J. Guy Edwards

Adverse effects of antianxiety drugs.

SummaryAntianxiety drugs, like other drugs used in psychiatry, can cause a wide range of adverse effects. Many physiological systems may be affected, but, as the main action of antianxiety drugs is on the central nervous system, this system is particularly vulnerable. All antianxiety drugs have the potential to produce untoward effects on higher cerebral functions, although the effect seen is also influenced by psychological and social factors. The most common effect is oversedation, which is a particular problem for the very young and the very old. It is also a serious problem for those who drive motor vehicles and may be a hazard when working in dangerous situations. Subjects are especially vulnerable when (a) antianxiety drugs are first introduced; (b) the dose is increased; and (c) these agents are taken in combination with alcohol and other drugs. Dependence on antianxiety drugs is well known, but only recently has it been recognised that dependence on benzodiazepines is a larger problem than previously realised. Other adverse effects are reviewed and summarised according to the system they predominantly affect.A review of this kind can easily give a biased impression of the dangers of antianxiety drugs; it should be made clear at the outset that many effects are rare, and in some instances a causal connection with the drug has not been established with certainty. Overall, benzodiazepines are the most widely used of all drugs and are remarkably safe — even when taken in massive overdoses.Some unwanted effects are readily preventable if antianxiety drugs are used with caution or avoided altogether in conditions where pathological disturbances of tissue sensitivity or drug disposition lead to exaggerated reactions. Particular care should be taken when prescribing these drugs for children and the elderly, and drugs that are not clearly essential for the well-being of the mother should be avoided during pregnancy and breast feeding.Antianxiety agents are grossly overprescribed. The frequency of occurrence of some adverse effects is therefore not so much a manifestation of the intrinsic toxicity of antianxiety drugs, but a reflection of their widespread use. Overprescribing and irrational prescribing also contribute to self-poisoning with these and other agents and to the cost of health services. The reasons for overprescribing are complex, but one contributing factor is the ready availability of effective antianxiety drugs.Antianxiety drugs, like other drugs used in psychiatry, can cause a wide range of adverse effects. Many physiological systems may be affected, but, as the main action of antianxiety drugs is on the central nervous system, this system is particularly vulnerable. All antianxiety drugs have the potential to produce untoward effects on higher cerebral functions, although the effect seen is also influenced by psychological and social factors. The most common effect is oversedation, which is a particular problem for the very young and the very old. It is also a serious problem for those who drive motor vehicles and may be a hazard when working in dangerous situations. Subjects are especially vulnerable when (a) antianxiety drugs are first introduced; (b) the dose is increased; and (c) these agents are taken in combination with alcohol and other drugs. Dependence on antianxiety drugs is well known, but only recently has it been recognised that dependence on benzodiazepines is a larger problem than previously realised. Other adverse effects are reviewed and summarised according to the system they predominantly affect. A review of this kind can easily give a biased impression of the dangers of antianxiety drugs; it should be made clear at the outset that many effects are rare, and in some instances a causal connection with the drug has not been established with certainty. Overall, benzodiazepines are the most widely used of all drugs and are remarkably safe — even when taken in massive overdoses. Some unwanted effects are readily preventable if antianxiety drugs are used with caution or avoided altogether in conditions where pathological disturbances of tissue sensitivity or drug disposition lead to exaggerated reactions. Particular care should be taken when prescribing these drugs for children and the elderly, and drugs that are not clearly essential for the well-being of the mother should be avoided during pregnancy and breast feeding. Antianxiety agents are grossly overprescribed. The frequency of occurrence of some adverse effects is therefore not so much a manifestation of the intrinsic toxicity of antianxiety drugs, but a reflection of their widespread use. Overprescribing and irrational prescribing also contribute to self-poisoning with these and other agents and to the cost of health services. The reasons for overprescribing are complex, but one contributing factor is the ready availability of effective antianxiety drugs.

