Understanding and Managing Weight Gain and Obesity in Mental Health: Pharmacological Approaches

NEUROBIOLOGY OF OBESITY

To tackle obesity in our patients, we need to understand the underlying neurobiology. [2]

Gut-central nervous system (CNS) communication occurs via vagal nerve afferents as well as peripheral hormones. Learn more about the gut-brain axis.

CNS stimuli relating to hunger and satiety is mediated by some peptides that either stimulate or suppress hunger.

The 4 of the most important peptides are:

1.Leptin

• Leptin is produced by adipose tissues and acts via receptors in the ventral tegmental area (VTA) – implicating dopamine – to reduce food consumption.

2. Ghrelin

• Ghrelin, on the other hand, is produced from the stomach and pancreas and serves to stimulate appetite: ghrelin receptors are also found in the VTA and stimulate dopaminergic neurones in the nucleus accumbens (NAc).

The diagram below shows how the balance between ghrelin and leptin is linked to appetite control.

3. Orexin

• Orexin is released in response to low blood glucose levels and promotes appetite. Orexin also plays an important role in the sleep wake cycle which is covered here.

4. Cholecystokinin (CCK)

• Food causes CCK to be released from cells in the duodenum, and this (via vagal mechanisms) signals satiety.
• In rodent studies, blocking CCK-A receptors results in a blocking of the satiety signal, such that the animals don’t stop eating even when they have eaten as much as they usually would.

A recent Melbourne study showed that after weight loss occurs, reductions in levels of leptin and CCK, and increased levels of ghrelin and orexin, can persist for more than a year; this makes maintenance of weight loss extremely difficult. [3]

Other hormones produced in the GI tract that decrease the amount of food intake include pancreatic polypeptide (PP), peptide tyrosine-tyrosine (PYY), and oxyntomodulin (OXM).

Role of Hypothalamus:

• The hypothalamus plays a central role in orchestrating the bodily response to food and hunger, controlling the release of leptin, ghrelin and orexin.
• Two key areas of the hypothalamus involved in appetite regulation are the arcuate nucleus (ARC) which reduces appetite) and lateral hypothalamus which increases appetite.

• In obesity, there is a perturbation of the homeostatic mechanisms outlined above, including, for example, reduced hypothalamic responsivity to leptin, with high circulating blood levels.

Neurotransmitters in Obesity:

• Whilst it is clear from the foregoing that dopaminergic pathways have an important role to play in appetitive function, serotonergic mechanisms are also implicated, notably via the 5HT2c receptor.
• This knowledge has informed recent investigation of lorcaserin, a 5HT2c receptor agonist, for the treatment of obesity.
• Also of relevance to new treatments for obesity is that glucagon-like peptide-1 (GLP-1) is released from intestinal cells as well as the nucleus tractus solitarius after ingestion of food, and serves to stimulate insulin release, hence decreasing blood glucose levels.
• A class of GLP-1 receptor agonists have shown good efficacy for managing both diabetes and obesity and some studies (see below) attest to an emerging place for their use in people with schizophrenia.

Behavioural aspects of Obesity and Overeating

Obesity is also known to be associated with  blunted feelings of reward and pleasure. Thus, greater consumption of food may be required to experience the same levels of enjoyment. Learn more about the neurobiology of addiction which is also the basis behind food addiction.

Both orexin and ghrelin receptors are found in the VTA and dysregulation of these markers are postulated to play a part in obesity.

MANAGEMENT OF OBESITY

Treating obesity in mental health settings requires a multifaceted approach.

Motivating obese people to address their weight can be tricky and many ‘scare tactic’ health messaging approaches only serve to demoralise people and make them feel stigmatised.

Lifestyle interventions

• Psychoeducation and advice about diet and exercise
• Monitoring of weight, waist circumference and serum glucose and lipids.
• Involving people in this process can help them take more ownership of the problem and hopefully empower them.
• Involvement of expert dieticians and exercise physiologists can be very helpful, as can peer workers who can, for example, accompany people to the gym and model better-eating behaviours.
• However, due to the complex neurobiology processes mentioned above, lifestyle intervention may not be enough to effect substantial weight loss and prevent weight regain.

Thus, treating obesity in the mental health population must involve addressing psychotropic hunger.

Managing expectations of patients on psychotropics is also important. It has been shown that weight loss of 5-10%  can reduce and reverse complications related to obesity and improve quality of life and these non-weight goals should be emphasised. [4]

A number of medication options for the treatment of obesity are either well established or are in development, but a number of these are not very suitable for people with schizophrenia either because of the requirement for strict adherence to diet (e.g. lipase inhibitors such as orlistat), or because they carry the risk of perturbation of mood or worsening of psychotic symptoms (e.g. stimulant-type anorectics).

Moreover, Orlistat is not centrally acting and does not address psychotropic hunger.

In this context, any pharmacological approach to management of obesity in schizophrenia needs to consider, firstly, whether prescribed mental health medications are adding to the obesity burden.

Antipsychotic medication choice

In particular, antipsychotics such as olanzapine and clozapine carry a strong signal for weight gain; risperidone and paliperidone less so.

