Saxenda® in Obese or Overweight Patients With Stable Bipolar Disorder (Investigator Initiated)
Saxenda® in Obese or Overweight Patients With Stable Bipolar Disorder (Investigator Initiated)
Taken together these data support the hypothesis that liraglutide 3.0 mg sc injection will
 reduce body weight and improve metabolic variables in obese or overweight patients with BP
 without worsening psychiatric symptoms. The investigators predict that liraglutide 3.0 mg sc
 injection will display greater efficacy as compared to placebo in decreasing body weight in
 patients with BP who are obese or overweight. To prove this hypothesis, investigators will
 conduct a single-center, randomized, placebo-controlled, double-blind, parallel-group, 2-arm
 clinical trial of liraglutide 3.0 mg sc injection in 60 obese or overweight outpatients with
 stable BP. The investigators have chosen BP rather than another SMI because it is the most
 common SMI (more common than schizophrenia or schizoaffective disorder) and has a
 particularly strong association with obesity.
BACKGROUND AND SIGNIFICANCE:

 Obesity is common among persons with severe mental illness (SMI), especially those with
 bipolar disorder (BP) (1-5). It is estimated that 45-55% of people with SMI are obese, making
 obesity 1.5-2 times more common among those with SMI than among the general population.
 Indeed, in a recent pragmatic lithium trial conducted in BP, 69% of the subjects were
 overweight or obese. Although the precise mechanism underlying the relationship between
 obesity and SMI is unknown, it is thought to be multifactorial, involving genetic factors,
 intrinsic features of SMI (e.g., overeating, poor dietary choices, sedentary lifestyle, and
 sleep dysregulation), and the weight-gaining effects of most of the psychotropic medication
 used to treat SMI.

 Importantly, obesity is thought to contribute to the well-documented elevated mortality from
 cardiovascular disease (CVD) among those with BP. Thus, weight reduction in obese people with
 BP might be important for reducing their morbidity and mortality from CVD and other
 obesity-related conditions (e.g., diabetes and metabolic syndrome). Conversely, the presence
 of obesity in patients with BP is associated with a more severe course of illness , a lower
 health-related quality of life (18), reductions in brain gray and white volumes (19, 20), and
 non-adherence with antipsychotic medications . Indeed, it has been hypothesized that
 successful treatment of obesity in those with BP might benefit mental as well as physical
 health. It is thus imperative that obesity be a focus of treatment in those with BP.

 Comprehensive behavioral weight management programs have shown some effectiveness for obesity
 in patients with SMI, but the weight loss is modest at best and such programs are difficult
 to implement and not widely available. Several medications have been shown to mitigate
 psychotropic-induced weight gain, particularly metformin and topiramate, but many patients
 either do not respond to these agents or are unable to tolerate them. Importantly, the
 efficacy and safety of newly available weight-loss agents have not been evaluated in people
 with SMI.

 In December 2014, the U.S. Food and Drug Administration approved liraglutide [rDNA origin] 3
 mg/day subcutaneous [sc] injection) (Saxenda®) as a treatment option for chronic weight
 management in individuals with obesity. The drug is approved for use in adults with a body
 mass index (BMI) of 30 or greater (obesity) or adults with a BMI of 27 or greater
 (overweight) who have at least one weight-related comorbid condition such as hypertension,
 type 2 diabetes, or dyslipidemia, in combination with reduced-calorie diet and increased
 physical activity. Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist.
 Saxenda® and Victoza® contain the same active ingredient (liraglutide) at different doses (3
 mg and 1.8 mg, respectively). However, unlike Victoza®, Saxenda® is not indicated for the
 treatment of type 2 diabetes, as the safety and efficacy of Saxenda® for the treatment of
 diabetes has not been established.

 Several lines of evidence suggest that liraglutide 3.0 mg sc injection (Saxenda®), in
 combination with a reduced-calorie diet and increased physical activity, would be a useful
 weight-loss treatment for patients with BP who are overweight or obese.

 First, GLP-1 is a gut/brain peptide that is secreted from intestinal mucosal enteroendocrine
 L cells in response and in proportion to nutrient stimulation of the gut, and that suppresses
 food intake by acting on receptors in key areas of the brain that regulate energy balance
 (e.g., hypothalamus and hindbrain) (34-37). In humans, administration of GLP-1 reduces food
 intake and increases satiation in a dose-dependent manner (37). Obesity in people with BP, as
 well as psychotropic-induced weight gain, are thought to be due to in part to increased food
 intake (2). It is thus possible that liraglutide 3.0 mg sc injection will decrease food
 intake in obese patients with BP, thereby reducing body weight.

