Milford Hospital

OBJECTIVE: An important consideration in the choice of an antidepressant is its safety and tolerability. METHOD: We present a review of literature, clinical trials and meta-analyses regarding the safety and tolerability of the tricyclic antidepressants (TCAs) and the selective serotonin reuptake inhibitors (SSRIs) in depressed patients. RESULTS: The SSRIs have a very favourable side-effect profile compared to the TCAs and are associated with fewer treatment discontinuations. Unlike the TCAs, they do not cause anticholinergic, hypotensive or sedating reactions, and are not associated with impaired cognitive function. Their most common side-effects (nausea, vomiting, nervousness, insomnia, headache and sexual dysfunction) are usually mild and typically disappear as treatment continues. The SSRIs also exhibit lower toxicity and lower lethality when taken in an overdose situation. Although the safety profiles of the principal SSRIs appear to be comparable, there is some data showing important differences in the severity and frequency of specific adverse events. CONCLUSION: The SSRIs have a more favourable safety profile than the TCAs in both acute and long-term treatment of major depression.

Abstract A comprehensive review was conducted to establish whether there were any grounds to the claim that nicotine can enhance human psychomotor performance. Among relevant studies, many failed to distinguish between absolute improvements due to the administration of nicotine (usually in the form of cigarettes) and the relief of the effects of nicotine abstinence among the preferred subject pool of tobacco smokers. However, a few investigations have avoided this anomaly by examining the effects of nicotine in minimally‐abstinent smokers or non‐smokers. The results of these studies suggest that nicotine has small, specific, positive effects on the central nervous system which may facilitate human attention, memory and sensori‐motor function.

Abstract Sixty‐six elderly depressed patients received fluoxetine 20 mg (FLU) or amitriptyline 75 mg (AMI) for 42 days in a double blind parallel group study. Each week, subjects completed a test battery which is sensitive to the residual effects of psychoactive drugs. The results show that FLU and AMI were equally effective in relieving depression. However, the psychometric test battery showed that, compared to FLU, AMI, as expected, produced impairments in cognitive function and psychomotor performance. The relative impairment of cognitive and psychomotor skills following the tricyclic AMI and the lack of such activity after administration of the selective serotonin reuptake inhibition, FLU are important considerations when prescribing antidepressants, especially when the safety and well being of ambulant patients is essential.

Fifteen healthy male volunteers aged over 60 years received acute and repeated doses of paroxetine 20 mg or placebo, and acute doses of lorazepam 1 mg (as a positive internal control) with or without alcohol (0.6 g/kg of body weight) administered openly in a double blind balanced crossover study in which each subject acted as his own control. Psychomotor performance and cognitive function were assessed using a test battery which included critical flicker fusion, choice reaction time, compensatory tracking, Stroop and memory scanning tests. Subjective ratings of mood and sleep were recorded using line analogue rating scales. The pattern of results indicated that paroxetine had little or no effect on most of the test variables, and in some instances (critical flicker fusion thresholds) improved information processing ability. This was in marked contrast to the lorazepam verum which produced sedation and disruption of performance. Paroxetine had a slight antagonistic effect on alcohol induced sedation whereas impairment of performance with lorazepam was potentiated by co-administration of alcohol. The low behavioural toxicity of paroxetine in elderly volunteers has important implications for the pharmacotherapy of depression.

Reboxetine is a novel antidepressant that has been shown to be effective in the treatment of major depressive disorders. The present experiment was designed to assess whether it affects the cognitive and psychomotor skills necessary for optimum function in everyday life. Ten healthy male volunteers received reboxetine 0.5 mg, 1 mg or 4 mg, amitriptyline 25 mg, or matched placebo with and without alcohol (0.6 mg kg-1) in a double-blind 10-way crossover study. A psychometric test battery was administered at baseline and at 1, 2.25, 3.5, 6 and 9 h post-dose. The results showed that reboxetine had little or no effect on performance at any dose, compared with placebo. Amitriptyline, however, with and without alcohol, lowered critical flicker fusion threshold compared with placebo and/or reboxetine at all test points (e.g. at 3.5 h: 28.51 vs 30.33 Hz; P < 0.05); increased reaction time (e.g. 619 vs 540 ms; P < 0.05); increased tracking error (e.g. 16.34 vs 8.54 RMS units; P < 0.05); and slowed short-term memory scanning (e.g. 742 vs 590 ms; P < 0.05). It is concluded that reboxetine at doses of 4 mg and below is free from disruptive effects on cognitive function and psychomotor performance, and that it does not act synergistically with alcohol, in contrast to amitriptyline.

