ANXIETY

What is anxiety?

Anxiety is a normal response to a dangerous situation, and helps ensure we avoid physical and mental damage. However, severe and/or persistent anxiety in situations where it is not appropriate can impair everyday life and social relationships and becomes an anxiety disorder. Symptoms of anxiety disorders include nervousness, sweating, trembling, palpitations, fear/panic, irritability and sleep disturbances.

There are several different types of anxiety disorder, including:

• Generalised anxiety disorder (GAD)
• Panic disorder
• Social phobia
• Obsessive-compulsive disorder (OCD)
• Post-traumatic stress disorder (PTSD).

Some anxiety disorders have specific triggers, appearing in response to specific situations (e.g. fear of public speaking), but others, such as panic attacks and GAD, do not seem to be related to an overtly threatening situation. Generalised anxiety disorder is the most common form of anxiety. Anxiety also often accompanies depression (see Depression). Panic disorders more commonly lead to people seeking medical help, however, because of the suddenness and severity of the symptoms.

Who does anxiety affect?

Generalised anxiety disorder and panic disorder most commonly occur for the first time when people are in their late teens or twenties. Social phobias and OCD, by contrast, often start during childhood or adolescence. Anxiety (including mixed anxiety and depression) affects women more often than men, whereas the other disorders affect men and women about equally. A survey in 2000 found that approximately 4.4 per cent of adults (aged 16-74) were affected by GAD, with a further 8.8 per cent experiencing mixed anxiety and depression.

Present treatments and shortcomings

Treatments for anxiety may be broadly divided into psychological therapies and medicines, complemented by self-help and relaxation techniques. Cognitive behavioural therapy (CBT), where available, is the recommended psychological therapy for both generalised anxiety disorder and panic disorder. Where immediate treatment is needed for rapid control of symptoms, short-term use of a benzodiazepine or a sedating antihistamine is recommended for GAD, and an SSRI antidepressant is recommended for panic disorder (benzodiazepines are not recommended in this case). For longer-term treatment, an SSRI antidepressant is recommended in both GAD, and panic disorder. Paroxetine (Seroxat, GSK) and escitalopram (Cipralex, Lundbeck) are specifically available for these conditions; a greater range of antidepressants, including tricyclics, are available for use in mixed anxiety and depression. Pregabalin (Lyrica, Pfizer) is also available for generalised anxiety disorder.

What's in the development pipeline?

Although the way they work is not entirely understood, a number of antidepressant medicines have been found to be helpful in reducing anxiety. So a number of compounds intended for treating depression are also being tested in anxiety disorders. Typically, these are medicines that interact with neurotransmitters in the brain, such as serotonin (5HT) and noradrenaline (NA), that are believed to be involved in mood and emotion. For example, the dual 5HT/NA reuptake inhibitor duloxetine (Cymbalta, Lilly) that has been indicated for use in depression is currently in Phase 3 trial for GAD. Another 5HT_1A agonist (MN-305, MediciNova) is in Phase 2 trials. Also in Phase 3 trial for GAD are quetiapine (Seroquel SR, AstraZeneca), which is a dual dopamine-D₂ and 5HT₂ receptor antagonist, and agomelatine (Servier and Novartis) a 5HT_2C antagonist and MT_1/2 (melatonin) receptor agonist, which is also in Phase 3 trials for depression.

Neurokines (NK) are other neurotransmitters that may be involved in anxiety and several experimental compounds that target them are being tested in anxiety disorders. An antagonist is a substance that blocks a chemical process in the body, such as the binding of a neurokine to its receptor. NK₁ receptor antagonists under study in Phase 2 trials include LY686017 (Lilly) in social phobia, and GSK679769 (casopitant, GSK) in anxiety. In addition, GSK has another compound (GW823296) in Phase 1 study. Sanofi-aventis also has an NK₂ receptor antagonist (Saredutant) in development for treating anxiety and this has reached Phase 3 trial.

Another class of compounds that is being intensively studied in anxiety states is that of selective inhibitors of receptors for a substance called corticotropin releasing factor (CRF), which is involved in response to long-term stress. CRF₁ receptor inhibitors are at an earlier stage in development than NK₁ receptor antagonists, with the most advanced being GSK876008 (Phase 2) and GSK 561679, under development by GSK, Ono Pharma's ONO 2333Ms, SSR 125543 from sanofi-aventis and TS-041 from Taisho and Janssen, in Phase 1 trials. In addition, Bristol-Myers Squibb has DMP696 and DMP904, that have shown promise in preclinical models.

Glutamate is a major neurotransmitter in the brain and limbic structures in the brain that are involved in the control of emotions and carry a type of receptor known as metabotropic glutamate receptors. Several companies are exploring antagonists of such receptors and Lilly's LY544344 has already reached Phase 3 trial. The company has another compound of this type (LY354740) in Phase 2 study. Other companies are investigating compounds at Phase 1 that bind to the type 5 subclass of receptors, including Addex Pharma (ADX-10059) AstraZeneca (AZD 2066) and Novartis (AFQ 056).

A considerable variety of other approaches are also being explored and tested, including:

• Adrenergic beta-3 receptor agonist (SR 58611, sanofi-aventis; Phase 2)
• Benzodiazepine agonist (XBD 173, Novartis; Phase 2)
• Alpha-2 delta calcium channel blocker (PD-332334, Pfizer; Phase 2)
• Vasopressin-1B antagonist (SSR 149415, sanofi-aventis; Phase 2)
• Phosphodiesterase-2 inhibitor (ND7001, Neuro3d; Phase 1)
• G-protein-coupled receptor modulator (R7090, Roche; Phase 1)
• GABA-A antagonist (TP003, Merck Sharp & Dohme; Phase 1)
• Mixed 5HT1 antagonist (163090 and 588045, GSK; Phase 1)
• Enkephalin receptor modulator (AZD 2327, AstraZeneca; Phase 1)
• Fatty acid hydrolase inhibitor (SSR 411298, sanofi-aventis; Phase 1)
• 5HT6 receptor agonist (WAY-181187, Wyeth; Phase 1).

There is a rich pipeline of new compounds being explored for the treatment of anxiety and the coming years promise to bring a worthwhile expansion of the options available. Nevertheless, in anxiety as well as in depression, psychological therapies and supportive and self-help measures will continue to play an important role in treatment.

FOR FURTHER INFORMATION CONTACT:

Anxiety Care
Cardinal Heenan Centre, 326 High Road
Ilford
Essex, IG1 1QP
Phone: 020 8478 3400 (Helpline)
Website: www.anxietycare.org.uk

Triumph over Phobia (TOP UK)
PO Box 3760
Bath, BA2 3WY
Phone: 0845 600 9601
Website: www.triumphoverphobia.com