Roger M. Pinder

Alcohol, wine and mental health: focus on dementia and stroke

The relative risks of coronary heart disease (CHD) and overall mortality are reduced by moderate consumption of alcoholic beverages, particularly wine, which has major implications for public health. It appears likely that this beneficial effect of alcohol will soon be extended to some mental disorders. Although data on psychosis and mood and anxiety disorders are currently lacking, it appears that the relative risks of developing ischaemic stroke and Alzheimer’s or vascular dementia are also lowered by moderate alcohol consumption. Such findings are still tentative because of the inherent methodological problems involved in population-based epidemiological studies, and it is unclear whether the benefit can be ascribed to alcohol itself or to other constituents specific to wine such as polyphenols. Plausible biological mechanisms have been advanced for the protective effect of alcohol and wine against CHD, many of which will also play roles in their protective actions against cerebrovascular disease and dementia. The specific antioxidant properties of wine polyphenols may be particularly important in preventing Alzheimer’s disease. Because of the substantially unpredictable risk of progression to problem drinking and alcohol abuse, the most sensible advice to the general public is that heavy drinkers should drink less or not at all, that abstainers should not be indiscriminately encouraged to begin drinking for health reasons, and that light to moderate drinkers need not change their drinking habits for health reasons, except in exceptional circumstances.

Do some antidepressants promote suicide

The recent letter of Feuerstein and Jakisch (1986) appeared to accept uncritically the hypothesis that some antidepressants promote suicide. Although this opinion is held by some there is no acceptable evidence from patients to support it. The only evidence that would be acceptable is the demonstration in a prospective double blind trial that a difference in suicide rates was consistently seen. There are some reports that particular antidepressants may be associated with a better reduction in suicidal thoughts than others but no evidence for an increase. There is no evidence at all for a differential suicide attempt rate with antidepressants and the title given to the Feuerstein and Jakisch letter is therefore misleading. Suicidal thoughts are an integral part of depression and overdosage with antidepressants is unfortunately common. The report of Kresser-Hermsdorf et al. (1985) suggests that between 3% and 50% of annual admissions to hospital for acute overdosage are associated with antidepressants. Reported mortality rates for individual antidepressants vary from 0.7% to 15.2% (Litovitz and Troutman 1983, Kiltie et al. 1984), but the generally accepted rate is about 2-3% of all antidepressant self-poisoning admissions (Crome and Newman 1971, Hulten and Heath 1983). The most accessible data for evaluating relative risk emanates from England and Wales where all fatal poisonings are reported at coroners inquests and published in annual surveys of mortality statistics (Office of Population Censuses and Surveys, annual). The data do not allow differentiation between deliberate and accidental overdosage, however, most accidental poisoning occurs in children. The total number of fatal poisonings in England and Wales declined from 2966 in 1977 to 2148 in 1984, while the percentage of deaths involving antidepressants remained fairly constant at about 14-15% (Office of Population Censuses and Surveys 197%1984). The magnitude of the problem seems to have changed little since the survey by Crome and Newman (1979b) of fatal tricyclic antidepressant poisonings, who reported that 11.6% of fatalities involved tricyclics in 1975 which was before the introduction of second generation antidepressants. Fatalities due to individual antidepressants during the period of 1977-1984 are listed in Table 1, where they are related to an estimate of numbers of patients treated during the same period. Only drugs with substantial usage are included, while nomifensin and trazodone are excluded because fatal overdosage has been rarely associated with their use (All and Crome 1984, Proudfoot 1986). Table 1. Fatahties following self-poisoning with antidepressants, intentional or accidental, for England and Wales in 1977-1984

Enhancing the Technology of Clinical Trials and the Trials Model to Evaluate Newly Developed, Targeted Antidepressants☆

