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Biomedical subjects

J F Deakin

Publications and source records attributed to J F Deakin.

At least 37 records · Page 2Linked to original sources
PubMed1998

The role of serotonin in panic, anxiety and depression.

Anxiety and depressive disorders occur across a broad spectrum, and each different disorder may involve distinct genetic and neurobiologica/neurochemical mechanisms. Many classes of drug are available for the treatment of these disorders and, as might be expected, these drugs exhibit a variety of biochemical actions. Paradoxically, the single-action selective serotonin reuptake inhibitors are effective in a range of these disorders. However, the paradox may be resolved by an understanding of the distinct ways in which serotonin modifies the physiological coping mechanisms that become dysfunctional in these disorders.

Adaptation, Psychological↗
PubMed1997

Ritanserin facilitates anxiety in a simulated public-speaking paradigm.

The effects of ritanserin, a 5-HT2A/2C (5-hydroxytryptamine) antagonist, have been investigated in simulated public speaking with healthy volunteers. The aim was to investigate the role of 5-HT in subjective experimental anxiety. There were three experimental groups each comprising four or five males and 11 females. Subjects received placebo, ritanserin 2.5 or 10 mg, p.o. They rated themselves using the Spielberger State-Trait Anxiety Inventory and visual analogue scales factored into anxiety, sedation and discontentment scores. Autonomic measures included skin conductance and heart rate. Subjects were told, 75 min after drug or placebo ingestion, without prior warning, to prepare a 4-min speech. Measures were taken before, during and after the speech. Ritanserin prolonged the anxiety induced by the procedure on the subjective ratings but had minimal effect on autonomic responses to the procedure. The result contrasts with an anxiolytic-like effect of ritanserin on aversively conditioned autonomic responses. The present finding is compatible with animal behavioural evidence that 5-HT has distinct and opposing roles in modulating conditioned and unconditioned anxiety.

Adolescent↗
PubMed1996

Autoradiography with [3H]8-OH-DPAT reveals increases in 5-HT(1A) receptors in ventral prefrontal cortex in schizophrenia.

We previously reported increased glutamatergic innervation in orbital frontal cortex in schizophrenia. In view of the evidence that one serotonin (5-HT) receptor, the 5-HT(1A) subtype, is associated with cortical glutamatergic neurons, we have used quantitative receptor autoradiography to measure the specific binding of the 5-HT(1A) receptor ligand [3H]8-OH-DPAT (2 nM) in sections of orbital frontal cortex taken from 18 control and 12 schizophrenic postmortem brains. Schizophrenic patients, as compared with controls, had increased 5-HT(1A) receptor binding in the three orbital frontal regions examined. These effects were pronounced in the male subgroup, and were most apparent in the outer cortical laminae. These data are consistent with the hypothesis that schizophrenia is associated with an abnormal glutamatergic afferent innervation of orbital frontal cortex.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1996

Neural activation during covert processing of positive emotional facial expressions.

Lesion studies indicate distinct neural systems for recognition of facial identity and emotion. Split-brain experiments also suggest that emotional evaluation of a stimulus can occur without conscious identification. The present study tested a hypothesis of a differential neural response, independent of explicit conscious mediation, to emotional compared to nonemotional faces. The experimental paradigm involved holding in mind an image of a face across a 45-s delay while regional cerebral blood flow was measured using positron emission tomography. Prior to the delay, a single face was presented with an explicit instruction to match it to one of two faces, photographed at different angles from the target face, presented at the end of the delay. Repeated blood flow measures were obtained while subjects held happy or neutral faces in mind or during a neutral control fixation condition without initial face presentation. The representation of emotional faces over a delay period, compared to either the nonemotional or the fixation condition, was associated with significant activation in the left ventral prefrontal cortex, the left anterior cingulate cortex, and the right fusiform gyrus. The findings support our hypothesis of a differential neural response to facial emotion, independent of conscious mediation, in regions implicated in the processing of faces and of emotions.

Adult↗
PubMed1996

Increased density of entorhinal glutamate-immunoreactive vertical fibers in schizophrenia.

