Do benzodiazepines still deserve a major role in the treatment of psychiatric disorders? A critical reappraisal.

Discovered in the late 1950s by Leo Sternbach, the first benzodiazepine (BZD) chlordiazepoxide was followed by several congeners, which rapidly constituted one of the largest and most widely prescribed classes of psychotropic compounds. After 50 years, BZDs are still routinely utilized not only in psychiatry but, more generally, in the whole of medicine. Despite their high therapeutic index which makes BZDs safer than other compounds like barbiturates, as well as their rapidity of onset, psychiatrists and family physicians are well aware about the controversy that surrounds the wide use - often not adequately based on scientific evidence - of BZDs in many psychiatric disorders. In this overview of international treatment guidelines, systematic reviews and randomized clinical trials, the aim was to provide a critical appraisal of the current use and role of BZDs in psychiatric disorders and their disadvantages, with specific emphasis on anxiety and affective disorders, sleep disorders, alcohol withdrawal, violent and aggressive behaviours in psychoses, and neuroleptic-induced disorders. In addition, specific emphasis has been given to the extent of usage of BZDs and its appropriateness through the assessment of available international surveys. Finally, the entire spectrum of BZD-related adverse effects including psychomotor effects, use in the elderly, paradoxical reactions, tolerance and rebound, teratologic risk, dependence, withdrawal and abuse issues was examined in detail.

Suicide attempts in a prospective cohort of patients with schizophrenia treated with sertindole or risperidone.

The incidence of suicide attempts (fatal and non-fatal) was analysed in a prospective cohort of patients with schizophrenia randomly assigned to sertindole (4905 patients) or risperidone (4904 patients) in a parallel-group open-label study with blinded classification of outcomes (the sertindole cohort prospective study--SCoP). The total exposure was 6978 and 7975 patient-years in the sertindole and risperidone groups, respectively. Suicide mortality in the study was low (0.21 and 0.28 per 100 patients per year with sertindole and risperidone, respectively). The majority (84%) of suicide attempts occurred within the first year of treatment. Cox's proportional hazards model analysis of the time to the first suicide attempt, reported by treating psychiatrists and blindly reviewed by an independent expert group according to the Columbia Classification Algorithm of Suicide Assessment (both defining suicide attempts by association of suicidal act and intent to die), showed a lower risk of suicide attempt for sertindole-treated patients than for risperidone-treated patients. The effect was statistically significant with both evaluation methods during the first year of randomized treatment (hazard ratios [95% CI]: 0.5 [0.31-0.82], p=0.006; and 0.57 [0.35-0.92], p=0.02, respectively). With classification by an independent safety committee using a broader definition including all incidences of intentional self-harm, also those without clear suicidal intent, the results were not significant. A history of previous suicide attempts was significantly associated with attempted suicides in both treatment groups.

Safety of sertindole versus risperidone in schizophrenia: principal results of the sertindole cohort prospective study (SCoP).

OBJECTIVE: To explore whether sertindole increases all-cause mortality or cardiac events requiring hospitalization, compared with risperidone. METHOD: Multinational randomized, open-label, parallel-group study, with blinded classification of outcomes, in 9858 patients with schizophrenia. RESULTS: After 14147 person-years, there was no effect of treatment on overall mortality (sertindole 64, risperidone 61 deaths, Hazard Ratio (HR) = 1.12 (90% CI: 0.83, 1.50)) or cardiac events requiring hospitalization [sertindole 10, risperidone 6, HR = 1.73 (95% CI: 0.63, 4.78)]: Of these, four were considered arrhythmia-related (three sertindole, one risperidone). Cardiac mortality was higher with sertindole (Independent Safety Committee (ISC): 31 vs. 12, HR=2.84 (95% CI: 1.45, 5.55), P = 0.0022; Investigators 17 vs. 8, HR=2.13 (95% CI: 0.91, 4.98), P = 0.081). There was no significant difference in completed suicide, but fewer sertindole recipients attempted suicide (ISC: 68 vs. 78, HR=0.93 (95% CI: 0.66, 1.29), P = 0.65; Investigators: 43 vs. 65, HR=0.67 (95% CI: 0.45, 0.99), P = 0.044). CONCLUSION: Sertindole did not increase all-cause mortality, but cardiac mortality was higher and suicide attempts may be lower with sertindole.

