Neurochemical Disorders Anxiety
Anxiety is a normal emotional reaction to threatening or potentially threatening situations, and is accompanied by sympathetic overactivity. In anxiety disorders the patient experiences anxiety that is disproportionate to the stimulus, and sometimes in the absence of any obvious stimulus. There is no organic basis for anxiety disorders, the symptoms resulting from overactivity of the brain areas involved in ‘normal’ anxiety. Psychiatric disorders that occur without any known brain pathology are called neuroses.
Anxiety disorders are subdivided into four main types: generalized anxiety disorder, panic disorder, stress reactions and phobias. Many transmitters seem to be involved in the neural mechanisms of anxiety, the evidence being especially strong for γ-aminobutyric acid (GABA) and 5-hydroxytryptamine (5-HT). Because intravenous injections of cholecystokinin (CCK4) into humans cause the symptoms of panic it has been suggested that abnormalities in different transmitter systems might be involved in particular types of anxiety disorder. This remains to be seen.
There is some evidence for decreased GABA binding in the left temporal pole, an area concerned with experiencing and controlling fear and anxiety.
There may be disturbances of serotoninergic and noradrenergic transmission in anxiety. Thus, chlorophenyl piperazine (a non- specific 5-HT1 and 5-HT2 agonist) increased anxiety in patients with a generalized anxiety disorder. These patients also show a reduced growth hormone response to clonidine (an α2-receptor agonist) suggesting a decrease in α2-receptor sensitivity. This response is also seen in patients with major depression. This is perhaps not surprising because genetic studies suggest that generalized anxiety disorder and major depression may have a common genetic basis and both disorders benefit from the administration of antidepressant drugs.
Treatment of mild anxiety disorders may only require simple supportive psychotherapy, but in severe anxiety anxiolytic drugs given for a short period are useful. The benzodiazepines (e.g. diazepam) produce their effects by enhancing GABA-mediated inhibition in many of the brain areas involved in anxiety, including the raphé nucleus. Some antidepressants (e.g. amitriptyline, paroxetine) have anxiolytic activity and they are used for the long-term treatment of anxiety disorders. Their mechanism of action in anxiety is unclear. β-adrenoceptor antagonists have a limited use in the treatment of situational anxiety (e.g. in musicians) where palpitations and tremor are the main symptoms. Efforts to discover non-sedative anxiolytics have led to the trial of several drugs that act on specific 5-HT receptors but only one, buspirone, has been introduced.
· Generalized anxiety disorders have both psychological and physical symptoms. The psychological symptoms include a feeling of fearful anticipation, difficulty in concentrating, irritability and repetitive worrying thoughts that are often linked to awareness of sympathetic overactivity.
· Phobic anxiety disorders have the same core symptoms as generalized anxiety disorders but occur only under certain circumstances, e.g. the appearance of a spider (arachnophobia).
· In contrast, panic attacks are episodic attacks of anxiety in which physical symptoms predominate (e.g. choking, palpitations, chest pain, sweating, trembling).
Benzodiazepines (e.g. diazepam) are orally active central depressants that induce sleep when given in high doses at night (see Chapter 43) and provide sedation and reduce anxiety when given in divided doses during the day. They also have anticonvulsant activity (see Chapter 61), are muscle relaxants and produce amnesia. All these actions are brought about by the potentiation of the action of GABA on the GABAA receptor, which consists of five subunits.
Benzodiazepines enhance the action of synaptically released GABA by binding to a benzodiazepine receptor site on the GABAA receptor complex. This causes a conformational change to the GABA binding site, increasing its affinity for GABA.
The main adverse effects of the benzodiazepines are drowsiness, impaired alertness, agitation and ataxia. In anxiety disorders, benzodiazepines should only be given for a maximum of 2–3 weeks because longer treatment risks the development of dependence. If this occurs, stopping the drug frequently leads to a withdrawal syndrome characterized by anxiety, tremor, sweating and insomnia – symptoms similar to the original complaint.
Sites of action of benzodiazepines in the brain
In general, limbic and brainstem structures seem important in mediating the anxiolytic actions of these drugs. In humans, cerebral blood flow and glucose metabolism studies using positron emission tomography (PET) have not revealed consistent differences in anxious and non-anxious subjects.
Serotonin (5-HT) cell bodies are located in the raphé nucleus of the midbrain and project to many areas of the brain including those thought to be important in anxiety (hippocampus, amygdala, frontal cortex; see Chapter 19). In rats, lesions of the raphé nucleus produce anxiolytic effects, while stimulation of 5-HT1A autoreceptors with agonists such as 8-hydroxy-DPAT produce anxiogenic effects. A role for 5-HT in anxiety was strengthened when it was found that benzodiazepines reduce the turnover of 5-HT in the brain and, when microinjected into the raphé nucleus, reduce the rate of neuronal firing and produce an anxiolytic effect. However, stimulation of postsynaptic 5-HT1A receptors in limbic areas has anxiogenic effects. These opposing pre and postsynaptic actions may explain why buspirone, a 5-HT1A partial agonist, has limited efficacy and works only after several weeks.
The evidence for the role of noradrenaline (norepinephrine) in anxiety is much less compelling than that for GABA and 5-HT. Nevertheless, β-adrenoceptor antagonists (e.g. propranolol) have a limited use in the treatment of patients with mild or transient anxiety and where autonomic symptoms such as palpitations and tremor are the most troublesome symptoms. The beneficial effects of β-blockers in these patients may result from a peripheral action because those (e.g. practolol) that do not pass the blood–brain barrier are equally effective.
Peptides and anxiety
Several neuropeptides have been implicated in anxiety. The strongest evidence is for the anxiogenic effect of corticotrophin-releasing hormone (CRH), and CRH has also been implicated in depression. This raises the theoretical possibility that a CRH receptor-1 antagonist may have anxiolytic actions and such drugs are under development. Substance P may also have anxiogenic effects and an NK1 receptor antagonist is in clinical trials for anxiety and depression. Cholecystokinin (CCK) is a gut peptide that is also present in many areas of the brainstem and midbrain and is involved in emotion, mood and arousal. Because CCK4 is one of the few agents (CO2 is another) that elicits genuine panic-like attacks, it was hoped that CCK antagonists would be useful anxiolytics. Unfortunately, clinical trials revealed that non-peptide CCK antagonists are inefective in anxiety disorders.