EVALUATION AND MANAGEMENT OF THE METABOLIC SIDE EFFECTS OF PSYCHOTROPIC MEDICATIONS

Educational Objectives

The goal of this program is to improve diagnosis and management of the metabolic side effects of psychotropic medications. After hearing and assimilating this program, the clinician will be better able to:

1. Classify antipsychotic medications based on the strengths of their associations with development of metabolic disorders.

2. List the metabolic effects of atypical antipsychotics.

3. Monitor patients on antipsychotic agents and use adjunctive therapies as needed to manage metabolic effects.

4. Recognize common side effects of drugs used to manage metabolic complications in patients on antipsychotic drugs.

5. Identify patients likely to benefit from treatment with melatonin to ameliorate metabolic side effects of antipsychotic drugs.

Summary

Overview: British Association for Psychopharmacology (BAP) has published peer-reviewed, evidence-based guidance; older guideline from American Psychiatric Association recommended lipid profile at baseline and every 5 yr, but some patients already have elevations in triglycerides (TGs) and low-density lipoprotein (LDL) cholesterol before starting treatment with antipsychotic drugs (APs); lifestyle issues contribute to problems in patients with serious mental illness; lifespan of patients with schizophrenia and bipolar disorder (BPD) shorter by ≈25 yr than general opopulation; obesity, smoking, substance use, and lack of exercise may contribute

Actions of APs: APs influence metabolism of glucose and lipids; clozapine and olanzapine present high risk for metabolic disorders and weight gain; low-risk medications include ziprasidone, aripiprazole, and lurasidone; moderate-risk drugs include brexpiprazole and cariprazine

Mechanisms of AP-induced diabetes: changes in insulin signaling pathways in muscle cells, hepatocytes, and adipocytes lead to insulin resistance (IR); olanzapine and other APs may directly damage pancreatic beta cells; duration of use correlated with risk for pancreatic damage; APs decrease phosphorylation of insulin receptor substrate, leading to impairment of glucose transport and insulin resistance (IR); inhibition of protein kinase 2 (AKT2) by APs decreases transport of glucose, leading to IR; blockade of 5-hydroxytryptamine 2C (5-HT2C), histamine 1, and dopamine 2 (D2) receptors increases appetite and obesity; obesity causes increases in free fatty acids, leptin, and tumor necrosis factor-α

Metabolic parameters: study evaluated fasting glucose and insulin, metabolic clearance rate, and oral glucose tolerance test in ≈124 patients with schizophrenia, BPD, or depression; findings similar across disease states; patients may exhibit elevated hemoglobin A1c (HbA1c), TGs, and LDL early in course of treatment with AP, suggesting that disease state itself increases risk for metabolic disorders (schizophrenia not simply disorder of brain)

Drug class: postprandial insulin levels lower in patients on atypical (second-generation) APs; first-generation APs have less influence on postprandial insulin

Duration of use: mean waist circumference (WC) and body mass index (BMI) significantly higher in patients on APs for >10 yr than those treated for <5 yr; rate of metabolic clearance of glucose progressively declines with longer duration of use

Children: in some cases, APs given without sufficient evidence (eg, as initial treatment for oppositional defiant disorder or aggressive behavior); recent study evaluated metabolic effects of 3 mo of initial exposure to aripiprazole, olanzapine, or risperidone in 144 children 6 to 18 yr of age; 30% of children overweight at time of initial prescription of AP; primary outcomes percentage of body fat and insulin sensitivity (IS) in muscle tissue; secondary outcomes included abdominal adiposity and IS in adipose and hepatic tissue; olanzapine may increase abdominal adiposity and alter metabolism of glucose in adipose tissue; changes observed with every AP in study, with largest changes found in patients on olanzapine; study showed that even low-risk APs associated with metabolic risk in children; every AP led to increased percentages of visceral and subcutaneous fat and decreases in IS

Studies in animals: olanzapine-induced hyperphagia has been observed in mice with 5-HT2C receptor but not in animals that lacked receptor; APs associated with inflammatory cytokines and central and peripheral changes in energy homeostasis; theories suggest relationship between mitochondrial dysfunction (decreased oxidative metabolism) and APs

Monitoring: some medications in BAP guideline not available in United States; guideline recommends baseline testing before starting AP and advocates monitoring BMI every 4 wk for 12 wk, then at 6 mo; fasting blood glucose should be followed, and HgbA1c checked at 12 wk, 6 mo, and then annually; if HgbA1c increases, it should be checked every 3 mo; blood pressure (BP) and lipids should be followed

Lifestyle: interventions such as exercise and eating properly should be emphasized, but patients who gain weight anyway may become discouraged; lifestyle interventions may decrease weight gain by 30%; losing weight more difficult for patients than preventing weight gain; group activities through community mental health centers recommended to allow patients to exercise with others who face same challenges

Switching APs: guidelines mention switching from olanzapine to aripiprazole or quetiapine; quetiapine has wide dose range and associated with several drug interactions; weight gain and metabolic changes occur earlier in patients on quetiapine than those taking risperidone; aripiprazole may be considered; using aripiprazole in combination with clozapine or other drugs may be associated with less weight gain

