Drugs to treat anxiety

This is a section from a longer article about psychophamacology

Antianxiety agents

Benzodiazepines

Benzodiazepines enhance the action of the neurotransmitter γ-aminobutyric acid (GABA) in the central nervous system by binding to a specific benzodiazepine receptor located in a complex with a GABA receptor and a chloride ion channel. The pharmacological effects of benzodiazepines are attributed to the facilitation of GABA neurotransmission.

Principal drugs

These are alprazolam, chlordiazepoxide, diazepam, flurazepam, lorazepam, lormetazepam, nitrazepam, and temazepam.

Indications and use

The prescription of benzodiazepines is decreasing following concern about their liability to produce dependence. Alternative therapies are available for most anxiety related disorders, and it is recommended that the drug treatment of anxiety and insomnia should be limited to a few weeks’ duration. The main indication for the use of benzodiazepines is to help patients in a crisis, when generalized anxiety and insomnia are causing functional impairment and reducing their ability to cope. Patients should be advised that the drug treatment will be of short duration to help them manage their immediate difficulties.

All benzodiazepines have hypnotic and anxiolytic properties, the main difference between them of clinical importance being their length of action. Derivatives with short half-lives, such as temazepam, are suitable hypnotics because of their relative lack of a hangover effect. Other benzodiazepines, e.g. diazepam, have long half-lives and are metabolized to active compounds. These may be used for the treatment of anxiety, either in the form of regular dosing, or on the now preferred ‘as required’ basis with an agreed maximum daily dose.

Side effects and interactions

Benzodiazepines have a low acute toxicity. Their adverse effects are extensions of their clinical effects and include the following: drowsiness, psychomotor impairment, dizziness, ataxia, and paradoxical aggression (rare). Benzodiazepines potentiate the effects of other centrally acting sedatives, particularly alcohol. The effects of benzodiazepines are potentiated by cimetidine.

Patients who have taken clinical doses of a benzodiazepine for more than a few weeks may show a withdrawal syndrome when the medication is stopped. In many respects this syndrome resembles an anxiety state, but perceptual disturbances and acute dysphoria may also occur. It is thus apparent that benzodiazepines can cause physical dependence, and although the withdrawal syndrome is less severe than that seen following the cessation of barbiturates, patients frequently find it difficult to stop their medication. A gradual reduction is usually best. Generally, withdrawal from a long-acting benzodiazepine is easier than from a short-acting preparation, and if patients taking short-acting benzodiazepines have difficulty withdrawing, then a switch to a long-acting preparation may be helpful.

Other drugs that increase brain GABA function

A number of nonbenzodiazepine agents with short half-lives (the Z drugs) also increase GABA function and are licensed as hypnotics. Whether the Z drugs have advantages over short-acting benzodiazepines such as temazepam is disputed. The treatment of insomnia with either benzodiazepines or the Z drugs should be short-term to avoid dependence.

Zopiclone, zolpidem, and zaleplon (the Z drugs)

Zopiclone is a cyclopyrrolone derivative marketed for the treatment of insomnia. It binds to a site close to the benzodiazepine receptor and thereby facilitates brain GABA function. By contrast to the benzodiazepines, which reduce the amount of slow-wave (deep) sleep at night, zopiclone has little effect on sleep architecture and is relatively free from a daytime ‘hangover’ effect. It is claimed to be less likely than benzodiazepine hypnotics to produce tolerance and withdrawal effects, but cases have been reported. The most common adverse effects of zopiclone include bitter taste, nausea, dry mouth, irritability, and headache.

Zolpidem is an imidazopyridine derivative that also binds to a site close to the benzodiazepine receptor. It has a very short duration of action and, like zopiclone, has little effect on sleep architecture or daytime performance. Its possible adverse effects include nausea, dizziness, headaches, and diarrhoea. Zaleplon is a pyrazolopyrimidine derivative with pharmacological properties similar to zopiclone and zolpidem, but its half-life is only about an hour such that it can be used to reinduce sleep after nocturnal waking.

Clomethiazole

Clomethiazole also binds at the GABA receptor complex, but its clinical effects resemble those of barbiturates rather more than those of the benzodiazepines. It can cause serious respiratory depression in overdose, particularly in combination with alcohol. Because of its short half-life (4–5 h), clomethiazole is used as a hypnotic in older people, but again only short-term use is recommended.

Drugs altering monoamine function

Buspirone

Buspirone is a 5-HT1A receptor agonist structurally unrelated to benzodiazepines. It is effective in the treatment of generalized anxiety disorder (less so in patients previously exposed to benzodiazepines), but has a slow onset of action (1–3 weeks). Unlike benzodiazepines, buspirone does not cause significant sedation or cognitive impairment and appears unlikely to cause dependence. It does not have hypnotic properties. Side effects include nervousness, dizziness, and headache.

Other drugs

SSRIs and TCAs are effective in the management of patients with a range of anxiety disorders, including generalized anxiety and phobic states. They are generally preferred to benzodiazepines for the treatment of agoraphobia with and without panic attacks. SSRIs are also effective in the treatment of obsessive–compulsive disorder and social phobia, but TCAs (with the exception of clomipramine) are not.