Concern about disappointing results from recent multi-center trials of new antidepressants prompted several ACNP workshops on “improving the technology of clinical trials.” The workshops focused on technical problems, such as patient screening, reliability of clinical ratings, and the role of the placebo control. They aimed to determine how to more effectively apply the current clinical trials model for evaluating antidepressant drugs. The problems confronting the field of clinical trials, however, extend beyond technology. They also included conceptual issues concerning changes in the understanding of depressive disorders and of the multiple actions of antidepressant drugs. Such problems have been further complicated by the rapidly changing field of drug development itself, which is continually refining the targeting of new antidepressant agents. Drugs are increasingly being developed to try to change specific behavioral facets more rapidly and may be less likely, therefore, to act initially on “whole” disorders. To address such issues, a symposium was held in Rhodes in 2000 that focused on such conceptual changes with the goal of developing recommendations to revise the clinical evaluation model. Its purpose was to integrate new knowledge on depression and the mechanisms of action of antidepressant drugs toward developing more efficient methods of drug development. Since the evaluation process will eventually require changes in governmental policy, senior staff from the National Institute of Mental Health (NIMH) and Food and Drug Administration (FDA) participated as well as members of academia, industry and clinical practice. Recommendations for altering clinical trial methodology were made in four areas: patient selection, methodology of evaluation, measuring onset of action, and FDA and NIMH perspectives on current practice. This article discusses these four areas and presents the consensus of the panel participants.

Mianserin: Pharmacological and clinical correlates

Antidepressants interact with a variety of neurotransmitter receptors to exert both their therapeutic and side effects. However, the problems of anticholinergic and cardiovascular side effects of the older antidepressants, irritating at therapeutic dose but potentially lethal in overdose, have been largely solved by introduction of newer atypical drugs which enhance patient compliance and are safer in overdose. Mianserin is an established atypical antidepressant which exerts its therapeutic action principally via antagonism at presynaptic α2 adrenoceptors controlling noradrenaline release rather than by inhibition of monoamine reuptake or oxidase. Serotonin (5-HT) antagonism may play a contributory role; mianserin is an antagonist at 5-HT1c, 5-HT2 and 5-HT3 receptors and enhances 5-HT neurotransmission upon chronic administration. Mianserin lacks anticholinergic activity and has no effects upon cardiac conduction, but it produces initial sedation via antagonism at histamine H1-receptors. This profile is r...

Chapter 1. Toward Third Generation Antidepressants

Publisher Summary In second generation anti-depressants, new tricyclics (TCAs), such as maprotiline and atypical agents, like mianserin, are used to reduce the cardiovascular and anti-cholinergic side effects of the first generation TCAs and monoamine oxidase inhibitors (MAOls), typified by amitriptyline and isocarboxazid. It continues with selective serotonin reuptake inhibitors (SSRls) and reversible inhibitors of monoamine oxidase A (RIMAs). Third generation agents retain the gains already made in minimizing side-effects and toxicity in overdosage. Chronic anti-depressant treatments produce adaptive hyporesponsitivity of the 5-HT 1A receptor–effector complex, as indicated by a decrease of hypothermic and neuroendocrine responses. Unravelling the functional alterations of components, of the intracellular signal transduction pathway, lead to new biochemical target mechanisms for future anti-depressants. Lithium is the most commonly used drug in bipolar disorders, for both acute mania and maintenance therapy. It is also effective in the acute treatment of depression, either alone or when used to augment mainline anti-depressant treatment, in refractory patients. In the enhancement of 5-HT transmission, lithium affects G protein-regulated phenomena, such as receptor-activated phosphatidyl-inositol and cyclic adenosine monophosphate (cAMP)-turnover, leading to altered functions of the inter-regulated cAMP-dependent protein kinase and protein kinase C. Lithium inhibits inositol monophosphatase, resulting in lowered cellular levels of ώ-inositol and reduced agonist-induced formation of inositol polyphosphate. Carbamazepine is now established as an alternative or adjunct to lithium.

The clinical profile of mianserin

Drug licensing authorities throughout the world share a common concern to ensure that the drugs which are licensed are both effective and safe. However, the relatively small number of patients exposed to a drug in clinical trials make it extremely unlikely that serious but rare adverse drug reactions (ADRs) will be detected early in a clinical testing programme. Estimates of incidence of rarely occurring ADRs can only be made during post-marketing surveillance. Deaths from serious ADRs are less common than deaths from toxicity in overdosage with the older tricyclic antidepressants. Nomifensine, for example, was withdrawn when it was shown to be associated with 7 deaths per million prescriptions and no deaths from overdosage whereas amitriptyline continues to be used despite being shown to be associated with 48 deaths from overdosage per million prescriptions. In the risk benefit calculation the advantage of mianserin in terms of increased safety in overdose needs to be weighed against the risks of dysiras...

