David Healy

Rhythm and blues. Neurochemical, neuropharmacological and neuropsychological implications of a hypothesis of circadian rhythm dysfunction in the affective disorders

Current views on the organisation and functions of the circadian rhythm system are outlined. Evidence is presented supportive of the notion that the pathophysiology of the affective disorders involves a disruption of circadian rhythms and that the primary locus of action of agents effective in the affective disorders is on the circadian rhythm system. Potential disruptions of this system are enumerated. Such a hypothesis, it is argued, might potentially unite the disparate neurochemical and neuroendocrinological findings emerging in both depression and mania. There are in addition neuropsychological and nosological implications of such a framework, which may help bridge the divide between molecular and behavioural approaches to research on the affective disorders which are outlined.

Dysrhythmia, dysphoria, and depression: the interaction of learned helplessness and circadian dysrhythmia in the pathogenesis of depression.

Analyse des multiples implications (neurophysiologiques, neuropsychologiques et nosologiques) des constats relatifs a la perturbation des rythmes circadiens dans la resignation apprise et dans la depression

Dysfunctional attitudes and vulnerability to persistent depression

Forty-four patients who met criteria for major depressive disorder were assessed for presence of dysfunctional attitudes and negative self-schema on admission. After six weeks, of sixteen patients who had shown high dysfunctional attitudes, six (35%) had not recovered. By contrast, of seventeen patients who had been equally severely depressed at the outset, but had low dysfunctional attitudes, only one (6%) had not recovered. The rating by the patients of themselves, as opposed to their attitudes, did not however predict. Thirty-one patients were tested six months later. Twenty-one (68%) remained asymptomatic, ten patients had relapsed or not responded to treatment, but neither type of admission measure predicted the state at this point. This is consistent with previous evidence which suggests that vulnerable attitudes assessed when symptomatic predict recovery, but that for prediction of relapse, cognitive measures need to be used when the patient is asymptomatic.

Monoamine transport in depression: Kinetics and dynamics

There appears to be an abnormality in monoamine transport in major depressive disorders that may be specific to these disorders, although it may not be primarily an aminergic lesion. Kinetic factors alone are insufficient to explain the observed effects of antidepressants on transport mechanisms, or changes in uptake with therapeutic response, suggesting dynamic influences on uptake processes that deserve further exploration. The investigation of these influences may indicate that platelet 5-HT uptake offers diagnostic and theoretical possibilities not adverted to at present and another rationale for the use of platelets in research on mental disorders.

The Circadian System and Affective Disorders: Clocks or Rhythms?

There have been a number of proposals that a pathology of the circadian system involving clock functioning underlies the affective disorders. It is argued that neither current findings from research into the neurophysiological substrates of the affective disorders, recent clinical findings regarding these illnesses or their phenomenology support such a contention. This does not mean however that there is not a primary pathological disturbance of the circadian system at the heart of the affective disorders. The same neurophysiological, phenomenological and clinical evidence can be offered in favour of a disturbance of circadian rhythms in the presence of grossly normal clock functioning. The research and remedial implications of this alternative are outlined briefly.

Neuroleptics and psychic indifference: a review.

Dopamine hypothesis of schizophrenia Following the introduction of neuroleptics, the earliest indication of their mode of action suggested that they blocked catecholamine neurotransmission1. It was subsequently suggestedthat dopamine was likely to be the pertinent catecholamine; a suggestion supported by findings that neuroleptic activity was correlated with dopamine receptor blockade. Findings that neuroleptics inhibited the production of dopamine sensitive adenylate cyclase supported the notion that they acted to blockade dopamine receptors. However, while such findings held for phenothiazine and thioxanthene compounds, they did not appear to hold for butyrophrenone compounds, a discrepancy which was resolved with the development of a D2 receptor assay. Subsequent studies clearly indicated that clinical potency of neuroleptics correlated well with the ability to bind to D2 receptors, This was complemented by findings of Johnstone et al.5 who compared the efficacies of cisand transisomers of flupenthixol. They found that the cis-isomer, which differs from the trans-isomer in binding to D2 receptors while both bind to noradrenergic, cholinergic and opiate receptors, also differed from the trans-isomer in being clinically potent. Given that neuroleptic activity correlates closely with D2 receptor blockade and thereby with blockade of dopamine neurotransmission and given the clinical utility of these drugs in the treatment of schizophrenia, the evolution of a dopamine and subsequently a dopamine receptor hypothesis of schizophrenia is not surprising. Supporting the hypothesis were findings that amphetamine abuse frequently led to a schizophreniform psychosis, that amphetamine aggravates schizophrenic psychoses, that this exacerbation can be treated with neuroleptics and that amphetamine enhanced dopamine release in the brain, In addition, postmortem studies have indicated an increased number of D2 receptors in the brains of schizophrenic patients (although prior neuroleptic treatment makes the results from these studies ambiguousi, A recent PET scan study of drug naive schizophrenics has also reported an increase in D2 reteptor number!, There are problems however over the technique used in this study and the drug naivety of the subjects and the findings were not replicated by Farde et al 12. As well as leading to identification of a likely subcellular site of neuroleptic activity, the dopamine hypothesis has stimulated research into neuropsychological functions, whose modification by D2 blockade might be therapeutic. As the function of the nigrostriatal dopaminergic pathways appears to be predominantly motor, this has not seemed to be the correct site for an antischizophrenic locus of action. Some progress was made towards this with the differentiation of a mesolimbic dopamine projection arising from the ventral tegmentum and projecting to the nucleus accumbensv and the demonstration that this system mediates more complex behaviours than those associated with the nigrostriatal pathway and in particular is involved in the functioning of an incentive motivational system-s. However, as there is no consensus to date on any lesion in this system in schizophrenic subjects, pressure to identify other substrates remains. This has led to the recent differentiation of a mesocortical dopaminergic projection, that appears specifically responsive to environmental stressors and is connected to the frontal lobes, disorders of which have long been associated with schizophrenia{.

