety
  • Panic disorder 1
• The response rate for SNRIs in treating anxiety disorders is comparable to SSRIs with a number needed to treat (NNT) of 4.94 1

Comparative Efficacy

• There is no substantial evidence for major differences between SNRIs and SSRIs in their efficacy for treating anxiety disorders 2
• Unlike SSRIs, SNRIs have demonstrated efficacy in treating chronic pain associated with and independent of depression, which may be relevant when irritability is related to pain 2
• The dual action on both serotonin and norepinephrine systems may provide a broader spectrum of efficacy in some patients 3, 4

Safety and Adverse Effects

• Common adverse effects of SNRIs include:

  • Diaphoresis, dry mouth
  • Gastrointestinal symptoms (abdominal discomfort, nausea, vomiting, diarrhea)
  • Neurological symptoms (dizziness, headache, tremor)
  • Sleep disturbances (insomnia, somnolence)
  • Decreased appetite and weight loss
  • Increased fatigue/somnolence (moderate strength of evidence) 1

• Serious but uncommon adverse effects include:

  • Suicidal thinking and behavior (through age 24 years)
  • Behavioral activation/agitation
  • Hypomania or mania
  • Sexual dysfunction
  • Seizures
  • Abnormal bleeding
  • Serotonin syndrome
  • Sustained clinical hypertension and increased blood pressure 1, 5

• Medication-specific concerns:

  • Venlafaxine may be associated with greater suicide risk than other SNRIs and has been linked to discontinuation symptoms 1, 6
  • Duloxetine has been associated with hepatic failure and severe skin reactions including Stevens-Johnson syndrome 1, 5

Dosing Considerations

• Extended-release formulations of venlafaxine, desvenlafaxine, and duloxetine allow for once-daily dosing due to their longer half-lives 1
• Immediate-release venlafaxine may require multiple daily doses due to its shorter half-life 1
• When discontinuing SNRIs, gradual dose reduction is recommended to minimize discontinuation symptoms 5, 6

Clinical Pearls and Caveats

• Careful monitoring is required when initiating treatment, particularly for signs of:

  • Suicidal ideation (especially in patients under 24 years)
  • Blood pressure changes
  • Activation of mania/hypomania in patients with mood disorders 5

• SNRIs should not be combined with:

  • MAOIs (risk of serotonin syndrome)
  • Other serotonergic drugs without careful monitoring 5

• Caution should be exercised when using SNRIs with:

  • NSAIDs, aspirin, or other anticoagulants due to increased bleeding risk 5
  • Weight loss agents (not recommended) 6

• For irritability specifically related to irritable bowel syndrome, SNRIs have not been as well studied as TCAs and SSRIs, though they may be considered when comorbid anxiety is present 1