Gluatamtergic fibers have been immunocytochemically localized in the entorhinal cortex of postmortem schizophrenic brains. The density of small caliber vertical fibers was higher in schizophrenics than controls, with no significant increase in the number of large caliber fibers. Increased glutamatergic fiber density has been previously reported in the cingulate cortex. It is proposed that increases in glutamatergic fibers from the amygdala may be responsible for these changes and that they may play a central role in the pathophysiology of schizophrenia.

Cadaver↗
PubMed1996

The effect of chronic fluvoxamine on hormonal and psychological responses to buspirone in normal volunteers.

We studied the effect of 3 weeks treatment with the selective serotonin reuptake inhibitor (SSRI), fluvoxamine, on hormonal and psychological responses to buspirone, a 5-HT1A receptor partial agonist which also binds to dopamine receptors, in normal male volunteers. Eleven subjects received buspirone, 30 mg, and placebo before, and in week 3 of fluvoxamine treatment (mean dose 127 mg/day). Placebo and buspirone were given in a balanced order, double-blind. Buspirone significantly elevated plasma prolactin (PRL) and growth hormone (GH) concentrations but had no significant effect on cortisol (CORT) or temperature. Significant psychological effects of lightheadedness, tiredness and difficulty thinking occurred. Fluvoxamine treatment resulted in a nearly 3-fold increase in plasma buspirone with a similar enhancement of the PRL response. In contrast the GH and psychological responses were blunted. The increased buspirone concentrations are likely to be due to inhibition of first pass liver metabolism by fluvoxamine acting on the cytochrome P-450 system. The PRL response is probably mediated by antagonism of pituitary dopamine-D2 receptors and its enhancement by fluvoxamine treatment may be a pharmacokinetic effect. The blunting of GH and psychological responses suggest that 5-HT1A receptor function is reduced by chronic fluvoxamine treatment.

Adult↗
PubMed1996

Role of 5-HT in stress, anxiety, and depression.

There are conflicting results on the function of 5-HT in anxiety and depression. To reconcile this evidence, Deakin and Graeff have suggested that the ascending 5-HT pathway that originates in the dorsal raphe nucleus (DRN) and innervates the amygdala and frontal cortex facilitates conditioned fear, while the DRN-periventricular pathway innervating the periventricular and periaqueductal gray matter inhibits inborn fight/flight reactions to impending danger, pain, or asphyxia. To study the role of the DRN 5-HT system in anxiety, we microinjected 8-OH-DPAT into the DRN to inhibit 5-HT release. This treatment impaired inhibitory avoidance (conditioned fear) without affecting one-way escape (unconditioned fear) in the elevated T-maze, a new animal model of anxiety. We also applied three drug treatments that increase 5-HT release from DRN terminals: 1) intra-DRN microinjection of the benzodiazepine inverse agonist FG 4172, 2) intra-DRN microinjection of the excitatory amino acid kainic acid, and 3) intraperitoneal injection of the 5-HT releaser and uptake blocker D-fenfluramine. All treatments enhanced inhibitory avoidance in T-maze. D-Fenfluramine and intra-DRN kainate also decreased one-way escape. In healthy volunteers, D-fenfluramine and the 5-HT agonist mCPP (mainly 5-HT2C) increased, while the antagonists ritanserin (5-HT2A/2C) and SR 46349B (5-HT2A) decreased skin conductance responses to an aversively conditioned stimulus (tone). In addition, D-fenfluramine decreased, whereas ritanserin increased subjective anxiety induced by simulated public speaking, thought to represent unconditioned anxiety. Overall, these results are compatible with the above hypothesis. Deakin and Graeff have suggested that the pathway connecting the median raphe nucleus (MRN) to the dorsal hippocampus promotes resistance to chronic, unavoidable stress. In the present study, we found that 24 h after electrolytic lesion of the rat MRN glandular gastric ulcers occurred, and the immune response to the mitogen concanavalin A was depressed. Seven days after the same lesion, the ulcerogenic effect of restraint was enhanced. Microinjection of 8-OH-DPAT, the nonselective agonist 5-MeO-DMT, or the 5-HT uptake inhibitor zimelidine into the dorsal hippocampus immediately after 2 h of restraint reversed the deficits of open arm exploration in the elevated plus-maze, measured 24 h after restraint. The effect of the two last drugs was antagonized by WAY-100135, a selective 5-HT1A receptor antagonist. These results are compatible with the hypothesis that the MRN-dorsal hippocampus 5-HT system attenuates stress by facilitation of hippocampal 5-HT1A-mediated neurotransmission. Clinical implications of these results are discussed, especially with regard to panic disorder and depression.

