N.J. Coupland

The 5-HT3 antagonist ondansetron reduces gastrointestinal side effects induced by a specific serotonin re-uptake inhibitor in man

The selective serotonin re-uptake inhibitors (SSRIs) are increasingly being used to treat depression and anxiety disorders. Gastrointestinal (GI) symptoms are the main side effects, probably resulting from the stimulation of central or peripheral 5-HT receptors. The present double-blind, placebo-controlled study was undertaken to see if the GI side effects of fluvoxamine could be attenuated by the co-administration of the 5-HT3 antagonist ondansetron. The results demonstrate that, in volunteers, a single 100 mg oral dose of fluvoxamine can produce GI symptoms. Co-administration of ondansetron significantly reduced peak nausea and GI side effects, compared with placebo.

Sleep changes during long-term treatment of depression with fluvoxamine--a home-based study.

Abstract Rationale: The effects of antidepressants on sleep in depression have been extensively investigated, although to date there have been relatively few studies of newer drug classes such as specific serotonin reuptake inhibitors (SSRIs). All reported studies on SSRIs have been conducted in patients admitted to sleep laboratories and very few longitudinal studies have continued to measure sleep beyond 5 weeks of treatment. The growing trend towards outpatient and community care has highlighted the need for studies of sleep in depression in a more naturalistic setting, and during longer periods of treatment in line with recommended clinical practice. Objectives: To establish if the changes in sleep architecture and continuity described during early treatment with SSRIs persist after 3 months, to relate these changes to clinical state, and to establish whether home recordings would yield similar results to previous laboratory studies. Methods: We have recorded objective sleep parameters in 12 depressed patients before and during 12-week treatment with an SSRI, fluvoxamine. All the sleep recordings were performed in the patients’ own homes, using the Oxford Medilog system. Results: At 12 weeks, 7/12 patients had responded (HAM-D decreased by >50%). REM latency showed the expected increase early in treatment; this change was less obvious at weeks 3 and 12. Amount of REM sleep was decreased at day 2 and week 3, but returned to baseline by week 12. Slow wave sleep was slightly increased at day 2 and decreased at week 12. Of the sleep continuity measures, the only significant change was in sleep onset latency, which was increased at week 3; the other measures showed non- significant worsening at night 2 and week 3, but most were better than baseline by 12 weeks. Subjective sleep (the three sleep items on the HAM-D) showed a progressive improvement over time, especially in the responders. Conclusions: The effects of the SSRI fluvoxamine on objective sleep measures are in the direction predicted by its pharmacological actions and some persist for at least 12 weeks. In addition subjective appraisal of sleep is strongly affected by mood state. All patients found the home recording procedure acceptable and only minimally disruptive.

The effects of clonidine on cardiovascular responses to standing in healthy volunteers

This study assessed the effects of clonidine on blood pressure (BP) and heart rate responses to active standing, recorded continuously using a Finapres monitor. Ten subjects were given a placebo infusion over 1 h, followed by clonidine hydrochloride 1.5 µg/kg over 2 h. During placebo and at 1, 3 and 19 h following the clonidine infusion, heart rate and blood pressure were recorded during the second half of supine rest for 10 min, active standing and quiet standing for 7 min. Clonidine did not alter the size of immediate drop in BP on standing, although the nadir was lower. BP recovery was impaired, with a loss of the usual BP overshoot in most subjects and with delays in reaching supine levels of diastolic BP (6.1 versus 9.6 s; p < 0.01) and systolic BP (8.1 versus 12.3 s; p < 0.05). The compensatory initial heart rate rise was significantly increased from 47 to 53 beats/min (p < 0.05), athough the peak rate reached was reduced from 114 to 104 beats/min (p < 0.05). These results demonstrate that impairment of central sympathetic vasomotor drive leads to a delay in BP recovery and loss of initial BP overshoot immediately after standing, together with impaired maintenance of early steady-state BP.

The relationship between benzodiazepine receptor sensitivity and neuroticism

Abstract The possibility that differences in GABA A /benzodiazepine receptor sensitivity might contribute to the personality trait of neuroticism was assessed. We compared the effects of the benzodiazepine agonist, midazolam, on saccadic eye movements and self-ratings of anxiety and sedation between two groups of volunteers with either low (≤ 4) or high (≥ 17) scores on the Neuroticism (N) scale of the Eysenck Personality Questionnaire. Baseline trait and state anxiety ratings were greater in the high-N subjects. Midazolam had a significantly smaller effect on saccade accuracy in the high-N compared with the low-N subjects, and produced a greater fall in anxiety ratings. The saccade data suggest that variations in the personality trait of neuroticism may be related to differences in the sensitivity of benzodiazepine receptors, and that these may also be implicated in nonpathological anxiety as well as clinical disorders.

Challenge tests: assessment of the noradrenergic and GABA systems in depression and anxiety disorders.

