An Open-label Feasibility Trial of Adjunctive Telmisartan in Patients With Treatment Resistant Schizophrenia
Phase: PHASE2
Conditions: Schizophrenia, Schizo Affective Disorder, Treatment-resistant Schizophrenia
Sponsor: Xiaoduo Fan

INVESTIGATOR STUDY PLAN- REQUIRED 
 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Protocol 
An open-label, feasibility trial of adjunctive telmisartan in patients with treatment 
resistant schizophrenia 
Xiaoduo Fan, MD, MPH 
Identifier: NCT03868839 
Document Date: 06/11/2018 
 
 
 
 
 
 
 
 

2 
 
 
A. BACKGROUND  
 
1. Treatment resistant schizophrenia (TRS): TRS, which affects approximately 1/3 of patients 
with schizophrenia (Meltzer 1997). Currently available antipsychotic agents all fall into the “D2, 
me too'' category. However, the abnormal presynaptic dopamine transmission usually seen in 
schizophrenia are absent in TRS (Demjaha et al 2012). Novel treatment approaches targeting 
alternative neural circuits or pathways are urgently needed. 
 
Increased glutamate levels have been reported in antipsychotic-naïve or free patients with 
schizophrenia (de la Fuente-Sandoval et al 2013, Kraguljac et al 2013). Some studies suggested 
that antipsychotic treatment may reduce brain glutamate to the levels similar as in healthy controls 
(de la Fuente-Sandoval et al 2013, Kegeles et al 2012). However, recent studies found higher 
glutamate levels in the anterior cingulate cortex of antipsychotic-treated first episode patients with 
unremitted psychotic symptoms, and in treatment-resistant patients than in medication 
responders (Demjaha et al 2014, Egerton et al 2012). Abnormal glutamatergic signaling 
secondary to excessive stimulation of non-NMDA glutamate receptors (i.e., AMPA and kainate) 
may result in calcium influx and neuronal injury, which likely lead to clinical symptoms including 
cognitive impairment in patients with schizophrenia (Deutsch et al 2001).    
 
3. Telmisartan, inflammation and oxidative stress: Studies have demonstrated that blockade 
of AT1R by telmisartan reduces inflammation, apoptosis, and oxidative stress (Jung et al 2007, 
Sato et al 2014). In addition, telmisartan activates the nuclear receptor peroxisome proliferator-
activated receptor γ (PPARγ), which regulates multiple pathways to counteract inflammation and 
oxidative stress, and promote neuroprotection (Min et al 2012, Pang et al 2012). 
 
4. Potential benefit of telmisartan in schizophrenia: We recently reported that adjunctive 
treatment with telmisartan improves schizophrenia symptoms (Fan et al 2017). We now further 
propose to examine whether telmisartan targets glutamatergic signaling in the brain with 
neuroimaging to measure concentrations of cerebral glutamate metabolites in patients with TRS.  
 
We propose a 4-week, open-label, feasibility trial of adjunctive telmisartan in adult patients with 
TRS. We plan to recruit 10 patients. All patients will receive telmisartan 80mg daily for 4 weeks.  
 
B. SPECIFIC AIMS 
Primary 
1. Evaluate changes in blood biomarkers for inflammation and oxidative stress. 
 
C. STUDY DESIGN 
 
Screening visit: After signing a HIPAA compliant informed consent form, subjects will undergo a 
review of medical history and concomitant medications, and a physical exam. The MINI 
International Neuropsychiatric Interview will be performed to confirm the psychiatric diagnosis. 
Subjects will also have a urine drug screen, urine pregnancy test, a complete blood count 
(CBC), complete metabolic panel (CMP), vital signs, 12-lead ECG.  
 
Baseline visit: After the screening visit, eligible subjects will undergo: 1) vital signs; 2) efficacy 
assessment battery; 3) safety assessment battery; 4) blood biomarkers for inflammation and 
oxidative stress, including glutathione (GSH), glutathione disulfide (GSSG), high sensitivity C 
reactive protein (hsCRP), interleukin 6 (IL-6) and tumor necrosis factor α (TNFα).  
 