Metformin: metformin may be given adjunctively; concerns include effects in patients with congestive heart failure or chronic obstructive pulmonary disease, but lactic acidosis rare; drug effective for polycystic ovary syndrome (which may be associated with valproic acid) and hyperprolactinemia

Other medications: BAP details levels of evidence for efficacy of medications; lorcaserin (Belviq) — used in United States to promote weight loss; drug is 5-HT2C agonist, useful for decreasing appetite, and schedule IV controlled substance; lorcaserin not studied in patients with mental health disorders; other drugs — include melatonin, topiramate, zonisamide, and glucagon-like peptide-1 (GLP-1) analog liraglutide (Victoza); no data on lorcaserin or combination of phentermine-topiramate in patients with mental health disorders

Systematic review of metformin: design and population — review included >700 patients in 12 studies; mean duration of studies 12 to 14 wk; most patients on low dose of 1000 mg/day metformin (usual target dose 2000 mg); challenges — patients sometimes reluctant to take preventive drug or do not tolerate gastrointestinal (GI) side effects of metformin; initial dose may be 500 mg with evening meal; dose increased to 1000 mg after 1 to 2 mo

Findings: patients with first episode of schizophrenia had better responses that those with chronic schizophrenia, suggesting that early treatment superior; study included 2 cohorts of children (9 to 11 yr of age and 10 to 17 yr of age); responses in children similar to those in adults; mean weight change ≥3 kg over 12 wk; BMI fell ≈1 point; IR decreased, and fasting blood glucose unchanged; metformin does not cause hypoglycemia; study confirmed efficacy of metformin; effect size larger in children; Klein et al evaluated children, and Arman et al studied those with first episode; patients with first episode showed best responses to metformin

Preventive role for metformin: studied for prevention of weight gain in 25 adults on olanzapine; patients received metformin or placebo for 24 wk; mean age of patients mid-30s; metformin titrated to 2 g/day; patients with prediabetes excluded; primary outcome change in weight and IR at 6 mo; metformin group had less weight gain (5.5 vs 13 lb) and smaller increase in BMI (<1 point vs >2 points); vitamin B12 levels should be followed in patients on metformin; study supports practice of offering metformin early

Adjunctive aripiprazole: dual treatment with antipsychotics may require prior authorization; low dose of aripiprazole may reduce weight gain and development of diabetes in patients on high-risk drugs such as clozapine and olanzapine; aripiprazole also used to treat hyperprolactinemia; study lasted 16 wk, with 12-wk extension available for responders; ≈200 adults on stable dose of clozapine for ≥3 mo randomized to aripiprazole or placebo; primary outcome change in weight; secondary outcomes changes in BMI and WC and clinical efficacy as evidenced by scores on Positive and Negative Syndrome Scale (PANSS); over 16 wk, aripiprazole group lost ≈3 kg, but placebo group lost 3.8 kg; BMI and WC decreased (but decrease in WC not significant); changes observed in total cholesterol and LDL; patients exhibited no change in PANSS score; patients received mean dose of 11 mg aripiprazole; aripiprazole has higher binding affinity at D2 receptor than other drugs (except brexpiprazole); during first month on aripiprazole, patients may have slight increase in psychotic symptoms, but problem usually resolves

Topiramate: patients like weight loss achievable with topiramate; rapid dose escalation may result in difficulties with word-finding; other possible side effects include intolerance to heat, oligohidrosis, and kidney stones; most patients tolerate topiramate well; ≈70 patients on olanzapine randomized to topiramate or placebo for 12 wk; topiramate group showed decreases in weight and BMI; topiramate associated with positive effects on fasting glucose, decreases in total cholesterol and LDL, and improvements in systolic and diastolic BP

Liraglutide: randomized controlled trial (RCT) included 103 patients; mean age 40 and mean BMI 34; patients on clozapine or olanzapine randomized to addition of liraglutide or placebo for 16 wk; primary outcome change in oral glucose tolerance; more patients in liraglutide group developed normal glucose tolerance (30 vs 8 patients); weight, WC, and other metabolic parameters improved throughout study; number needed to treat 2; oral forms of GLP-1 agonists available

Zonisamide: studied in randomized, 10-wk trial in ≈40 patients on atypical or typical AP; outcomes included changes in weight, BMI, and PANSS; patients on zonisamide had decreases in weight (>1 kg, vs gain of 2 kg in placebo group), decreases in BMI (BMI increased in placebo group), and improvements in PANSS scores; drowsiness and nervousness most prominent side effects; drug may not be given to patients allergic to sulfonamides

Melatonin: 8-wk RCT included patients with BPD or schizophrenia being treated with quetiapine, risperidone, olanzapine, or clozapine; 44 patients received melatonin or placebo; melatonin associated with decreases in weight and BP; benefits greater in patients with BPD, and this group responsible for positive findings of study; decreases in diastolic BP seen in patients on melatonin, and these changes significantly greater in patients with BPD than those with schizophrenia; TGs decreased in patients with BPD but increased in those with schizophrenia; fat mass decreased in patients with BPD but unchanged in those with schizophrenia

