Letters

opioid use disorders.3 The emphasis on engagement in treat- Liraglutide for the Treatment
ment after overdose reversal should be established nation- of Antipsychotic Drug-Induced Weight Gain
wide. National efforts should expand the focus on educa- To the Editor Treatment with certain antipsychotic drugs
tional campaigns to increase awareness of treatment (APDs) causes weight gain, leading to metabolic syndrome
availability and reduce stigma among the general public, which and inc reasing c ardiovascular-assoc iated mortality.
includes those with an opioid use disorder and their friends Although several pharmacologic agents and some behavioral
and relatives. Of course, the success of such efforts is predi- interventions attenuate APD-elicited weight gain, the effects
cated on treatment availability and having the health insur- are modest and rarely reduce body weight to baseline levels.
ance needed to pay for it. In addition, as Saxon and In JAMA Psychiatry, Larsen et al1 report that the antidiabetic
McCance-Katz3 note, research is urgently needed to better un- agent liraglutide, a glucagon-like peptide-1 (GLP-1) receptor
derstand reasons for treatment dropout and how to improve agonist, reduces body weight, improves glucose tolerance,
retention. A 2017 report from the National Academies of Sci- and decreases systolic blood pressure in patients with
ences, Engineering, and Medicine4 also encourages investing schizophrenia receiving clozapine or olanzapine, 2 APDs
in research to improve understanding of the neurobiology of with high weight-gain liability. The magnitude of weight loss
pain to discover alternative, nonopioid treatments for pain; to seen in response to liraglutide in APD-treated patients with
determine factors associated with accessing treatment; and to schizophrenia was consistent with previous studies of lira-
better characterize the prescription opioid and heroin- glutide in patients with type 2 diabetes and in patients with-
fentanyl epidemics.4 As discussed by Madras,5 physicians can out diabetes and with obesity, despite administration of a
also limit the amount of opioids prescribed by following the relatively low dose (1.8 mg) of liraglutide. Liraglutide-
US Centers for Disease Control and Prevention 2016 guide- elicited weight loss was somewhat greater than that reported
lines on treatment and management of chronic pain. Finally, in studies of metformin, a biguanide antidiabetic agent used
the national epidemic of opioid-related deaths has occurred to attenuate APD-elicited weight gain. Liraglutide is poten-
in the context of increasing economic insecurity,6 which should tially an important addition to the therapeutic armamen-
not be ignored. In sum, tackling the opioid epidemic will re- tarium for APD-elicited weight gain and associated meta-
quire coordinated efforts both at the prevention and treat- bolic and cardiovascular changes.
ment levels. Liraglutide and other GLP-1 receptor agonists inhibit glu-
cagon secretion and promote glucose-induced insulin secre-
Silvia S. Martins, MD, PhD tion. However, a 2014 study in mice that lack GLP-1 receptors
Julian Santaella-Tenorio, MSc in the brain but not periphery indicates that GLP-1 receptor ago-
Deborah S. Hasin, PhD nists act centrally to elicit weight loss.2 Neurons expressing
GLP-1 receptors are widely distributed in the brain, including
Author Affiliations: Department of Epidemiology, Mailman School of Public not only the brainstem and hypothalamus but also forebrain
Health, Columbia University, New York, New York (Martins, Santaella-Tenorio, areas.3 Among these areas is the nucleus accumbens, which
Hasin); Department of Psychiatry, College of Physicians and Surgeons, Columbia
receives dopamine afferents from the midbrain and has long
University, New York, New York (Hasin).
been associated with reward. Genetic ablation of GLP-1 recep-
Corresponding Author: Silvia S. Martins, MD, PhD, Department of
Epidemiology, Mailman School of Public Health, Columbia University, 722 W tors in mice enhances the reinforcing properties of cocaine,4
168th St, Room 509, New York, NY 10032 (ssm2183@cumc.columbia.edu). consistent with GLP-1 receptor agonists dampening hedonic
Published Online: September 13, 2017. doi:10.1001/jamapsychiatry.2017.2431 processes. Similarly, in vivo imaging studies in humans re-
Conflict of Interest Disclosures: Dr Hasin reports serving as the principal port that GLP-1 receptor agonists decrease activation of brain
investigator of a study on a measure of addiction to prescription opioids funded reward pathways.5
by InVentive Health Consulting, which combines support from 9
Larsen et al1 reported that administration of liraglutide
pharmaceutical companies. No other disclosures were reported.
