Biomedical subjects
T Bullock
Publications and source records attributed to T Bullock.
Lack of efficacy of fluoxetine in recurrent brief depression and suicidal attempts.
Recurrent brief depression (RBD) fulfills DSM-III-R symptom criteria for major depression but the episodes are of shorter duration than the 2 weeks required by DSM-III-R. The clinical importance of the disorder has been observed in prophylactic studies of suicidal behavior. The possibility that antidepressants with selective action on the reuptake of serotonin might be effective in preventing recurrences of brief depression has been investigated. Fluoxetine in a dose of 120 mg a week, administered biweekly, had no effect on the recurrence rate, which was maintained at approximately the same rate on fluoxetine (1 every 18.7 days) as with placebo (1 every 17.6 days). In a group of patients with two or more prior episodes of suicidal behavior, there were 18 attempted suicides in the 54 patients treated with fluoxetine and the same number in the 53 patients treated with placebo. Fluoxetine neither raised nor lowered the suicide attempt rate as compared with placebo, providing no evidence to support the drug's role in either suicide provocation or prevention. Since fluoxetine is clearly effective with recurrent major depression, it would appear that recurrent brief depression has a different pharmacology.
The lymphoblast beta-adrenergic receptor in bipolar depressed patients: effect of chronic incubation with lithium chloride.
We have recently reported a study of beta-adrenergic receptor binding characteristics in lymphoblast cell lines derived from patients with bipolar disorder (BD) and healthy, matched control subjects. In the present study we have investigated the effects of incubating cells from the same subjects with lithium chloride (1 mM) for 7 days prior to assay. There was no difference in beta-adrenergic receptor number between control and BD cell lines and incubation with lithium had no effect on receptor number in either group. Exposure of the cells to isoprenaline (1 nM) for 24 h immediately prior to assay caused significantly less down-regulation in BD cells (15 +/- 5%) than control cells (39 +/- 4%), as described previously. Incubation with lithium significantly increased the down-regulation response to isoprenaline in BD cells (39 +/- 6%) but not in control cells (30 +/- 7%). After lithium, the agonist-induced decrease in beta-AR number in BD cells was no longer significantly different from that in control cells. We conclude that lithium selectively enhanced the agonist down-regulation of beta-adrenergic receptors in cells derived from patients with bipolar disorder. The functional significance of this result and the potential biochemical mechanisms responsible for this effect are discussed.
[Depressive states and chronic asthenic syndromes in general practice].
It has been shown in Great Britain that general practitioners fail to recognize as many as 50% of the cases of depressive illness that present to them. The diagnosis is missed particularly when it is the physical type of symptom, such as asthenia, that is prominent. The Royal College of Psychiatrists, in association with the Royal College of General Practitioners, has launched the "Defeat Depression" campaign which includes amongst its aims the intention to provide up-to-date educational materials to family doctors on the recognition and treatment of depression. We have held two consensus meetings jointly with psychiatrists and primary care physicians and the results have been published in the British Medical Journal (2). One of our key recommendations is that, when medication is used to treat depressive illness in general practice, the antidepressants should be continued for six months after full remission has taken place. At present patients in general practice take their drugs for a total of three or four weeks. One of the reasons for patients abandoning their medication prematurely has been revealed by surveys that we have carried out on the general public. The lay person has little confidence in the efficacy of antidepressants and, perhaps more importantly, believes that they are addictive. It is therefore no surprise, then, that patients are keen to stop their antidepressants before they become dependent on them.(ABSTRACT TRUNCATED AT 250 WORDS)
Refined atomic model of wheat serine carboxypeptidase II at 2.2-A resolution.
The crystal structure of the homodimeric serine carboxypeptidase II from wheat (CPDW-II, M(r) 120K) has been determined and fully refined at 2.2-A resolution to a standard crystallographic R factor of 16.9% using synchrotron data collected at the Brookhaven National Laboratory. The model has an rms deviation from ideal bond lengths of 0.018 A and from bond angles of 2.8 degrees. The model supports the general conclusions of an earlier study at 3.5-A resolution and will form the basis for investigation into substrate binding and mechanistic studies. The enzyme has an alpha + beta fold, consisting of a central 11-stranded beta-sheet with a total of 15 helices on either side. The enzyme, like other serine proteinases, contains a "catalytic triad" Ser146-His397-Asp338 and a presumed "oxyanion hole" consisting of the backbone amides of Tyr147 and Gly53. The carboxylate of Asp338 and imidazole of His397 are not coplanar in contrast to the other serine proteinases. A comparison of the active site features of the three families of serine proteinases suggests that the "catalytic triad" should actually be regarded as two diads, a His-Asp diad and a His-Ser diad, and that the relative orientation of one diad with respect to the other is not particularly important. Four active site residues (52, 53, 65, and 146) have unfavorable backbone conformations but have well-defined electron density, suggesting that there is some strain in the active site region. The binding of the free amino acid arginine has been analyzed by difference Fourier methods, locating the binding site for the C-terminal carboxylate of the leaving group. The carboxylate makes hydrogen bonds to Glu145, Asn51, and the amide of Gly52. The carboxylate of Glu145 also makes a hydrogen bond with that of Glu65, suggesting that one or both may be protonated. Thus, the loss of peptidase activity at pH > 7 may in part be due to deprotonation of Glu145. The active site does not reveal exposed peptide amides and carbonyl oxygen atoms that could interact with substrate in an extended beta-sheet fashion. The fold of the polypeptide backbone is completely different than that of trypsin or subtilisin, suggesting that this is a third example of convergent molecular evolution to a common enzymatic activity. Furthermore, it is suggested that the active site sequence motif "G-X-S-X-G/A", often considered the hallmark of serine peptidase or esterase activity, is fortuitous and not the result of divergent evolution.(ABSTRACT TRUNCATED AT 400 WORDS)
Diarrhoea during treatment with clozapine: association with lymphocyte count.
