n o r1 O O «i tricyclic antidepressants (TCAs) and the non-specific MAOIs such as phenelzine affect both the noradrenergic and serotonergic systems it was unclear which of these neurotransmitters was causally related to the beneficial effects of antidepressant treatment. However, by determining the plasma concentrations of imipramine (which inhibits the reuptake of both noradrenaline and serotonin) and its major metabolite desipramine (which is selective in inhibiting noradrenaline reuptake) it has been shown that the antipanic action of imipramine is largely attributable to its effect on serotonergic function. This view has been strengthened in recent years by the widespread use of clomipramine, the most specific inhibitor of 5-HT reuptake of the conventional TCAs, in the treatment of panic disorder. However, there is convincing clinical evidence that other TCAs such as the ''second generation'' tricyclic lofepramine which inhibits both noradrena-line and 5-HT uptake, is equi-effective with clomipramine and has an advantage of fewer adverse effects.

Undoubtedly one of the major advances in the treatment of panic disorder in the last two decades has resulted from the introduction of the selective 5-HT reuptake inhibitors (the SSRIs). Detailed double-blind placebo-controlled studies have shown that these drugs are effective in reducing the frequency of panic attacks, anxiety and the associated symptoms of the disorder. The importance of the serotonergic system in the therapeutic response to the SSRIs is indicated by studies in which fluvoxamine was compared with the selective noradrenaline reuptake inhibitor maprotiline. Whereas the number of panic attacks and the severity of anxiety significantly decreased following fluvoxamine, no such beneficial effects were seen following maprotiline treatment. Thus the SSRIs would appear to exhibit specific antipanic properties which are related to their chronic modulatory effects on serotonergic transmission. Generally all the SSRIs show a latency of several weeks before the optimal antipanic effect is established. This suggests that major changes in 5-HT receptor function must occur before the full clinical effect is manifest, a situation which is similar to that occurring when these drugs are used in the treatment of depression. In support of this hypothesis it has been found that a transient increase in anxiety frequently occurs when patients start treatment on an SSRI; this generally disappears as treatment proceeds and has been explained by an initial hypersensitivity of 5-HT1A receptor subtypes which normalize following chronic drug treatment.

Despite the clear evidence that the serotonergic system is involved in the therapeutic efficacy of the antidepressants, it should be noted that the antipanic effect of the triazolobenzodiazepine alprazolam does not appear to be directly mediated by changes in the serotonergic system. This further emphasizes the complexity of the inter-relationships between the various biogenic amine and peptide (for example, cholecystokinin which has been implicated in the aetiology of panic disorder) neurotransmitters and also accounts for the diverse range of drugs that have been used in the treatment of the disorder.

Biology of obsessive-compulsive disorder

According to the DSM-IV classification, anxiety as a disorder can be divided into panic disorder with or without agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder (OCD) and social phobia. Patients with generalized anxiety disorder appear to respond best to anxiolytic benzodiazepines; the properties and adverse effects of these drugs have been discussed in detail elsewhere. In recent years there have been a number of ''open'' and ''placebo-controlled'' studies showing that the SSRIs and the reversible MAOI moclobemide are effective in the treatment of social phobia. However considerable attention has been paid recently to the pharmacological treatment of OCD, a condition which, until it was discovered that clomipramine could effectively attenuate some of the symptoms, was largely unaffected by drug treatment including anti-depressants that enhance noradrenergic function.

By using imaging methods it has been shown that blood flow rates were greater in parts of the cortex in OCD patients than in matched control subjects. Similarly PET imaging studies in which the uptake of fluorodeoxyglucose was used to determine the activity of different brain regions, showed that the activity of the inferior prefrontal cortex was significantly greater in untreated OCD patients (Figure 9.9). There is evidence that these increased glucose metabolism indicates hyperactivity in the inferior prefrontal cortex normal (.antral normal (.antral

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