3 
 
Week 1, 2, 3 visits: Vital signs will be assessed. Treatment compliance and possible adverse 
effects will be evaluated. Subjects will receive one week supply of study medication. Urine drug 
screen will be repeated at week 2 only.  
 
Week 4 visit: Subjects will undergo: 1) vital signs; 2) efficacy assessment battery; 3) safety 
assessment battery; 4) blood biomarkers for inflammation and oxidative stress, including GSH, 
GSSG, hsCRP, IL-6 and TNFα. Lab samples for CBC and CMP will also be collected.  
 
Early termination visit: Subjects will undergo: 1) vital signs; 2) safety assessment battery; 3) 
CBC and CMP. 
 
D. STUDY POPULATION 
 
Subject eligibility 
Inclusion Criteria 
Each subject must meet all of the following criteria to be eligible for this study: 
1. Age 18-65 years inclusive. 
2. Primary diagnosis of Schizophrenia established by a structured psychiatric evaluation 
(MINI) based on Diagnostic and Statistical Manual of Mental Disorders Fifth Edition 
(DSM-V) criteria. 
3. A Positive and Negative Syndrome Scale (PANSS) (Kay et al 1987) total score ≥ 70 with 
a score of > 4 on two or more of the following PANSS items: delusions, conceptual 
disorganization, hallucinatory behavior, suspiciousness, and unusual thought content.  
4. A score of ≥4 on the Clinical Global Impression—Severity (CGI-S) (Guy, 1976).  
5. Must have ongoing antipsychotic treatment for at least 8 weeks, with a stable dose for at 
least 4 weeks. Subjects who have failed to achieve clinically-recognized symptom 
reduction to at least 1 marketed antipsychotic agent, given at a Physician Desk 
Reference (PDR)-defined therapeutic dose for ≥ 8 weeks during the past 12 months, will 
be eligible. 
6. Women of childbearing potential must have a negative pregnancy test performed at 
screening visit prior to randomization. Women enrolled in this trial must use adequate 
birth control. 
7. Understands and is able, willing, and (in the opinion of the investigator) likely to fully 
comply with the study procedures and restrictions. 
 
Exclusionary Criteria 
Subjects who meet any of the following criteria will be excluded from the study: 
1. Psychiatrically unstable. 
2. Subjects with any clinically significant abnormalities as determined by medical history, 
physical exam, clinical and lab evaluation suggestive of an underlying disease state that 
may, in the opinion of the investigator, confound the results of study, increase risk to the 
subject, or lead to difficulty complying with the protocol.  
3. Current insulin treatment for diabetes. 
4. History of immunosuppression. 
5. Current or recent radiation or chemotherapy treatment for cancer. 
6. Chronic use of steroids (except local use or inhaler). 
7. Pregnancy or breastfeeding. 
8. Use of diuretics, ACE inhibitors, spironolactone, potassium supplements, digoxin or 
warfarin because the possible drug-drug interaction with telmisartan. 
9. Tested positive for the urine drug screen. 

4 
 
10. Subjects at imminent risk of suicide or injury to self or others, as per the opinion of the 
investigator, or history of significant suicide attempt within the last 6 months as per the 
Columbia Suicide Severity Rating Scale (C-SSRS). 
11. Subjects that have taken an investigational drug or taken part in a clinical trial within 30 
days prior to screening. 
12. Subjects with a current (within the last 3 months) DSM-V diagnosis of alcohol or 
substance use disorder (excluding nicotine and caffeine) as established by the clinical 
assessment (MINI) at the screening visit will be excluded.  
13. Any other reason that, in the opinion of the investigator, would compromise patient 
safety or integrity of the study. 
14. Subjects with the lab values defined as exclusionary safety values in Table 1. 
 
