Clinical trial NCT03943537
Conditions: Psychosis Schizophrenia Schizo Affective Disorder Bipolar I Disorder
Keywords: Psychosis Insulin Brain Metabolism Cognition
Sponsor: Mclean Hospital
Start date: 2019-10-01; Completion date: 2024-02-23
Enrollment: 87 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This clinical trial is a single center, single dose study of the acute effects of intranasal insulin on energy metabolism and cognitive function in patients with schizophrenia, schizoaffective and bipolar disorders, compared and healthy controls.

Detailed description:
Psychotic disorders are common and severe psychiatric disorders. Despite advances in understanding the pathophysiology of these disorders, more effective and tolerable treatments are still needed. Evidence suggests that energy metabolism is altered in psychotic disorders. The investigators recently developed non-invasive MRI-based techniques to quantify redox balance and ATP generation in the brain. Targeting insulin pathways in the brain may allow for modulating abnormalities in energy metabolism. The investigators seek to examine whether intranasal insulin can modulate energy metabolism and improve cognition in patients with psychotic disorders. The study will use magnetic resonance spectroscopy (MRS) technology to measure in vivo energy metabolism processes in the brain, before and after the administration of intranasal insulin. Investigators will also measure changes in cognition with the administration of intranasal insulin.

Arms: arm 1: 40 IU Novolin-R insulin will be administered one time using the ViaNase intranasal delivery device.
Interventions: intervention 1: Intranasal Insulin
Intervention descriptions: intervention 1: 40 units Novolin R administered intranasally using ViaNase device.

Protocol documents:
Prot_SAP_000.pdf: 
                         
July 24, 2019                    1 
 
 
PRINCIPAL/OVERALL INVESTIGATOR 
Virginie-Anne Chouinard, MD 
Phone: (617)855-3034 
Email: vchouinard@partners.org 
 
Schizophrenia and Bipolar Disorder Program 
McLean Hospital 
115 Mill St, 108 
Belmont, MA 02478 
 
 
PROTOCOL TITLE 
Effects of intranasal insulin on neuroimaging markers and cognition in patients with psychotic 
disorders.  
 
 
ClinicalTrials.gov ID 
NCT03943537 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


                         
July 24, 2019                    2 
 
BACKGROUND SUMMARY 
 
Psychotic disorders are common and severe psychiatric disorders. Despite advances in 
understanding the pathophysiology of these disorders, more effective and tolerable treatments 
are still needed. Several lines of evidence have shown metabolic abnormalities in psychotic 
disorders in the brain and periphery. There is a disproportionately high rate of T2DM in patients 
with psychotic disorders, which is two to three-fold that found in the general population[1, 2]. 
Recent evidence shows that glucose metabolism abnormalities are present at psychotic illness 
onset and in drug-naïve patients with psychotic disorders[3-6]. We recently found that both first 
episode psychosis patients and unaffected, untreated, siblings, who share genetic determinants, 
have impaired insulin signaling compared to controls[7]. The brain is an insulin sensitive organ 
and insulin receptors and insulin-activated pathways are prominent in the brain [8-10]. Given 
insulin’s effects on metabolism, impaired insulin signaling may play a key role in the emergence 
of neuronal dysfunction in psychosis. Metabolic functions are essential for maintaining 
fundamental processes in the brain, including synaptic neurotransmission, intracellular signaling 
and maintenance of ion gradients. Targeting these processes may thus be promising for 
treatment of psychotic disorders. We will examine whether intranasal insulin can modulate 
neurometabolic markers and improve cognition in patients with psychotic disorders. The study 
will use magnetic resonance spectroscopy (MRS) technology to measure changes in 
neurochemical markers, before and after the administration of intranasal insulin. We will also 
measure changes in cognition with the administration of intranasal insulin. 
 
 
SUBJECT SELECTION 
 
ELIGIBILITY:  
Patients:  
Eligible patient participants will be women and men ages 18-40 with Diagnostic and Statistical 
Manual of Mental Disorders (DSM) diagnoses of schizophrenia, schizoaffective disorder or 
bipolar disorder with psychotic features. Eligible participants must be stable with respect to their 
psychiatric and medical conditions, documented by no hospitalizations in the prior 4 weeks. We 
will not alter the dosing of any previously prescribed medication.  
 
Controls: 
Healthy controls will be women and men ages 18-40 with no history of DSM psychiatric 
diagnoses, nor history of the same in first-degree relatives.  
 