to patients with schizophrenia was not accompanied by sig-
1. Martins SS, Sarvet A, Santaella-Tenorio J, Saha T, Grant BF, Hasin DS. Changes
in US lifetime heroin use and heroin use disorder: prevalence from the nificant psychiatric adverse events. However, they used
2001-2002 to 2012-2013 National Epidemiologic Survey on Alcohol and Related broad functional scales (such as the Schizophrenia Quality
Conditions. JAMA Psychiatry. 2017;74(5):445-455. of Life Scale and the Clinical Global Impressions Scale) that
2. Centers for Disease Control and Prevention. Opioid overdose. https://www.cdc do not target negative symptoms to track psychiatric
.gov/drugoverdose/pubs/index.html#tabs-760094-4. Accessed August 3, 2017.
changes. Because GLP-1 receptor agonists dampen activa-
3. Saxon AJ, McCance-Katz EF. Some additional considerations regarding the
tion of reward pathways, a detailed assessment of
American Society of Addiction Medicine National Practice Guideline for the Use
of Medications in the Treatment of Addiction Involving Opioid Use. J Addict Med. liraglutide-induced psychiatric symptoms, particularly
2016;10(3):140-142. negative symptoms such as anhedonia, avolitional behav-
4. The National Academies of Sciences, Engineering, and Medicine. Pain ior, and blunted affect, should be performed before GLP-1
management and the opioid epidemic: balancing societal and individual receptor agonists are used to counter APD-elicited weight
benefits and risks of prescription opioid use. https://www.nap.edu/read/24781
gain and metabolic effects.
/chapter/1. Accessed August 1, 2017.
5. Madras BK. The surge of opioid use, addiction, and overdoses: responsibility Ariel Y. Deutch, PhD
and response of the US health care system. JAMA Psychiatry. 2017;74(5):441-442.
6. Case A, Deaton A. Rising morbidity and mortality in midlife among white Author Affiliations: Department of Psychiatry and Behavioral Sciences,
non-Hispanic Americans in the 21st century. Proc Natl Acad Sci U S A. 2015;112 Vanderbilt University Medical Center, Nashville, Tennessee; Department of
(49):15078-15083. Pharmacology, Vanderbilt University, Nashville, Tennessee.

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Corresponding Author: Ariel Y. Deutch, PhD, PMB407933, 8122 MRBIII, completed the PANSS rating. Therefore, the study was
465 21 Ave, Nashville, TN 37240-7933 (ariel.deutch@vanderbilt.edu). potentially underpowered to detect exenatide effects on
Published Online: September 27, 2017. doi:10.1001/jamapsychiatry.2017.3053 PANSS-negative scores (the power calculation was based on
Conflict of Interest Disclosures: None reported. body weight loss). However, more studies are under way: a
1. Larsen JR, Vedtofte L, Jakobsen MSL, et al. Effect of liraglutide treatment on larger randomized, placebo-controlled clinical study in
prediabetes and overweight or obesity in clozapine- or olanzapine-treated
patients with schizophrenia investigating the effect of
patients with schizophrenia spectrum disorder: a randomized clinical trial. JAMA
Psychiatry. 2017;74(7):719-728. exenatide on negative symptoms using PANSS is currently
2. Baggio LL, Drucker DJ. Glucagon-like peptide-1 receptors in the brain: recruiting patients, and a study protocol for a pilot random-
controlling food intake and body weight. J Clin Invest. 2014;124(10): ized clinical exenatide trial in patients with schizophrenia
4223-4226. was published in 2015.4
3. Heppner KM, Kirigiti M, Secher A, et al. Expression and distribution of Pooled data from several large clinical liraglutide weight
glucagon-like peptide-1 receptor mRNA, protein and binding in the male
management trials reported no major effects of liraglutide
nonhuman primate (Macaca mulatta) brain. Endocrinology. 2015;156(1):
255-267. (up to 3.0 mg once daily) on psychiatric symptoms in a