Table 1. Exclusionary Safety Values of Potential Clinical Concern  
Complete Blood Count 
Leukocytes 
<2 or >17.5 x 103/mm3 
Platelets 
<75 or >700 x 103/mm3 
Comprehensive Metabolic Panel 
Sodium 
<1.1 times the lower limit or >1.1 times upper limit of the reference 
Potassium 
<1.1 times the lower limit or >1.1 times upper limit of the reference 
Blood Urea Nitrogen (BUN) 
>1.3 times upper limit of the reference range 
Creatinine 
>1.3 times upper limit of the reference range 
Glomerular Filtration Rate 
< 60 
Aspartate amino transferase (AST) >3 times upper limit of the reference range 
Alanine amino transferase (ALT) 
>3 times upper limit of the reference range 
 
 
E. ASSESSMENT PROCEDURES 
 
Medical history 
A detailed medical history will be obtained by the PI or designee during the screening visit. This 
will include information regarding the subject’ full history of medical and psychiatric conditions, 
diagnoses, procedures, treatments, demographic information, and any other noteworthy medical 
information, including suicidality, with dates of start and finish. Any updates to medical history 
information that the PI or designee becomes aware of will be captured throughout the study. 
 
Physical exam 
The PI, or medically qualified designee, will perform the physical exam at the screening visit. If 
any clinically significant change is noted from screening, it will be reported as an adverse event 
and will be followed up to resolution or upon reaching a stable endpoint. 
 
Vital signs 
Evaluation of vital signs will be performed by qualified personnel after the subject has been 
supine for 5 minutes, and will include a measurement of systolic and diastolic blood pressure, 
pulse rate, and oral temperature. Systolic and diastolic blood pressure should be then measured 
from supine to standing to assess orthostatic hypotension. Vital sign measurements will be 
obtained at the time points indicated in the schedule of events (SOE).  
 

5 
 
If clinically significant findings, as determined by the PI or medically qualified designee, occur in 
any vital sign measurement, that measurement should be captured as an adverse event and will 
be repeated at medically appropriate intervals until the value returns to an acceptable range, a 
specific diagnosis is established, or the condition is otherwise explained. 
 
Laboratory assays 
Fasting blood samples will be obtained and laboratory tests will be performed at the time points 
indicated in the SOE. 
 
Complete blood count (CBC): White blood cell (WBC) count with differential (absolute neutrophil 
count, lymphocytes, monocytes, basophils, and eosinophils), red blood cell (RBC) count, 
hemoglobin (Hgb), hematocrit (Hct), and platelet count. 
 
Comprehensive metabolic panel (CMP):  glucose, sodium, potassium, calcium, chloride, carbon 
dioxide, blood urea nitrogen (BUN), creatinine, calculated glomerular filtration rate, uric acid, 
phosphorus, magnesium, total protein, albumin, aspartate amino transferase (AST), alanine 
amino transferase (ALT), alkaline phosphatase (ALP), total bilirubin. 
 
Blood levels of GSH, GSSG, hsCRP, IL-6, TNFα: Blood samples for GSH, GSSG, hsCRP, IL6 
and TNF-alpha will be run at the UMass Memorial labs. 
 
The PI, or medically qualified designee, should mark either “CS” for Clinically Significant or 
“NCS” for Not Clinically Significant in the margin of the laboratory result source document for 
items outside the normal range. 
 
Urine drug screen: The test includes the following substances: opioids, cocaine, amphetamines, 
methadone, cannabinoids, barbiturates, benzodiazepines, methamphetamine, and 
phencyclidine. 
 
Urine pregnancy test: The test will be performed in female subjects of childbearing potential 
using a dipstick urine test during the screening visit.  
 
 
12-Lead Electrocardiogram (EGG) 
A 12-lead ECG will be taken at following a supine rest for 5 minutes. The ECGs will be reviewed 
by the PI or medically qualified designee, and a cardiologist to assess any immediate 
abnormalities. The findings of the ECGs will be marked as normal, abnormal-not clinically 
significant, or abnormal-clinically significant. 
 