We will exclude participants who: 
1. Have unstable/active disease or potential contraindications, such as liver disease 
(AST>2*ULN; ALT> 2*ULN; A1c>6.5%), kidney disease (creatinine≥1.4 mg/dL or 
GFR<60 mL/min/1.73m2), uncontrolled hypertension (BP > 140 / 90), cardiac arrhythmia 
(QTc>500ms on ECG), significant or unstable medical illness. 
2. Have a known diagnosis of diabetes or by fasting plasma glucose concentration at 126 
mg per deciliter, according to the criteria of the American Diabetes Association[11]. 
3. Are currently prescribed any antidiabetic agents, including oral antidiabetic medications 
and insulin, intranasal medications, steroids, weight loss agents. 
4. Are pregnant or breast-feeding, and/or have not been using an effective form of 
contraception for at least 3 months or abstinent for 1 month prior to enrollment.  
5. Have a history of significant head injury. 
6. Have a contraindication to MR scan (claustrophobia, cardiac pacemakers, metal clips 
and stents on blood vessels, artificial heart valves, artificial arms, hands, legs, etc., brain 


                         
July 24, 2019                    3 
 
stimulator devices, implanted drug pumps, ear implants, eye implants or known metal 
fragments in eyes, exposure to shrapnel or metal filings, other metallic surgical hardware 
in vital areas, certain tattoos with metallic ink, certain transdermal patches, metal-
containing IUDs). 
7. Have any medical condition that would prevent blood draws.  
8. Have a history of electroconvulsive therapy (ECT) or transcranial magnetic stimulation 
(TMS) within the last 3 months. 
9. Have a current diagnosis or history of a substance use disorder in the last month. 
10. Have a BMI >35 or body weight >350 lbs or a BMI <18 
 
 
RECRUITMENT: We will recruit patients with schizophrenia, schizoaffective disorder or bipolar 
disorder with psychotic features from the Psychotic Disorders Division at McLean (outpatient 
programs, including OnTrack program for first episode psychosis, Schizophrenia and Bipolar 
Disorder Outpatient Clinic, Program of Assertive Community Treatment (PACT), and the 
Waverley Place community program, as well as both inpatient programs (AB2 and NB2), and 
the McLean Appleton residential program). Patients will also be recruited through RALLY and 
Mass General Brigham RPDR.   
In addition, we will recruit age- and sex-matched controls using online RALLY advertisements 
and flyers. We will additionally post flyers in the greater Boston area on community boards, 
college campuses, and agreeable storefronts and businesses.  
The research team will approach potential participants to describe the study, go through the 
screening document, obtain consent, and schedule the initial visit. All participants will provide 
written informed consent.  
 
 
STUDY PROCEDURES 
 
This study will be a single center, single dose study of the acute effects of intranasal insulin on 
neurochemical markers and cognitive function in patients with schizophrenia, schizoaffective 
and bipolar disorders, compared to healthy controls. 40 units of insulin (Novolin-R) will be 
administered using a ViaNase device (Kurve Technologies, Inc.), as directed by study staff. 
Assessments for neuroimaging markers and cognitive symptoms will be performed prior to 
administration of the intranasal insulin and immediately following administration. The Eligibility 
Screening procedures may be scheduled over one or two visits. Study procedures for each visit 
are outlined below. 
 
Study Procedures 
Eligibility Screening Visit(s) 
• 
Medical Screening 
o Fasting Blood Samples 
o Vital Signs 
o Medical History and Interview with MD 
o ECG (for participants with a history of cardiac issues) 
o Urine Toxicology and Pregnancy Test (for female participants) 
• 
Clinical Interview 
• 
Diagnostic MRI 
Intervention Visit: Neuroimaging, cognitive assessments and administration of 
intranasal insulin  


                         
July 24, 2019                    4 
 
Baseline assessments: 
 
 
• 
Participants will be instructed to fast for 8 hours 
prior to the study visit. 
• 
Blood draw for glucose and insulin levels  
• 
Vital signs, finger stick for glucose, review of 
systems  
• 
Columbia Suicide Rating Scale 
• 
Urine Toxicology and Pregnancy Test (for female 
participants) 
• 
Cognitive Assessment  
• 
31P MRS Scan  
Intranasal Administration of 
40units of Novolin-R 
• 
Finger glucose stick 
• 
Collect Vital Signs 
• 
Intranasal insulin administration 
• 
Assess Medication Tolerance  
Final assessments 
• 
31P MRS Scan 
• 
Scanner Debriefing Interview 
• 
Cognitive Assessment 
• 
Finger Glucose Stick  
• 
Assess Medication Tolerance  
• 
Blood draw for glucose and insulin levels  
• 
Vital Signs 
• 
Meal provided from the McLean Cafeteria 
 
Participants will undergo a urine toxicology screening and pregnancy test (for female subjects) 
prior to all imaging procedures. 
 
Screening Fasting Blood Samples: Comprehensive Metabolic Panel (CMP), Complete Blood 
Count with Differential (CBC diff), Lipid panel, Hemoglobin A1c, serum Insulin, plasma Glucose, 
Prolactin, Magnesium, TSH, free T4 and total T3, C-Reactive Protein. 
 
