Clinical trial NCT03414151: Gut Microbiome in AP Naive
Official title: Gut Microbiome and Metabolic Dysfunction in Antipsychotic Naïve Patients
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Psychotic Disorder
Schizophrenia
Lead sponsor: Centre for Addiction and Mental Health
Sponsor class: OTHER
Collaborators: name: McMaster University
First posted: 2018-01-29
Enrollment: 25
Sex: ALL
Minimum age (years): 12
Maximum age (years): 35
Standard ages: CHILD
ADULT
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Participants will include individuals who are either antipsychotic naïve or have not taken antipsychotics for at least 3 months prior to study participation. Participants will be between 12 and 35 years of age with a diagnosis of schizophrenia, schizoaffective disorder, or other specified schizophrenia spectrum and other psychotic disorder, as per DSM-V criteria.

Brief summary: Antipsychotic (AP) medications are currently the cornerstone of treatment for schizophrenia (SCZ), with off-label prescription rapidly increasing in youth, with an established two-fold increase in standardized mortality ratio attributable to cardiovascular disease in this population. However, APs have been associated with common and serious metabolic adverse effects including weight gain and diabetes, to which youth are disproportionally vulnerable. The Gut Microbiome (GMB) has been suggested as a potential target warranting further study as a mechanism of AP induced weight gain and has also been linked directly with cognition and behavior. It is hypothesized that there will be changes in the gut microbiome overtime with treatment correlated with metabolic measures and that APs will produce changes in glucose tolerance, insulin sensitivity, adipokines, glucagon like peptide (GLP)-1, lipids, fasting glucose, body weight, and cognition.

Detailed description: The objectives of the study are to examine the gut microbiome composition and diversity in patients with schizophrenia, schizoaffective disorder, or other specified schizophrenia spectrum and other psychotic disorder at 6 weeks and 3 months post antipsychotic initiation. Furthermore, the team aims to investigate causality of antipsychotic (AP)-induced changes in the GMB in relation to metabolic changes. This will be accomplished by transplanting human gut microbiota from patients initiating an AP treatment into germ-free mice (independent animal protocol). The final objective is to observe changes in cognition associated with changes in metabolic factors and gut microbiome.

The hypotheses of the study are twofold: the primary hypothesis is that there will be changes in the gut microbiome overtime with treatment correlated with metabolic measures (i.e. weight, insulin sensitivity, glucose tolerance, lipids) due to treatment in antipsychotic naïve patients, and the gut microbiome of treated patients transplanted into germ-free mice will induce similar metabolic proving causality (separate animal protocol). The secondary hypothesis is that APs will produce changes psychopathology and cognitive outcome measures which will correlate with changes in gutmicrobiome.

Participants will include individuals who are either antipsychotic naïve or have not taken antipsychotics for at least 3 months prior to study participation. Participants will be between 12 and 35 years of age with a diagnosis of schizophrenia, schizoaffective disorder, or other specified schizophrenia spectrum and other psychotic disorder, as per DSM-V criteria. Participants will be enrolled to reach n=25 complete data sets. Participants who drop out or who are withdrawn will be replaced.

Following provision of written informed consent, participants will be assessed for suitability for inclusion in the study based on the inclusion and exclusion criteria. Participants will be seen across 5 timepoints, including a screening and baseline visit, as well as 3 follow-up appointments.

Within-group analyses will be conducted to evaluate changes in participants at different time points on measures including anthropometric measures, clinical scales, and fasting bloodwork results. Microbiome analysis will include α-diversity metrics for each sample and β-diversity measures (weighted and unweighted unifrac, Specifically we will analyze changes in the microbiome pre- and post- antipsychotic treatment and whether changes in the microbiome associate with other clinical and biochemical measures. We will also determine whether patients that develop metabolic side effects with antipsychotic treatment have different microbial profiles than those who do not develop these side effects.

Whole body insulin sensitivity is calculated based on the original description by Matsuda at baseline and endpoint. HOMA-IR will be calculated at baseline, week 6, and week 12 to determine change in insulin resistance over time.

A blood sample will be collected for DNA extraction to examine for the genes that that are hypothesized to be associated to response or side effects following antipsychotic medication. Fecal DNA analyses will be completed at McMaster University. Stool samples will be collected from participants at baseline, weeks 3 and 6. Participants will be given stool collection kits (OMNIgene•GUT, DNA Genotek Ottawa, ON). Participants will return the sample at their earliest convenience. Once returned, samples will be immediately frozen and stored at -80°C.

Eligibility criteria: Inclusion Criteria:

* Ages 12-35
* Antipsychotic naïve or antipsychotic treatment for equal to or less than 2 weeks within the past 3 months; the minimum AP dose will be left to the discretion of the PI
* DSM-5 diagnosis (using SCID-IV-TR with supplemental questions from SCID-5 or SCID-5) of schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, and brief psychotic disorder, psychotic disorder NOS. and/or antipsychotic treatment for schizophrenia, schizoaffective disorder, or other specified schizophrenia spectrum and other psychotic disorder.

