Search PubMed⌕ Search

Biomedical subjects

M Lader

Publications and source records attributed to M Lader.

At least 37 records · Page 2Linked to original sources
PubMed1995

Quality of treatment: what do new antidepressants offer?

The development of new antidepressant drugs has raised many questions concerning their benefits, risks and costs relative to older established compounds, the tricyclic antidepressants. Nevertheless, it must be borne in mind that all of the newer compounds [atypical tricyclics, selective serotonin reuptake inhibitors (SSRIs) and reversible inhibitors of monoamine oxidase] are no more effective than the tricyclic antidepressants (TCAs). The reasons for this limited efficacy are unclear, as are predictors of response. The upshot is the problem of managing the refractory depressive and many stratagems have been proposed. Adverse effects vary greatly from class to class and to some extent within class. The TCAs affect many systems reflecting their multiple binding capabilities; the SSRIs have side effects stemming from their actions on central 5-HT mechanisms. By and large, SSRIs are somewhat better tolerated than TCAs, but whether this translates into better compliance is not known. Rare putative side effects, such as suicidal ideation, have received undue attention but further studies are justified. The pharmacokinetics of antidepressants are typically complex and routine monitoring of plasma drug concentrations is not helpful. The cost of even the most expensive antidepressants is but a fraction of the direct costs of unsuccessful treatment, let alone the indirect costs.

Antidepressive Agents↗
PubMed1994

Flumazenil has an anxiolytic effect in simulated stress.

This study was designed to test whether or not flumazenil (1 mg IV) would change levels of anxiety induced by simulation of public speaking (PSS). Forty normal volunteers were randomly allocated in a parallel groups design to treatment with flumazenil or placebo (double-blind) and one of two stress conditions (PSS/control task). PSS increased anxiety and flumazenil antagonized this effect. The anxiolytic activity of flumazenil was particularly strong on anticipatory anxiety measures. The results were discussed in terms of the involvement of endogenous benzodiazepine-type ligands in the regulation of the human response to stress.

Adolescent↗
PubMed1994

Anxiety or depression during withdrawal of hypnotic treatments.

The prescription of hypnotics, mostly benzodiazepines, continues at a high level, long-, medium- and short-acting compounds all being used. The indication for these hypnotics is the symptom of insomnia which is often secondary to a primary anxiety or depressive disorder. One problem with the use of hypnotics, particularly shorter-acting ones, is rebound insomnia in that discontinuation may be followed by sleep which is worse than pretreatment levels. Anxiety, which may well have been assuaged by the hypnotic treatment, may also rebound but depression, usually not really helped by the hypnotic, does not alter much. A second problem, on discontinuation of long-term treatment, particularly longer-acting hypnotics, is a physical withdrawal syndrome characterized by general malaise, and perceptual symptoms as well as marked increases in anxiety and insomnia. In some patients, however, depressive symptoms predominate. These may be an exaggeration of an on-going depressive disorder or it may appear to arise de novo in patients hitherto free of such an illness. The depression can be quite severe and need rigorous treatment in its own right. It is always useful to enquire about hypnotic/anxiolytic withdrawal in patients presenting with a depressive disorder. Depression is also a prognostic indicator of poor outcome (failure to withdraw successfully) in patients taking benzodiazepine hypnotics chronically.

Anti-Anxiety Agents↗
PubMed1994

Anxiolytic drugs: dependence, addiction and abuse.

The concepts of dependence, addiction and abuse comprise overlapping clinical phenomena. The earlier anxiolytic drugs, in particular the barbiturates, were prone to abuse, i.e., non-medical use, and to high-dose misuse. Their modern counterparts, the benzodiazepines, are abused in a patchy way and are sometimes taken in regularly high doses. However, the main problem is physical dependence as manifested by a withdrawal syndrome on discontinuation of the drug. The withdrawal syndrome has been carefully described and comprises physical and psychological features. In particular, perceptual symptoms such as photophobia, hyperacusis and feelings of unsteadiness may predominate. The syndrome may come on during dosage reduction but generally starts 2-10 days after cessation of the benzodiazepine, depending on its elimination half-life. About a third of long-term users suffer a recognisable syndrome even after a tapered withdrawal, its duration usually being only a few weeks. A few patients go on to a prolonged withdrawal syndrome, often characterised by muscular spasm. The treatment of the withdrawal syndrome is supportive and non-specific. A few patients started on benzodiazepine therapy escalate the dose. They tend to show the characteristic 'passive-dependent' personality features and may previously have misused other CNS depressants such as the barbiturates and alcohol. Abuse of benzodiazepines occurs in a rather varied way from country to country. Worldwide, flunitrazepam has caused concern but, in the UK, the main problem has been the intravenous use of temazepam. The molecular pharmacology of the benzodiazepine receptor has been extensively studied and is undoubtedly complex.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Anxiety Agents↗
PubMed1994

