Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fenfluramine has been used for a number of years as a short-term adjunct to diet in the management of obesity. Controlled studies and clinical experience have shown that it possesses anorectic activity at least as good as that of other therapeutically useful drugs of its type, but like these drugs it has only a limited role in the overall management of obesity. Tolerance to the anorectic effects of fenfluramine may possibly develop more slowly than to other chemically related drugs in patients with refractory obesity. The mechanism of its anorectic action is probably by an effect on the appetite control centres in the hypothalamus, rather than by an effect on glucose and lipid metabolism. However, its effect in enhancing glucose uptake into skeletal muscle may be of advantage in diabetes mellitus, preliminary studies suggesting that it is of potential use in maturity-onset obese diabetics who cannot be adequately controlled by dietary measures alone. The starting dosage in obesity of 40mg daily should be increased gradually over 2 to 4 weeks to 60 to 120mg. In general, little extra benefit is gained by higher dosage. When a course of therapy is to be discontinued, fenfluramine dosage should be reduced gradually over a period of 2 to 4 weeks in order to avoid mood depression which has occurred in some patients on abrupt withdrawal of the drug. With these recommendations, the majority of patients tolerate fenfluramine satisfactorily, although some patients may have to discontinue the drug because of troublesome gastro-intestinal problems, diarrhoea, drowsiness or dizziness. Unlike other amphetamine-derived anorectics, fenfluramine is not a central stimulant in therapeutic doses, and it probably has little abuse potential.
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PMID:Fenfluramine: a review of its pharmacological properties and therapeutic efficacy in obesity. 76

The treatment of obesity is one of the major measures available today in the field of preventive medicine. In particular, the coronary epidemic of Western civilisation would be halted, and most cases of maturity-onset diabetes prevented, if obesity were to be treated effectively. Anorectic drugs act mainly on the satiety centre in the hypothalamus to produce anorexia. They also have various metabolic effects involving fat and carbohydrate metabolism, but many of these may be secondary to loss of weight. Most of the drugs are related directly or indirectly to amphetamine and in addition act by increasing general physical activity. Anorectic drugs tend to lose their effect after some months, and part of this reduction in effect may be due to chemical alterations produced by the drugs in the brain. All the drugs, with the exception of fenfluramine, have a stimulant effect on the central nervous system in some individuals, resulting in restlessness and nervousness, irritability and insomnia. Fenfluramine commonly produces drowsiness in normal doses, but has stimulant effects with overdosage. Dexamphetamine, phenmetrazine and benzphetamine all tend to cause euphoria and the risk of addiction is therefore considerable. Euphoria occasionally occurs with diethylpropion, phentermine and chlorphentermine, but to a much lesser extent. Side-effects also occur due to sympathetic stimulation and gastro-intestinal irritation. These side-effects may cause some individuals to stop taking the drug, but are never serious or dangerous. Drug interactions may occur with monoamine oxidase inhibitors and to a clinically unimportant extent, with antihypertensive drugs. The anorectic drugs have a very definite part to play in the treatment of obesity, mainly for those individuals who have altered their eating habits but have come to a plateau of weight which they find difficult to get below. The drugs are best given in a long-acting form and can safely be continued as long as weight loss persists, provided that the clinician exercises careful supervision. Dexamphetamine, phenmetrazine and benzphetamine should rarely be used because of the danger of addiction, and chlorphentermine is potentially hazardous for long-term use. Diethylpropion emerges as the drug of first choice, as fenfluramine has a tendency to cause depression and has a higher incidence of side-effects. Fenfluramine is mainly useful for people who are especially tense and for obese maturity-onset diabetics who have been unable to lose weight with the biguanides. Mazindol and phentermine appear to be useful as alternative drugs.
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PMID:Anorectic drugs: use in general practice. 78 35