Aripiprazole, brexpiprazole, lurasidone, asenapine and ziprasidone are generally not associated with large weight gain signals, albeit some individuals do gain weight on any of these agents and all patients prescribed antipsychotics should receive dietary/exercise advice and metabolic monitoring.

A general mantra should be to try to avoid medications that are likely to cause or exacerbate weight gain, as once the person has gained weight it is difficult to lose.

In particular, olanzapine should generally not be instituted first line, and this advice is reflected in the RANZCP Clinical Practice Guideline (CPG) for psychotic disorders. [5]

If the person has gained weight on a particular antipsychotic, consideration should be given to a switch to a drug less likely to exacerbate the problem: of course, due consideration needs to be given to the risk of relapse of psychosis, and any switch needs to be performed carefully and with the full engagement of the patient (and carers, where appropriate).

Learn more about management of metabolic syndrome with antipsychotics through talks from Prof Correll and Dr Stahl.

For example, an instructive recent study showed that patients who had gained weight on olanzapine could be switched to lurasidone with beneficial effects for weight and no worsening of psychotic symptom control. [6]

If the individual either cannot be switched to another antipsychotic or does not lose weight after switching, a number of strategies might be considered.

Metformin

Perhaps the easiest and best validated is the addition of metformin (500mg twice a day is a usual target dose, but higher doses have been used in some clinical trials).

There are few side effects, and a number of studies (mostly using it as an adjunct to olanzapine) attest to modest weight loss (2-3kg) in addition to beneficial effects in terms of improving insulin resistance. [7]

Augmentation with dopamine partial agonists

Adding the partial dopamine agonist aripiprazole to clozapine has also found support in the literature and favour amongst clinicians: an added benefit is the ability, often, to reduce overall clozapine dose. [8]

Whether the newer dopamine partial agonist, brexpiprazole, will be another option in this scenario, awaits study.

Topiramate

Topiramate has also been used as an adjunct to antipsychotics, but many patients find that it impacts cognition and there is also a risk of increased suicidality in some patients.

When tolerated, doses of up to 100mg can be very effective in producing a complete disinterest in food resulting in a substantial reduction in calorie intake.

Other strategies

• Antidepressant/smoking cessation agent bupropion
• The sympathomimetic amine phentermine
• Lorcaserin (5HT2C agonist)
• Opioid antagonist naltrexone
• However, safety and efficacy of these medications (or combinations thereof) in schizophrenia have not been established.

Glucagon-like peptide-1 (GLP-1) receptor analogues

There is, however, emerging evidence and current excitement – as outlined above – about the potential of the glucagon-like peptide-1 receptor analogues such as liraglutide to reduce weight and reverse glucose intolerance in people who have gained weight on antipsychotics: weight loss is more dramatic than that seen in trials of metformin because of its ability to reduce psychotropic hunger and increase satiety. Glucose tolerance can also be reversed. [9]

The dose of 3.0mg has been approved in Australia for weight loss and 1.8mg for diabetes.

A study evaluating 3731 non-mental health patients published in the NEJM using a dose of 3.0mg for 52 weeks, produced an average weight loss of 8.4 kg with 33.1% of participants losing more than 10% of their weight. [10]

Further studies using the 3.0 mg dose need to be evaluated in the mental health population.

Bariatric Surgery

Finally, in extreme cases, bariatric surgical procedures might be explored.

Diabetes Australia has recently come out with a new position statement stating that those with a BMI over 35 and have type 2 diabetes should be considered for bariatric surgery. Many mental health patients would fit these criteria. Read more about the role of the psychiatrist in obesity and bariatric surgery.

Having a severe mental health issue such as schizophrenia is not an exclusion for such interventions, but extra care needs to be taken in the work-up, consent process and peri-surgical support and aftercare.

Some people find the dietary restrictions required very difficult to adhere to, and can become frustrated and demoralised.

Very few studies have examined bariatric procedures in people with schizophrenia, but the small number of reported cases do point to utility and tolerability. [11]

However, a study by Bhatti et al. (2016) reported that self-harm emergencies increased by 50% after surgery: the highest risk was in the 2^nd and 3^rd postoperative years. [12]

These patients were almost exclusively patients who had a history of mental illness. It is therefore imperative that patients are carefully screened and supported over extended periods. Larger studies with longer follow-up are required.

CONCLUSION

Obesity is a world-wide problem and carries numerous medical risks. People with psychotic disorders such as schizophrenia are at even greater risk than the general population of obesity.

Psychiatrists need to ensure that they do not unnecessarily increase this risk in their patients, by using medications known to be associated with substantial weight gain, unless there are no clinically sustainable alternatives.

If patients do gain excessive weight on a particular medication, consideration should be given to switching to another agent with less predilection to weight gain.

If that proves impossible or fails to reduce weight, various other options can be considered, including the addition of metformin and a range of other agents.

All patients going on to antipsychotics should be warned about potential weight gain, provided with advice about diet and exercise, and have their metabolic profile regularly monitored.