Chapter 6. Formation and Degradation of Neuropeptides

Publisher Summary Synaptic communication was long thought to be mediated solely by classical neurotransmitters such as monoamines, amino acids and acetylcholine. In the last decade, however, an increasing number of peptides have been found in CIS neurons. Leuropeptides can be defined as those peptides who affect communication between neurons either by direct transmitter action or indirectly via neuro-modulation. The availability of newer diagnostic and analytical techniques has greatly facilitated the identification of such peptides. The situation is further complicated by the frequent coexistence of neuropeptides with each other or with classical neurotransmitters. Co-transmitters may greatly increase the number of chemical signals available for neuronal communication. Neuropeptides are involved in homeostatic systems, including the regulation of pain, blood pressure, temperature, thirst, feeding, learning, memory and tropic function. Neuropeptides have also been implicated in neurological diseases such as Alzheimers disease, schizophrenia, huntingtons chorea and epilepsy, as well as in the immune system. The amino acid sequences of the majority of characterized neuropeptides have been provided in this chapter that discusses biosynthesis and post-translational processing of peptides. The discussion is on neuropeptides in mammalian CIS, the human POWC precursor molecule and products of its cleavage at paired basic amino acid residues. The chapter also provides details on enzymatic degradation of neuropeptides in the CNS.

Chapter 1. Antidepressants

Publisher Summary This chapter comprehensively reviews the pharmacological and biochemical properties of new antidepressants, neuroendocrine aspects of depression reassessed, sleep, depression, and antidepressants. The role of tricyclic antidepressants (TCA) in therapeutics has been of great significance in the field of antidepressants. It was once claimed that particular depressive symptoms and response to particular types of antidepressant were associated with high or low 31nethox -4-hydroxyphenylglycol (MHPG) excretion. The role of MHPG as an index of central noradrenergic (NA) activity is already known. Suggestions that clinical response to tertiary amino TCA depended upon their rate of demethylation were not confirmed for amitriptyline in a double-blind trial. However, the 2-hydroxy metabolites of amitriptyline and imipramine, and their desmethyl analogs, were as potent as the parent TCA in inhibiting the uptake of NA and 5-hydroxytryptamine (5-HT) in rat brain, and the plasma level measurements in depressed patients supported a role for such metabolites as the major active drug components during antidepressant treatment. Supersensitivity to 5-HT may also be involved in depression. Evidence was presented that chronic TCA treatment decreases the density of 5-HT receptors in rat brain. However, electrophysiological studies indicated that such treatment produced 5-HT receptor supersensitivity rather than subsensitivity.

Chapter 6 Neuropeptides and Their Processing: Targets for Drug Design

Publisher Summary This chapter discusses the enzyme inhibitors and neuropeptides as enzymes, as drugs still present serious problems in the context of access to the central nervous system (CNS). The chapter explains a previous survey of the formation and degradation of neuropeptides, and describes progress in designing drugs that can influence these processes. In principle, this includes enzymes, enzyme inhibitors, and neuropeptide agonists or antagonists. Precursors for neuropeptides processed at paired basic amino acid residues appear to share a common β-turn secondary structure around the cleavage site, while monobasic processing may be directed by adjacent proline residues. New endopeptidases include a rat metallopeptidase cleaving NT at the Pro-Tyr bond and a bovine enzyme cleaving the occupational therapy (OT) precursor on the carboxyl side of the Lys-Arg doublet. Rat brain may contain a specific thyrotropin-releasing hormone (TRH)-degrading enzyme that is distinct from the more widely distributed pyroglutaniyl peptidase. A free radical, alternative mechanism has been suggested for peptide α-amidation on the basis of studies with an abiotic system. New exopeptidases include a serine carboxypeptidase of porcine origin that processes human adrenocorticotropic hormone (ACTH) and β-LPH, and cathepsin B (a preferential peptidyl dipeptidase) that cleaves pro-opioid oligopeptides.

Chemistry and pharmacology of novel antidepressants

Depression is a common, recurrent and debilitating condition which carries substantial personal, familial and societal costs. It causes significant suffering, disability and social dysfunction frequently leading to disruption of normal life and work. Depressed patients struggle to recover, often over several months and sometimes even years, and many follow a chronic and remorseless course. The high morbidity is accompanied by a substantial mortality, such that as many as 15% of depressed patients take their own lives. Many more attempt suicide at some time during their lives. The economic impact of depression on society is considerable and is comparable to that of other major disorders such as coronary heart disease. However, depression is often not properly recognised, it exacts costs over a longer period of time and places a particularly heavy burden on employers because of lost productivity. Annual costs have been estimated for the USA at about US