Table of Contents

Psychotropics and Obesity

BODY WEIGHT CHANGES DURING TREATMENT WITH PSYCHOTROPIC DRUGS (reference : ((TREVOR SILVERSTONE, JANE ELMSLIE : UNIVERSITY OF OTAGO DUNEDIN, NEW ZEALAND))

Serotonin Reuptake Inhibitors

Serotonin reuptake inhibitors do not cause weight gain, but instead seem to cause weight loss.

Several studies have demonstrated weight loss with fluoxetine in both depressed and non-depressed individuals. This drug reduces appetite.

Another selective serotonin reuptake inhibitor, fluvoxamine, has been shown in one patient to increase metabolic rate and thus promote weight loss.

LITHIUM

Weight gain is a commonly reported side-effect among patients receiving long-term lithium prophylaxis for manic-depressive illness. Weight gain is likely to adversely influence compliance with a consequent increase in the likelihood of relapse.

The mean weight gain of 10.6kg/23.31b in those with an increased appetite did not differ significantly from that observed in the patients who did not experience greater hunger. Increased thirst was noted by 62 (89%) of the patients and there appeared to be a positive correlation between increased thirst and weight gain.

The prevalence of obesity among patients regularly receiving lithium was more than twice that in the general population. The mechanism by which lithium induces weight gain is poorly understood. At least a proportion of the weight gain in patients receiving lithium occurs secondary to an increased consumption of high-calorie drinks. A simple measure to prevent this would be to advise patients on lithium to assuage their thirst with plain water or low-calorie beverages, rather than with drinks containing a large number of calories.

Low-calorie diets were therefore recommended as the treatment of choice for lithium-induced obesity, but it is important that a normal sodium intake is maintained.

Twenty-one percent of patients gained more than 10kg, with 2% of patients gaining over 20kg. The mean weight gain was 4kg and was positively correlated with pre-treatment weight and concurrent administration of antidepressant medication.

PSYCHOPHARMACOLOGY OF APPETITE

The weight promoting properties of antipsychotic drugs such as chlorpromazine and antidepressants such as amitriptyline might be related to a direct blocking action at noradrenergic receptors and/or serotonergic receptors.

The central neurochemical mechanisms through which appetite suppressant drugs act may reveal neurotransmitters which are potentially implicated in producing psychotropic drug-induced obesity.

Amphetamine causes the release of two neurotransmitters, dopamine and noradrenaline, from presynaptic neurones. The stimulant activity of low doses of amphetamine is dependent on dopamine pathways, whereas the anorectic action is not. In human subjects, the dose-response curve for dextroamphetamine-induced anorexia differs from those for the drug's stimulant and euphoriant effects. Dextroamphetamine-induced arousal in humans is mediated through central dopaminergic pathways, whereas dextroamphetamine-induced anorexia may be mediated through noradrenergic pathways.

The anorectic effect of fenfluramine is mediated via serotonergic pathways because this action is attenuated by the serotonin (5-HT) receptor blocking compound metergoline. The 5-HT receptor which is most closely involved in the anorectic response. The 5-HT receptor blocking drug ritanserin significantly reduced the anorectic response. Clinically, treatment with d-fenfluramine appears to help patients with neuroleptic-induced obesity without causing an exacerbation of their underlying psychopathology.

The regulation of appetite and food intake involves a reciprocal interaction between catecholamine and serotonergic pathways in the brain.

Severe loss of weight may reflect serious somatic pathology, or a profound depressive illness. Anorexia nervosa is potentially is a life-threatening syndrome which actually presents with loss of weight.

Although loss of weight is important, we will look at the association between weight gain and treatment with psychotropic drugs, especially antipsychotic drugs, certain antidepressants and lithium. Drug-related weight increases are due to an increase in food intake itself, secondary to drug-induced stimulation of appetite. Any significant increases in body weight should be taken seriously. It presents a potential threat to the patient's health, and it is frequently socially embarrassing, especially in women.

Being significantly overweight can lead to an increase in blood pressure with a risk of cerebrovascular damage, myocardial ischaemia and renal pathology. It also causes insulin resistance which predisposes to maturity onset diabetes. It is accompanied by osteoarthritis, an increased risk of gall stones and varicose veins, and a definite increase in morbidity during surgical operations.