Summary: metabolic problems more difficult to treat in patients on APs exposed for longer duration of use or at higher doses; duration of use and dosing of APs should be judicious; metabolic side effects may not respond to changes in lifestyle; metformin likely effective for preventing weight gain; patients may experience decreases in levels of vitamin B12 and GI effects; AGs should be started at low doses and titrated upward slowly; more studies needed on topiramate and liraglutide; 100-mg dose of topiramate adequate; dose of adjunctive aripiprazole 5 to 10 mg; drug may improve PANSS scores in patients on clozapine

Questions and Answers

Control of appetite in patients on atypical APs: lorcaserin blocks increase in leptin that leads to greater appetite; drug not studied in patients with mental health disorders but approved for management of weight in other patients; Food and Drug Administration recognizes potential for misuse of lorcaserin; drug probably agonist at 5-HT2C receptor

Metformin and weight loss: weight loss on metformin observed in patients with mental health disorders but not in general population; although weight loss not substantial, preventive effects of metformin still important; patients may present with changes in metabolic parameters at time of first episode of schizophrenia, indicating that schizophrenia alters IR

Melatonin: may contribute to weight loss in patients with BPD; other options 8 mg ramelteon or tasimelteon (tasimelteon indicated for disorders of circadian rhythm); neither ramelteon nor tasimelteon studied in patients with mental health disorders; usual dose of melatonin ≈5 mg

Initiating treatment with metformin: when considering whether to start treatment, clinician should discuss side effects with patient; metformin may be offered early, especially to adults on high and moderate-risk medications

Readings

Akinlade KS et al: Beta-cell function and metabolic clearance rate of glucose in patients with major mental health disorders on antipsychotic drug treatment. J Natl Med Assoc 2018 Oct;110(5):504-511; Arman S et al: A randomized, double-blind, placebo-controlled trial of metformin treatment for weight gain associated with initiation of risperidone in children and adolescents. Saudi Med J 2008 Aug;29(8):1130-4; Bozymski KM et al: Monitoring and treating metabolic abnormalities in patients with early psychosis initiated on antipsychotic medications. Community Ment Health J 2018 Aug;54(6):717-724; Cooper SJ et al: BAP guidelines on the management of weight gain, metabolic disturbances and cardiovascular risk associated with psychosis and antipsychotic drug treatment. J Psychopharmacol 2016 Aug;30(8):717-48; de Silva VA et al: Metformin in prevention and treatment of antipsychotic induced weight gain: a systematic review and meta-analysis. BMC Psychiatry 2016 Oct 3;16(1):341; Fleischhacker WW et al: Effects of adjunctive treatment with aripiprazole on body weight and clinical efficacy in schizophrenia patients treated with clozapine: a randomized, double-blind, placebo-controlled trial. Int J Neuropsychopharmacol 2010 Sep;13(8):1115-25; Ghanizadeh A et al: The effect of zonisamide on antipsychotic-associated weight gain in patients with schizophrenia: a randomized, double-blind, placebo-controlled clinical trial. Schizophr Res 2013 Jun;147(1):110-115; Klein DJ et al: A randomized, double-blind, placebo-controlled trial of metformin treatment of weight gain associated with initiation of atypical antipsychotic therapy in children and adolescents. Am J Psychiatry 2006 Dec;163(12):2072-9; Larsen JR et al: Effect of liraglutide treatment on prediabetes and overweight or obesity in clozapine- or olanzapine-treated patients with schizophrenia spectrum disorder: a randomized clinical trial. JAMA Psychiatry 2017 Jul 1;74(7):719-728; Nicol GE et al: Metabolic effects of antipsychotics on adiposity and insulin sensitivity in youths: a randomized clinical trial. JAMA Psychiatry 2018 Aug 1;75(8):788-796; Rado J et al: A naturalistic randomized placebo-controlled trial of extended-release metformin to prevent weight gain associated with olanzapine in a US community-dwelling population. J Clin Psychopharmacol 2016 Apr;36(2):163-8; Romo-Nava F et al: Melatonin attenuates antipsychotic metabolic effects: an eight-week randomized, double-blind, parallel-group, placebo-controlled clinical trial. Bipolar Disord; 2014 Jun;16(4):410-21; Zhang Y et al: The metabolic side effects of 12 antipsychotic drugs used for the treatment of schizophrenia on glucose: a network meta-analysis. BMC Psychiatry 2017 Nov 21;17(1):373.

Disclosures

In her lecture, Dr. Ott presents information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Ott was recorded at the 2018 Indiana Psychiatric Society Fall Symposium, presented by the American Psychiatric Association, in joint providership with the Indiana Psychiatric Society, and held December 1, 2018, in Carmel, IN. To learn about the Regional Integrated Mental Health Conference, to be presented by the Indiana Psychiatric Society and scheduled for April 26-28, 2019, in West Baden Springs, IN, please visit indianapsychiatricsociety.org. The Audio Digest Foundation thanks Dr. Ott, the American Psychiatric Association, and the Indiana Psychiatric Society for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

PS480401

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.