The level 2 codes in Table 1 run from anesthetics to other nervous system drugs, and the endpoint, not the drug, sets the model structure: processed EEG in N01 [1], daily seizure counts in N03 [2] and bounded PANSS scores in N05 [3] each demand a different likelihood.
On 29 March 1948 John Cade gave lithium citrate to W.B., in manic excitement for five years; W.B. left hospital months later and returned to his old job [4,5].
Modeling notes
Endpoint. Analysing composite PANSS totals as continuous data discards information and violates the scale’s numerical nature; item response theory models the items instead [3]. Depression trials have been modeled on the HAMD-17 total [6].
Placebo first (N05, N06). Placebo arms in schizophrenia and depression improve over weeks, so a placebo time course is fitted before estimating any drug effect [7].
Easy to overlook. PET occupancy bridges dose and effect in N05: patients with acute extrapyramidal syndromes had higher D2 occupancy than those without [8], and model-based analysis quantifies it against efficacy and those symptoms [9].
Mechanistic extrapolation. Human CNS distribution data are scarce, so physiologically based models combined with microdialysis predict unbound extracellular concentrations at the target site [10]. A separately developed pediatric brain PBPK model predicted CSF concentrations and was checked against CSF observed in children, meningitis included [11].
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