The Neurobiology of Appetite

Metabolic set point 

People alter the quantity and frequency of food consumption daily and yet the brain seems to have a regulatory process that allows people to maintain a relatively stable body weight. 

Isn’t that crazy? 

Anyone who has ever tried to diet knows all too well about this metabolic set point. There are staggeringly low rates of success with diet programs. A systematic review of studies published between 1931 and 1999 found that only 15% of patients achieved dietary success after 5 years. Most people who diet will slowly return to their preexisting weight within 1 year.

This metabolic set point appears to be controlled by our genetics. There is a strong correlation between the body mass of biological parents and adoptees in adoption-based studies. In the case of weight, genetics has far more influence than environmental factors. 

Despite all this obesity rates in the United States as well as other developed countries continues to rise, so what gives? 

Our genes have difficulty responding to the modern environment. 3000 years ago, when food sources were scarce, it was advantageous to consume and store as many calories as possible. However, in the modern world where there is no shortage of opportunity to consume calorie dense foods, our genetics are working against us. The weight issue is genetic but also influenced by availability of high-calorie delicious food. 

When it comes to weight, energy in (food) must equal energy out (heat and work). The energy out is made up of the resting metabolic rate (calories burned when the body is stationary) and physical activity. The brain has a unique mechanism for managing the RMR. When more calories are consumed the RMR increases and when we diet the RMR is turned down. 

To solidify the point, we can look no further than The Biggest Loser competition. Investigators assessed 14 of the 16 contestants before the competition, after completion of the 30-week program, and 6 years after the show. 13 of the 14 study participants regained weight and 4 were heavier than when they started the competition 6 years ago. The real downer was they all burned less calories at rest 6 years after the show ended. Despite exercising more and theoretically being much healthier their RMR decreased. 

What are the important signals used by the body that indicate when to eat and when to stop eating?

Short-Term signels include: 

Glucose: This is the primary nutrient that mediates satiety. Hypoglycemia will stimulate hunger and increase eating, while glucose infusions will decrease food intake. 

Mechanoreceptors in the gut: The physical presence of food in the stomach activates these receptors due to stretching, the vagus nerve transmits signals of gastric stretch to the hindbrain to decrease eating. 

Gut Hormones: The most well understood is cholecystokinin (CCK) which is released by endocrine cells in the small intestine. This will inhibit further food intake by stimulating the vagus nerve and decreasing gastric emptying. People have tried using CCK as a weight loss measure but all it does is decrease the size of meals but increases the frequency of eating thus producing a net zero effect on weight loss.

Ghrelin is the only gut hormone that stimulates hunger. Some suggest that decreased ghrelin produced by the stomach is the reason gastric bypass surgery is effective for weight loss. 

It’s now known that adipose tissue releases a hormone that conveys information about energy stores. Leptin is produced by fat cells and increases or decreases based on the total amount of fat. Leptin is a hormone that tells the body to stop eating. In the case of obesity leptin levels are high and energy expenditure increases while food intake decreases. When someone goes on a diet and fat stores decrease leptin decreases resulting in decreased energy expenditure and increased food intake. 

Two groups of neurons in the arcuate nucleus of the hypothalamus mediate the leptin signal, proopiomelanocortin (POMC) and neuropeptide Y (NPY). POMC stops eating and NPY increases food intake and decreases energy expenditure. In obesity there is increased leptin which inhibits NPY and activates POMC resulting in increased energy expenditure and decreased food intake. The opposite is true for the lean individual. 

Eating and Pleasure

It’s well established that eating can result in pleasure, we have all had this experience after a stressful week a good meal can instantly change our mindset. The pleasure from food is likely an adaptation that enhanced survival when food sources were scarce. Increased dopamine in the nucleus accumbens and release of endogenous opioids appears to be more active when we are eating a meal we enjoy. 

Olanzapine (Zyprexa) Without the Weight Gain

While Olanzapine is an effective medication, it’s side effect profile can be nasty. Things like weight gain, changes in blood lipids, and changes in blood glucose are common. ALKS 3831 attempts to fix this problem by adding Samidorphan to olanzapine to reduce weight gain.