Vital Signs: Assessment of blood pressure, heart rate, temperature, height, weight, waist and 
hip circumference. 
 
Clinical Interview: 
A standard structured clinical evaluation (SCID), lasting approximately 2 hours, will be 
conducted in order to verify participants’ psychiatric diagnoses and to assess for severity of 
psychiatric symptoms.  
 
MRI Scan Protocols:  
All scans will take place at the Brain Imaging Center at McLean Hospital using either a Siemens 
3T Prisma or Prisma-Fit whole-body clinical MR scanner or full-body Varian/UnityInova 4 Tesla 
scanner. All MRS processing will be carried out blinded to diagnosis and disease episode. All 
MRS/MRI recordings will be obtained using parameters that are within FDA safety guidelines for 
exposure to static magnetic fields, radio-frequency energy deposition, magnetic field switching 
rates and acoustic noise levels.  
 
Cognitive Measures: Brief Assessment of Cognition in Schizophrenia and Stroop Task 


                         
July 24, 2019                    5 
 
Cognitive function will be assessed using the Stroop task and 3 items from the Brief 
Assessment of Cognition in Schizophrenia (BACS) battery[12]. Our Cognitive Assessments will 
include the following:  
• 
Stroop task 
• 
BACS Symbol coding (WMs-III Spatial Span, Letter-Number Span) 
• 
BACS Digit Sequencing (Brief Visuospatial Memory Test-Revised) 
• 
BACS Verbal Fluency (Mayer-Salovey-Caruso Emotional Intelligence Test) 
 
Study Medication: 
The study physician will prescribe a one-time dose of 40 units of insulin (Novolin-R), which will 
be administered using a ViaNase device (Kurve Technologies, Inc.).  
 
 
Statistical analysis plan 
 
Chi-square and t-tests will be used as appropriate to compare baseline demographic, clinical, 
metabolic, cognitive and MRS variables between groups. Within-group comparisons between 
the pre- and post-insulin administration measures of MRS and cognitive function in either 
patients or healthy controls will be conducted using paired t-tests. Hypothesis tests will be two-
sided at a significance level of 0.05. 
 
 


                         
July 24, 2019                    6 
 
X. REFERENCE 
 
1. 
M, D.E.H., et al., Physical illness in patients with severe mental disorders. I. Prevalence, 
impact of medications and disparities in health care. World Psychiatry, 2011. 10(1): p. 
52-77. 
2. 
Crump, C., et al., Comorbidities and mortality in bipolar disorder: a Swedish national 
cohort study. JAMA Psychiatry, 2013. 70(9): p. 931-9. 
3. 
Perry, B.I., et al., The association between first-episode psychosis and abnormal 
glycaemic control: systematic review and meta-analysis. Lancet Psychiatry, 2016. 3(11): 
p. 1049-1058. 
4. 
Pillinger, T., et al., Impaired Glucose Homeostasis in First-Episode Schizophrenia: A 
Systematic Review and Meta-analysis. JAMA Psychiatry, 2017. 74(3): p. 261-269. 
5. 
Rajkumar, A.P., et al., Endogenous and Antipsychotic-Related Risks for Diabetes 
Mellitus in Young People With Schizophrenia: A Danish Population-Based Cohort Study. 
Am J Psychiatry, 2017: p. appiajp201616040442. 
6. 
Correll, C.U., et al., Cardiometabolic Risk in Patients With First-Episode Schizophrenia 
Spectrum Disorders: Baseline Results From the RAISE-ETP Study. JAMA Psychiatry, 
2014. 
7. 
Chouinard, V.A., et al., Impaired insulin signaling in unaffected siblings and patients with 
first-episode psychosis. Mol Psychiatry, 2018. 
8. 
Havrankova, J., J. Roth, and M. Brownstein, Insulin receptors are widely distributed in 
the central nervous system of the rat. Nature, 1978. 272(5656): p. 827-9. 
9. 
Zhao, W.Q., et al., Insulin and the insulin receptor in experimental models of learning 
and memory. Eur J Pharmacol, 2004. 490(1-3): p. 71-81. 
10. 
Unger, J.W., J.N. Livingston, and A.M. Moss, Insulin receptors in the central nervous 
system: localization, signalling mechanisms and functional aspects. Prog Neurobiol, 
1991. 36(5): p. 343-62. 
11. 
American Diabetes, A., Diagnosis and classification of diabetes mellitus. Diabetes Care, 
2010. 33 Suppl 1: p. S62-9. 
12. 
Keefe, R.S., et al., The Brief Assessment of Cognition in Schizophrenia: reliability, 
sensitivity, and comparison with a standard neurocognitive battery. Schizophr Res, 
2004. 68(2-3): p. 283-97.