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Domperidone as an unintended antipsychotic

Domperidone, a potent blocker of the dopamine D2 receptor, used at 30 to 80 mg/d to increase gastric motility and decrease nausea, is also prescribed to promote lactation at up to 160 mg/d, as pointed out in a recent case report of withdrawal symptoms.1 That these withdrawal symptoms could have a central nervous system etiology was not considered because it has been widely held that domperidone does not cross the blood-brain barrier.2,3 
 
However, the blood-brain barrier has limits. Rejection of domperidone at the blood-brain barrier is a function of the endothelial P-glycoprotein system4,5 and perhaps other parts of the ATP-binding cassette (ABC) efflux system.6-10 Domperidone at the blood-brain barrier has been investigated to some extent,2,4,5 and other studies have reported the ratio of the free concentration of various molecules in the blood plasma water to that in the brain tissue fluid.10 The maximum ratio for the P-glycoprotein system by itself is about 304,8-10 and for the entire ABC system about 100.6,9,10 For domperidone, this is likely to be between 30 and 100. 
 
Steady-state free concentration of domperidone in the plasma water of an average adult taking 160 mg/d would be 20 to 25 nM, with the lower value being a linear extrapolation from the total concentration of 21 ng/mL at 30 mg/d,3,11 which is 1.7 ng/mL of free concentration.3 The upper estimate takes into account nonlinearity at this dose.3,12 Free concentration in the brain tissue fluid is then 0.2 to 0.8 nM. At 80 mg/d, the free plasma estimate would be 10 nM, with the brain having 0.1 to 0.3 nM; at 30 mg/d, it would be about 3.9 nM of free plasma concentration, with 0.04 to 0.13 nM of free concentration in the brain. 
 
Most measurements of the dissociation constant for domperidone at the D2 receptor are from 0.1 to 0.4 nM.13-18 Thus, there could be D2 blockage in the brain of 33% to 89% for 160 mg/d, 20% to 77% for 80 mg/d and 9% to 57% for 30 mg/d. A higher estimate for the minimum blood-brain ratio of 70 lowers the upper estimates of blocking to 78%, 59% and 36%, respectively. The therapeutic range of D2 blocking by the antipsychotic drugs is 50% to 75%.19,20 Domperidone has a relatively lower effect on D3 receptors than intended antipsychotics,21 but the importance of this is unknown.22 The prevailing theory is that antipsychotics work by blocking D2 receptors.20,23 We see that domperidone between 30 and 160 mg/d could function as an antipsychotic. 
 
It seems plausible that domperidone could produce the same adverse effects as intended antipsychotics, which have many side effects24 and poorly understood withdrawal effects.25,26