Quetiapine for ADHD

Quetiapine is an atypical antipsychotic.¹
It has an antidepressant effect at the same time.²

In lower doses, it is used as a sleep aid. The relatively short plasma half-life of 2.5 to 5 hours³ is favorable for this.

• 1. Quetiapine is an antagonist of
• 2. Quetiapine is an agonist of
• 3. Use of quetiapine

1. Quetiapine is an antagonist of¶

• Serotonin receptor 5-HT2A²
  • Thereby increasing the dopamine level in the PFC
• Serotonin receptor 5-HT2C via the metabolite norquetiapine²
  • Receptor binding in the PFC of 72% after 2 hours at 450 mg³
  • Receptor binding of 50% after 26 hours at 450 mg³
• Dopamine receptor D2
  • Leads to antipsychotic effect
  • Receptor binding in the striatum of 44% after 2 hours at 450 mg³
  • Receptor binding after 26 hours as in untreated healthy subjects at 450 mg³
  • The D2 antagonism of quetiapine is thus weaker than the 5HT antagonism.⁴
  • Relatively low affinity for dopamine D2 receptors, with an occupancy half-life of 10 hours, thus about twice as long as that of plasma³
• Σ-Adrenergic receptor (especially A2)²
  • Thereby increasing the dopamine level in the PFC
• Noradrenaline transporter NAT via the metabolite norquetiapine²
  • Thereby increased norepinephrine level
• Histamine receptor H1
• Glutamate NMDA
  • Quetiapine reduces mRNA levels for some subunits of the glutamate NMDA receptor NR-1 and NR-2.²
  • Reduction in the density of NMDA receptors in the caudate nucleus (putamen) (but not in the cortex or limbic system), as well as clozapine or haloperidol²

2. Quetiapine is an agonist of¶

• Serotonin receptor 5-HT1A (partial)²
  • Thereby increasing the dopamine level in the PFC
• Glutamate AMPA
  • Increase in the density of glutamate AMPA receptors in the caudate nucleus (putamen) (but not in the cortex or limbic system), as well as clozapine or haloperidol ²
  • Quetiapine caused a significant increase in the GluR-B and GluR-C subunits of the AMPA receptor in rat hippocampus.²
• Sigma-1 receptors
  • Mediates antidepressant effect⁵
    • Can be additionally increased by σ1-agonist (+)-pentazocine
    • Can be reduced by σ1-antagonist BD1063

Indirect inhibition of 5-HT2C receptors causes inhibition of GABA release in the brainstem, which in turn causes release of norepinephrine and dopamine in the PFC.²

According to this understanding, GABA is underrepresented in ADHD-I and overrepresented in ADHD-HI. Given this background, quetiapine would hypothetically be more useful in ADHD-HI and less recommended in ADHD-I,

3. Use of quetiapine¶

Quetiapine is used primarily for schizophrenia and bipolar disorder (manic-depressive).
Primary use to date tends to be in relation to (massive) comorbidities, not ADHD itself.

A study of the treatment of ODD by concomitant quetiapine administration (= augmentation) to SSRI administration found no significant improvement in effect.⁶

In ADHD, quetiapine is used off-label in low doses in relation to the frequent sleep problems. Because of its short half-life, it is said to be applicable for this purpose despite its (albeit relatively weak) D2 antagonism.⁷ Nevertheless, at 450 mg, qetiapine showed a receptor occupancy of dopamine D2 receptors in the striatum of 44% within 2 h, which only returned to the level of untreated healthy subjects after 26 h. The study found that the drug was effective as a sleep aid.³ As a sleep aid, however, the dosage is much lower at between 12.5 and 100 mg.