Anxiety symptoms and anxiety disorders are common in primary and secondary medical care. Most anxiety symptoms are mild and transient, but many people are troubled by severe and distressing symptoms that impair social and occupational function. Many people who could benefit from treatment are not recognized or treated by healthcare professionals, but some patients receive unnecessary or inappropriate treatment.
Recognition relies on being familiar with the psychological and physical symptoms that are seen in all anxiety disorders, but accurate diagnosis rests on identifying the characteristic features of specific disorders.
Treatment decisions should be guided by the severity and persistence of symptoms and their impact on everyday life, the presence of coexisting depressive symptoms, and other features such as the response to and tolerability of previous treatments. The choice of particular treatment is influenced by its evidence base, patient characteristics, and patient and doctor preferences. There is much overlap between the anxiety and related disorders for evidence-based and effective therapies, such as treatment with a selective serotonin reuptake inhibitor (SSRI) or undergoing individual cognitive–behavioural therapy (CBT), but there are some important differences between disorders and it helps to be familiar with the characteristic features and evidence-base for each condition.¹
The traditional view is that the efficacy of psychological and pharmacological approaches in the acute treatment of anxiety disorders is broadly similar, with the best evidence for judicious prescription of an SSRI or manualised CBT delivered by trained and supervised staff. This may be incorrect as a recent meta-analysis of acute treatment for generalised anxiety disorder (GAD), panic disorder, and social phobia provides clear evidence that the efficacy of medications is somewhat greater.²
In some anxiety disorders, it is uncertain whether combining an SSRI with CBT is more effective than either treatment when given alone, so it is best to plan patient management in sequential steps. Whichever treatment is undertaken, it makes sense to warn patients that their symptoms might worsen transiently at the start, and that prolonged treatment is needed to consolidate an initial response.
SSRIs have ‘broad spectrum’ efficacy in short-term and long-term treatment, and are usually fairly well tolerated. For these reasons, SSRIs are the first-line pharmacological approach in patients with anxiety disorders, obsessive-compulsive disorder (OCD) and post-traumatic stress disorder (PTSD). SSRIs have potentially troublesome adverse effects, including initial increased nervousness, insomnia, nausea and sexual dysfunction. Fluoxetine and paroxetine inhibit some cytochrome P450 enzymes, so may interact with some other psychotropic drugs and treatments for physical illness. When stopped abruptly, SSRIs can produce a discontinuation syndrome characterised by dizziness, insomnia and flu-like symptoms.
When should other pharmacological treatments be used?
The serotonin-noradrenaline reuptake inhibitors (SNRIs), duloxetine and venlafaxine, are efficacious in short-term and long-term treatment of GAD, and venlafaxine is also efficacious in acute treatment and relapse prevention in panic disorder.
The tolerability profiles of SSRIs and SNRIs in patients with anxiety disorders are not established fully, but systematic reviews of studies in depressed patients suggest duloxetine and venlafaxine are less well tolerated than SSRIs. Abrupt withdrawal of duloxetine or venlafaxine is associated with discontinuation symptoms. Venlafaxine treatment can be associated with an increase in blood pressure, so monitoring is recommended at higher daily doses. Duloxetine should be avoided in patients with known liver disease and patients considered to be at risk of hepatic dysfunction.
Agomelatine is efficacious in acute treatment and relapse prevention in GAD, and sexual dysfunction is less likely with agomelatine than with SSRI or SNRI antidepressants, as are discontinuation symptoms. Elevations of hepatic enzymes occur in more than 1% of treated patients and regular monitoring of liver function tests is required in the early months of treatment.
The evidence for the efficacy of mirtazapine in anxiety disorders is limited and inconsistent, although treatment-emergent sexual dysfunction is probably less frequent than with SSRIs.
Pregabalin is efficacious in acute treatment and prevention of relapse in GAD and social anxiety disorder. It can reduce depressive symptoms of mild to moderate intensity in patients with GAD. Common adverse effects include drowsiness and dizziness³, although it may be better tolerated than other medications in acute treatment of GAD. Spontaneous reports of adverse sexual side effects are uncommon, but the incidence of treatment-emergent sexual dysfunction with pregabalin is uncertain. It is not subject to hepatic metabolism and is excreted unchanged in the urine, which is advantageous in patients with hepatic impairment and in patients taking other drugs metabolised by the liver, but disadvantageous in patients with renal disease.
Discontinuation symptoms after abrupt withdrawal of pregabalin have been reported, as has the abuse of pregabalin generally in individuals with a history of other substance abuse and concern has been raised about the potential for developing tolerance and abuse.⁴
Second generation (‘atypical’) antipsychotic drugs are often prescribed to patients with anxiety disorders, but the strongest evidence for benefit is restricted to acute treatment and prevention of relapse with quetiapine in GAD and the augmentation of SSRI antidepressants in patients with OCD.
The tolerability profile of antipsychotic drugs means they should be reserved for treatment after a non-response to other interventions.
There are occasions when patients should be referred to secondary care mental health services. These include:
- After a non-response to two evidence-based treatments.
- When symptoms have recurred despite continuing with treatment.
- When anxiety disorders are ‘comorbid’ with other conditions, such as depression or alcohol dependence.
- When more specialist interventions are needed such as antipsychotic augmentation after partial response to an SSRI.
A treatment course of between eight to 20 hours of CBT is recommended for the treatment of anxiety disorders. In GAD and panic disorder, typical treatment consists of 16 to 20 hours, of up to half can be conducted by the patient in supervised ‘homework’ sessions, over approximately four months.
In social anxiety disorder (social phobia), a standard course consists of up to 14 sessions of 90 minutes’ duration over four months.