The serotonin reuptake inhibitors (SSRIs) are generally better tolerated than the traditional tricyclic antidepressants (TCAs) in the treatment of major depression. In particular the SSRIs are relatively free from cognitive and psychomotor effects likely to cause behavioural toxicity. Behavioural toxicity is studied using a battery of psychometric assessments. This paper discusses the effects of the TCAs and SSRIs on two such assessments, choice reaction time (CRT) and critical flicker fusion threshold (CFFT). CRT measures psychomotor speed, and CFFT assesses the information processing capacity of the CNS. The behavioural toxicity associated with the traditional TCAs can lead to an increased accident risk, whereas the SSRIs are not associated with such effects. Clinically relevant differences in the behavioural toxicity of the SSRIs are highlighted.

A very large variation (44-fold) was observed in the ability of short-term organ cultures of peripheral lung tissue from lung-cancer patients to metabolize the environmental carcinogen benzo(alpha)pyrene to organic solvent-soluble metabolites. The amounts of benzo(alpha)pyrene (2 microM) metabolized ranged from little (1%) to almost total (96.2%) metabolism within 24 h of culture. Previous work by Kellerman et al. (1973) has suggested a relationship between susceptibility to lung cancer and the indicibility of aryl hydrocarbon hydroxylase activity in cultured human lymphocytes. The metabolic fate of carcinogenic polycyclic aromatic hydrocarbons in the respiratory tract in vivo is undoubtedly more closely mimicked by short-term organ culture of human lung than by cultured lymphocytes. Thus the very wide interindividual variation observed in pulmonary metabolism of benzo(alpha)pyrene in this study and the large variations in covalent binding to human bronchial DNA observed by Harris et al. (1976) strongly suggest that there may be little basis for screening humans for variations in lymphocyte aryl hydrocarbon hydroxylase activity as a means of assessing their susceptibility to lung cancer.

The objective of this study was to determine whether there is a greater incidence of psychotropic drugs in the blood of those 'responsible' for an accident compared with those not 'responsible' for an accident. Blood samples were taken from people involved in accidents presenting at the accident and emergency departments of two teaching hospitals over a five-month period and analysed for the presence of alcohol, tricyclic anti-depressants (TCAs) and benzodiazepines (BZs). Details of the accident were used to produce a test group (accidents where a drug may have contributed) and a control group (accidents where the presence of a drug could not have been a factor). In total, 229 samples were collected. The only criterion for inclusion in the study was that the accident was of sufficient severity to merit the routine taking of a blood sample, in which case an additional amount was taken for the purposes of this investigation. In all, 63 samples (27.5%) were positive for at least one of alcohol, TCA or BZ. Of the accidents represented by these samples, 48 could have been caused by the presence of the drug (responsible group) and 15 could not (not responsible group). There was a significantly greater representation of TCAs and BZs in the blood taken from the responsible group compared with the not responsible group (P < 0.0045).

Hindmarch I. Psychometric aspects of antihistamines.

A double-blind study was conducted to investigate the psychomotor effects of cigarette smoking on a 1-hour computer-based simulation of driving comprising continuous tracking and brake reaction time tasks. Twelve minimally abstinent smoker subjects were asked to operate the simulator on four occasions while smoking single cigarettes yielding varying levels of nicotine (< 0.1, 0.6, 1.0 or 2.1 mg) but similar levels (8-10 mg) of tar. Data were transformed with regard to baseline scores to counter day-to-day differences in performance and showed brake reaction times to be improved after all active treatments (p < 0.01) but tracking accuracy to be enhanced after the two cigarettes of middle strength alone (p < 0.05). These results suggest that, among smokers cigarette smoking may improve driving performance and that there may exist an optimal nicotine dose for the enhancement of cognitive and psychomotor function.