Patients will take matters into their own hands and simply stop taking the prescribed medication. Such a step will lead to a relapse of schizophrenic illness or to a reoccurrence of disruptive manic symptoms.

Weight gain in 123 patients admitted for acute schizophrenia

^Drug ^gaining weight (%) ^Mean weight gain (kg)^ |Chlorpromazine |(85%) |2.3| |Thiothixine |(82%) |2.0| |Haloperidol |(60%) |1.0| |Trifluoperazine|(50%) |0.5| |Fluphenazine |(39%) || |Thioridazine |(100%) | 4.4|

There is a clear-cut dose relationship between chlorpromazine and appetite; those patients who were receiving a higher dose of chlorpromazine had higher hunger ratings and showed a greater weight gain than those receiving a lower dose.

The effect of phenothiazines on body weight may be mediated via an alteration in metabolic rate. Clozapine, despite having few extrapyramidal side-effects, has been shown to exert a pronounced effect on body weight. The average weight gain during six months of clozapine therapy was 7.6kg/16.91b. Weight gains of at least 4.5kg/101b were experienced by 75% of patients. Gains of as much as 20.4kg/451b were documented over 16 weeks. There is a significant correlation between improvement in symptoms and weight gain. The rate of weight gain decreased over time.

Although risperidone does cause an increase in weight, the increase is only clinically relevant in about one-third of patients. After a gradual increase in weight in the first six months of treatment, body weight gain appeared to reach a plateau, with a mean increase at end-point of 2.3kg (5.11b).

Depot Neuroleptics

In patients receiving either fluphenazine decanoate or flupenthixol decanoate over a six-month period, twenty-eight percent of the patients gained more than 3kg/6.61b during this time. There was no difference between fluphenazine and flupenthixol with regard to weight gain. There was no statistically significant correlation between dose and weight change, those on the highest doses of the two drugs did gain more weight than those on the lowest doses. The maximum weight gain occurred during the first 18 months of treatment, although some further increase in weight was frequently observed after this period.

Antiparkinsonian drugs appeared to make no difference to weight change. The maximum weight gain occurs during the initial months of treatment with depot antipsychotic drugs. Long-term maintenance treatment with depot injections of fluphenazine and flupenthixol is associated with at least a four-fold increase in the prevalence of clinically relevant obesity. Whereas this was not observed in patients taking pipothiazine palmitate.

A double-blind comparative trial of haloperidol decanoate and fluphenazine decanoate revealed that there was significantly less likelihood of weight gain occurring with haloperidol than with fluphenazine. Dopaminergic blockade has no influence on subjective hunger. Chlorpromazine, fluphenazine and flupenthixol all have other neuropharmacological actions apart from dopamine receptor blockade; these include a serotonergic and noradrenergic receptor blocking activity which could well underlie their appetite and weight increasing potential. Management of Antipsychotic-induced Obesity

All patient should be weighed before starting treatment and at regular intervals thereafter. At the first sign of a persistent gain in weight the patient should be advised to reduce calorie intake to a point where body weight is no longer increasing, preferably by a trained dietitian. The dose of the drug should be reviewed to see whether it might be reduced without compromising the patient's mental state. Consideration to using an alternative preparation, such as haloperidol decanoate, which has less appetite stimulating effect.

Consideration must be given to administering an appetite suppressant. All of the stimulant appetite suppressant drugs (diethylpropion, phentermine and mazindol) can exacerbate psychotic symptoms. Clinical trials with this group of drugs did not demonstrate any value.

A non-stimulant appetite suppressant compound, fenfluramine, has shown some benefit. Fenfluramine did not appear to exacerbate psychotic symptoms. The dextrorotatory isomer of fenfluramine (dexfenfluramine) was effective in helping obese patients on depot medication to lose weight. There were no adverse effects with regard to the patients' mental state.Tryptophan, a precursor of serotonin which is sometimes used as a treatment for depression, has also been found to reduce food intake in normal human subjects.

Imipramine has been associated with weight gain. This effect is mediated by a reduction in metabolic rate. The resting metabolic rate (RMR) was reduced by as much as 17-24%.

The "significant increase in the desire for 'sweets'(carbohydrate/fat rich foods) during a depressive episode compared to periods when the patients reported feeling well.