Memory functions, alprazolam and exposure therapy: a controlled longitudinal study of agoraphobia with panic disorder.

Benzodiazepines (BZs) produce transient anterograde amnesia when given to normal subjects. The present longitudinal study assessed whether BZs impair memory functions in a clinically anxious group. Eighty-two agoraphobics with panic disorder were randomly allocated to one of four treatment groups resulting from a combination of two drug treatments (alprazolam or placebo) and two psychological treatments (exposure or relaxation). Of these, 38 subjects were assessed on a range of objective and subjective indices of memory and mood at three time points: before treatment, after 8 weeks of treatment and again at 24 weeks when patients had been free of medication from 5-8 weeks. Alprazolam produced pronounced impairments on a word recall task. At the 24-week medication-free follow-up, alprazolam patients were still impaired on the task compared with placebo patients. Alprazolam did not impair performance on an implicit memory task and did not affect digit span. Differences between psychological treatments emerged mainly in subjective memory effects. Findings are discussed in terms of the specificity of BZ-induced amnesia and differential tolerance to the varying effects of BZs. Implications are drawn out for the patient's ability to function optimally in daily life while taking alprazolam.

Adult↗
PubMed1994

Selective serotonin reuptake inhibitors: meta-analysis of discontinuation rates.

A meta-analysis was carried out of 42 published randomized controlled studies comparing the selective serotonin reuptake inhibitors (SSRIs) with the tricyclic antidepressants (TCAs) that measured discontinuation rates for side effects and lack of efficacy by treatment group in order to compare the discontinuation rates for side effects and lack of efficacy. These discontinuation rates were pooled to produce the main outcome measure. Seven studies were placebo controlled and the discontinuation rates in these studies were also pooled in a separate analysis. Significantly fewer patients receiving SSRIs discontinued treatment because of side effects (14.9%) compared with those receiving TCAs (19%) (p < 0.01). There was also a significant difference in discontinuation rates due to side effects in the placebo- and TCA-controlled studies analysed separately, SSRIs (19%) compared with TCAs (27%) (p < 0.01). In both analyses a similar proportion of patients discontinued for lack of efficacy on SSRIs and TCAs. There is a significant and clinically important advantage for the SSRIs compared with the TCAs in the acceptability of treatment measured by the number of discontinuations due to side effects reported in published studies. The risk-benefit calculation favours the SSRIs since there were similar levels of efficacy but more discontinuations with the TCAs. The selection of an antidepressant for first-line treatment requires critical evaluation of the full risk-benefit equation.

Antidepressive Agents, Tricyclic↗
PubMed1994

Systemic absorption and abuse liability of snorted flunitrazepam.

Benzodiazepine hypnotics are widely abused as part of a polydrug misuse culture. This study set out to investigate some pharmacokinetic and pharmacodynamic characteristics of a novel method of abuse, snorting, of flunitrazepam. Twenty healthy volunteers took part: three took 0.5 mg, three took 1 mg, three took 1.5 mg, six took 2 mg and five took placebo. Blood was sampled and ratings of mood, bodily symptoms, strength and liking of drug effect were completed pre- and at 5, 15, 30, 60, 90, 120 and 240 minutes and at 24 hours post-drug. It was found that flunitrazepam could be detected in venous blood 5 minutes after intake. As the dose increased, the peak plasma concentration was higher but also occurred progressively later, the levels reached being comparable to oral or intramuscular administration at 110 minutes. Subjects reported sedation but complained of few side-effects. They liked the drug effects and subjective ratings of strength were correlated with liking and with plasma drug levels.

