N: Nervous system
ATC group N holds the drugs acting on the nervous system, from the anesthetics (N01) to other nervous system drugs (N07) [1]. Their effects are measured in very different ways: as processed electroencephalogram (EEG) under anesthesia, as daily seizure counts, and on psychiatric rating scales such as the Positive and Negative Syndrome Scale (PANSS).
On 29 March 1948 John Cade gave lithium (N05AN01), as lithium citrate, to W.B., a man who had been in manic excitement for five years. W.B. left hospital four months later and returned to the job he had held before his admission. Cade published the results in 1949 [2].
| Description | In plain terms | Example drug | |
|---|---|---|---|
| N01 | Anesthetics | Propofol (N01AX10) / bupivacaine (N01BB01) | |
| N02 | Analgesics | Paracetamol (N02BE01) / morphine (N02AA01) | |
| N03 | Antiepileptics | Levetiracetam (N03AX14) / lamotrigine (N03AX09) | |
| N04 | Anti-Parkinson drugs | Levodopa and decarboxylase inhibitor (N04BA02) / pramipexole (N04BC05) | |
| N05 | Psycholeptics | calming: antipsychotics, anxiolytics, hypnotics | Olanzapine (N05AH03) / lorazepam (N05BA06) |
| N06 | Psychoanaleptics | stimulating: antidepressants, stimulants, anti-dementia drugs | Sertraline (N06AB06) / escitalopram (N06AB10) |
| N07 | Other nervous system drugs | Buprenorphine (N07BC01) / varenicline (N07BA03) |
Placebo response in psychiatric trials
In psychiatry, large variation in the placebo response within and between clinical trials can substantially affect the conclusions about a new drug’s efficacy. A model of the placebo time course helps separate the drug effect from this response, and such models have been published for schizophrenia, depression, Alzheimer’s disease and Parkinson’s disease. High dropout rates are also common in the placebo arms of psychiatric trials [3]. How dropout is modeled in schizophrenia trials is described in the schizophrenia primer.
In antidepressant trials, about 40% of patients have a placebo response. In 691 patients from seven depression trials, a Weibull/linear model described the placebo time course of the Hamilton Rating Scale for Depression (HAMD-17) total score, and the scores at weeks 2 and 4 predicted which patients would turn out to be placebo responders [4].
Reaching the brain
For a drug acting in the central nervous system (CNS), it is the unbound drug that crosses membranes and reaches the target, so the unbound concentration in brain extracellular fluid is the one of interest. Microdialysis is the only technique that measures it over time in vivo. Human CNS distribution data are scarce, so preclinical microdialysis data are combined with physiologically based pharmacokinetic (PBPK) models to predict human target-site concentrations [5].