Psychiatric diagnostic assessment 
Mini International Neuropsychiatric Interview (MINI v7.0): The MINI 7.0 is a short clinician 
administered structured diagnostic interview for major psychiatric diagnoses in DSM-5 with an 
administration of around 20 minutes. 
 
Efficacy assessment battery 
The Positive and Negative Syndrome Scale (PANSS) (KAY ET AL 1987): The PANSS will be 
used to measure symptom severity in this trial. The PANSS is a 30-item questionnaire used to 
evaluate schizophrenia symptoms, based on the clinical interview as well as reports of family 
members or primary care hospital workers. The PANSS consists of Positive Symptom subscale 
(7 items), Negative Symptom subscale (7 items), and General Psychopathology subscale (16 
items). Each item is scored on a 7-point scale with higher scores representing increasing levels 

6 
 
of psychopathology: 1) Absent, 2) Minimal, 3) Mild, 4) Moderate, 5) Moderate severe, 6) Severe, 
and 7) Extreme. 
 
Scale for Assessment of Negative Symptoms (SANS) (Andreasen 1989): The SANS assesses 5 
domains: affective flattening, alogia, avolition/apathy, anhedonia/asociality, and attention. Within 
each domain, separate symptoms are related from 0 (absent) to 5 (severe).  
 
Clinical Global Impressions–Severity (CGI-S) and Clinical Global Impressions–Improvement 
(CGI-I) Scales (Guy, 1976): The CGI-S is an observer-rated scale that measures illness 
severity. The severity is measured using a 7 point Likert scale: 1) Normal, not at all ill, 2) 
Borderline mentally ill, 3) Mildly ill, 4) Moderately ill, 5) Markedly ill, 6) Severely ill, and 7) Among 
the most extremely ill patient. The CGI-I is an observer-rated scale that measures illness 
improvement. Improvement is measured using a 7 point Likert scale: 1) Very much improved, 2) 
Much improved, 3) Minimally improved, 4) No change 5) Minimally worse, 6) Much worse, 7) 
Very much worse.  
 
Safety assessment battery 
Adverse Events (AE): Adverse events will be monitored at each study visit. The PI or medically 
qualified designee will review adverse events at every study visit. AE information is collected and 
recorded starting on the day the consent is signed until the end of an individual’s participation in 
the study.  
 
The Columbia Suicide Severity Rating Scale (C-SSRS) (Posner et al 2007): The C-SSRS is a 
low-burden measure of the spectrum of suicidal ideation and behavior that was developed in the 
National Institute of Mental Health Treatment of Adolescent Suicide Attempters Study to assess 
severity and track suicidal events through any treatment. It is a clinical interview providing a 
summary of both ideation and behavior that can be administered during any evaluation or risk 
assessment to identify the level and type of suicidality present. The C-SSRS can also be used 
during treatment to monitor for clinical worsening. The C-SSRS will be performed to assess 
suicidal ideation and behavior.  It contains a 1-to-5 rating scale for suicidal ideation of increasing 
severity (from a “wish list to die” to an “active thought of killing oneself with plan and intent”). 
The time frame is the past six months for the Baseline/Screening scale and since the last visit 
for the Since Last Visit scale. 
 
Monitoring and Reporting of Adverse Events 
 
Continuous data and safety monitoring will be conducted by the PI. Any adverse effect reported 
to study personnel will be reviewed with the PI or sub-investigator who will determine whether 
they are mild, moderate or severe and the likelihood (definitely/possible/probable) that it is 
related to the study medication. All AEs will be followed until resolution, until deemed stable by 
the investigator or until the subject is deemed by the investigator to be lost to follow-up 
 
Intensity 
Definition 
Mild 
Causes transient or mild discomfort ; no limitation of usual activities; 
no medical intervention required. 
Moderate 
Causes mild to moderate limitation in activity; some limitation of usual 
activities: no or minimal medical intervention or therapy is required. 
Severe 
Causes marked limitation in activity; some assistance is usually 
required; medical intervention or therapy is required; hospitalization is 
probable. 