 Second, preliminary preclinical and clinical findings suggest liraglutide 3.0 mg sc injection
 may be effective for antipsychotic-induced weight gain and antipsychotic-induced obesity
 (38). Thus, liraglutide has been shown to produce weight loss in animal models of
 olanzapine-induced weight gain. In one of these studies, liraglutide also produced
 antidepressant-like effects. (Indeed, other animal studies suggest that liraglutide may have
 antipsychotic properties. In the only published case of liraglutide use in a patient with
 SMI, an obese (BMI 33.5=mg/kg2) 60-year-old woman with schizophrenia treated with clozapine,
 liraglutide (1.8mg/day) produced a sustained weight loss of 7.7 kg (an 8.7% body weight
 reduction) over two years. Liraglutide was well tolerated and there were no psychiatric
 adverse events (i.e., the patient's schizophrenia remained stable). At our own center, we
 have treated a 32-year-old woman with schizoaffective disorder, bipolar type and obesity
 (BMI=36 mg/kg2) receiving one depot and two oral antipsychotics with liraglutide 3.0 mg sc
 injection and, to date, she has lost 7.5 kg (an 8.3% body weight reduction) over a 4-month
 period. She reports the liraglutide 3.0 mg sc injection has reduced her hunger and improved
 her satiety. She has tolerated liraglutide 3.0 mg sc injection well and has had no
 difficulties with giving herself the injections, her psychological symptoms have remained
 stable, and there have been no adverse psychiatric effects. Indeed, her mild tardive
 dyskinesia is much improved

 Third, relative to other weight loss agents, liraglutide 3.0 mg sc injection has a favorable
 psychiatric and cardiovascular adverse event profile. Regarding psychiatric events, in the
 pivotal liraglutide 3.0 mg sc injection clinical trials, 6 (0.2%) of 3384 liraglutide 3.0 mg
 sc injection-treated patients had suicidal ideation (one of these individuals made a suicide
 attempt) compared with none of the 1941 placebo-treated patients. Additionally, 2.4% of
 liraglutide 3.0 mg sc injection recipients had insomnia and 2.0% had anxiety, compared with
 1.7% and 1.6 %, respectively, of placebo recipients. Conversely, lorcaserin (Belviq®) was
 associated with euphoria (0.2% vs < 0.1% for placebo) and is contraindicated in patient's
 receiving serotonergic medications (and many psychotropics enhance serotonin function).
 Phenermine/topiramate combination (Qsymia®), at the highest approved dose, was associated
 with insomnia (11.1% vs 5.8% for placebo), depression/mood problems (7.6% vs 3.4% for
 placebo), and anxiety (7.9% vs 2.6% for placebo). Additionally, one of the components of
 Qsymia®, topiramate, is associated with suicidality. Bupropion/naltrexone combination
 (Contrave®), at the highest recommended dose, was associated insomnia (9.2% vs 5.9% for
 placebo), anxiety (4.2% vs 2.8% for placebo), and irritability (2.6% vs 1.8% for placebo).
 Moreover, there are reports of components of these latter medications (e.g., phentermine and
 bupropion) causing severe adverse psychiatric events, such as mania and psychosis. Taken
 together, these findings suggest that liraglutide 3.0 mg sc injection may be the least likely
 of these weight management medications to exacerbate psychiatric symptoms in people with BP.
 Indeed, GLP-1 analogues have been reported to produce enhanced well-being in patients with
 diabetes.

 Taken together these data support the hypothesis that liraglutide 3.0 mg sc injection will
 reduce body weight and improve metabolic variables in obese or overweight patients with BP
 without worsening psychiatric symptoms. We predict that liraglutide 3.0 mg sc injection will
 display greater efficacy as compared to placebo in decreasing body weight in patients with BP
 who are obese or overweight. To prove this hypothesis, we will conduct a single-center,
 randomized, placebo-controlled, double-blind, parallel-group, 2-arm clinical trial of
 liraglutide 3.0 mg sc injection in 60 obese or overweight outpatients with stable BP. We have
 chosen BP rather than another SMI because it is the most common SMI (more common than
 schizophrenia or schizoaffective disorder) and has a particularly strong association with
 obesity.

