Obesity is a growing health problem leading to high rates of mortality and morbidity in patients with severe mental illness (SMI) [1–4]. Studies demonstrate the prevalence of obesity and related diseases are much higher in patients with SMI than in general population [2, 5–7]. It was found that 42% of individuals with schizophrenia had a Body Mass Index (BMI) of 27 or greater, compared to 27% of the general population . In the Northern Finland 1966 birth cohort study, rates of obesity in patients with schizophrenia were 42% compared to 13% for rest of the cohort . A review of 45 studies including patients with bipolar disorder shows the overall prevalence of overweight and obesity is higher in bipolar patients than in control populations . The increased rates of obesity can be mostly attributed to antipsychotic (AP) medication use. In a landmark study, Allison et al. reviewed available research data and found that, on average, patients gain weight after 10 weeks of treatment with any antipsychotic medication, but that there were differences across medications: patients taking clozapine had a mean weight gain of 3.99 kg, followed by a mean weight gain of 3.51 kg for olanzapine treated patients, 2.10 kg for chlorpromazine, 2.00 kg for risperidone, 0.48 kg for haloperidol, 0.43 kg for fluphenazine, and 0.04 kg for ziprasidone . In the CATIE trial, >7% of baseline weight gain occurred in 30% of patients taking olanzapine over 18 months, but only 7% to 16% of patients taking other antipsychotics had this clinically significant weight gain . Even aripiprazole and ziprasidone, with their more favorable weight gain profiles, produce over 7% total body weight gain in approximately 10% of clinical trial subjects. In a large study of first episode psychosis patients, participants gained an average of 16 kg on olanzapine and 7.5 kg on haloperidol . The mechanism of weight gain associated with the novel antipsychotics has not been fully elucidated, but may be related to blockade of histamine (H1), serotonin 2C (5HT2c) and alpha 1- adrenergic receptors on hypothalamic neurons, resulting in distortion of signals from the gastrointestinal (GI) tract to the brain. [13–16]. While these two receptors may explain the excess weight gain that is observed with newer agents, they fail to explain the weight gain produced by agents like haloperidol, which have no affinity to these receptors. In fact, the sole effect of haloperidol is to block Dopamine 2 (D2) receptors, an action that is shared to a varying degree by all approved antipsychotic agents. Thus, D2 receptor blockade appears to play an additional role in weight gain. D2 receptors are not directly involved with energy regulation; however, they do play an important role in the brain's food reward system. Food is one of the primary substrates of the reward system in higher living organisms. Highly storable energy sources, such as fats and sugars, are extremely enjoyable through the actions of opiate receptors, which are partly mediated by D2 receptors . D2 receptor blockade in animals is shown to produce an effect similar to dilution of the reward itself . Blockade of D2 receptors may make the whole system less sensitive to stimuli, and thereby push the organism to eat more in order to achieve similar levels of enjoyment.
Reward system, opioid receptors and appetite
Like any non-automatic function that is essential for survival, mammalian feeding behavior is closely modulated by the reward circuits in the brain. Endogenous opioids play an important role in these reward circuits . Following the discovery of endogenous opioids, it was found that opioid receptor antagonists (ORA) decrease self-feeding in food deprived rats . Since then, the animal literature has expanded significantly, and this finding has been replicated in non-food deprived rats and many other mammalian species . It is now fairly clear that ORAs have little effect on initiation of feeding, but rather attenuates preference for “palatable diets” and eating behavior . Injecting animals with opioids increases the preference for high carbohydrate, and even more so, high fat diets, an effect readily blocked by ORAs. There is no evidence that ORAs actually block the taste sensation in animals or humans . Human studies revealed intact taste, but a decrease in the pleasantness of sweets, after administering the ORA naltrexone . Since ORAs block the preference for saccharin solutions in rats, it appears that the macronutrient or caloric content of food does not activate opioid pathways . Other findings show that palatable foods result in endogenous opiate release, related mRNA expression, and opioid receptor occupation in sites of the brain that are critical for both feeding and overall reward circuits, most strikingly in the nucleus accumbens and hypothalamus . The rewarding effects of opioids are exerted mainly through dopamine . Obese human subjects are shown to have significant increases in their circulating β-endorphin levels compared to non-obese controls . Also, more palatable foods are shown to induce higher circulating β-endorphin levels in normal weight human subjects . Increased extracellular dopamine levels occur in the nucleus accumbens and striatum in response to rewarding food stimuli. Notably, obese subjects have been shown to have lower striatal D2 receptor availability at a rate that is inversely proportional to the level of obesity [25–27]. A mechanism for obesity in this population has been proposed here, in which overeating occurs as an attempt to stimulate the dopamine system.
