The effects of idazoxan on reaction times, eye movements and the mood of healthy volunteers and patients with upper respiratory tract illnesses.

An experiment was carried out to determine whether idazoxan, a drug which increases the turnover of central noradrenaline, removes the malaise (reduced alertness, slower psychomotor performance) associated with upper respiratory tract illness (URTI). Eighty-one volunteers were tested when healthy and 17 returned to the laboratory when they developed URTIs. Those who remained healthy were then recalled as a control group. Volunteers were tested before and after receiving either idazoxan (40mg) or a lactose placebo. Idazoxan removed the URTI-induced slowing in a simple reaction time task and this group performed at a comparable level to the healthy group. No significant stimulant effect of idazoxan was found in the healthy subjects. The results suggest that at least part of the malaise induced by URTIs may reflect reductions in central noradrenaline and that this can be reversed by compounds such as idazoxan.     

Discriminative stimulus produced by the imidazoline I2 site ligand, 2 -BFI

2-(2-Benzofuranyl)-2-imidazoline, RX801077 (2-BFI) which has high affinity for imidazoline I(2) binding sites and very low aflinity for α(2)-adrenoceptors, has been investigated for its ability to produce a discriminative stimulus (cue) in drug-discrimination studies in rats since the existence of such a cue could assist in determining the functionality of I(2) sites. All rats subjected to training proved able to discriminate the training dose of 2-BFI (33 μmol/kg i.p) from saline vehicle and lower (5-14 μmol/kg) doses exhibited dose-dependent substitution. The mixed α(2)-adrenoceptor/I( 2) site ligand idazoxan fully substituted at 40μmol/kg. However, ethoxy idazoxan (11 μmol/kg) and fluparoxan (13 μmol/kg), selective α( 2)-adrenoceptor antagonists, also fully substituted for 2- BFI as did the monoamine oxidase (MAO) inhibitors moclobemide (99 μmol/kg) and pargyline (153 μmol/kg). A lower dose of moclobemide (16 μmol/kg) exhibited partial substitution. The α( 2)-adrenoceptor agonists clonidine (0.1 μmol/kg) and guanabenz (1.4 μmol/kg), and the benzodiazepine diazepam (14 μmol/kg), failed to substitute for 2-BFI indicating cue specificity. However, 2-BFI (14-50 μmol/kg) substituted partially but dose-dependently for clonidine (0.1 μmol/kg) in rats trained to distinguish the latter from saline. Changes in rates of response were independent of the degree of substitution. The observed pattern of drug substitution is consistent with the previously reported ability of 2-BFI to decrease MAO activity and thus increase extracellular monoamines.     

Sedative antidepressants impair visual detection mechanisms in humans

The safety of sedative antidepressants is a topical issue in the treatment of depression, with driving impairment being of particular concern. We have recently completed a study with normal male volunteers comparing the actions of dothiepin (a traditional, sedating antidepressant) with those of fluvoxamine (one of the selective serotonin re-uptake-inhibiting SSRI class of newer antidepressants) on psychomotor functions relevant to driving. We set out to investigate whether these drugs impair visual selective attention (focused and divided) by employing the 'odd-ball' task. Subjects were required to respond to letters of the alphabet (T for target and other letters for non-targets) that were presented at the centre and/or periphery of the computer screen. The task has been shown to be useful in detecting differences between drugs in their effects on selective attention. Preliminary results show that dothiepin delayed responses to single targets compared with fluvoxamine and placebo. There was also preliminary evidence that it mainly affected response times to peripheral targets. Furthermore, there was preliminary evidence that both drugs delayed responses to central targets compared with placebo on the divided attention trials. Finally, response accuracy in detecting peripheral targets was greater under placebo compared with fluvoxamine and dothiepin. The impairment produced by dothiepin is presumably a consequence of the central blockade of cholinergic muscarinic or histaminergic H1 receptors. It could contribute to the reported association between the tricyclic class of antidepressants and road traffic accidents, and would be worth further investigation in depressed patients taking both classes of drug.     

Imipramine in panic disorder. 1. Clinical response and pharmacological changes

Clinical and biochemical variables were monitored in 18 patients with panic disorder before and during treatment with imipramine over 16 weeks. Imipramine dosage was slowly increased from a starting dose of 10 mg daily, to prevent early treatment drop-outs. All patients were effectively treated for at least 6 weeks, and only two patients dropped out before the end of the study. There were substantial reductions in panic attack frequency, ratings of depression and avoidance behaviour, but only small reductions in ratings of state and general anxiety. Plasma levels of the noradrenaline metabolite 3-methoxy-4-hydroxyphenyl- ethylene glycol initially fell after starting imipramine, but returned to pre-treatment levels by week 8 of treatment. Plasma imipramine and/or desipramine concentrations were very variable and did not correlate with either psychological or biochemical changes during treatment.     

Imipramine in panic disorder. 2. Effects on α2-adrenoceptor function

Untreated patients with panic disorder have been shown to have altered α(2)-adrenoceptor sensitivity, as assessed by clonidine challenge testing. We investigated clonidine-induced biochemical, physiological, hor monal and psychological responses in six panic patients, before and after treatment with imipramine. Comparison of the clonidine-induced fall in plasma MHPG pre- and post-treatment showed it to be sig nificantly reduced after imipramine. Significantly smaller clonidine-induced falls in diastolic blood pressure and heart rate occurred after imipramine treatment. However, growth hormone and sedation responses were not altered. These data suggest that reduced sensitivity of some central α(2)-adrenoceptors occurs during treatment of panic disorder with imipramine. However, these changes do not fully explain the therapeutic actions of antidepressants in this condition.     

The effects and after effects of the α2-adrenoceptor antagonist idazoxan on mood, memory and attention in normal volunteers

Idazoxan, an α( 2)-adrenoceptor antagonist, is an effective antidepressant with a mode of action different from that of conventional antidepressants. As it is used as an antidepressant it is important to know whether there are any unwanted CNS side effects. Study of its effects will also provide information on the relationship between noradrenergic function and mood and performance. Twelve normal male volunteers who were given the drug (40 mg orally three times daily for 21 days) were compared with 12 matched controls. A computerized test battery was used to assess mood and various aspects of memory and attention. Many of the tests of memory and attention in the battery have been widely used over the last 20 years, and in addition two new selective attention tasks were included. The subjects were tested 3 days before starting the drug, on days 3 and 17 while on the drug, and after they had stopped taking the drug (4 days after and 24 days after). Control subjects followed a similar testing schedule. The results showed that the drug had no effect on mood, logical reasoning, retrieval from semantic memory or sustained attention. However, the drug did improve one aspect of selective attention (the place repetition effect), although this effect was only observed on the third day on the drug. Overall, the results suggest that idazoxan produces selective performance improvements, and that the measures of selective attention used here may be more sensitive indicators of drug effects than some of the traditional tasks currently in use.