Nonresponse to initial pharmacotherapy for generalised anxiety disorder in adults and young people

Consider modifying treatment for generalised anxiety disorder in an adult or young person if symptoms persist despite:

using an effective dose of at least 2 selective serotonin reuptake inhibitors (SSRIs) or serotonin noradrenaline reuptake inhibitors (SNRIs) as sequential monotherapy, each for a minimum of 4 weeks (full benefit may take 6 weeks or longer); and
discounting alternative reasons for treatment nonresponse.

Options for treatment modification include:

combining psychosocial interventions (if not already used) with pharmacotherapy
referral to a psychiatrist or age-appropriate mental health service
using pregabalin, quetiapine or a benzodiazepine (see below)
using mirtazapine or agomelatine (see below).

For treatment considerations for females of childbearing potential, including advice on contraception, preconception planning and psychotropic use, see here.

For considerations in managing anxiety disorders such as generalised anxiety disorder in the perinatal period, see here or for considerations in partners, see here.

Pregabalin is a rapidly effective drug for generalised anxiety disorder—effects are usually seen within a week. Early response (a 20 to 30% improvement within 2 weeks) is predictive of a more substantial long-term response. Before prescribing, consider the potential for harm with pregabalin use, including severe adverse effects, potential for dependence, abuse and toxicity in overdose. Pregabalin has been associated with altered or worsening mood, and emergent suicidal thoughts and behaviours; the risk may be particularly high in young people. See also Principles of using drugs associated with emergent suicidality.

A suitable regimen of pregabalin for generalised anxiety disorder is:

pregabalin 25 mg orally, twice daily. Assess the patient’s response to therapy after 7 days to determine whether dose adjustment is needed. If it is, increase the daily dose by 100 mg every 7 days, as tolerated, until an acceptable response is achieved or a daily dose of 450 mg is reached. If there is an acceptable response, continue at the same dose for at least 1 year, then consider deprescribing. generalised anxiety disorder pregabalin pregabalin pregabalin

Lower doses may be needed in older people; consult a source of drug information.

When stopping pregabalin, gradually decrease the dose to avoid precipitating a seizure. There is limited evidence regarding an appropriate deprescribing regimen, but a reasonable approach is to reduce the dose by approximately 25 to 30% every 2 weeks. Regularly assess for re-emergence of anxiety symptoms.

Quetiapine reduces generalised anxiety symptoms. Quetiapine has antihistaminergic effects at low doses. However, use of quetiapine is limited by the risk of cardiometabolic adverse effects, problem use and overdose, and is subject to monitoring by drug diversion monitoring systems in some Australian states. Discuss with the patient potential adverse effects associated with antipsychotic use and how these effects are monitored, and potentially prevented or addressed. Establish baseline values of parameters that can be affected by antipsychotic therapy—see Baseline parameters potentially affected by antipsychotic therapy. Dosage should be guided by response to therapy and tolerability (regularly monitor for adverse effects). Slower dose escalation may be required for people who are antipsychotic naive, to reduce the likelihood of antipsychotic adverse effects. Lower doses may be needed in older people; consult a source of drug information. A suitable regimen of quetiapine for generalised anxiety disorder is:

quetiapine modified-release 50 mg orally, daily. For patients with severe symptoms, the dose can be increased to 150 mg daily on the third day. Assess the patient’s response to therapy after 7 days to determine whether dose adjustment is needed. If it is, increase the daily dose by 50 mg no more frequently than every 7 days, as tolerated, until an acceptable response is achieved or a daily dose of 300 mg is reached. If there is an acceptable response, continue at the same dose for at least 1 year, then consider deprescribing. generalised anxiety disorder quetiapine quetiapine quetiapine

There is limited evidence regarding an appropriate deprescribing regimen for quetiapine when used for generalised anxiety disorder. Ideally, reduce the dose by approximately 25% every 1 to 2 weeks. Regularly assess for re-emergence of anxiety symptoms.

Benzodiazepines are effective in reducing symptoms of generalised anxiety disorder. However, they should not be used as first-line pharmacotherapy because of potential harms (including increased risk of falls, memory problems, accidents, daytime sedation and dependence). Caution is needed in older people and patients who have a history of problem substance use (particularly problem alcohol use). If a benzodiazepine is used for an older person, lower doses may be needed; consult a source of drug information.

Benzodiazepine use is usually restricted to acute crises and short-term initial therapy. In treatment resistance, they may be considered for maintenance therapy, ideally in consultation with a psychiatrist. Follow the principles for the use of benzodiazepines in anxiety disorders.

If a benzodiazepine is considered appropriate for generalised anxiety disorder, a suitable regimen is:

1 diazepam 2 mg orally, daily. Assess the patient’s response to therapy after 2 weeks to determine whether dose adjustment is needed. If it is, increase the daily dose by 2 mg every 2 weeks, as tolerated, until an acceptable response is achieved or a daily dose of 10 mg (as a single dose or in 2 divided doses) is reached. If there is an acceptable response, continue at the same dose for at least 1 year, then consider deprescribing generalised anxiety disorder, maintenance therapy diazepam diazepam diazepam

1 lorazepam 0.5 mg orally, daily. Assess the patient’s response to therapy after 2 weeks to determine whether dose adjustment is needed. If it is, increase the daily dose by 0.5 mg every 2 weeks, as tolerated, until an acceptable response is achieved or a daily dose of 2 mg (as a single dose or in divided doses) is reached. If there is an acceptable response, continue at the same dose for at least 1 year, then consider deprescribing ¹ generalised anxiety disorder, maintenance therapy lorazepam lorazepam lorazepam

Other drugs that may be considered for generalised anxiety disorder include agomelatine and mirtazapine; however, their efficacy and tolerability are only supported by studies with small sample sizes. If agomelatine or mirtazapine is considered appropriate for generalised anxiety disorder, a suitable regimen is:

1 agomelatine 25 mg orally, daily. Assess the patient’s response to therapy after 2 weeks to determine whether dose adjustment is needed. If it is, increase the dose to 50 mg daily. If there is an acceptable response, continue at the same dose for at least 1 year, then consider deprescribing generalised anxiety disorder agomelatine agomelatine agomelatine

1 mirtazapine 15 mg orally, at night for a few days, then increase to 30 mg orally, at night. Assess the patient’s response to therapy after 2 to 4 weeks to determine whether dose adjustment is needed. If it is, increase by 15 mg every 2 to 4 weeks, as tolerated, until an acceptable response is achieved or a daily dose of 60 mg is reached. If there is an acceptable response, continue at the same dose for at least 1 year, then consider deprescribing. generalised anxiety disorder mirtazapine mirtazapine mirtazapine

Lower doses may be needed in older people; consult a source of drug information.

¹ Lorazepam tablets can be administered sublingually but are less bioavailable than when administered orally.Return