Exclusion Criteria:

* Previous antipsychotic treatment (greater than two weeks within the preceding 3 months)
* Presence of DSM-5 diagnosis which is not schizophrenia, schizoaffective disorder, or other specified schizophrenia spectrum and other psychotic disorder
* Use of any other medications for treatment of lipids, glucose, or weight as deemed to be clinically significant by the PI
* Use of other medications where the dose has changed within the past 6 weeks which are deemed by the PI to be clinically significant
* Pregnancy
* Eating disorder - active or previous
* Major medical or surgical event within the preceding 3 months
* Acute suicidal risk
* Irritable bowel disease, Crohn's disease, and/or diverticulitis/diverticulosis
* Type I diabetes, kidney/liver disease, and/or cancer
* Organ transplant
* Moderate to severe alcohol use , use of street drugs, and/or cannabis use (as deemed by PI)
* Immunosuppressants and/or anti-inflammatory medications
* Antibiotic/probiotic use within past 4 weeks
* Any other medical conditions or lifestyle habits deemed by the PI to impact the integrity of the sample/microbiota

Primary outcomes:
measure: Change in Gut microbiome and DNA
timeFrame: 12 weeks (baseline, week 6, week 12)
Secondary outcomes:
measure: Oral glucose tolerance test
timeFrame: 12 weeks (baseline and week 12)
measure: Height
timeFrame: 12 weeks
measure: Weight
timeFrame: 12 weeks
measure: Blood pressure
timeFrame: 12 weeks
measure: Heart Rate
timeFrame: 12 weeks
measure: Waist Circumference
timeFrame: 12 weeks
measure: BMI
timeFrame: 12 weeks
measure: Prolactin
timeFrame: 12 weeks (baseline, week 6, week 12)
measure: Liver enzymes
timeFrame: 12 weeks (baseline, week 6, week 12)
measure: Bilirubin
timeFrame: 12 weeks (baseline, week 6, week 12)
measure: GGT
timeFrame: 12 weeks (baseline, week 6, week 12)
measure: Albumin
timeFrame: 12 weeks (baseline, week 6, week 12)
measure: HbA1c
timeFrame: 12 weeks (baseline, week 6, week 12)
measure: Fasting blood work
timeFrame: 12 weeks (baseline, week 6, week 12)
measure: CBC
timeFrame: 12 weeks (baseline, week 6, week 12)
measure: Thyroid Stimulating Hormone (TSH)
timeFrame: 12 weeks (baseline, week 6, week 12)
measure: Insulin
timeFrame: 12 weeks (baseline, week 6, week 12)
measure: Leptin
timeFrame: 12 weeks (baseline, week 6, week 12)
measure: Free Fatty Acids (FFA)
timeFrame: 12 weeks (baseline, week 6, week 12)
measure: C-peptide
timeFrame: 12 weeks (baseline, week 6, week 12)
measure: Cortisol
timeFrame: 12 weeks (baseline, week 6, week 12)
measure: DNA
timeFrame: Baseline measure
measure: Brief Psychiatric Rating Scale 18 item (BPRS)
timeFrame: 12 weeks (baseline, week 6, week 12)
measure: The Positive and Negative Symptom Questionnaire (SANS)
timeFrame: 12 weeks (baseline, week 6, week 12)
measure: Clinical Global Impression (CGI)
timeFrame: 12 weeks (baseline, week 6, week 12)
measure: The Calgary Depression Scale for Schizophrenia (CDSS)
timeFrame: 12 weeks (baseline, week 6, week 12)
measure: Quality of Life Scale (QLS)
timeFrame: 12 weeks (baseline, week 6, week 12)
measure: Birchwood Social Functioning Scale (BSFS)
timeFrame: 12 weeks (baseline, week 6, week 12)
measure: UKU Side Effects Scale
timeFrame: 12 weeks (all time points)
measure: Abnormal Involuntary Movement Scale (AIMS)
timeFrame: 12 weeks (baseline, week 12)
measure: Barnes Akathisia Scale (BAS)
timeFrame: 12 weeks (baseline, week 12)
measure: Simpson Angus Scale (SAS)
timeFrame: 12 weeks (baseline, week 12)
measure: Food Cravings Questionnaire (FCQ)
timeFrame: 12 weeks (baseline, week 6, week 12)
measure: Visual Analog Scale (VAS)
timeFrame: 12 weeks (baseline, week 6, week 12)
measure: Harvard Youth/Adolescent Questionnaire (YAQ)
timeFrame: 12 weeks (baseline, week 6, week 12)
measure: International Physical Activity Questionnaire (IPAQ)
timeFrame: 12 weeks (baseline and week 12)
measure: MATRICS Consensus Cognitive Battery
timeFrame: 12 weeks (baseline and week 12)
measure: Investigation of Mental Rotation, Allocentricity-Egocentricity, and Perspective Taking (IMAP)
timeFrame: 12 weeks (baseline and week 12)
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: Centre For Addiction and Mental Health
state: Ontario
Study officials:
affiliation: Centre for Addiction and Mental Health
name: Margaret K Hahn, PhD, MD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Gold SM, Dziobek I, Sweat V, Tirsi A, Rogers K, Bruehl H, Tsui W, Richardson S, Javier E, Convit A. Hippocampal damage and memory impairments as possible early brain complications of type 2 diabetes. Diabetologia. 2007 Apr;50(4):711-9. doi: 10.1007/s00125-007-0602-7. Epub 2007 Feb 14.
citation: Letourneau G, Bentaleb LA, Stip B, Luck D, Stip E. Relationships between Brain Structure and Metabolic Changes in Schizophrenia Patients Treated with Olanzapine: A Voxel-Based Morphometric Study. Schizophr Res Treatment. 2011;2011:862350. doi: 10.1155/2011/862350. Epub 2011 May 25.
citation: Bora E, Akdede BB, Alptekin K. The relationship between cognitive impairment in schizophrenia and metabolic syndrome: a systematic review and meta-analysis. Psychol Med. 2017 Apr;47(6):1030-1040. doi: 10.1017/S0033291716003366. Epub 2016 Dec 29.