A variety of methods have been developed for the study of noradrenergic and GABA systems in health and disease in man. These include measurements of neurotransmitters in peripheral blood and CSF; studies of neuronal anatomy, neurotransmitter levels and receptor binding in post-mortem brain tissue; measures of binding and function in peripheral receptors, which may model those in the brain; characterisation of the genes and their products involved in neurotransmission; and scanning techniques such as PET and SPECT, which allow the study of receptor binding and metabolic activity in the living brain. Challenge studies have the advantage of being dynamic tests of brain function, which may reveal abnormalities not measurable in an unstressed state. When specific pharmacological agents are used, differences in responses across diagnoses or symptom groups and during treatment or after recovery can help elucidate the receptor abnormalities involved. The lack of an identified neurotransmitter or peripheral CNS-type benzodiazepine receptor to study means that much of our understanding of changes in the benzodiazepine/GABA system must come from challenge testing. Finally, the findings in man can be compared with animal studies where techniques are available for investigating central changes more directly.

Digital infarction in a patient with Raynaud's phenomenon associated with treatment with a specific serotonin reuptake inhibitor. A case report.

The authors report the worsening of preexisting Raynauds phenomenon during treatment of depression with a selective serotonin reuptake inhibitor, fluvoxamine.

A pharmacodynamic study of the α2‐adrenergic receptor antagonist ethoxyidazoxan in healthy volunteers

Ethoxyidazoxan, a potent and highly selective α2‐adrenergic receptor antagonist, was administered intravenously to six healthy male volunteers in a double‐blind, placebo‐controlled, dose‐rising design. Doses of 6 µg/kg and 8 µg/kg infused intravenously over 30 minutes produced significant elevations of plasma norepinephrine and body temperature and inhibited norepinephrine‐induced platelet aggregation. Central activity was shown by reversal of the slowing of saccadic eye movements and an increase in saccade peak velocity at the higher dose. Modest increases in blood pressure were produced without change in heart rate. Ethoxyidazoxan was well tolerated, with slight changes in subjective alertness and sedation.

Neurobiology of Anxiety and Panic

Anxiety disorders can be subdivided into groups according to various criteria, the most reliably recognized is the presence of panic attacks, which are made distinctive by their sudden onset and intense somatic symptoms. Phobias are characterized by the relationship of anxiety to cues and avoidance behavior. Post-traumatic stress disorder is distinguished particularly by intrusive thoughts, images or dreams related to specific traumatic experiences. In addition to being able to explain these defining features, a comprehensive neurobiological theory should also make sense of associated features, the natural history of the disorders, putative etiological factors such as life stresses, family history, genetic loading, substance abuse, the association of anxiety with depression, the effects of treatments and findings in physiological, pharmacological and psychological tests. To date, our understanding comes mainly from findings in cross-sectional comparisons between diagnostic groups, with some longitudinal data from treatment studies, and we have to rely largely on animal data to fit this into a theoretical framework. For example, the group of Gorman et al has proposed a neuroanatomical model for panic disorder, with processes in the brain stem, limbic system and prefrontal cortex being related to panic attacks, anticipatory anxiety and phobic avoidance respectively.1

Benzodiazepine receptors and panic

Abstract The finding that flumazenil will precipitate panic attacks in patients with panic disorder has emphasized the importance of the GABA-A/benzodiazepine receptor complex in this conditions. Current studies are now being directed at determining the diagnostic specificity of this finding, its relation to the ongoing state of the illness, and the effects of treatment on it.

An investigation of effects of fluvoxamine and dothiepin on sleep and daytime sleepiness in normal volunteers

Tricyclic antidepressants and the newer specific serotonin reuptake inhibitors (SSRIs) are both effective in depression but patients taking tricyclics often have problems with daytime sleepiness (Ray et al., 1992) which do not appear to be encountered during treatment with SSRIs. This study set out to quantify daytime sleepiness after a standard dose of dothiepin, the most widely used tricyclic in the UK, and fluvoxamine, a popular SSRI. As daytime sleepiness may be affected by the previous nights sleep, drug effects on sleep were quantified also. The ambulatory Medilog system was used as it is ideal for measuring both nighttime sleep and EEG during daytime activities. In a double-blind, randomised crossover study, six male subjects were recruited, age range 20--34, and screened for physical and biochemical abnormalities. On three days at least a week apart electrodes were attached in the evening for 24-h monitoring using the Medilog system, then the subjects were dosed with dothiepin (DOTH) 100 mg, fluvoxamine 100 mg (FLUV) or placebo (PLAC) at 21.30 and returned home to sleep. The next day the subjects did a battery of performance tests every 2 h (not reported here), each followed by a Sleep Opportunity Period (SOP), a modification of the MSLT (Alford et al., 1992). At the end of the day the equipment was removed and the tapes analysed and classified by sleep stage according to the criteria of Rechtschaffen and Kales, using automatic analysis with visual checking for the sleep staging, and visual analysis by an experienced observer for the daytime sleep periods. The Leeds sleep evaluation questionnaire (LSEQ) was given to the subjects on the morning after each study night. Results of sleep staging are given in Table 1. Significant effects on REM sleep were seen with both antidepressants, although there was no REM latency effect of fluvoxamine, probably because the first REM period occurred before peak plasma effect was achieved. However fluvoxamine significantly reduced REM time, and disrupted sleep as shown by the decreased total sleep time (TST) and increased waking time after sleep onset (WASO). Dothiepin was associated with increased stage 2 sleep, decreased waking time and increased total sleep time. In the daytime there were differences in time to fall asleep at all the SOPs, with a shorter sleep latency after dothiepin, reaching significance at the late afternoon test. Table I.