4. Harasta AE, Power JM, von Jonquieres G, et al. Septal glucagon-like peptide 1 population of patients with obesity.5 However, data from
receptor expression determines suppression of cocaine-induced behavior. this study cannot be extrapolated to a population with
Neuropsychopharmacology. 2015;40(8):1969-1978. schizophrenia because in these obesity studies, patients
5. Farr OM, Sofopoulos M, Tsoukas MA, et al. GLP-1 receptors exist in the were excluded in case of severe psychiatric illness.5
parietal cortex, hypothalamus and medulla of human brains and the GLP-1
There is an urgent need for treating metabolic distur-
analogue liraglutide alters brain activity related to highly desirable food cues in
individuals with diabetes: a crossover, randomised, placebo-controlled trial. bances in antipsychotic-treated patients with obesity and
Diabetologia. 2016;59(5):954-965. schizophrenia without and, especially, with prediabetes. Fur-
ther clinical investigations on the possible role of GLP-1 on psy-
In Reply We thank Deutch for his thoughtful response to our chopathology are important, but based on the current data we
study, 1 in which we reported that the gluc agon-like do not believe that there are strong arguments for postpon-
peptide-1 (GLP-1) receptor agonist, liraglutide, reduces body ing the use of GLP-1 receptor agonist in patients with predia-
weight, improves glucose tolerance, and decreases systolic betes, obesity, and schizophrenia until further psychopathol-
blood pressure in patients with schizophrenia receiving ogy data are available.
clozapine or olanzapine. Deutch correctly pointed out that
GLP-1 receptor stimulation can dampen activation of the Anders Fink-Jensen, MD, DMSc
reward pathways (eg, reduction of cocaine-induced dopa- Christoph U. Correll, MD
mine elevation2) and therefore suggested that a detailed Tina Vilsbøll, MD, DMSc
assessment of liraglutide-induced psychiatric symptoms,
particularly the so-called negative symptoms, such as anhe-
Author Affiliations: Psychiatric Centre Copenhagen, University Hospital
donia and blunted affect, should be performed before GLP-1 Copenhagen and Laboratory of Neuropsychiatry, University of Copenhagen,
receptor agonists are used to counter antipsychotic-induced Copenhagen, Denmark (Fink-Jensen); Department of Clinical Medicine, Faculty
body weight gain and metabolic disturbances. of Health and Medical Sciences, University of Copenhagen, Copenhagen,
Denmark (Fink-Jensen, Vilsbøll); Psychiatry Research, Zucker Hillside Hospital,
We agree that a pharmacologic intervention that inter- Northwell Health, Glen Oaks, New York (Correll); Department of Psychiatry and
acts with the limbic dopaminergic reward system may theo- Molecular Medicine, Hofstra Northwell School of Medicine, Hempstead,
retically influence the psychopathology observed in patients New York (Correll); Center for Psychiatric Neuroscience, Feinstein Institute for
Medical Research, Manhasset, New York (Correll); Department of Psychiatry
with schizophrenia. Although a dampening effect on the me-
and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, New York
solimbic reward system may theoretically reduce positive (Correll); Center for Diabetes Research, Gentofte Hospital, University of
symptoms (eg, hallucinations and delusions), it may, from a Copenhagen, Copenhagen, Denmark (Vilsbøll); Steno Diabetes Center
theoretical standpoint, worsen negative symptoms in pa- Copenhagen, University of Copenhagen, Copenhagen, Denmark (Vilsbøll).

tients with schizophrenia. Corresponding Author: Anders Fink-Jensen, MD, DMSc, Psychiatric Center
However, in our clinical trial1 we did not observe any Copenhagen, University of Copenhagen, Edel Sauntes Alle 10, DK-2100
Copenhagen O, Denmark (anders.fink-jensen@regionh.dk).
