N05: Psycholeptics
N05 holds the antipsychotics (N05A), the anxiolytics (N05B), and the hypnotics and sedatives (N05C) [1]. Schizophrenia, the disease in most of the antipsychotic studies below, is described in the schizophrenia primer.
How do psycholeptics work?
Antipsychotics block dopamine D2 receptors, and the receptor occupancy can be measured in patients with positron emission tomography (PET). In structures deep in the brain (basal ganglia), clinical doses of classical antipsychotics, such as haloperidol (N05AD01), occupied 70% to 89% of D2 receptors, while clozapine (N05AH02) occupied 38% to 63% [2].
Benzodiazepines, such as diazepam (N05BA01) and lorazepam (N05BA06), are used as anxiolytics and hypnotics, and also as anticonvulsants, muscle relaxants and anesthetics [3]. Like the benzodiazepines, the hypnotics zolpidem (N05CF02), zopiclone (N05CF01) and zaleplon (N05CF03) act at the GABA receptor complex, but they appear to be more selective for certain receptor subunits [4].
Efficacy
Efficacy in schizophrenia trials is measured on symptom rating scales such as the Positive and Negative Syndrome Scale (PANSS), described in the schizophrenia primer together with the placebo response and dropout [5].
D2 receptor occupancy has also been used as a biomarker linking dose to efficacy. A model connecting antipsychotic dose, pharmacokinetics, D2 occupancy, PANSS response and drug-induced movement disorders (extrapyramidal symptoms) on the Simpson-Angus Scale was used to choose doses of asenapine (N05AH05) for its phase II and III trials [6].
For benzodiazepines in healthy volunteers, the most consistent biomarkers were saccadic peak velocity, a continuous eye-movement measure, and visual analogue scales of alertness. A dose-response for temazepam (N05CD07) on saccadic peak velocity gave dose equivalents for seven benzodiazepines, which correlated with their lowest recommended maintenance doses [7].
Safety
Extrapyramidal symptoms, the movement disorders caused by antipsychotics, are related to D2 occupancy: patients with acute extrapyramidal syndromes had a higher D2 occupancy than those without [2].
In a network meta-analysis of 212 trials, antipsychotics differed substantially in side effects. Against placebo, the odds ratio for extrapyramidal side effects ranged from 0.30 for clozapine to 4.76 for haloperidol. Weight gain was greatest with olanzapine (N05AH03), and prolactin increase greatest with paliperidone. QTc prolongation and sedation also differed between drugs, and the results challenge the usual split into first- and second-generation antipsychotics [8].
The adverse effects of benzodiazepines are sedation, and cognitive and psychomotor impairment, which can compromise complex skills such as driving. Perhaps a third of those who have used them for more than 6 months have withdrawal symptoms when they try to stop. Benzodiazepines are also drugs of abuse, alone or together with opioids and stimulants [3]. Zolpidem and zopiclone are eliminated more slowly than zaleplon, which can cause residual sedation after a bedtime dose [4].