7 
 
 
The PI is ultimately responsible for assessing and reporting all adverse events as outlined in the 
study plan. The assessment of AEs may be delegated to a medically qualified Sub-Investigator, 
trained on this study plan. The PI will report adverse events to the IRB in accordance with IRB 
guidelines. 
 
Reporting of Serious Adverse Events 
 
The PI will report all SAEs to UMass IRB. The PI will inform the IRB regarding any AE (does not 
have to be causally related) that is both serious and unexpected; or that represents a series of 
AEs that, on analysis, is unanticipated, or occurs at an unanticipated frequency, or otherwise 
represents an unanticipated safety risk to the study subject in accordance with UMass IRB 
reporting guidelines.   
 
F. TREATMENT 
 
Dosing 
Subjects will start telmisartan 40mg once a day during week 1; the dose will be increased to 
80mg (target dose) or as tolerated during the remaining weeks.   
 
Study medication Supplies and Administration 
Telmisartan has 20mg, 40mg and 80mg dose strengths. Subjects will be given one 40mg pill 
per day during week 1, and one 40mg pill plus two 20mg pills per day for the remaining weeks.   
 
Potential risks of telmisartan 
When telmisartan was co-administered with digoxin, median increases in digoxin peak plasma 
concentration (49%) and in trough concentration (20%) were observed. It is therefore 
recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing 
telmisartan. Telmisartan administered for 10 days slightly decreased the mean warfarin trough 
plasma concentration; this decrease did not result in a change in International Normalized Ratio 
(INR). Telmisartan can cause fetal and neonatal morbidity and death when administered to 
pregnant women. In volume- and/or salt-depleted patients (e.g., those being treated with high 
doses of diuretics), symptomatic hypotension may occur after initiation of therapy with 
telmisartan. Adverse events occurring at an incidence of 1% or more in patients treated with 
telmisartan and at a greater rate than in patients treated with placebo, irrespective of their 
causal association, include upper respiratory tract infection, back pain, sinusitis, diarrhea and 
pharyngitis. Common adverse experiences have generally been mild and transient in nature and 
have only infrequently required discontinuation of therapy. In placebo-controlled trials involving 
1,041 patients treated with various doses of telmisartan (20-160mg) monotherapy for up to 12 
weeks, an overall incidence of adverse events similar to that of placebo was observed. 
(Micardis® package insert, revised, February 2018). 
 
For the proposed study, patients will be excluded if they are on diuretics, ACE inhibitors, digoxin 
or warfarin because the possible drug-drug interaction with telmisartan. Subjects will be 
excluded from the study if they have an abnormal potassium blood level out of the defined cutoff 
range at screening. Subjects will be terminated from the study if they have an abnormal 
potassium blood level at screening. For female patients of childbearing potential, a urine 
pregnancy test must be negative at screening. These patients must agree to practice 
appropriate birth control methods during the study.   
 
Discontinuation from Study Treatment 

8 
 
 
The reasons for early discontinuation include the following: 1) request of patient, 2) decision of 
the PI, 3) serious adverse event. 
 
Procedures for discontinuation from study 
If a patient discontinues from the study before randomization, then no further follow-up will be 
expected. However, if the patient discontinues after randomization, but before receiving any 
study treatment, the patient will be asked to return for a final study visit, during which the 
procedures outlined in the early termination visit procedures will be completed, including AEs 
and concomitant medication assessments. 
 
If a patient discontinues from the study before completion and has received the dose of study 
drug, the patient will be asked to return for a final study visit, at which the procedures outlined in 
the early termination visit will be completed. Every effort will be made to follow up with patients 
who discontinue from the study. If the patient refuses follow-up, the reason for the refusal and 
last contact date should be documented in the CRF. 
 