 RESEARCH DESIGN AND METHODS

 Study hypothesis (es):

 The central research question is whether liraglutide 3.0 mg sc injection is efficacious for
 reducing body weight in obese or overweight patients with BP. We hypothesize that liraglutide
 3.0 mg sc injection will be an efficacious, safe, and well tolerated treatment for weight
 loss in obese or overweight patients with stable BP. We predict that liraglutide 3.0 mg sc
 injection will display greater efficacy as compared to placebo in decreasing body weight in
 patients with BP who are overweight or obese without increasing psychiatric adverse events.
 We also predict that liraglutide 3.0 mg sc injection will produce a greater percentage of
 patients who lose ≥ 5% of baseline body weight, and improve BMI, waist circumference, fasting
 lipid and glucose levels, HgA1c levels, and measures of eating psychopathology.

 Endpoints:

 The primary endpoint will be the percent change in body weight from Baseline (Week 0) to week
 40/Early Termination (ET) (see Table 1 for a schedule of assessments). Secondary endpoints
 will include proportion of participants who lose ≥ 5% of baseline body weight, and change
 from baseline in body weight (kg), BMI, waist circumference, and metabolic variables (fasting
 lipids and glucose, and HgA1c levels). Exploratory secondary endpoints will be change from
 baseline in eating psychopathology, assessed with the Three Factor Eating Questionnaire
 (TFEQ) and Binge Eating Scale (BES). Safety endpoints assessed at each study visit will be
 mental status examination, clinically-administered scales that assess psychopathology (CGI-BP
 scale [both Severity and Improvement subscales], YMRS, MADRS, and CSSRS), vital signs, and
 adverse events determined by clinical interview. Laboratory tests and 12-lead
 electrocardiograms (ECGs) will be obtained at Screening, week 8, week 16/ET, and week 40/ET.
 Compliance will be assessed at each visit with inspection of returned multi-dose pens.
 Potential interactions between liraglutide and psychiatric medications will be monitored and
 recorded on the Potential Drug Interaction form (see p. 28).

 Study type:

 This is a single-center, randomized, placebo-controlled, double-blind, two-arm,
 parallel-group, fixed-dose efficacy and safety study with 3 phases: a 3-27 day Screening
 period; a 40-week randomized, double-blind Treatment period (4 weeks of dose titration and 36
 weeks of dose maintenance); and a 1-week Follow-up (drug discontinuation) period. The purpose
 of the 40-week Blinded Treatment phase is to establish the efficacy of liraglutide 3.0 mg sc
 injection for weight loss in obese patients with stable BP.

 Study population:

 We expect to screen about 90 subjects in order to randomize 60 subjects in a 1:1 ratio to
 drug or placebo. Patients will be recruited from the Lindner Center of HOPE, Mason, OH, a
 University of Cincinnati College of Medicine Affiliate. Patients will be recruited by
 clinician referral and advertisement.

 Participants will include 60 outpatients with a DSM-5 diagnosis of BP that is stable, who are
 obese or overweight with at least one weight-related comorbidity, and who have been receiving
 a stable psychotropic regimen for the past three months. The weight-related comorbidities to
 be included will be hypertension, type 2 diabetes, and dyslipidemia. Allowed psychotropic
 medications for BP will include mood stabilizers (lithium, valproate, and lamotrigine),
 antipsychotics (asenapine, aripiprazole, cariprazine, chlorpromazine, clozapine, haloperidol,
 loxapine, olanzapine, paliperidone, perphenazine, quetiapine, resperidone, thiothixene,
 trifluoperazine, or ziprasidone), antidepressants, and anxiolytics (benzodiazepines,
 gabapentin or pregabalin, and buspirone). Stable BP will be operationally defined as a
 CGI-BP-Severity score of 1through 3 (1= normal, not at all; 2= borderline mentally ill;
 3=mildly ill); a YMRS score ≤12; a MADRS score ≤19, and the absence of clinically significant
 suicidality and psychosis. Participants must be 18 through 65 years of age, be able to
 provide informed consent, and if female, be postmenopausal, surgically incapable of
 childbearing, or practicing a medically acceptable method(s) of contraception (e.g., hormonal
 method, intrauterine device) for at least 1 month prior to study entry and throughout the
 study. Exclusion criteria include subjects with a lifetime DSM-5 Axis I diagnosis of
 dementia, a psychotic or depressive disorder, or a substance use disorder within the past
 three months; those with clinically significant psychotic features or suicidal ideation;
 those with serious or unstable general medical illnesses; those with a personal or family
 history of medullary thyroid cancer or Multiple Endocrine Neoplasia syndrome type 2; those
 who are allergic to or who have demonstrated hypersensitivity to liraglutide 3.0 mg sc
 injection or any of its components; and females who are pregnant, nursing, or intend to
 become pregnant. Specific entry criteria are listed below.
Inclusion Criteria:

 1. Men and women, ages of 18-65 years, inclusive.

 2. Participants will have a DSM-5 bipolar disorder that is clinically stable.

 3. Participants will have received a stable major psychotropic drug regimen (except for
 minor dosage adjustments) for at least 3 months prior study entry. Major psychotropic
 drugs are antipsychotics, mood stabilizers, and antidepressants. Subjects may have had
 changes in adjunctive benzodiazepines and hypnotic agents.

