Saxenda® in Obese or Overweight Patients With Stable Bipolar Disorder (Investigator Initiated)
Condition: Bipolar Disorder; Obesity
MeSH terms: Overweight; Bipolar Disorder
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): LIRAGLUTIDE; Placebo
Intervention type(s): Drug; Other
Intervention description(s): 3 Mg/0.5 mL (18 Mg/3 mL) SUB-Q PEN INJECTOR (ML); Placebo injection
Other intervention name(s): Saxenda
Intervention MeSH terms: Liraglutide
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: 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.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment