A model of sedative load based on the therapeutic reference range

Sedation is one of the most common side effects in psychiatric pharmacotherapy. Moreover, polymedication raises the risk of an unintentional over-sedation. In general, sedation is triggered by inhibition of the central histamine-1-receptor, by activation of the GABA_A-receptor, and/or by activation of the µ-opioid receptor. To date there is no validated model to estimate the risk of sedation. For this reason, we aim to create a model that estimates the risk of unintentional sedation and warns in case of threat.

In the first step of developing such a model we calculated the sedative load in monotherapy from the therapeutic serum levels. The occupancy of receptors triggering this effect is calculated as scale for the depth of sedation.

On average histamine-1-receptors are occupied by therapeutic concentrations of neuroleptics to 72.1% (± 34.8%). However, investigating exclusively the subset of newer antipsychotics launched since 1971 reveals an occupancy of 89.6% (± 15%). The average occupancy by therapeutic concentrations of antidepressants is 62.2% (± 42.1%). The mean occupancy of only tri- and tetracyclic drugs is 94.5% (± 8.9%). Therapeutic concentrations of tranquillizers occupy an average of 69.5% (± 26.1%) of the GABA_A-receptors.

In summary, the model calculates a sedative load which can be compared both within the same and between different receptor systems. It returns a realistic value on a numerous scale of sedation not using surrogate parameters like k_D, k_i or only a plus/minus assessment.