The effect of escitalopram on sleep problems in depressed patients.

The results from three 8-week escitalopram studies in major depressive disorder are presented with respect to efficacy and the effect on sleep quality, both in the full population and the subpopulation of patients with sleep problems at baseline. Analysis of pooled data from these randomized, double-blind, placebo-controlled, studies in which citalopram was the active reference, showed a significant improvement for escitalopram-treated patients (n = 52.0) in the Montgomery-Asberg depression rating scale (MADRS) item 4 ('reduced sleep') scores at weeks 6 and 8 compared with placebo (n=398; p < 0.01) and at weeks 4, 6 and 8 (n = 403; p < 0.05) compared with citalopram.Escitalopram-treated patients with sleep problems (MADRS item 4 score > or = 4; n = 254) at baseline showed a statistically significant improvement in mean MADRS item 4 scores at weeks 4, 6 and 8 compared with patients treated with placebo (n = 191; p < 0.05) or citalopram (n = 193; p < 0.01). These patients also showed a statistically significant (p < 0.05) and clinically relevant improvement in MADRS total score after escitalopram treatment compared with citalopram at weeks 1, 4, 6 and 8 (observed cases) and endpoint (-2.45; last observation carried forward [LOCF]). Statistical significance in favour of escitalopram versus placebo treatment was found at all visits, including endpoint (-4.2; LOCF).Thus, these post-hoc analyses suggest that escitalopram has a significant beneficial effect compared with placebo or citalopram in reducing sleep disturbance in patients suffering from major depressive disorder. The effect of escitalopram in improving 'reduced sleep' scores was clearly seen in patients with more severe sleep disturbance at baseline. A further prospective study is needed to establish this useful clinical effect in insomniac depressives.

Implications of hypnotic flexibility on patterns of clinical use.

Insomnia is common among the primary care patient population, 1.3 times more common in women than men, and the prevalence increases with age. Until recently, benzodiazepines (BZs) were the only first-line hypnotics, but with the availability of non-BZ sleep agents, the management of insomnia is changing. Zolpidem and zopiclone have adverse-effect profiles similar to BZs but lack next-day residual effects with bedtime dosing. Zaleplon is a fast-onset, rapidly eliminated medication that allows for dosing at bedtime or during the night with minimal concern for residual effects. In addition, the BZ-associated problems of tolerance and rebound effects are not evident with long-term zaleplon use. The pharmacokinetic profile of zaleplon has the potential to allow for the treatment of symptoms of sleeplessness when they occur, an approach that could replace the standard practice of always treating in anticipation of a problem.

Social phobia: diagnosis and epidemiology, neurobiology and pharmacology, comorbidity and treatment.

Social phobia is a common disorder associated with significant psychosocial impairment, representing a substantial public health problem largely determined by the high prevalence, and the lifelong chronicity. Social phobia starts in early childhood or adolescence and is often comorbid with depression, other anxiety disorders, alcohol and substance abuse or eating disorders. This cascade of comorbidity, usually secondary to social phobia, increases the disability associated with the condition. The possibility that social phobia may be a trigger for later developing comorbid disorders directs attention to the need for early effective treatment as a preventive measure. The most recent drug class to be investigated for the psychopharmacological treatment of social phobia is the SSRI group for which there is growing support. The other drug classes that have been evaluated are monoamine oxidase inhibitors (MAOIs), benzodiazepines, and beta-blockers. The SSRIs represent a new and attractive therapeutic choice for patients with generalized social phobia. Recently the first, large scale, placebo-controlled study to assess the efficacy of drug treatment in generalized social phobia has been completed with paroxetine. Paroxetine was more effective in reducing the symptoms than placebo and was well tolerated. Many now regard SSRIs as the drugs of choice in social phobia because of their effectiveness and because they avoid the problems of treatment with benzodiazepines or classical MAOIs.

Brain uptake of iomazenil in cirrhotic patients: a single photon emission tomography study.