Animals↗
PubMed1996

The relative abundance of dopamine D4 receptor mRNA in post mortem brains of schizophrenics and controls.

An increase in dopamine D4 receptors has recently been reported in post mortem brain samples from schizophrenics. We have attempted to complement this finding by assessing the levels of the specific messenger RNA (mRNA) for the D4 receptor, using the technique of quantitative RNA-PCR. No significant differences in the levels of expression of mRNA for the D4 receptor were found in the brains from schizophrenics compared to controls. The relationship between D4 receptors and schizophrenia, therefore, remains unclear.

Adult↗
PubMed1996

Does selectivity matter?

An important aim of drug development has been to retain efficacy while reducing side effects and toxicity. It is now clear that selective serotonin reuptake inhibitors (SSRIs) are more effective than noradrenaline reuptake inhibitors (NARIs) in the treatment of obsessional compulsive disorder, and obsessional features in depression predict a responsivity to SSRIs. Furthermore, panic disorder and depression may be more responsive to SSRIs than NARIs. However, there is evidence that inhibition of both sites produces slightly greater efficacy and the addition of an NARI has been reported to potentiate the antidepressant effect of SSRIs. Tricyclic noradrenaline-serotonin uptake inhibitors have many other pharmacological properties, which probably relate to high rates of side effects and cardiotoxicity. Whether in practice these features reduce compliance or increase deaths from suicide is debatable, but it seems wrong to subject patients to burdensome side effects. Certainly, in overdose, older non-selective antidepressants are far more likely to kill than SSRIs. SSRIs have their own side effects, such as nausea and anorgasmia, due to their potency at the uptake site, but these are reversible and sometimes treatable. Clearly, selectivity for specific uptake sites matters for efficacy, and selectivity for uptake over other sites matters for tolerability and safety.

Antidepressive Agents↗
PubMed1995

Use of MRI for measuring structures in frozen postmortem brain.

A method was developed for magnetic resonance imaging (MRI) of human autopsy brains stored long-term at -70 degrees C. Scanning brains at temperatures between -70 and -8 degrees C gave minimal MRI signals consistent with protons having limited freedom of movement at low temperature. Raising brain temperature improved the signal such that scanning at -1 degree C generated images with good in-plane resolution, grey/white matter contrast, and fine detail of cortical sulcal/gyral patterns. To validate the method, volume and area measurements were made using computerized image analysis on stored digital images of 14 brains from adult subjects of both genders and various ages. The data confirmed that brain volume was inversely correlated with age, and female subjects had smaller brains. This is a valuable new method for acquiring morphometric data from previously unscanned pathologic brains that are to be used for neurochemical and molecular investigations.

Analysis of Variance↗
PubMed1994

The abundance of mRNA for dopamine D2 receptor isoforms in brain tissue from controls and schizophrenics.

The possibility that schizophrenia is associated with a differential expression, in the brain, of the short and long isoforms of the dopamine D2 receptor has been investigated by assessing the abundance of mRNA for each of the isoforms. Using a quantitative RNA-PCR technique, increased mRNA for both isoforms of the D2 receptor were observed in some brain regions, with no differential distribution between the isoforms in the schizophrenics compared to controls.

Base Sequence↗
PubMed1994

Neuropsychological implications of brain changes in schizophrenia: an overview.