Emotional sympomatology data on 78 obese females treated for 3 weeks with fenfluramine, dextroamphetamine, or placebo were evaluated. These obese females were shown to be considerably less emotionally disturbed than neurotic females, and similar in emotional symptomatology to other females seeing physicians for nonpsychiatric complaints. Even within these marginally sympatomatic patients, fenfluramine and dextroamphetamine were significantly more effective than placebo in reducing anxious, depressive, and anxious-depressive symptomatology. Fenfluramine was particularly effective in alleviating anxiety in patients who were initially higher in anxiety. Most important, fenfluramine produced significantly greater weight loss than dextroamphetamine in patients with higher levels of anxiety and depression, while dextroamphetamine was an especially effective anorexic in low anxious patients. Differences in initial anxiety and depression, even within relatively normal patients, may well affect results obtained with fenfluramine and dextroamphetamine in the short-term treatment of obesity.
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PMID:Emotional symptomatology in obese patients treated with fenfluramine and dextroamphetamine. 79 95

(+)-Amphetamine and fenfluramine depressed both the food intake during the first 2 h of feeding of mice adapted to feed between 12:00 and 15:00 daily and the food intake of free feeding mice between 24:00 and 02:00 (lighting on, 09:00-21:00) in a dose-dependent manner. Higher doses of each drug were needed to produce a significant depression in the latter case. However, (+)-amphetamine (0.5-2 mg/kg) markedly increased the negligible food intake of free feeding mice between 12:00 and 14:00, an effect which rapidly disappeared at higher doses. Fenfluramine at doses up to 40 mg/kg had no effect on the feeding of these mice. Nevertheless, as caffeine (10-40 mg/kg) also increased feeding, behavioural arousal might be an important factor in this anomalous feeding response, although a specific action by (+)-amphetamine and caffeine on the feeding centres of the satiated mouse cannot be ruled out.
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PMID:The effects of (+)-amphetamine and fenfluramine on feeding in starved and satiated mice. 82 84

The success of serotonergic reuptake inhibitors in the treatment of obsessive-compulsive disorder (OCD) has suggested that serotonergic neurotransmission may play a role in the pathogenisis of this disorder. Prolactin responses to a 60-mg oral dose of fenfluramine in 26 medication-free patients with a DSM-III-R diagnosis of OCD were compared with those of 20 controls subjects. Fenfluramine produced a significant elevation of prolactin levels in both OCD patients and controls. Prolactin responses were significantly blunted in OCD patients compared with responses in control subjects. Female subjects in both groups showed greater prolactin responses to fenfluramine than did their male counterparts. There was a significant interaction between sex and the presence of OCD such that female patients had lower prolactin responses than their controls, while the difference between male patients and controls was not significant. Prolactin responses were not correlated with age, weight, drug level, depression, anxiety, or degree of OCD symptoms. The results are consistent with a relative reduction in serotonergic efficacy in the setting of OCD.
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PMID:Fenfluramine stimulation of prolactin in obsessive-compulsive disorder. 160 84

1. The authors investigated the role of serotonin in the hypothalamo pituitary adrenal escape from depression. 2. Maximal dose of fenfluramine was administered to normal individuals pretreated with dexamethasone. 3. Fenfluramine had only a minimal and inconsistent effect on the hypothalamo pituitary adrenal axis in the presence of dexamethasone.
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PMID:Role of serotonin in hypothalamo pituitary adrenal axis escape from dexamethasone suppression. 165 24

The chronic ingestion of fenfluramine results in a sustained depression in body weight despite the return of ad libitum food intake to normal levels. This chronic suppression of body weight is immediately reversed after discontinuation of the drug treatment. Such a phenomenon indicates that the drug must increase metabolic rate. However, studies in both humans and animals have failed to demonstrate an increase in metabolic rate after the administration of the drug. Instead, fenfluramine appears to potentiate the expenditure of energy whenever increases in energy expenditure occur. Fenfluramine potentiates the thermic effect of food (TEF) both in animals as well as in humans. Moreover, the energy cost of locomotor behavior also appears to be potentiated by this drug. Most importantly from a therapeutic perspective, unlike the anorectic effect of fenfluramine, tolerance does not appear to develop to its ability to potentiate energy expenditure.
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PMID:Metabolic consequences of fenfluramine for the control of body weight. 172 28

