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.
Anxiety disorders
· 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).
Treatment
Benzodiazepines
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.
Buspirone
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.
β-blockers
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.