G. ETHICAL CONSIDERATION 
 
Informed consent 
The investigator must ensure that patients are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical trials in which they volunteer to 
participate.  
All subjects will receive the consent form for the study. Any questions, concerns, or ambiguities 
will be clarified by the PI or medically qualified designee prior to the patient signing consent. 
Subjects will sign informed consent and only then will begin participation in the study. 
 
IRB review 
Before study initiation, the investigator will have written and dated approval from the UMass IRB 
for the protocol, consent form, patient recruitment materials and process (e.g., advertisements), 
and any other written information to be provided to subjects. 
 
The investigator will provide the IRB with reports, updates, and other information (e.g., safety 
updates, amendments) according to regulatory requirements and institution procedures. 
 
H. DATA ANALYSIS 
 
There are no published data yet about the effect of telmisartan treatment on the levels of 
glutamate and GABA in the brain in patients with schizophrenia. The study is intended to 
provide preliminary evidence of target engagement in the brain, as well as an indication of effect 
size for the purpose of designing future studies. Paired sample t tests will be used to examine 
the difference in outcome measures between week 4 and baseline. In addition, Pearson 
correlation analysis or partial correlation analysis will be used to examine the relationship 
between changes in biomarkers and changes in symptom outcome measures.    
 

INVESTIGATOR STUDY PLAN- REQUIRED 
 
9 
 
SCHEDULE OF EVENTS 
Procedure 
Visit 
Screening 
Baseline 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Early 
Termination 
(ET) Visit 
Study Week 
 
Week 0 
Week 1 
Week 2 
Week 3 
Week 4 
 
Medical History 
X 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
MINI 
X 
 
 
 
 
 
 
Pregnancy Test (Females only) 
X 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
Labs (CMP, CBC) 
X 
 
 
 
 
X 
X 
Labs (GSH, GSSG, hsCRP, IL-6, TNFα)  
 
X 
 
 
 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
Urine Drug Screen 
X 
 
 
X 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
PANSS 
 
X 
 
 
 
X 
 
SANS 
 
X 
 
 
 
X 
 
CGI-S and CGI-I 
 
X 
X 
X 
X 
X 
 
CSSRS 
 
X 
 
 
 
X 
X 
Drug dispensing 
 
X 
X 
X 
X 
 
 
Patient Medication Log  
 
X 
X 
X 
X 
 
X 
Pill Count  
 
 
X 
X 
X 
X 
X 

10 
 
 
 
