1. Antipsychotic-induced weight gain
Presentation to first episode schizophrenia treatment group
March 23, 2017
Erik Messamore, MD, PhD
Sara Dugan, PharmD
Option 1

2. Best Practices in Schizophrenia Treatment (BeST) Center at NEOMED
The BeST Center’s mission:
Promote recovery and improve the lives of as many individuals with schizophrenia as quickly as possible
Accelerate the use and dissemination of effective treatments and best practices
Build capacity of local systems to deliver state-of-the-art care to people affected by schizophrenia and their families
The BeST Center offers:
Training
Consultation
Education and outreach activities
Services research and evaluation
The BeST Center was established:
Department of Psychiatry, Northeast Ohio Medical University in 2009
Supported by The Margaret Clark Morgan Foundation and other private foundations and governmental agencies

3. Weight Gain and Metabolic Syndrome
Schizophrenia is an independent risk factor for obesity and metabolic syndrome.
Individuals with schizophrenia are more likely to gain weight, experience insulin resistance and metabolic syndrome – even without exposure to medication

4. Disordered glucose regulation in schizophrenia was known in the pre-neuroleptic era
Lorenz WF: Sugar tolerance in dementia praecox and other mental disorders. Arch Neurol Psychiatry 1922; 8:184–196
Braceland FJ, Meduna LJ, Vaichulis JA: Delayed action of insulin in schizophrenia. Am J Psychiatry 1945; 102:108–110
Freeman H: Resistance to insulin in mentally disturbed soldiers. Arch Neurol Psychiatry 1946; 56:74–78
Langfeldt G: The insulin tolerance test in mental disorders. Acta Psychiatr Scand 1952; 80(suppl):189–200

5. Glucose intolerance in schizophrenia, in the pre-neuroleptic era
Braceland et al. Am J Psych 102: , 1945

6. Anti-insulin factor in schizophrenia blood?
Pretreatment
Insulin injection
Glucose level
None
Rabbit + Insulin 
Human blood, intraperitoneal injection
Schizophrenia blood, intraperitoneal injection
Goldner & Ricketts. Arch Neurol Psychiatry 48: , 1942

7. Metabolic risks as a feature of the illness
Rates of Type 2 Diabetes
First-degree relatives of people with schizophrenia
19% - 30%
Population at large
1.2% - 6.3%
Family studies suggest genetic predisposition to insulin resistance in schizophrenia
Mukherjee, S., Schnur, D. B. & Reddy, R. (1989) Family history of type 2 diabetes in schizophrenic patients (letter). Lancet, i, 495

8. Metabolic Syndrome Obesity High triglycerides Low HDL Hypertension
Insulin resistance
Associated with pro-inflammatory state
Associated with pro-thrombotic state
Pro-inflammatory cytokines may exacerbate psychiatric symptoms
Rats made obese from daily olanzapine injections showed increased immobility in the forced swim test, a rodent model of depression
Antidepressant efficacy correlates inversely with BMI
Atherogenic dyslipidemia

9. Weight Gain and Metabolic Syndrome
Weight gain from antipsychotic drugs can be rapid
Higher risk of occurrence in children & adolescents
Higher risk of occurrence in first episode schizophrenia
Is a leading cause of non-adherence to treatment

10. Worrisome meta-analysis conclusions
Given prolonged exposure, virtually all AP are associated with weight gain.
The rational of switching AP to achieve weight reduction may be overrated.
In AP-naive patients, weight gain is more pronounced.
Bak, M., Fransen, A., Janssen, J., van Os, J. & Drukker, M. Almost all antipsychotics result in weight gain: a meta-analysis. PLoS ONE 9, e94112 (2014).
(Open access article)

11. General strategy to mitigate weight gain risk
Preferentially utilize lower-risk medications
But even with lower-risk meds, there is a vulnerable subset of patients
Behavioral treatments
Pharmacological adjuncts
Regular monitoring

12. Weight Gain Clozapine +++ Olanzapine Quetiapine ++ Asenapine
Risperidone
Paliperidone
Iloperidone
Aripiprazole
Brexpiprazole
Ziprasidone
Cariprazine +
Lurasidone
Haloperidol
Reported Weight Gain:
+++: >30%
++: – 30%
+: – 10%
Data compiled from systemic reviews, meta-analyses, clinical trials and package inserts

13. Efficacy of Behavioral Interventions for treatment or prevention
Caemmerer, J. et al., Schizophr. Res. 140, 159–168 (2012).

14. Behavioral Interventions
Appear highly successful, based on published research
However, this research is subject to self-selection bias
Up to a third will decline entry into such programs, thus self-selecting more motivated participants
Combinations of nutritional education, individual and group support, and exercise are optimal.
Group-based interventions, or group components of comprehensive plans will likely have added benefits, for example in opportunities for socialization and psychological support.