Drug Choice in Depression

SummarySelective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) are no more effective or rapid in their onset of action than tricyclic antidepressants (TCAs). Meta-analyses of comparative trials suggest that there are no significant differences between these 2 classes of drugs in overall dropout rates or those due to inefficacy alone. However, a small difference in dropout rates due to adverse effects in favour of SSRIs has been reported. It is not known if this difference exists in general practice, where most antidepressants are prescribed, or if it will be sustained during longer term treatment, during which adaptation to some adverse effects might be expected to occur. There could be differences between individual drugs in each class.SSRIs cause less sedation and anticholinergic effects than TCAs, but more gastrointestinal disturbances. In the short term (at least), SSRIs cause less impairment on tests of cognition and psychomotor functioning, including tests that reflect performance in real life situations. This suggests that they could be less liable to cause, or contribute to, accidents in the home, in the workplace and on the road. SSRIs also have less anti-α-adrenergic effects than TCAs and may therefore be less prone to cause hypotension and falls, especially in the elderly. However, there are few epidemiological data available to support the view that SSRIs actually cause less falls or accidents in the real world.The selective reuptake inhibitors cause less serious cardiovascular effects than TCAs and are less lethal in overdose. However, patients treated with the former agents do not have a lower suicide rate than those treated with TCAs. This is consistent with the view that individuals who genuinely want to kill themselves will find a means of doing so.TCAs interact with more drugs than SSRIs, although most of the interactions with TCAs are due to the summation of sedative and antimuscarinic effects. Similar numbers of hazardous interactions occur with both classes of drugs.Although drug safety monitoring shows that SSRIs only rarely cause serious problems, some of the drugs are relatively new and it is, therefore, necessary to remain alert to the possibility of hitherto unrecognised adverse effects, especially after long term use. This holds true for the possibility of teratogenic effects because, in spite of the warnings issued, many women take drugs during pregnancy or become pregnant after taking them.SSRIs cost more than TCAs, although a proper assessment of costs and benefits has to take into consideration much more than just acquisition costs. Whether the advantages of SSRIs justify the additional cost compared with TCAs is a value judgement, but one that should be based on a critical overview of the scientific evidence rather than on other factors known to influence prescribing.

THE SIDE-EFFECTS OF ANTIPSYCHOTIC DRUGS. I. CNS AND NEUROMUSCULAR EFFECTS

Publisher Summary The side-effect profiles of the present antipsychotic drugs tend to determine the clinical choice. This chapter reviews the neuropsychiatric adverse effects that are associated with these drugs, principally the consequences of their actions on the autonomic system, effects on cognition and behavior, epileptogenic effects, the acute extra-pyramidal phenomena and the late-onset movement disorders, such as tardive dyskinesia. The motor disorders associated with the antipsychotic drugs are major disadvantages. They are common, often distressing and disabling, and a major cause of poor compliance with treatment, which has implications for relapse, hospitalization and morbidity. Furthermore, the overlap in symptoms between some of the drug-induced movement disorders and psychiatric symptoms can confound the clinical assessment of patients. Tardive dyskinesia is a common problem in individuals receiving long-term antipsychotic drug treatment. It is not usually progressive and tends to follow a fluctuating course with spontaneous remissions, although there are occasional reports of tardive dyskinesia worsening during a continued drug therapy.

Lithium and the kidney: an update

It is a little over a decade since Hestbech et al. (1977) reported histological changes in renal biopsy specimens taken from patients who had been treated with lithium. The more recent studies are considered in this review and recommendations for clinical practice are offered

Remoxipride and haloperidol in the acute phase of schizophrenia: a double‐blind comparison

The efficacy and safety of remoxipride in the treatment of schizophrenia were compared with those of haloperidol in a multicentre double‐blind 6‐week study which was randomized with a parallel group design and was preceded by a washout period. Eighty‐nine consecutively admitted men and women meeting the Research Diagnostic Criteria for schizophrenia in an acute phase of the illness were treated with remoxipride 75–300 mg twice daily or haloperidol 5–20 mg twice daily. The efficacy assessments were the Brief Psychiatric Rating Scale, Krawiecka Rating Scale, and Clinical Global Impression. Both antipsychotic drugs produced clinical improvement with no significant differences between the efficacy of the two drugs. There were relatively few side effects. There were significantly fewer extrapyramidal symptoms and instances of blurred vision with remoxipride and less constipation with haloperidol. The results indicate that remoxipride is as effective an antipsychotic as haloperidol. Remoxipride has an advantage over haloperidol in respect to extrapyramidal side effects.