This paper reviews the effects of alcohol on human psychomotor performance and cognitive function. It concentrates particularly on effects on reaction time and on skills related to car driving. The effects of alcohol on performance are very variable at low doses (under 1 g per kg body weight). The variability is due to the different measures and methods employed by the researchers and to the large interindividual and interoccasional differences in the effects of alcohol. That is, alcohol affects different people in different ways and it affects the same person differently on separate occasions. Greater performance deficits are observed as the dose increases and as the tasks become more complex. Although results vary, both nicotine and caffeine appear to antagonize the detrimental effects of alcohol on performance. Many other drugs interact with alcohol, the most important of which are sedative agents that can combine synergistically with alcohol to produce profound psychomotor and cognitive impairment. © 1998 John Wiley & Sons, Ltd.

The psychopharmacological profiles of 15 psychotropic drugs used as antidepressants are reviewed, and their relative behavioural toxicity ratings are compared. The pharmacodynamic activity of these drugs was assessed using a standardized test battery which included critical flicker fusion threshold (CFF), choice reaction time (CRT), tracking and subjective rating scales. It is reported that there is a wide range of behavioural toxicity exhibited by these compounds, although there is little measurable difference in their clinical efficacy. Drugs which have low behavioural toxicity should therefore be preferred as they are less disruptive of patients' everyday activities, produce better quality of life and are not counter-therapeutic.

Abstract An extensive review of the literature was performed in order to identify those psychometric variables and conditions which have proved to be sensitive to the CNS effects of antihistamines. It is hoped that the result of this review will allow the formulation of a series of guidelines which would be useful both to researchers, when deciding on the methodology of future trials, and to readers when assessing the validity of a particular volunteer study with a antihistamine.

There does not appear to be a single hypothesis or theory which can adequately explain the aetiology of anxiety, although there is no short-age of contenders. Neurochemical, existential, sociogenic, familial, pathological, psychodynamic and behavioural explanations have all been offered as putative reasons for the psychological disorder, which in its various representations (panic disorder, obsessive-compulsive disorder, phobias, post-traumatic stress disorder, generalized anxiety disorders, etc.) can affect up to 20% of the population on a lifetime basis (1). Notwithstanding the variety of theories and the diversity of presentation of anxiety disorders, it would appear that cognitive dysfunction of one sort or another is a characteristic feature of anxiety in all its manifestations. Indeed, it is possible to argue that a cognitive impairment is the primary presenting feature of pathological anxiety, with the characteristic syndrome of somatic symptoms as secondary or necessary consequences of such cognitive disorder.

The effects of 4 mg/kg and 8 mg/kg caffeine nocte as a model of insomnia, and its potential for reversal with an hypnotic (temazepam 20 mg) were investigated in two double-blind placebo controlled crossover studies, each with six healthy volunteers. Following an adaption night and day, two nights per treatment were assessed with multiple sleep latency tests (MSLTs), performance measures and subjective questionnaires undertaken the following day. In comparison to placebo significant (P < 0.05) increases in sleep onset latency of 30 and 40 min were seen for low and high doses respectively. Significant reductions in sleep duration were limited to the higher dose (total sleep time 80 min, sleep efficiency 17 per cent), as were reductions in slow wave sleep and non-REM sleep which contrasted with increased waking. However, contrast analysis revealed significant dose-related effects for these measures, whilst the lower dose produced more stable effects across nights, suggesting it as more suitable for a model of insomnia in healthy sleepers. Significant decrements in critical flicker fusion (CFF) performance and reduced MSLT latencies reflected increased daytime sleepiness following both doses; although significant subjective changes to sleep and sleep tendency next day were limited to the higher dose. Co-administration of temazepam elixir successfully reversed increased sleep latency seen with the lower caffeine dose and improved subjective sleep, but significant effects on other sleep measures were more limited despite improved mean trends. Similarly, improvements in CFF performance and MSLT latencies failed to achieve significance, suggesting a possible limitation of the hypnotic in overcoming the effects of sleep disturbance and consequences for waking function next day.