Platelet α2-adrenoceptors, defined with agonist and antagonist ligands, in depressed patients, prior to and following treatment

Saturation binding of the alpha 2-adrenoceptor antagonist, 3H-yohimbine, and displacement of 3H-yohimbine with the alpha 2-adrenoceptor agonist, UK-14,304, were performed concurrently in platelet membranes obtained from drug-free depressed patients and healthy volunteers. Where possible platelet binding was repeated in depressed patients following treatment. The number and affinity of 3H-yohimbine binding sites did not differ between controls and depressed patients, or when depressed patients were divided on the basis of endogenicity (Newcastle or RDC criteria) or dexamethasone test result. The proportion of alpha 2-adrenoceptor binding sites with high affinity for UK-14,304 and KD values for the two states of the receptor did not differ in the total sample of depressed patients compared to controls. The KD for both states of the receptor and the proportion of sites with high affinity for UK-14,304 was lower in RDC non-endogenous patients than RDC endogenous patients. Treatment did not alter the total number of alpha 2-adrenoceptors or the proportion of sites with high affinity for UK-14,304, but reduced the KD for 3H-yohimbine and the KD of UK-14,304 for the low affinity state of the alpha 2-adrenoceptor.

The Intersection of Psychopharmacology and Psychiatry in the Second Half of the Twentieth Century

In 1930, Bleckwenn described the response of acute catatonia to barbiturates.1 In 1935, Meduna demonstrated a response of catatonic states to clinically induced convulsions.2 This was followed by Bini and Cerletti’s demonstration of the effectiveness of electroconvulsive therapy for catatonic states.3 In the course of the decade, Rolv Gjessing demonstrated that periodic catatonias respond to infusions of high doses of thyroxine.4 Gjessing’s work complemented basic research in the late 1920s and early 1930s by Baruk and De Jong demonstrating an experimental induction of catatonia with agents such as bulbocapnine and later with mescaline and other psychotogenic agents. By the end of the decade even some of the arch skeptics in psychiatry such as Aubrey Lewis could state that a cure for one of the forms of schizophrenia, catatonia, had been found.5 Allied to the discovery of how to cure dementia paralytica, which in some settings had accounted for between 10% and 20% of admissions to asylums, the discoveries on how to model and treat catatonia marked the emergence of modern biological psychiatry

The comparative psychopathology of affective disorders in animals and humans

Reviews of animal models of affective disorders commonly concentrate on the behavioural features thereof, the supposed neurochemical substrates, the mode of production and the response to treatment of the state in question but ignore questions of psycho pathology. An attempt is made to deal critically with the psychopathology of human and animal affective disorders in the light of current operational criteria for the diagnosis of major depressive disorders. It is argued thatthe psychopathological tradition stemming from Jaspers may be more appropriate to a consideration of animal models of affective disorders than the psychopathological positions implicit in psychoanalysis, behaviourism or current cognitive psychologies and in addition more suited to meet these criteria. The adoption of such a perspective results in a shift of emphasis from abnormalities of psychological content to demonstrable neuropsychological deficits and a definition of affective disorders, whether in animals or humans, as psychosomatic illnesses, possibly involving a pathology of circadian rhythmicity. This perspective also suggests that animal models may be useful in the devel opment of more refined diagnostic criteria for affective disorders in humans.