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.

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.

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.

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.

Differentiating the effects of centrally acting drugs on arousal and memory: an event-related potential study of scopolamine, lorazepam and diphenhydramine.

The degree to which apparent amnesic effects of various centrally acting drugs are secondary to their effects on arousal remains a contentious issue. The present study uses two methods to dissociate memory and arousal effects of the cholinergic antagonist, scopolamine (SP), and the GABA-A/benzodiazepine receptor agonist, lorazepam (LZ). First, it compared their effects to those of an antihistamine, diphenhydramine (DPh), to provide an active control for arousal reduction. Second, it used the same measure--event-related potentials (ERPs)--as as a parallel index of both the arousal and cognitive effects of the drugs. Fifty participants were allocated to one of five parallel treatment groups (0.6 mg SP; 2 mg LZ; 25, 50 mg DPh; placebo). ERPs were recorded during a continuous word recognition task as well as during an "oddball" task. SP, LZ and 50 mg DPh produced a similar profile of effects on certain indices of arousal and on early components of ERPs. However, SP and LZ (but not DPh) produced marked impairments of episodic memory, and this pattern was similar to that on later components of ERPs. Memory impairments by SP and LZ were highly significant on retention in the continuous recognition task and further, no drug effects were found on response bias. Subsequent free recall was similarly very impaired by SP and LOR but not by the antihistamine. We conclude that benzodiazepines and anticholinergic drugs both reduce arousal and induce amnesia, but these effects are not interdependent. Our findings provide strong evidence for a dissociation between the effects on episodic memory and on arousal of these centrally acting compounds.

Irreversible lithium neurotoxicity: an overview.

Lithium is widely used, and most of its side effects are well established and recognized. Persistent neurologic sequelae or dysfunctions are not common, but they are serious side effects. They usually persist after acute toxicity following accidental or suicidal overdose or during maintenance therapy, when toxicity is more insidious. The irreversible neurologic sequelae are generally cerebellar signs, especially ataxia and dysarthria. Risk factors are sometimes present and recognizable, but more often they are not well identified. Persistent neurologic handicaps greatly reduce the quality of life and are difficult to manage. Lithium toxicity can be avoided by conservative prescribing, care in combining drug therapies, and, above all, educating the patient and caregivers to recognize early signs of the condition. A review of the literature is presented, together with vignettes of a further seven cases.

Tolerability and safety: essentials in antidepressant pharmacotherapy.

Current antidepressants achieve similar efficacy, with 60% to 80% of patients responding adequately. Clinical response is gradual, and differential response factors are difficult to discern. However, side effect profiles and toxicity vary substantially, so the choice of medication depends primarily on tolerability and safety. Dry mouth is prevalent with tricyclic antidepressants (TCAs), whereas nausea occurs more frequently with a serotonin selective reuptake inhibitor (SSRI). Long-term unwanted effects tend not to be a major problem, with a dropout rate of approximately 5% due to side effects. The relationship between suicidality and antidepressants remains under debate. Many TCAs are highly toxic in overdose whereas the SSRIs appear much safer. Nefazodone is a unique antidepressant with demonstrated efficacy. It is different from other antidepressants because of its two actions in the serotonin system, moderate serotonin selective reuptake blocking properties and direct 5-HT2 antagonism, which also can enhance 5-HT1 neurotransmission. The 5-HT2 antagonist properties may limit serotonin-mediated effects and, as a result, nefazodone may be more anxiolytic than other antidepressants. Nefazodone also moderately inhibits norepinephrine reuptake and blocks alpha 1-adrenergic receptors. The data base on the safety of nefazodone currently comprises approximately 3,500 patients from all research trials, which include controlled trials that allow comparisons of nefazodone treatment with several hundred patients taking TCAs or SSRIs and nearly 900 patients receiving placebo. The most frequent adverse experiences with nefazodone as compared with placebo treatment are nausea (21% vs. 14%), somnolence (19% vs. 13%), dry mouth (19% vs. 13%), dizziness (12% vs. 6%), constipation (11% vs. 7%), asthenia (11% vs. 6%), light-headedness (10% vs. 4%), and amblyopia (blurred vision; 6% vs. 3%). Approximately 12% of nefazodone-treated patients dropped out because of adverse experiences, as compared with 7.4% on placebo, 10.4% on SSRIs, but 21.8% on imipramine after short-term exposure in placebo-controlled trials. Long-term safety data include nearly 1,300 patients; nefazodone was well tolerated. Nefazodone was evaluated in normal subjects by the author and was found to produce less impairment than imipramine and was less likely to interact with alcohol. In summary, nefazodone has a favorable adverse-event profile as compared with the TCAs and a rather different one from the SSRIs. It appears to be safe and well tolerated after both acute and long-term use.

Central benzodiazepine receptor imaging and quantitation with single photon emission computerised tomography: SPECT.

This review discusses the current use of single photon emission computerised tomography (SPECT) for central benzodiazepine receptor imaging and quantitation. The general principles underlying SPECT imaging and receptor quantitation methods such as the kinetic, pseudo-equilibrium and steady-state (tracer infusion and bolus) approaches are described. The advantages and practical drawbacks of these techniques are highlighted.

The effects of D-fenfluramine on mood and performance, and on neuroendocrine indicators of 5-HT function.