The cognitive system is structured from sets of schema, patterns of neural activity that allow the assimilation or accommodation of new experiences and so, by a process of consolidation, the gradual development of knowledge and understanding. As well as schema for purely cognitive processes, there are similar structures that enable individuals to deal with sexual behaviour and affectual relationships (e.g. hedonia, self-esteem, personal preferences and body image). In depression, there is a well established disruption of cognitive function that results in anhedonia and a loss of pleasure, including that from sexual activities. Many antidepressants also have a direct pharmacological action on the central nervous system and disrupt cognitive function, so increasing anhedonia and impairing sexual function. Drug actions on cognitive structures, which in turn increase anhedonia and reduce sexual libido, are over and above any direct pharmacological effects on the more overt behavioural activities associated with sex, including orgasm, erectile function, potency and ejaculation. The tricyclic antidepressants, for example, destroy the cognitive structures that are vital to maintain normal libido as well as disturbing overt sexual behaviours. Some selective serotonin reuptake inhibitors (SSRIs; paroxetine and sertraline) are associated with behavioural activation that is also responsible for an impairment of sexual function. However, there are clear differences between the SSRIs, and fluvoxamine (relative to the other SSRIs) has little effect on objective measures of cognition or on cerebral and behavioural components of sexual function.

This short review paper examines two aspects of addiction controversies: whether there is such an entity as an addictive personality, and the question of whether free choice is involved in substance use. The former is part of an argument with a long history, with the case for the existence of an addictive personality being put more often, particularly in the USA. The latter is a more recent development in the debate that raises important issues in the research on substance use and addition. It is concluded that there is no evidence for the existence of a personality type that is prone to addiction, and that free choice can be seen to be a part of substance use, i.e. the compulsion element is lacking. © 1996 John Wiley & Sons, Ltd.

Human Psychopharmacology Research Unit, University of Surrey, Milford Hospital, Godalming, Surrey GU7 1US, UK

The effects of ginseng in fatigued night nurses were assessed by self rating scales for competence, mood and bodily feeling, objective tests of psychophysiological performance, hematological and biochemical tests. The results were compared to placebo and normal daytime work. Night duty impaired performance in all mood scales and most of the bodily feeling scales. Ginseng improved the self rating scales for competence, mood and performance in one of the psychophysical tests. Some variables of bodily feeling improved and others were rated as worse on ginseng. Compared to placebo, ginseng had no effect on the blood tests.

Three doses of citalopram (10, 20 and 40 mg), and placebo were administered to healthy volunteers for periods of 8 days each. Dothiepin 75 mg was given as an acute dose on days 1 and 8 only, with placebo dothiepin on days 2–7. Subjects were tested on days 1 and 8 of the dosing periods on a battery of psychometric tests. The results showed that citalopram at all doses had no detrimental effects on psychomotor performance. The effect of citalopram on critical flicker fusion (CFF) was to raise thresholds. This indicates an improvement in CNS function, i.e. an elevation of cognitive processing ability, with no evidence of an arousing or alerting effect. The effects were apparent after both acute and sub-chronic dosing. These data are in contrast to those collected for dothiepin, which showed significant impairment of cognitive and psychomotor function on most of the measures employed. The most frequent adverse events reported for citalopram were drowsiness, nausea and headache, with the nausea appearing to be dose dependent. The main adverse events reported for dothiepin were drowsiness, sleepiness and dizziness. The rates of adverse events for all active treatments were not statistically significantly different to placebo. It is concluded that citalopram is relatively free from behavioural toxicity and so represents a significant improvement over the older antidepressant agents such as dothiepin. © 1997 by John Wiley & Sons, Ltd.