Administration, Inhalation↗
PubMed1994

Biological processes in benzodiazepine dependence.

The indications for the benzodiazepines include anxiety, insomnia, muscle spasm and epilepsy and each disorder has a variety of biological substrates. Limbic structures and the neurotransmitters noradrenaline, 5-HT and GABA have all been implicated. Benzodiazepines act on allosteric receptor sites and potentiate the actions of GABA in modulating chloride ionophores across nerve membranes. These effects can be blocked by the benzodiazepine antagonist, flumazenil. The molecular pharmacology of the benzodiazepine-GABA-chloride receptor is complex, with a wide range of different subunits. Animal models of dependence have suggested that the changes associated with long-term benzodiazepine use are related more to receptor-effector coupling than to the receptor characteristics themselves. Thus, benzodiazepine agonists on long-term use lose their efficacy, antagonists become partial inverse antagonists, and inverse agonists increase in efficacy. Various clinical implications are explored, including the use of flumazenil to prevent and to treat benzodiazepine withdrawal syndromes.

Animals↗
PubMed1994

Post-mortem antipsychotic drug concentrations and unexplained deaths.

BACKGROUND: The relationship between antipsychotic drug treatment and sudden unexplained death remains unclear. The estimation of post-mortem blood drug concentrations should be helpful. METHOD: Eight medico-legal cases were reviewed with respect to behaviour of patient, type and dosage of drug treatment, mode of death, post-mortem findings and drug concentrations. RESULTS: The problems of evaluating such drug levels are discussed. Five of the eight patients had probably toxic concentrations of antipsychotic and/or antidepressants, which caused death, usually involving cardiac arrhythmias. CONCLUSIONS: In cases of sudden unexpected death, a sample of blood from a peripheral vein should be obtained immediately death is pronounced or the body discovered, and sent for analysis. To minimise such fatalities, the patient should be monitored carefully, with ECG if feasible, and electrolyte balance checked. The drug regimen used should be kept simple and large doses of antipsychotics and/or antidepressants avoided wherever possible.

Adult↗
PubMed1994

Neuroleptic-induced deficit syndrome. Historical introduction.

The treatment of psychotic illness has long been inextricably associated with society's view in general on social deviance. In medieval times, psychotic individuals were contained within the community, a situation which still prevails in many developing countries. Aggregation of such patients in asylums followed the increasing industrialization of communities in the nineteenth century, when the ability of the disadvantaged of all kinds to survive was greatly jeopardized. The twentieth century has seen a gradual reversal of this process, as attitudes towards mentally ill people have become a little more enlightened and liberal. However, the swing against the great lunatic asylums of the last century has proceeded at such an administrative rate that our patients are again in danger of succumbing medically and economically within our communities. It is common to see desperately poor and damaged psychotic individuals on our streets. The advent of neuroleptics was a major factor in the change from a custodial to an ostensibly rehabilitative approach in the treatment of schizophrenia. However, classic neuroleptics have a long list of well-recognized side effects such as affective and cognitive impairment that lead to poor treatment compliance, psychiatric relapse and social decompensation, the state of affairs of our street psychotics. Treatments that lessen the probability of this unfortunate process are desperately needed. The introduction of new neuroleptic drugs with favourable side effect profiles is to be welcomed as a major step in increasing the quality of life of our patients, both in hospital and functioning in the community.

Antipsychotic Agents↗
PubMed1993

Measurement of plasma serotonin by high-performance liquid chromatography with electrochemical detection as an index of the in vivo activity of fluvoxamine.

A reversed-phase high-performance liquid chromatographic method is described for the measurement of plasma serotonin concentrations. Sample preparation is by a simple solid-phase extraction using C18 columns. An isocratic separation is used with electrochemical detection. The application of the method to the measurement of plasma serotonin concentrations following the administration of fluvoxamine (a serotonin re-uptake inhibitor), maprotiline (a noradrenaline re-uptake inhibitor) and placebo to normal subjects for a seven-day period is reported. Fluvoxamine significantly decreases plasma serotonin over this time period in a linear fashion. No effect on plasma serotonin was seen for maprotiline or placebo. Plasma serotonin concentrations can be used to monitor compliance with fluvoxamine therapy.

