Signs of physical dependence and true addiction, although relatively rare, undoubtedly occur in chronic benzodiazepine users, even in those taking therapeutic doses. The withdrawal symptoms are much the same as those that follow the chronic use of other sedative drugs (anxiety, jitteriness, insomnia, seizures) but may not appear until the third day after the cessation of the drug and may not reach their peak of severity until the fifth day (Hollister, 1990). In chronic benzodiazepine users, the gradual tapering of dosage over a period of 1 to 2 weeks minimizes the withdrawal effects. However, we have observed numerous cases over the years in which the cessation of moderate doses of chronically used diazepines has resulted in one or more seizures. This is likely to happen when the patient is hospitalized for other reasons and the accustomed sleeping or anxiolytic medication is omitted.
A class of antianxiety agents, exemplified by the selective 5-HT1A receptor serotonergic agonist buspirone, is chemically and pharmacologically different from the benzodiazepines, barbiturates, and other sedatives. Its distinctive nature is confirmed by the observation that it does not block the withdrawal syndrome of other sedative-hypnotic drugs. Because of its apparently reduced potential for abuse and tolerance, it is not included in the list of controlled pharmaceutical substances in the United States but adverse interactions with monoamine oxidase (MAO) inhibitors are known. Its use with other psychotropic drugs is still under investigation (see Chap. 49).
Also mentioned here, because neurologists are often asked to consult on these cases, is a curious effect of the anesthetic propofol. Seizures and myoclonic-like movements have been seen in a small number of individuals, presumably as an idiosyncratic effect. Sometimes these take the form of less-organized twitching, opisthotonus, or involuntary movements. Some inhaled anesthetics such as enflurane can cause seizures in susceptible patients. In our own experience, the seizures have occurred in the first hour after emergence from anesthesia, but as many cases are reported with seizures occurring during induction, emergence, and after the use of the drug (see Walder et al).
In the mid-1950s, a large series of pharmacologic agents, originally referred to as tranquilizers (later, as psychotropic or neuroleptic drugs), came into prominent use, mainly for the control of schizophrenia, psychotic states associated with “organic brain syndromes,” and affective disorders (depression and bipolar disease). The mechanisms by which these drugs ameliorate disturbances of thought and affect in psychotic states are not fully understood, but presumably they act by blocking the postsynaptic mesolimbic dopamine receptors of which there are four subtypes, termed D1 through D4 on neuronal membranes (see Table 4-2, and discussion of dopamine receptor subtypes). The D2 receptors are located mainly in the frontal cortex, hippocampus, and limbic cortex, and the D1 receptors are in the striatum, as discussed in Chap. 4. The blockade of dopamine receptors in the striatum is probably responsible for the parkinsonian side effects of this entire class of drugs, and the blockade of another dopaminergic (tuberoinfundibular) system, for the increased prolactin secretion by the pituitary. These drugs also produce some adrenergic blocking effect. The newer “atypical” antipsychotic drugs, exemplified by clozapine, apparently achieve the same degree of D2 and D3 blockade in the temporal and limbic lobes while exhibiting substantially less antagonistic activity in the striatum—accounting also for their lesser parkinsonian side effects. These drugs also block subsets of serotonin receptors.