D-fenfluramine has multiple actions which enhance 5-HT transmission and make it a useful neuroendocrine challenge agent, but little is known of its effects on mood or performance. In this study, two doses (15 and 30 mg) and placebo were administered to six male and six female healthy volunteers according to a double blind, cross-over design. Blood was sampled and self-ratings completed pre- and hourly up to 5 h post-challenge. Performance tests were administered pre- and at 2 and 4 h. Plasma concentrations of prolactin and cortisol decreased after all treatments at 1 h and then increased post-drug to a peak at 4 h. Body temperature showed a similar pattern. D-fenfluramine was well tolerated with few side effects. It caused only minor sedation and little psychomotor impairment but there was some decrement in episodic memory. The 30 mg dose produced a mild anxiolytic and anti-aggressive action.

The effects of alprazolam alone and combined with alcohol on central integrative activity.

The effects of alprazolam 1 mg both alone and in combination with 0.5 g/kg of alcohol were examined on self-ratings of intoxication and measures of central and peripheral activity such as EEG, auditory evoked response, tremor at 90, 150 and 210 min post drug. Forty-eight healthy volunteers were assigned randomly to 4 independent groups who received: alprazolam and placebo drink, alprazolam and alcohol, placebo capsule and alcohol, placebo capsule and placebo drink respectively. Alprazolam decreased the amplitudes of the 3 potentials of the evoked response, decreased activity in the 8-13 Hz and increased activity in the 13.5-26 Hz wavebands of the EEG and decreased the frequency at which fusion was perceived. Alcohol prolonged reaction time and increased tremor. The effects were not always additive and alprazolam was dominant in the combination.

A pilot study of the effects of flumazenil on symptoms persisting after benzodiazepine withdrawal.

The potential of the benzodiazepine antagonist flumazenil (Ro 15-1788) to lessen persisting benzodiazepine withdrawal symptoms was demonstrated in 11 patients who had been drug free for between 1 month and 5 years. Doses ranging from 0.2 to 2.0 mg divided into three intravenous injections over a few hours relieved long-standing symptoms to varying extents. These included clouded thinking, tiredness, muscular symptoms such as neck tension, cramps and shaking and the characteristic perceptual symptoms of benzodiazepine withdrawal, namely, pins and needles, burning skin, pain and subjective sensations of bodily distortion. Mood disorder, when present, also improved but the reduction in anxiety and depression may have reflected relief of physical symptoms. The onset of maximum response was sometimes delayed by as much as a day but was usually prompt. Side effects were reported to be either absent or typically described as lightheadedness or dizziness, lasted only a few minutes and were usually well tolerated. The benefits last between a few hours and several days despite flumazenil's otherwise short duration of action. However, symptoms did return to varying degrees in most cases, suggesting the need for repeated doses.

Failure of clonidine treatment in benzodiazepine withdrawal.

Six subjects, dependent on benzodiazepines for at least 2 years, were gradually withdrawn, using placebo substitution, while taking clonidine. After withdrawal was complete, subjects were switched to clonidine-placebo. Despite administration of clonidine at doses sufficient to produce a fall in blood pressure, an abstinence syndrome was seen in five of the subjects. In none of these cases was the withdrawal syndrome exacerbated by changing from clonidine to clonidine-placebo. Scores of depression, subjective anxiety, observed anxiety and somatic symptoms did not change throughout the study.

Self-report reliability and symptomatology of habitual caffeine consumption.

1. A large body of research on the demography of caffeine use and its potential health consequences has been undermined by the absence of empirical data on the reliability of retrospective self-reports of caffeine consumption. 2. The principal aim of the present study was to use standard bioanalytic method to assess the reliability of subjects' self-reported caffeine use. Saliva samples were obtained from 142 first-and second-year medical students and assayed for caffeine and paraxanthine. 3. Self-reported caffeine use was found to be significantly correlated with salivary caffeine (r = 0.31, P less than 0.001) and paraxanthine (r = 0.42, P less than 0.001), thereby providing qualified support for use of questionnaires to estimate patterns of caffeine consumption. 4. A secondary aim of the study was to extend previous research concerning the symptomatology of caffeine use by examining the association between caffeine exposure and a variety of measures of somatic and psychological health. Caffeine consumption was reliably associated with the self-reported occurrence of somatic symptoms, but not psychological well-being.

The effects of alcohol on psychological functions in normal volunteers after 8 days' treatment with pipequaline (PK 8165), diazepam or placebo.

The effects of daily administration for 8 days of 50 mg pipequaline, 10 mg diazepam and placebo were assessed in a double-blind cross-over study with 12 healthy volunteers. This study also tested for an interaction between the drugs and alcohol on the eighth day. Subjective ratings, psychomotor and memory performance were evaluated. Diazepam produced the typical pattern of changes, namely impairments in psychomotor performance and reductions in the retention of newly memorised information. In contrast, the effects of pipequaline were relatively minor. In general, neither drug potentiated the effects of alcohol on performance, only isolated instances of non-additive interactions occurring. Subjective reports revealed that whereas both active drugs increased feelings of calmness, this result was accomplished by pipequaline with considerably less drowsiness, no euphoria and a general absence of the adverse side effects of diazepam.