Adult↗
PubMed1993

The effects of single doses of CL284,846, lorazepam, and placebo on psychomotor and memory function in normal male volunteers.

The effects of single doses of CL284,846 (20 mg), lorazepam (2 mg) and placebo on psychomotor performance, memory function and subjective feelings were assessed in 12 normal, healthy male volunteers. Each subject received each treatment in balanced order and a minimum of 6 days was left between treatments. The subjects performance on a comprehensive battery of tests of psychomotor performance, memory function and subjective ratings was assessed pre-treatment and at 1, 3 and 5 h post-treatment. In general, the effects of CL284,846 on memory were similar to those of lorazepam at 1 h post-treatment but, recovery was rapid with CL284,846. Impairments induced by lorazepam persisted throughout the post-drug testing sessions. This pattern of effects was repeated across most of the variables tested. However, at 1 h, CL284,846 produced less marked psychomotor impairment than lorazepam. The results of this study suggest that CL284,846 is a safe, rapid acting and effective sedative with some clear advantages over lorazepam with respect to unwanted cognitive and psychomotor impairments.

Acetamides↗
PubMed1993

Computed axial brain tomograms in long-term benzodiazepine users.

Computed axial brain tomograms were recorded in four groups of subjects: (a) subjects who had never taken benzodiazepines (n = 25); (b) subjects who had taken them in the past for less than a year (n = 9); (c) patients currently taking benzodiazepines (n = 30); and (d) patients who had taken benzodiazepines in the past for at least a year and who had been withdrawn from medication for at least 6 months (n = 17). Ventricle-to-brain ratios and tissue absorption to X-rays were computed. No overall differences were found between the main groups. However, a few brain regions differed in density between nonusers and heavy users, particularly those taking lorazepam.

Adult↗
PubMed1993

The effects of nefazodone, imipramine and placebo, alone and combined with alcohol, in normal subjects.

Nefazodone (200 mg, 400 mg/day) imipramine (150 mg/day) and placebo were administered to 12 normal, healthy volunteer subjects for a period of 8 days each. A measured dose of alcohol was consumed with the drug on day 8. A battery of physiological, psychomotor, cognitive and subjective tests was carried out before drug administration and 2 h after drug administration on days 1, 7, and 8. Nefazodone had little effect on heart rate and blood pressure whereas imipramine increased both heart rate and diastolic blood pressure. Nefazodone 400 mg impaired the critical flicker fusion threshold. Dose-dependent improvements in psychomotor performance (Gibson Spiral Maze) and complex memory performance (learning, pursuit rotor, and visual working memory) were produced by nefazodone while imipramine administration impaired performance on these tasks. Subjective changes in alertness and bodily symptoms were produced by all active compounds. While nefazodone failed to potentiate the sedative-hypnotic (depressant) effects of alcohol, imipramine tended to enhance them for psychomotor performance, memory assessments, and some subjective ratings. Thus, nefazodone, particularly at lower dose levels, causes less disruption of human performance than imipramine. This effect probably reflects the lack of anticholinergic activity of nefazodone. Also, nefazodone failed to potentiate the depressant effects of alcohol, perhaps because of its minimal alpha-blockade.

Adolescent↗
PubMed1993

A comparison of alpidem and placebo in relieving benzodiazepine withdrawal symptoms.

Chronic normal-dose benzodiazepine users requesting drug withdrawal were allocated to substitution with either the new anxiolytic alpidem (n = 13) or placebo (n = 12). During the first 2 weeks of the tapering programme, the dose of benzodiazepine was kept constant; for the next 2 weeks it was halved and half-dose alpidem (25 mg twice daily) or placebo substituted; for weeks 5 and 6, the benzodiazepine was discontinued and full-dose alpidem or placebo given; next alpidem or placebo were tapered to half-dose and then finally discontinued. Regular anxiety and tranquillizer withdrawal ratings were made. Nine of 12 patients given placebo withdrew successfully compared with four of 13 alpidem-treated patients. Anxiety and other symptom levels increased in the alpidem but not the placebo patients. It was concluded that alpidem is not helpful in helping patients withdrawing from a benzodiazepine withdrawal perhaps because of partial agonist properties. These actions may imply a lesser propensity to induce dependence on long-term use.

Adult↗