 4. Participants will be obese (defined as a BMI ≥ 30 mg/kg2) or overweight (defined as
 BMI ≥ 27 kg/m2) with at least one weight-related comorbidity, such as hypertension,
 type 2 diabetes, or dyslipidemia.

 5 Participants in treatment for a weight-related comorbidity (hypertension, type 2
 diabetes, and/or dyslipidemia) must be on a stable and allowed treatment regimen for that
 condition for at least 3 months prior to study enrollment.

 6 Participants will be able to provide informed consent before any trial-related
 activities.

 Exclusion Criteria:

 1. Women who are pregnant, lactating, or of childbearing potential who are not using
 adequate contraceptive measures. The following are considered to be adequate methods
 of birth control: 1.Intrauterine device (IUD); 2. Barrier protection; 3.Contraceptive
 implantation system (Norplant); 4.Oral contraceptive pills; 5. A surgically sterile
 partner; and 6. Abstinence. Women who are > 2 years post-menopausal or
 surgically-sterile are not considered of childbearing potential. All female
 participants will have a negative pregnancy test prior to randomization.

 2. Participants who have made a suicide attempt in the last 10 years, who are displaying
 clinically significant psychotic features, suicidality, or homicidality on mental
 status examination, or who have suicidal ideation or behavior as assessed with the
 C-SSRS.

 3. Participants who are receiving behavioral weight loss treatment (BWLT) (e.g., Weight
 Watchers) that was begun within the 3 months before study entry. Participants who are
 receiving BWLT that was started 3 months prior to the beginning of the study will be
 allowed to continue to receive their BWLT during the trial only if they have had no
 weight loss in the past 3 months and they agree to not make any changes in the
 frequency or nature of their BWLT during the course of the drug trial.

 4. A DSM-5 diagnosis of a substance-related or addictive disorder (except a
 tobacco-related disorder) within the 3 months prior to enrollment.

 5. A DSM-5 diagnosis of dementia, a psychotic disorder, or a depressive disorder.

 6. History of any psychiatric disorder which might interfere with a diagnostic
 assessment, treatment, or compliance.

 7. Clinically unstable medical disease, including cardiovascular, hepatic, renal,
 gastrointestinal, pulmonary, neurological, metabolic, endocrine, or other systemic
 disease. Clinically stable hypertension, type 2 diabetes, or dyslipidemia are not
 exclusionary.

 8. Have a history of a structural cardiac abnormality, valvular cardiac disease,
 cardiomyopathy, serious heart rhythm abnormality, coronary artery disease, congestive
 heart failure, stroke, or other serious cardiovascular problem.

 9. Have an ECG with significant arrhythmias or conduction abnormalities, which in the
 opinion of the physician investigator preclude study participation.

 10. Have clinically relevant abnormal laboratory results.

 11. Participants requiring treatment with any drug which might interact adversely with or
 obscure the action of the study medication. This includes anti-obesity drugs,
 psychostimulants, modafinil or armodafinil, topiramate or zonisamide, and
 antipsychotics. Participants receiving metformin at a stable dose for ≥ 3 months can
 be included.

 12. Participants receiving GLP-1 based therapies, sodium-glucose co-transporter 2
 inhibitors (SGLT2s), thiazolidinediones, sulfonylureas, or insulin.

 13. Participants with a personal or family history of medullary thyroid carcinoma or
 Multiple Endocrine Neoplasia syndrome type 2.

 14. Participants who have received any investigational medication within three months
 prior to randomization.

 15. Participants previously screen-failed or randomised to participate in this trial.

 16. Participants who have a known or suspected allergy to liraglutide 3.0 mg sc injection,
 its constituents, or related products.

 17. Participants with a urine drug screen positive for a drug that, in the opinion of the
 investigator, is being abused.

 18. Participants with a past medical history of pancreatitis.

 19. Participants who had received any investigational drug within 3 months prior to this
 trial.

 20. Participants who require bariatric surgery or are anticipated to require it during the
 course of the trial. If such surgery becomes warranted during the study, such patients
 will be excluded from the primary endpoint analysis.