Assessment of epileptogenic potential: experimental, clinical and epidemiological approaches:

There are experimental, clinical and epidemiological methods of assessing the epileptogenic potential of psychotropic drugs. In the laboratory it has been shown that there is a range of cellular and synaptic processes in the cerebral cortex and hippocampus that give rise to epileptiform neuronal activity. In addition to the classical suppression of GABA-mediated inhibitory synaptic mechanisms, in vitro studies in animal models of epilepsy and on human tissue suggest a prominent role for the N-methyl D-aspartate (NMDA) subtype of excitatory amino acid receptors. Any mechanism that leads to the depolarization of the neurones is likely to result in a facilitation of the NMDA-receptor involvement in excitatory neurotransmission. This is particularly true in the cortex and hippocampus where the densities of the NMDA-receptor are highest. Data are presented in this paper on how this epileptogenic mechanism can be studied in vitro. In humans, the importance of an accurate diagnosis is stressed and the advantages and disadvantages of routine EEG recordings and ambulatory monitoring discussed. Descriptions of large-scale systems of drug safety monitoring and their application to the assessment of the epileptogenic properties of psychotropic drugs are given.There are experimental, clinical and epidemiological methods of assessing the epileptogenic potential of psychotropic drugs. In the laboratory it has been shown that there is a range of cellular and synaptic processes in the cerebral cortex and hippocampus that give rise to epileptiform neuronal activity. In addition to the classical suppression of GABA-mediated inhibitory synaptic mechanisms, in vitro studies in animal models of epilepsy and on human tissue suggest a prominent role for the N-methyl D-aspartate (NMDA) subtype of excitatory amino acid receptors. Any mechanism that leads to the depolarization of the neurones is likely to result in a facilitation of the NMDA-receptor involvement in excitatory neurotransmission. This is particularly true in the cortex and hippocampus where the densities of the NMDA-receptor are highest. Data are presented in this paper on how this epileptogenic mechanism can be studied in vitro. In humans, the importance of an accurate diagnosis is stressed and the advantages and disadvantages of routine EEG recordings and ambulatory monitoring discussed. Descriptions of large-scale systems of drug safety monitoring and their application to the assessment of the epileptogenic properties of psychotropic drugs are given.

Fluoxetine, amitriptyline and the electroencephalogram

Electroencephalograms recorded before and after 4 weeks treatment of depressed patients with fluoxetine or amitriptyline were assessed visually and by power spectrum analysis blind to patient, treatment and whether the recordings were carried out before or after treatment. No significant between-group differences in alpha, beta or theta activity were found on visual assessment. Power spectrum analysis revealed a significant decrease in the amount of beta activity at week 4. There was no EEG evidence of drowsiness or epileptiform activity in either of the treatment groups.

Prognostic factors determining response to antidepressant drugs in psychiatric out-patients and general practice

The outcome of antidepressant drug treatment was measured in 200 patients, 145 seen in psychiatric out-patient clinics and 55 in general practice, after 4 weeks of therapy. The results of the 200 patients taken together suggested that prognosis was largely determined by factors dependent on the natural history of the disorder and that clinical symptoms were unimportant, but when the results for patients in each drug group were analysed separately symptoms were more important than natural history factors. We conclude that clinical symptoms are only important predictors of response to antidepressant drugs when the patients studied are homogeneous with regard to natural history factors, particularly duration of illness.

THE SIDE-EFFECTS OF ANTIPSYCHOTIC DRUGS. II. EFFECTS ON OTHER PHYSIOLOGICAL SYSTEMS

Publisher Summary Antipsychotic drugs may influence hypothalamic-pituitary function through their effects on neurotransmission, as a non-specific action mediated hemodynamically or via their influence on thermoregulation. Neuroleptics stimulate the release of prolactin, melanocyte-stimulating hormone (MSH) and anti-diuretic hormone (ADH), while they suppress corticotrophin (ACTH), growth hormone (GH), thyrotrophin (TSH), follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Antipsychotic drugs decrease the availability of dopamine at its receptors by receptor blockade leading to increased plasma prolactin levels. Neuroleptics can cause a variety of hematological abnormalities but the most serious is agranulocytosis. Agranulocytosis has been reported more often in older subjects and more often in women than men, possibly because phenothiazines have been prescribed more often for females. Antipsychotic drugs, especially phenothiazines administered in large doses, may cause atrio-ventricular block, bundle branch block, atrial and ventricular extrasystoles, atrial flutter, ventricular tachycardia and ventricular fibrillation. The elderly, notably those who have pre-existing heart disease, are particularly vulnerable to cardiac effects and neuroleptics are capable of precipitating congestive cardiac failure in predisposed subjects.

An unusual case of nicotine dependence

The case of a 49-year-old woman who has been brushing her teeth for 12 years with large amounts of snuff is described. She was dependent on the habit and had plasma nicotine and cotinine levels similar to those found in heavy smokers. Historical and cultural aspects of the use of snuff are discussed.