Brain uptake of 123I-iomazenil was studied in seven cirrhotic patients and eight normal controls using single photon emission computerized tomography. The highest concentration of the ligand was found in the occipital cortex, which corresponds to the brain region with the highest concentration of benzodiazepine receptors. The peak uptake was delayed in patients across all brain regions. The uptake in occipital cortex was higher in low albumin cirrhotics. Patients with low albumin also presented a more delayed peak uptake in occipital cortex and a higher volume of distribution of iomazenil in plasma, compared to patients with normal albumin levels and controls. The changes in brain uptake (delayed peak uptake and increased maximal uptake in occipital cortex) appears to reflect changes in the pharmacokinetics of the ligand, particularly in cirrhotics with low levels of plasma albumin. The curve of brain uptake of the tracer was modelled into a two compartments equation, which seems to provide a practical and reliable method to calculate the slopes of acquisition and decay, time to peak and maximal acquisition.

The influences of age and caffeine on psychomotor and cognitive function.

RATIONALE: The response to caffeine is affected by a number of factors, including age. Older subjects may be more sensitive to the objective effects than younger but report fewer subjective effects. OBJECTIVE: This study assessed the influence of age on the effects of caffeine on a variety of psychomotor, cognitive and subjective tests. METHODS: Forty-eight healthy subjects, male and female, were recruited, 24 in the age range 20-25 and 24 in the range 50-65 years. All subjects were regular moderate caffeine drinkers and were not withdrawn from caffeine before entry to the study. A double-blind parallel group design was used with two groups of 12 subjects in each age range. One group in each age range received placebo and the other 250 mg caffeine B.P. A range of tests was used to assess psychomotor, cognitive and subjective functioning before and 1 h post-treatment. RESULTS: Before treatment, young subjects generally performed better than older on psychomotor and cognitive tests. On the subjective tests, however, older subjects rated themselves as more alert and less tired than the younger ones. After placebo, performance and alertness improved in the younger group but declined in the older. After caffeine there were improvements in psychomotor performance and cognitive functioning in both groups, particularly in offsetting declining performance over time in the older subjects. It also produced subjective improvements in alertness. One factor to emerge was that on most assessments older subjects were better earlier in the day whereas in younger subjects performance did not show the same magnitude of decline throughout the day. CONCLUSIONS: Caffeine induced small but significant improvements in vigilance and psychomotor performance.

Some adverse effects of antipsychotics: prevention and treatment.

Antipsychotic medication causes a wide range of adverse effects, which can be serious and may further imperil both the physical and psychological health of schizophrenic patients. The range of side effects patients commonly encounter includes weight gain, endocrine disturbances, sedation, anticholinergic effects, hypotension, seizures, and extrapyramidal symptoms. Less common and unpredictable reactions are blood dyscrasias, cardiotoxicity, sudden death, and the neuroleptic malignant syndrome. Antipsychotic drugs differ significantly regarding their propensity to cause these reactions. Patients should undergo comprehensive health checks before an antipsychotic is prescribed, and drug therapy should be individualized to take account of any preexisting symptoms. Side effects and the wider implications of drug treatment, such as effects on occupational and social functioning, should be discussed with the patient before initiating therapy. Patients should be regularly monitored for side effects during treatment and switched to alternative therapy if side effects are serious and/or persistent.

The influence of drugs upon testimony.

A wide range of drugs (medicines) are used currently, many of which are designed to affect brain function. Others do so as a side-effect. The effects depend on how the body deals with the drug (pharmacokinetics) and how the drug affects the body, including the brain (pharmacodynamics). An extensive range of effects on the brain and psychological functioning can ensue, including effects on intellectual functioning, dexterity, memory, learning and subjective effects. Individual factors are important and can profoundly influence both the type and extent of drug effects. Relevant drugs can be divided into: 1. Those prescribed primarily to treat psychiatric disorders. These include sleeping tablets, tranquillizers, antidepressants and antipsychotics. 2. Those used to treat neurological disorders that have psychological side-effects. Examples are anticonvulsants and anti-parkinsonian drugs. 3. Those used to treat non-nervous disorders that may have psychological side-effects. 4. Illicit drugs used in the non-medical context by drug addicts. Drug-induced states that can influence testimony are mainly sedation, disinhibition, paradoxical reactions and alterations in memory. A list of pointers was given in this paper with respect to practical considerations in assessing the possible effects of drugs on testimony.

Limitations on the use of benzodiazepines in anxiety and insomnia: are they justified?