In PTSD, psychological treatment might involve eight to 12 sessions of trauma-focused CBT, delivered at weekly intervals.
In OCD, typical treatment includes approximately 16 hours of intervention based on exposure and response prevention, with longer and more intensive treatment in housebound patients.
What drugs treatments have fallen out of favour?
Certain tricyclic antidepressants (TCAs) are efficacious in some anxiety disorders, but they impose a greater burden of adverse effects than either SSRIs or SNRIs, so should be reserved for use after a non-response to an SSRI or SNRI.
TCAs should be avoided in patients at risk of suicide due to their potential fatal toxicity after overdose. As with some SSRIs, many possible pharmacokinetic interactions limit their use in patients taking concomitant medication. Like other antidepressants, stopping TCAs abruptly can cause discontinuation symptoms.
The traditional irreversible monoamine oxidase inhibitor (MAOI) phenelzine is efficacious in panic disorder and social phobia, but side effects and the need to follow stringent dietary restrictions limit its use, and it should be reserved for when patients have not responded to other treatment approaches. Phenelzine overdose is potentially fatal and it should usually be avoided in patients at risk of suicide. The reversible inhibitor of mono-amine oxidase A (RIMA) moclobemide is efficacious in social phobia and may be helpful in panic disorder. The reversibility of its action reduces the need for dietary restrictions at lower daily doses, but avoidance of tyramine-containing foods – principally cheese – is advisable at higher doses.
Some benzodiazepines are efficacious in the treatment of patients with panic disorder, GAD and social anxiety disorder, but benzodiazepines can cause troublesome sedation and cognitive impairment in short-term and long-term treatment, and tolerance and dependence can occur, especially in predisposed patients, with prolonged use.
There is no evidence of efficacy for benzodiazepines in the acute treatment of patients with minor depression and antidepressants should be preferred over benzodiazepines in patients with significant coexisting depressive symptoms. Benzodiazepines will usually be reserved for the further treatment of patients who have not responded to at least four previous treatments, such as after non-response to an SSRI, an SNRI, pregabalin and a psychological intervention. Concerns about potential problems in long-term use should not prevent their use in some patients with persistent, severe, distressing, and impairing anxiety symptoms, when other treatments have proved ineffective.⁵
The role of self-help, complementary and alternative treatments
Many patients and their carers derive considerable practical and emotional support from local self-help groups and national self-help organisations (such as the organisations Anxiety-UK and Obsessive Action), though formal evaluations of the effectiveness of participation in self-help groups are uncommon.
A systematic review of 21 studies in patients with depression or anxiety disorders suggests that guided self-help has similar effectiveness to face-to-face psychotherapy, but another review of 31 randomized controlled trials in anxiety disorders found that self-help interventions are more effective than being placed on a waiting list, but less effective than therapist-administered treatments. Another systematic review of 26 studies in individuals with depression or anxiety disorders suggests that internet-based interventions offer some promise in overall patient management.
Many patients with anxiety disorders wonder whether taking herbal preparations or nutritional supplements might prove beneficial, either alone or combined with standard pharmacological or psychological treatments. Systematic reviews find some evidence for the potential effectiveness of a number of ‘phytomedicines’, including Passiflora extracts, Kava (Piper methysticum), and combinations of l-lysine and l-arginine, but there is no current convincing evidence for the effectiveness of homeopathic preparations in the treatment of patients with anxiety disorders. Kava preparations appeared beneficial in patients with GAD, but have been withdrawn in many countries due to potential hepatotoxic effects.
Other complementary approaches include regular exercise and interventions based on meditation techniques. Exercise training reduces anxiety symptoms in sedentary patients with long-term medical conditions and regular walking may enhance the efficacy of group CBT, across a range of anxiety disorders.
Meditation and yoga practices are often advocated as part of the overall management of patients with anxiety disorders. A systematic review found that relaxation training, which often includes components of meditation, is effective in reducing anxiety symptoms in non-clinical and clinical groups meditative therapies are effective in reducing anxiety symptoms, although their effect in anxiety disorders is uncertain.
Special or atypical cases and their treatment, including non-drug options
First-line treatment of a patient with OCD would typically involve either an SSRI prescribed in primary care, or CBT delivered through IAPT or on-line services. Treatment response is often limited and combining an SSRI with CBT delivered within secondary (mental health) care may be needed. Even with combination treatment in secondary care, many patients do not respond, and in this situation augmentation with a second generation antipsychotic drug may be beneficial. Referral to regional specialist services may also be needed.
Treatment-resistant generalised anxiety disorder
Current first-line treatments include applied relaxation or CBT, or an SSRI. NICE recommends sertraline for pharmacological treatment, although it is not licensed for treatment of GAD. Patients who make a partial response to an SSRI at the limit of tolerance may benefit from augmentation with pregabalin or olanzapine. At present, it is uncertain whether the combination of CBT with an SSRI is better than either treatment alone.
Routine ‘de-briefing’ after a traumatic incident should be avoided and patients should be encouraged to resume normal domestic and external commitments as swiftly as possible, instead. Trauma-focused CBT, some SSRIs and venlafaxine can all be beneficial, but it is uncertain whether combining psychological with pharmacological treatment is more effective than either given alone. Monitor patients carefully for depressive symptoms and suicidal thoughts and for comorbid substance and alcohol use disorders.
Professor David Baldwin is professor of psychiatry and head of mental health group at the University of Southampton Faculty of Medicine
Declaration of interest: DB is the Chair of the Anxiety Disorders consensus group of the British Association for Psychopharmacology. His employer (University of Southampton) has received research grants from H. Lundbeck A/S and Pfizer Ltd. EM and QK have no potential conflicts of interest.