15. Pharmacological interventions
Best clinical studies evidence for:
Metformin
Topiramate
Reboxetine
Fenfluramine
Sibutramine
Interesting studies on:
Melatonin
Betahistine
Liraglutide

16. Metformin
Most extensively researched for antipsychotic-induced weight gain
Improves insulin sensitivity
Decreases intestinal absorption of glucose
Decreases hepatic glucose production
Suppresses appetite
Has been used in treatment of obesity in non-diabetic patients

17. Metformin Studies
de Silva, V. A. et al. Metformin in prevention and treatment of antipsychotic induced weight gain: a systematic review and meta-analysis. BMC Psychiatry 16, 341 (2016).

18. Metformin might ameliorate antipsychotic-induced hyperprolactinemia

19. Metformin effects on prolactin level and menstruation
Reference
Prolactin decrease
Regained menses
Wu et al., 2012
84.2 (metformin)
8.4 (placebo)
67% (metformin)
5% (placebo)
Liang, 2013
 84.2 (metformin)
91% (metformin)
Shi & Ding, 2013
 17.7
N/A

20. Topiramate Well-known weight loss side effect
Reduces serum leptin levels
Diminishes reward-quality of food
May be useful as an adjunctive tx for schizophrenia in some cases
But there are several case reports of de novo or exacerbated psychosis associated with topiramate

21. Prevented weight gain during first 12 weeks of olanzapine therapy in FEP

22. Topiramate and Metformin reduce body weight
Topiramate and Metformin reduce body weight. Improvements may persist beyond period of treatment
Study done in long-term inpatient setting
Continuing benefit in metformin group may depend on regulated diet and activity schedule
Peng, P.-J., Ho, P.-S., Tsai, C.-K., Huang, S.-Y. & Liang, C.-S. A Pilot Study of Randomized, Head-to-Head of Metformin Versus Topiramate in Obese People With Schizophrenia. Clin Neuropharmacol 39, 306–310 (2016).

23. Melatonin

24. Attenuated weight gain, improved PANSS General score, in melatonin group
N=18 per group
Olanzapine avg dose 20 mg/d in each group
Melatonin dose, 3 mg/night, pbo controlled
All received 2 mg/night clonazepam to control for sleep enhancement

25. Bipolar-selective benefit of melatonin in preventing SGA weight gain?
Romo-Nava, F. et al. Melatonin attenuates antipsychotic metabolic effects: an eight-week randomized, double-blind, parallel-group, placebo-controlled clinical trial. Bipolar Disord 16, 410–421 (2014).

26. Melatonin & weight loss in migraine
Melatonin 3-month effect on weight
in migraneurs
And was effective in reducing headache frequency
Gonçalves, A. L. et al. Randomised clinical trial comparing melatonin 3 mg, amitriptyline 25 mg and placebo for migraine prevention. J Neurol Neurosurg Psychiatry 87, 1127–1132 (2016).

27. Melatonin summary Small, but interesting evidence base
Comparatively low side effect risk
High patient acceptability

28. Glucagon-like Peptide-1 Receptor Agonists
GLP-1 is an incretin hormone, which is secreted from endocrine L-cells of the small intestine in response to nutrients in the gut lumen
GLP-1 also binds to receptors in the brainstem, hypothalamus, and amygdala, where it may promote satiety and therefore decrease energy intake.
Reduces blood glucose levels, but with negligible risk of hypoglycemia
Stimulates glucose-induced insulin secretion
Inhibist glucagon secretion
Reduces GI motility, appetite, and food intake
Reduces weight in patients without type 2 diabetes
Liraglutide (Victoza, Saxenda) is approved by FDA for marketing as a treatment for non-diabetic-associated obesity

29. Liraglutide case report
60 yo woman, long-term treated with clozapine 375 mg/d.
Had type 2 diabetes at time of intervention
Initial BMI: 33.5
8.7% body weight reduction after 2 years
Ishøy, P. L., et al., Sustained Weight Loss After Treatment With a Glucagon-Like Peptide-1 Receptor Agonist in an Obese Patient With Schizophrenia and Type 2 Diabetes. AJP 170, 681–682 (2013).

30. Treatment vs Prevention
More evidence for efficacy of treatment of SGA-induced weight gain
Effects of treatment are much more robust in FEP
Metformin NNT for treatment = 3
Metformin NNT for prevention = 10
But discussion of weight management at outset of treatment may strengthen therapeutic alliance.
Consider offering, or referring to medicine colleague, prevention at outset in shared decision making framework

31. Monitoring guidelines

32. Summary Weight issue is important
Reduces treatment willingness and medication adherence
Increases disease/mortality risk
Promotes inflammation, may worsen psychiatric symptoms
Low metabolic risk meds are preferable, if possible
Behavioral interventions are effective
Best outcomes from multidisciplinary and blended individual/group support
Monitoring is important
Presenting graphs of weight at each visit can motivate (some) patients
Treatment should be offered
Prevention should be considered
Metformin has strongest evidence base, no known psychiatric adverse effects
Topiramate has evidence base
may benefit psychiatric symptoms in some,
cognitive impairment is common
may cause or exacerbate psychosis in a small minority of patients
Liraglutide, melatonin are interesting potential options