How does atomoxetine (Strattera) cause chills?

How Atomoxetine Causes Chills

Atomoxetine can cause chills primarily through its noradrenergic effects on thermoregulation and peripheral vasculature. This mechanism is related to its primary pharmacological action as a selective norepinephrine reuptake inhibitor.

Pharmacological Mechanism

Atomoxetine (Strattera) works by selectively inhibiting the presynaptic norepinephrine transporter, which results in:

• Increased norepinephrine levels in synapses throughout the brain and periphery 1
• Increased dopamine levels specifically in the prefrontal cortex (due to norepinephrine transporters regulating dopamine reuptake in this region) 1

Pathways Leading to Chills

1. Peripheral Vascular Effects:

   • Noradrenergic stimulation can cause peripheral vasoconstriction
   • FDA labeling specifically mentions "peripheral coldness" as a reported adverse effect, particularly in CYP2D6 poor metabolizers (3% of PMs vs 1% of EMs) 2
   • This vasoconstriction can manifest as Raynaud's phenomenon in some patients 2

2. Thermoregulatory Disruption:

   • Norepinephrine plays a key role in central temperature regulation
   • Altered noradrenergic signaling can disrupt normal thermoregulatory processes
   • In rare cases, this can lead to hypothermia, as documented in case reports 3

3. Autonomic Nervous System Effects:

   • Atomoxetine affects the sympathetic nervous system, which controls temperature regulation
   • This can lead to autonomic symptoms including chills and sweating (hyperhidrosis is reported in 4% of patients) 2

Risk Factors for Developing Chills

Certain patient populations are at higher risk for experiencing chills with atomoxetine:

• CYP2D6 Poor Metabolizers: These patients have significantly higher plasma levels and longer half-lives of atomoxetine 1, 2

  • Peripheral coldness occurs in 3% of poor metabolizers vs 1% of extensive metabolizers 2
  • Hyperhidrosis occurs in 15% of poor metabolizers vs 7% of extensive metabolizers 2

• Patients on Interacting Medications:

  • SSRIs and other medications that inhibit CYP2D6 can increase atomoxetine levels 1
  • This can lead to drug interactions that mimic the poor metabolizer phenotype

Clinical Implications

When a patient reports chills while taking atomoxetine:

1. Rule out serotonin syndrome: While atomoxetine primarily affects norepinephrine, it's important to consider serotonin syndrome if the patient is on multiple serotonergic medications 1

2. Assess for other symptoms:

   • Peripheral coldness or Raynaud's phenomenon
   • Changes in vital signs, particularly heart rate and blood pressure
   • Other autonomic symptoms (sweating, dizziness)

3. Management options:

   • Dose reduction may help if symptoms are mild
   • Consider switching to alternative ADHD medication if symptoms are intolerable
   • For patients with significant chills, evaluate for possible hypothermia 3

Important Caveats

• Chills are not among the most commonly reported side effects of atomoxetine but are documented in post-marketing surveillance 2
• The risk appears higher in poor metabolizers of CYP2D6, suggesting a dose-dependent effect 2
• While rare, severe cases can progress to hypothermia, which is a medical emergency 3

Monitoring for peripheral vascular symptoms and autonomic effects is important when initiating atomoxetine therapy, particularly in patients who may be CYP2D6 poor metabolizers or who are taking medications that inhibit this enzyme.