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Recent advances in antidepressant drugs.
Tricyclic antidepressants (TCAs) are notorious for a number of disadvantages, but particularly for an array of side-effects that leads to poor compliance, and also for a dangerous toxicity in overdose. Lofepramine is a new tricyclic that seems safer. Selective serotonin reuptake inhibitors (SSRIs) are more limited in their actions. Side-effects include nausea and insomnia, but on the whole the side-effect profile is an improvement on the TCAs. A miscellaneous group of novel antidepressants includes mianserin and trazodone (which both produce drowsiness) and viloxazine (which causes nausea). The reversible inhibitors of monoamine oxidase A (RIMAs) are a group of drugs that, by producing inhibition selectively of monoamine oxidase A (MOA-A), still allow metabolism of tyramine by MAO-B. Moclobemide is a RIMA that has proved itself to be very effective in severe depressive illness. It is remarkably safe and has an exceptionally low incidence of side-effects. It may be expected to be associated with a high acceptability in depressed patients.
The nature and recurrence of RBD on placebo.
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Has recurrent brief depression a different pharmacology.
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Selective serotonin reuptake inhibitors in OCD.
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Serotonin reuptake inhibitors are the treatment of choice in obsessive compulsive disorder.
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The provocation and prevention of suicide attempts.
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Pharmacotherapy in the prevention of suicidal behavior.
Prevention or reduction of suicide remains a serious challenge for the medical community. Psychotherapeutic and psychosocial interventions have not been shown to reduce the incidence of suicide attempts and analytic psychotherapy has been shown to increase suicidal behavior. The efficacy of pharmacotherapy in reducing suicide attempts in patients with a history of repeated suicidal behavior has been shown with low doses of the neuroleptic agent flupenthixol compared with placebo. Supporting findings have been reported with trifluoperazine. There is evidence to suggest that some antidepressants may not be neutral in their effect on suicidal behavior. Maprotiline, for example, was associated with an increase in suicide attempts compared with placebo in a large long-term treatment study despite its significant efficacy in preventing relapse of depression. Differential lethality indices taken from large community studies support the notion that noradrenergic drugs such as maprotiline, desipramine, and nortriptyline are associated with a higher than expected incidence of death from overdose, and the suicide-provoking potential may relate to some noradrenergic property. The studies of serotonergic antidepressants do not suggest that they are suicide-provoking agents; rather they appear to be neutral or protective. Prospective prophylactic studies are needed to test the ability of potential treatments for the reduction of suicidal behavior.
5-HT reuptake inhibitors, tricyclic antidepressants and suicidal behaviour.
Antidepressant drugs undoubtedly reduce much of the morbidity and mortality associated with a variety of depressive disorders. Certain types of antidepressant drugs have been shown to exert a relative advantage in the reduction of suicidal thoughts, and it is interesting that recent reports have noted an association between the prescription of some antidepressants and the development of suicidal and aggressive thoughts and behaviour. An analysis of the data from double-blind controlled trials of fluvoxamine, fluoxetine and paroxetine indicates that 5-HT uptake inhibitors exercise some protective effects on the emergence of suicidal thoughts, whereas the data from the studies with maprotiline show an increase in suicidal thoughts compared with placebo.
Serotonin selectivity for obsessive compulsive and panic disorders.
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Crystallization of serine carboxypeptidases.
Crystallization of three different serine carboxypeptidases has been achieved by the method of hanging-drop vapor diffusion. Serine carboxypeptidases II from wheat bran and malted barley crystallize isomorphously from polyethylene glycol solutions at room temperature (pH 4 to 7) in space group P4(1)2(1)2 or enantiomorph with cell dimensions of a = b = 98.2 A and c = 209.5 A. The crystals diffract to about 2.3 A resolution using rotating-anode X-ray generators. Assuming a dimer of Mr 120,000 in the asymmetric unit, Vm = 2.1 A3/dalton. These crystals appear suitable for structural studies. A genetically engineered serine carboxypeptidase from yeast, which lacks three of four glycosylation sites present in the wild-type, has also been crystallized by vapor diffusion against methylpentanediol at 4 degrees C, pH 6.4 to 8.0.