The clinical efficacy of lithium augmentation in refractory depression is hypothesized to depend on the ability of lithium to enhance presynaptic 5-hydroxytryptamine (5-HT) function. Since fenfluramine promotes release and inhibits reuptake of presynaptic 5-HT, we assessed its efficacy in augmenting ongoing tricyclic antidepressant treatment of refractory depression. Fifteen patients with DSM-III major depression failed to respond to treatment with desipramine 2.5 mg/kg/day or more (plasma levels of at least 125 ng/ml) given for at least 4 weeks. Fenfluramine 40-120 mg/day was then added to the ongoing desipramine in a placebo substitution design. There was no statistically significant evidence of either transient or sustained clinical improvement during the 2 weeks of fenfluramine augmentation. One patient appeared to respond to the treatment, but one appeared to worsen. Fenfluramine more than doubled steady-state plasma levels of desipramine. These findings suggest that lithium's efficacy as an augmenting agent depends on properties that are not shared by fenfluramine. Fenfluramine cannot be recommended in the routine management of refractory depression.
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PMID:Fenfluramine augmentation in tricyclic-refractory depression. 225 48

The ability of d-fenfluramine, a drug that releases brain serotonin and blocks its reuptake, to relieve premenstrual depression and excessive calorie and carbohydrate intakes was examined in 17 women with premenstrual syndrome. Subjects received d-fenfluramine (15 mg twice daily) or placebo, in random order, during the luteal phases of six menstrual cycles; ie, for three control and three treatment cycles each. Behavior was assessed with the Hamilton Rating Scale for Depression and its Addendum, and intakes of calories and nutrients were measured by allowing subjects unlimited access to isocaloric meal and snack foods rich in carbohydrates or protein. Pre-treatment follicular scores using the Hamilton Rating Scale for Depression and its Addendum were 2.0 +/- 0.5 and 0.5 +/- 0.5 (mean +/- SEM), respectively; corresponding luteal scores were 21.2 +/- 0.8 and 10.2 +/- 0.6 (P less than .0001). Luteal phase intakes of kilocalories, carbohydrates, and fats were also increased above follicular levels (P less than .01). d-Fenfluramine decreased premenstrual Hamilton Rating Scale for Depression and Addendum scores by 62% (P less than .001) and 60% (P less than .001), respectively; placebo reduced them by only 28% (P less than .02) and 30% (P less than .02). d-Fenfluramine also fully suppressed the premenstrual rise in kilocalorie, carbohydrate, and fat intakes (P less than .01).
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PMID:d-Fenfluramine suppresses the increased calorie and carbohydrate intakes and improves the mood of women with premenstrual depression. 237 Oct 34

The neurochemical mechanisms by which drugs acting on central serotoninergic system modify feeding were reviewed. Fenfluramine, a clinically effective appetite suppressant, releases serotonin from nerve terminals and inhibits its reuptake, and considerable evidence suggests that these effects mediate its anorectic activity. The D isomer of fenfluramine is particularly specific in affecting serotonin mechanisms and causing anorexia. Transmitters other than serotonin such as acetylcholine, catecholamines and GABA are also affected by systemic administration of fenfluramine, but some of these effects are secondary to fenfluramine's action on serotoninergic mechanisms. Moreover, there is no evidence that these brain substances are involved in fenfluramine's ability to cause anorexia. Several studies with drugs affecting different serotonin mechanisms such as release and uptake or mimicking the action of serotonin at post-synaptic receptors suggest that increase serotonin release and direct stimulation of postsynaptic receptors are the most effective mechanisms for causing depression of food intake, although inhibition of serotonin uptake may also contribute in appropriate conditions. Development of serotonin receptor hyposensitivity and, in some instances, decreased serotonin levels may lead to tolerance to the anorectic activity of drugs enhancing serotonin transmission, the degree of this depending critically on the type of effect on serotonin mechanisms and intensity and duration of serotonin receptor activation. Recent evidence suggests that a decrease in serotonin function causes stimulation of feeding. This may lead to development of new strategies for the treatment of clinical anorexias.
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PMID:Neurochemical mechanism of action of drugs which modify feeding via the serotoninergic system. 242 23


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