The benzodiazepines are still extensively used in psychiatry, neurology and medicine in general. Anxiety disorder and severe insomnia are important syndromal indications, but these drugs are widely prescribed at the symptomatic level, resulting in potential overuse. The official data sheets recommend short durations of usage and conservative dosage. Although short-term efficacy is established, long-term efficacy remains controversial, as relevant data are scanty and relapse, rebound and dependence on withdrawal not clearly distinguished. The risks of the benzodiazepines are well-documented and comprise psychological and physical effects. Among the former are subjective sedation, paradoxical release of anxiety and/or hostility, psychomotor impairment, memory disruption, and risks of accidents. Physical effects include vertigo, dysarthria, ataxia with falls, especially in the elderly. Dependence can supervene on long-term use, occasionally with dose escalation. The benzodiazepines are now recognised as major drugs of abuse and addiction. Other drug and non-drug therapies are available and have a superior risk benefit ratio in long-term use. It is concluded that benzodiazepines should be reserved for short-term use--up to 4 weeks--and in conservative dosage.

The clinical relevance of treating social phobia.

Social phobia is an extreme fear of being scrutinized by others in social situations that often culminates in avoidance of those situations. Studies have demonstrated marked educational, occupational and social disabilities in patients with social phobia. However, many sufferers do not seek help and are not detected when seeking medical advice for other conditions. The advent of a range of effective treatments, in particular the selective serotonin reuptake inhibitors, has substantially improved the prognosis in these sufferers, both symptomatically and in terms of quality of life.

A multicentre double-blind comparison of hydroxyzine, buspirone and placebo in patients with generalized anxiety disorder.

The efficacy of hydroxyzine and buspirone, controlled by placebo, was investigated in a double-blind, parallel group, multicentre study conducted in France and the UK. A total of 244 patients with generalised anxiety disorder in primary care was allocated randomly to treatments with hydroxyzine (12.5 mg morning and mid-day, 25 mg evening), buspirone (5 mg morning and mid-day, 10 mg evening) or placebo (three capsules/day) for 4 weeks, preceded by a 1-week single-blind placebo run-in and followed by 1-week single-blind placebo administration. Rating scales were applied on days -7,0,7,14, 12,28 and 35. Seventy percent of the patients were female, the average age was 41 +/- 11 years, and the mean Hamilton Anxiety Score at day 0 was 26.5 +/- 4.2. Only 31 of the 244 patients dropped out, but equally in the three groups. Intention-to-treat LOCF analyses on the primary variable showed a significant difference only between hydroxyzine and placebo with respect to improvement on the Hamilton Anxiety Scale (10.75 versus 7.23 points, respectively). Secondary variables such as CGI and self-ratings (HAD scale) showed both hydroxyzine and buspirone to be more efficacious than placebo. Thus, hydroxyzine is a useful treatment for GAD.

Interaction of pharmacological and psychological treatments of anxiety.

BACKGROUND: Pharmacological and psychological treatments for anxiety are often combined in clinical practice but there is little research from which to predict the effects. METHOD: The theoretical outcomes of combining treatments and methods of investigating these as well as methodological difficulties are described. Studies which have been completed in anxiety disorders are reviewed. A double-blind trial, using a factorial design, evaluated buspirone v. placebo and anxiety management training v. non-directive therapy in 60 patients with generalised anxiety disorder (GAD). RESULTS: Relatively few germane studies have been carried out in the anxiety disorders except for panic disorder with agoraphobia. There is some evidence that short-term, combined treatment does confer additional benefits which are evident both in speed of onset and lasting remission. All four treatment combinations proved effective in the short-term treatment of GAD. CONCLUSIONS: More studies examining combined treatment are needed. Although differences may not be apparent at the end of the treatment period, psychological treatment appears to confer advantages at follow-up.

The nature and duration of treatment for GAD.

It is becoming increasingly evident that GAD is a chronic condition with repeated acute-on-chronic episodes. Treatment in the short term relies on the benzodiazepines, which are rapid in action, providing substantial symptomatic relief with a low incidence of side-effects and low toxicity in overdose. The risk of more serious unwanted effects in the long term, including some risk of physical dependence, has led to a move towards alternative treatments both pharmacological and psychotherapeutic. Antidepressants are being used on a long-term basis, but data are sparse to confirm their efficacy in GAD. Anxiety management and cognitive-behavioural techniques are rivalling pharmacotherapy in popularity. None the less, research seeking optimal ways of combining therapies remains an urgent priority.