REFERENCES 
 
Andreasen NC. 1989. The Scale for the Assessment of Negative Symptoms (SANS): conceptual and theoretical 
foundations. The British journal of psychiatry. Supplement: 49-58 
de la Fuente-Sandoval C, Leon-Ortiz P, Azcarraga M, Stephano S, Favila R, et al. 2013. Glutamate levels in the 
associative striatum before and after 4 weeks of antipsychotic treatment in first-episode psychosis: a 
longitudinal proton magnetic resonance spectroscopy study. JAMA psychiatry 70: 1057-66 
Demjaha A, Egerton A, Murray RM, Kapur S, Howes OD, et al. 2014. Antipsychotic treatment resistance in 
schizophrenia associated with elevated glutamate levels but normal dopamine function. Biol. Psychiatry 75: 
e11-3 
Demjaha A, Murray RM, McGuire PK, Kapur S, Howes OD. 2012. Dopamine synthesis capacity in patients with 
treatment-resistant schizophrenia. Am. J. Psychiatry 169: 1203-10 
Deutsch SI, Rosse RB, Schwartz BL, Mastropaolo J. 2001. A revised excitotoxic hypothesis of schizophrenia: 
therapeutic implications. Clin. Neuropharmacol. 24: 43-9 
Egerton A, Brugger S, Raffin M, Barker GJ, Lythgoe DJ, et al. 2012. Anterior cingulate glutamate levels related to 
clinical status following treatment in first-episode schizophrenia. Neuropsychopharmacology 37: 2515-21 
Fan X, Song X, Zhao M, Jarskog LF, Natarajan R, et al. 2017. The effect of adjunctive telmisartan treatment on 
psychopathology and cognition in patients with schizophrenia. Acta Psychiatr. Scand. 136: 465-72 
Gohlke P, Weiss S, Jansen A, Wienen W, Stangier J, et al. 2001. AT1 receptor antagonist telmisartan administered 
peripherally inhibits central responses to angiotensin II in conscious rats. J. Pharmacol. Exp. Ther. 298: 62-
70 
Jung KH, Chu K, Lee ST, Kim SJ, Song EC, et al. 2007. Blockade of AT1 receptor reduces apoptosis, 
inflammation, and oxidative stress in normotensive rats with intracerebral hemorrhage. J. Pharmacol. Exp. 
Ther. 322: 1051-8 
Kay SR, Fiszbein A, Opler LA. 1987. The positive and negative syndrome scale (PANSS) for schizophrenia. 
Schizophr. Bull. 13: 261-76 
Kegeles LS, Mao X, Stanford AD, Girgis R, Ojeil N, et al. 2012. Elevated prefrontal cortex gamma-aminobutyric 
acid and glutamate-glutamine levels in schizophrenia measured in vivo with proton magnetic resonance 
spectroscopy. Arch. Gen. Psychiatry 69: 449-59 
Kraguljac NV, White DM, Reid MA, Lahti AC. 2013. Increased hippocampal glutamate and volumetric deficits in 
unmedicated patients with schizophrenia. JAMA psychiatry 70: 1294-302 
Meltzer HY. 1997. Treatment-resistant schizophrenia--the role of clozapine. Curr. Med. Res. Opin. 14: 1-20 
Min LJ, Mogi M, Shudou M, Jing F, Tsukuda K, et al. 2012. Peroxisome proliferator-activated receptor-gamma 
activation with angiotensin II type 1 receptor blockade is pivotal for the prevention of blood-brain barrier 
impairment and cognitive decline in type 2 diabetic mice. Hypertension 59: 1079-88 
Noda A, Fushiki H, Murakami Y, Sasaki H, Miyoshi S, et al. 2012. Brain penetration of telmisartan, a unique 
centrally acting angiotensin II type 1 receptor blocker, studied by PET in conscious rhesus macaques. Nucl. 
Med. Biol. 39: 1232-5 
Pang T, Benicky J, Wang J, Orecna M, Sanchez-Lemus E, Saavedra JM. 2012. Telmisartan ameliorates 
lipopolysaccharide-induced innate immune response through peroxisome proliferator-activated receptor-
gamma activation in human monocytes. J. Hypertens. 30: 87-96 
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. 2007. Columbia Classification Algorithm of Suicide 
Assessment (C-CASA): classification of suicidal events in the FDA's pediatric suicidal risk analysis of 
antidepressants. Am. J. Psychiatry 164: 1035-43 
Saavedra JM. 2012. Angiotensin II AT(1) receptor blockers as treatments for inflammatory brain disorders. Clin. 
Sci. (Lond.) 123: 567-90 
Sato K, Yamashita T, Kurata T, Lukic V, Fukui Y, et al. 2014. Telmisartan reduces progressive oxidative stress and 
phosphorylated alpha-synuclein accumulation in stroke-resistant spontaneously hypertensive rats after 
transient middle cerebral artery occlusion. J. Stroke Cerebrovasc. Dis. 23: 1554-63 
Wang J, Pang T, Hafko R, Benicky J, Sanchez-Lemus E, Saavedra JM. 2014. Telmisartan ameliorates glutamate-
induced neurotoxicity: roles of AT(1) receptor blockade and PPARgamma activation. Neuropharmacology 
79: 249-61 

11