Synopsis: Fenfluramine2 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.

Fenfluramine: a review of its pharmacological properties and therapeutic efficacy in obesity.

Objectives. —Obesity is an important clinical problem, and the use of dexfenfluramine hydrochloride for weight reduction has been widely publicized since its approval by the Food and Drug Administration. However, animal and human studies have demonstrated toxic effects of fenfluramines that clinicians should be aware of when considering prescribing the drugs. Our purpose was to systematically review data on brain serotonin neurotoxicity in animals treated with fenfluramines and the evidence linking fenfluramines to primary pulmonary hypertension (PPH). Data Sources. —Archival articles and reviews identified through a computerized search of MEDLINE from 1966 to April 1997 using "fenfluramine(s)," "serotonin," "neurotoxicity," "behavior," "anorexigens," "weight loss," and "primary pulmonary hypertension" as index terms. Study Selection. —Reports dealing with long-term effects of fenfluramines on brain serotonin neurons, body weight, and pulmonary function in animals and humans. Data Extraction. —Reports were reviewed by individuals with expertise in serotonin neurobiology, neurotoxicity, neuropsychiatry, and pulmonary medicine and evaluated for appropriateness for inclusion in this review. Data Synthesis. —Fenfluramines cause dose-related, long-lasting reductions in serotonin axonal markers in all the animal species tested and with all the routes of drug administration used. Doses of fenfluramines that produce signs of brain serotonin neurotoxicity in animals are on the same order as those used to treat humans for weight loss when one takes into account known relations between body mass and drug clearance. However, no human studies have been conducted, and the pathological and clinical potential for neurotoxicity in humans is unknown. Appetite suppressants—most commonly fenfluramines—increase the risk of developing PPH (odds ratio, 6.3), particularly when used for more than 3 months (odds ratio, >20). Conclusions. —Fenfluramine and dexfenfluramine have been demonstrated to damage brain serotonin neurons in animal studies. It is not known if such damage occurs in humans or if there are clinical consequences. Use of fenfluramines is associated with an increased risk of PPH. Future studies should address the long-term consequences of prolonged use of fenfluramines.

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Brain Serotonin Neurotoxicity and Primary Pulmonary Hypertension From Fenfluramine and Dexfenfluramine: A Systematic Review of the Evidence

Moderate or severe depression is now one of the most common diseases of our time with a prevalence of nearly 3 %. It seems likely that this prevalence has increased as a result of the wider use of drugs which have an effect on the neurotransmitters. Changes in the levels of these neurotransmitters in the central nervous system are thought to he the biochemical basis for the development of at least some depressive illnesses. Drug-induced depressions are more likely to occur in those individuals who are genetically predisposed to depression or who have had a previous depressive illness. Other groups who are particularly susceptible to these effects are the elderly. Many groups of drugs have a primary or secondary action on the central nervous system neurotransmitter function. Some 200 drugs have been claimed to cause depression in certain patients, but only a relatively small number precipitate depressive symptoms with any frequency. Those most commonly implicated are the long-acting antipsychotics, barbiturates, ethanol, oral contraceptives and antihypertensive agents. It is important to remember that some drugs, such as reserpine, cause depression as a side-effect during their therapeutic use whereas others, such as fenfluramine, cause depression mainly when they are withdrawn too rapidly. In those patients presenting with depression, it is important to review the current drug therapy in order to assess the part played by these drugs in the development of the depression. Following this assessment, drug therapy should be adjusted appropriately. However, a distinction must be made between the symptoms of depression, those physiological changes which occur during treatment with a variety of drugs, and the patient’s reaction to the disease for which they are being treated.

Drugs and Depression

It has been only 20 years since Brodie and Shore first suggested that brain serotonin neurons might play an important role in mediating the behavioral states of sleeping and waking. In the relatively brief period of time that has since elapsed, many investigations, which utilized a variety of techniques, much too numerous to even list, have confirmed the importance of brain serotonergic neurons for many behavioral states other than sleep and arousal. The initial report concerning the possible selective neurotoxic action of 5,6-dihydroxytryptamine (5,6-DHT) on brain serotonergic nerves by Baumgarten et al.' appeared only six years ago; since that time, several other drugs [5,7-dihydroxytryptamine (5,7-DHT) ,3 p-chloroamphetamine (p-CA) ;I fenfluramine 5 ] with neurotoxic effects on these brain neurons have also been identified. It now seems evident that the mechanisms by which these various compounds produce lesions of brain serotonergic nerve tracts differ from one another (see, for example, the papers by Creveling and Rotman, Schlossberger, Klemm and Baumgarten, and Horn in this monograph); moreover, these drugs do not appear to exert the specific and selective neurotoxic effects on brain serotonin-containing neurons that they had been thought to possess previously. Despite these shortcomings, the use of serotonergic neurotoxic drugs has contributed substantially to our understanding of the behavioral importance of brain neurons that release serotonin as their neurotransmitter. This paper will briefly review the evidence regarding the nature of the various behavioral changes that result after administration of neurotoxic drugs and will compare the behavioral effects of these drugs to those seen in animals subjected to other surgical, pharmacologic, or dietary manipulations of brain serotonergic neurotransmission.

Behavioral effects of serotonin neurotoxins: an overview*

According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R), drug-induced depression may be classified as an Organic Mood Syndrome, Depressed Type. Unfortunately, the DSM-III-R diagnostic criteria are not sufficiently precise for application in research, and studies of drug-induced depression have rarely utilised these criteria. Research concerned with drug-induced depression is characterised by a number of methodological complications. These include differing definitions of depression, including depression defined as a symptom, a syndrome, or by diagnostic criteria for a specific mental disorder. In addition, patients undergoing pharmacological treatments for medical illnesses are typically exposed to considerable psychosocial stress due to the suffering and disability associated with illness. These psychosocial factors may in themselves precipitate episodes of depression. Due to these complicating factors, sophisticated study designs are required to confirm an aetiological role for medications as risk factors for depression. Unfortunately, adequate studies have rarely been conducted, and much of the literature consists of case reports and clinical observations. Consequently, clinicians are frequently required to make clinical judgements about the aetiology of patients' depressive symptoms in the absence of definitive scientific information about the role of drugs. Nevertheless, a knowledge of the relevant literature will assist clinicians in making reasoned judgements about the aetiology, prevention and management of these disorders.

Drug-induced depression. Incidence, avoidance and management.

PITTS' AND McCLURE'S LACTATE-ANXIETY STUDY REVISITED DEAR Sm, Grosz and Farmer (Journal, April 1972, 120, 4:5â€”8) have reported the results of an interesting study showing that anxiety symptoms can be preci pitated by the production of metabolic alkalosis. Unfortunately, they present their results as a refuta tion of the previous conclusions of Pitts and McClure (New Eng.3. Med. 1967, 27, :329â€”36,) that an anxiety state can be induced by elevating blood lactate concentration. It is true that the data of Grosz and Farmer, if confirmed, would lead to a new interpretation of the previous conclusions regarding blood lactate. However, these newer findings should be viewed simply as an extension and refinement of the hypothesis of Pius and McClure. The tendency in psychiatric research to view an incomplete or partially correct theory as an error discourages investi

T Harding

Papers

Depression following fenfluramine withdrawal.