Medication Side Effects: Doctor I’m Gaining Weight!

One of the biggest challenges we face in the field of psychiatry is medication adherence. A large portion of the people fail to get better either because they do not start the medication, or do not take it as prescribed. One of the most common reason cited by patients for stopping medication is weight gain. In this article I will detail the approach I take to weight management for patients on psychiatric medications. 

Initial Visit: 

Weight management is a discussion that should happen between the patient and clinician at the first meeting. It’s important to use primary prevention (preventing the onset of weight gain) if possible. We always obtain some objective measures such as height, weight, and calculate the BMI on the initial visit and subsequent visits. Additional tests that may be ordered include HBA1C, fasting blood glucose, and lipid profile. This is where I will take the opportunity to discuss the importance of diet and exercise. For people with little diet or exercise experience I will keep the information very basic. The discussion will center around eliminating processed foods, calorie containing beverages, increasing fruit and vegetable intake, and making good choices when shopping at the food store. I have several handouts with food choices on them that help guide the patient when making food choices at the grocery store. I also recommend patient’s keep a food diary or track their food intake on a mobile app such as my fitness pal. This will help us to understand more about the patient’s eating habits and identify potential areas for improvement. I will build on diet interventions and monitor progress with the food diary or app at each visit. I do not recommend a specific diet, as it’s far more important for the patient to pick something they can be consistent with, and there are multiple ways to achieve weight management goals. At this time the closest diet we have that I’m comfortable recommending is the Mediterranean diet. There is some good evidence that the Mediterranean diet can have an antidepressant effect which is an added bonus.

Exercise

Exercise is the next area to address. I like to ask some screening questions about what type of physical activity the patient engages in, and how much experience they have with fitness/athletics. I will then ask them to track their exercise over the subsequent weeks prior to returning for follow up visit. On the initial visit I will recommend they begin a basic walking program of at least 30 minutes per day preferably seven days per week. This is a simple thing to incorporate on a daily basis, and does not require any special equipment or gym membership. We can improve on this routine and incorporate resistance training on a case by case basis. 

Medication Choice

The next step in the process is to make a medication choice that limits the potential for weight gain. Most psychiatric medications cause weight gain. This is an unavoidable fact. Avoiding the use of medications with the highest propensity of weight gain including Clozapine, Olanzapine, and Mirtazapine is good planning on the physician’s part. It’s important to note that it’s not always possible to avoid these medications. Medications such as Aripiprazole which are considered to be weight neutral, from clinical experience are not weight neutral at all. It’s important for the clinician to make good choices if weight gain is a potential issue that will interfere with treatment.

Medication For Weight Management

My last line of defense against weight gain which often comes too late is medication management. I like to start with Metformin extended release 500 mg daily after the largest meal. This is to test the patient’s tolerance for the medication. The goal is to titrate to 2000 mg/day in divided doses. A B12 level should be checked once per year as Metformin has been known to reduce levels. There is evidence in the literature from a Meta-analysis of all RCTs supporting the use of Metformin for antipsychotic induced weight gain. The important thing to remember is to start the medication at the earliest signs of weight gain, or even before the onset of weight gain in high risk patients. The patients most likely to benefit are those who are younger, more recently started on antipsychotics, overweight but nor obese, and those that had rapid weight gain. 

The second medication I will talk about is Topiramate There is evidence from RCTs to support the use of Topiramate for antipsychotic induced weight gain. There is greater weight loss with Topiramate over placebo, with a mean decrease of 2.8 kg. The effective dose for the medication is 100 to 200 mg/day depending on the patient’s tolerance. Getting to an effective dose can often take some time with this medication.

Final Points

Weight management discussions begin day one when medications are going to be used. Prevention is the first line option with lifestyle modification including diet and exercise. Medication choice also plays a big role. When initiating medication being mindful of the propensity for weight gain, and using medications that are weight neutral if possible, can help. If these measures fail, there are a few options backed by research evidence which can be used but I believe lifestyle modification is the best option. 

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