A working hypothesis of antipsychotic induced weight gain
Patients with schizophrenia treated using antipsychotic medications have been shown to have a preference for diets high in fat and sugar . Patients with schizophrenia also typically seek behaviors that increase dopamine mediated reward in the brain such as smoking and substance use, both of which occur more frequently in this group than in the general population . We propose a model where patients with schizophrenia increase their intake of foods high in sugar and fat in order to increase their low dopaminergic tone, which results from dopamine receptor blockade, via endogenous opioid release. The finding that medicated obese women with schizophrenia have been shown to possess higher circulating β-endorphin levels than matched controls provides partial support for this hypothesis . Medications with additional H1 receptor blockage impair satiety signaling from GI tract to the hypothalamus; thus, there is no “stop” signal for reward eating, which in turn causes further weight gain.
Clinical trials with the opioid receptor antagonist naltrexone for obesity
Naltrexone is an oral agent that competitively antagonizes all known opioid receptors in the brain. Human studies were completed in individuals with a range of illnesses, including schizophrenia, and naltrexone has been shown to be a safe and easy agent to use. It is shown to decrease craving in alcoholics and is approved by the The Food and Drug Administration (FDA) for the treatment of alcohol dependence . Naltrexone is reported to decrease craving for other substances of abuse, like nicotine. Furthermore, it has been shown to prevent secondary weight gain due to cessation of cigarette smoking at low (25 mg and 50 mg), but not higher doses . Naltrexone has been tested in human feeding studies, and has been shown to reduce both the quantity of food eaten and the choice of palatable foods . A study that was conducted for antidepressant- and lithium-induced weight gain in bipolar women reported weight loss during naltrexone treatment; however, weight on average returned to baseline after cessation of active treatment. Patients reported decrease in food cravings while they received naltrexone, but not while taking placebo in this study . There is also a well-studied bupropion/naltrexone combination for obesity treatment [34, 35]. Among several bupropion studies for smoking cessation in schizophrenia concomitant to antipsychotic use, only one –from our center- reported weight effects. In this study, both bupropion and placebo groups gained similar levels of weight regardless of their quit status .
Rationale and significance
In summary, obesity interventions in populations with SMI are urgently needed. Current available medications for this purpose are limited and have not been effective in this population. Antipsychotic medication actions on H1 and 5HT2 receptors only partly explain why they cause weight gain. We developed a working hypothesis that D2 receptor blockade might be partly responsible for weight gain by interacting with the dopamine-opioid system. Thus, we propose a randomized, double blind, placebo controlled study of two different doses of naltrexone (25 mg & 50 mg) for adequate duration to counteract antipsychotic induced weight gain.
To determine the efficacy of naltrexone versus placebo for weight and health risk reduction in 144 obese individuals with SMI treated with an antipsychotic medication.
Subjects receiving naltrexone 25 mg and 50 mg for 52 weeks will lose weight, and improve BMI and waist circumference, at a greater level than the subjects who receive placebo.
Both naltrexone arms will improve health risk markers such as serum lipid profile, fasting glucose, and glycosylated hemoglobin (HbA1c), better than placebo.
To determine the optimum effective dose of naltrexone to counteract antipsychotic induced weight gain.