Schizophrenia is associated with structural changes in the brain but it is not clear whether the changes are localized. Studies in Manchester and elsewhere have reported abnormalities in biochemical markers of glutamate- and GABA-containing neurones in post-mortem brains from schizophrenic patients. The abnormalities occur in the ventral frontal cortex and anterior temporal lobe. It is suggested that these regions of the brain specifically encode information about social communication-language, gesture and facial expression. Many of the symptoms of schizophrenia become neuropsychologically understandable when seen as disturbances of social communication. In this and the following papers, experimental tests of this hypothesis are described.

Awareness↗
PubMed1994

Affect judgement and facial recognition memory in schizophrenia.

Two experiments are described in which the performance of schizophrenic subjects was investigated, using tests of affect judgement and recognition memory for faces (Warrington), words, and semi-abstract patterns. Schizophrenic subjects were impaired in their ability to describe the emotional states portrayed by actors and presented on video and were more likely to comment on the physical description of the actor or to fail to comment on the emotion at all. Performance on the Warrington Recognition Memory Test for faces suggests a marked impairment in schizophrenia, although impaired performance on recognition memory tests for words and patterns indicates that this abnormality may not be specific for faces.

Adolescent↗
PubMed1994

Receptive and expressive social communication in schizophrenia.

Twenty-three schizophrenic subjects and 19 controls completed selected neuropsychological tests of frontal and temporal lobe function and a subgroup of subjects completed a series of tests to assess receptive and expressive aspects of social communication. This was to examine the relationship between deficits of receptive social communication and deficits of temporal lobe function, and deficits of expressive social communication and deficits of frontal lobe function. Schizophrenic subjects were significantly impaired compared to normal control subjects on measures of social communication. Normal performance on a word recognition task contrasted with impaired performance on a face recognition task. No clear pattern of relationships between neuropsychological tests of regional brain function and receptive or expressive social communication emerged. A stepwise logistic regression analysis generated three factors which discriminated between the two groups of subjects; two of these factors were measures involving the information conveyed in a human face.

Affect↗
PubMed1994

Fluvoxamine versus clomipramine in the treatment of obsessive compulsive disorder: a multicenter, randomized, double-blind, parallel group comparison.

BACKGROUND: To examine the efficacy of fluvoxamine and clomipramine in obsessive compulsive disorder and to compare their tolerabilities. METHOD: In this multicenter, randomized, double-blind trial, fluvoxamine (100-250 mg/day) was compared with clomipramine (100-250 mg/day) for 10 weeks in the treatment of 66 psychiatric outpatients, aged 18 to 65 years, with a diagnosis of obsessive compulsive disorder. The main efficacy variable was the Yale-Brown Obsessive Compulsive Scale; secondary variables were the National Institute of Mental Health Global Obsessive Compulsive Scale and the Clinical Global Impressions-Improvement scale. RESULTS: Seventeen patients withdrew prematurely, 6 in the fluvoxamine group and 11 in the clomipramine group. In the intent-to-treat population (34 fluvoxamine patients and 30 clomipramine patients), there were no significant differences with respect to the mean reduction in total Yale-Brown Obsessive Compulsive Scale score (last observation carried forward) at any time-point; a mean reduction of 8.6 (33%) was seen in the fluvoxamine group and 7.8 (31%) in the clomipramine group. Similar results were obtained in virtually all secondary variables. The only exception was the obsession-free interval for the Yale-Brown Obsessive Compulsive Scale, which was significantly longer in the fluvoxamine group, especially in a population of patients with disease of > 12 months' duration (F = 5.298, df = 1, p = .026). Adverse events were mostly tolerable; 9 patients (5 receiving fluvoxamine, 4 receiving clomipramine) withdrew due to adverse events related to treatment. CONCLUSION: Fluvoxamine and clomipramine were equally effective in the treatment of obsessive compulsive disorder. Both agents were well tolerated; fluvoxamine produced fewer anticholinergic side effects and caused less sexual dysfunction than clomipramine, but more reports of headache and insomnia.

Adult↗