improvement or worsening of psychopathology based on
either the Clinical Global Impressions Scale severity score or Published Online: September 27, 2017. doi:10.1001/jamapsychiatry.2017.2702

from patient-reported symptoms or adverse events. Never- Conflict of Interest Disclosures: Dr Fink-Jensen reports sponsoring the study
theless, as correctly pointed out by Deutch, if the aim was to and receiving an unrestricted grant from Novo Nordisk A/S. Dr Correll reports
consulting and/or advising or receiving honoraria from AbbVie, Acadia, Actavis,
detect more subtle changes in specific symptoms (eg, the Actelion, Alexza, Alkermes, Bristol-Myers Squibb, Cephalon, Eli Lilly and
negative symptoms), more detailed rating scales, such as Company, Forum, Genentech, Gerson Lehrman Group, IntraCellular Therapies,
the Positive and Negative Syndrome Scale (PANSS), should Janssen/J&J, Lundbeck, Medavante, Medscape, Merck Sharp & Dohme, Otsuka,
Pfizer, ProPhase, Reviva, Roche, Sunovion, Supernus, Takeda, Teva, and Vanda;
be applied. This scale was administered in a 2017 placebo-
providing expert testimony for Bristol-Myers Squibb, Janssen, and Otsuka;
controlled, randomized study investigating the effect of the serving on a data safety monitoring board for Eli Lilly and Company, Janssen,
G L P -1 re c e p to r a go n i s t exe n at i d e i n p at i e nt s w it h Lundbeck, Pfizer, Takeda, and Otsuka; and receiving grant support from
schizophrenia.3 No significant differences in PANSS-total, Bristol-Myers Squibb, Otsuka, Lundbeck, and Takeda. Dr Vilsbøll reports
receiving lecture fees from Amgen, AstraZeneca, Boehringer Ingelheim
PANSS-positive, or PANSS-negative ratings were detected
Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly and Company, Merck Sharp
between patients receiving exenatide and placebo.3 Of the & Dohme, Novo Nordisk A/C, Sanofi, and Zealand Pharma and serving on the
45 patients undergoing randomization, 37 patients (82.2%) advisory boards of AstraZeneca, Boehringer Ingelheim Pharmaceuticals,

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Bristol-Myers Squibb, Eli Lilly and Company, Merck Sharp & Dohme, Novo 5. O’Neil PM, Aroda VR, Astrup A, et al; Satiety and Clinical Adiposity -
Nordisk A/C, and Sanofi. Liraglutide Evidence in individuals with and without diabetes (SCALE) study
groups. Neuropsychiatric safety with liraglutide 3.0 mg for weight
1. Larsen JR, Vedtofte L, Jakobsen MSL, et al. Effect of liraglutide treatment on
management: Results from randomized controlled phase 2 and 3a trials].
prediabetes and overweight or obesity in clozapine- or olanzapine-treated
Diabetes Obes Metab. 2017. doi:10.1111/dom.12963
patients with schizophrenia spectrum disorder: a randomized clinical trial. JAMA
Psychiatry. 2017;74(7):719-728.
CORRECTION
2. Sørensen G, Reddy IA, Weikop P, et al. The glucagon-like peptide 1 (GLP-1)
receptor agonist exendin-4 reduces cocaine self-administration in mice. Physiol Correction of Misspelled Author Name: In the Original Investigation titled “De-
Behav. 2015;149:262-268. velopmental Trajectories of Impaired Community Functioning in Schizophrenia,”
3. Ishøy PL, Fagerlund B, Broberg BV, et al. No cognitive-enhancing effect of published in the January 2016 issue of JAMA Psychiatry,1 the surname of one of
GLP-1 receptor agonism in antipsychotic-treated, obese patients with the authors was misspelled in the byline, Author Affiliations, and Author Contri-
schizophrenia. Acta Psychiatr Scand. 2017;136(1):52-62. butions. The third author’s name was given as “Ori Kapara, BA,” but should have
4. Mayfield K, Siskind D, Winckel K, Hollingworth S, Kisely S, Russell AW. appeared as “Ori Kapra, BA.” This article was corrected online.
Treatment of clozapine-associated obesity and diabetes with exenatide 1. Velthorst E, Reichenberg A, Kapra O, et al. Developmental trajectories of
(CODEX) in adults with schizophrenia: study protocol for a pilot randomised impaired community functioning in schizophrenia. JAMA Psychiatry. 2016;73(1):
controlled trial. BJPsych Open. 2015;1(1):67-73. 48-55.

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