Clinical trial NCT02118610
Conditions: Schizophrenia
Sponsor: University of Maryland, Baltimore
Start date: 2014-09-01; Completion date: 2019-06-01
Enrollment: 63 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Schizophrenia is a devastating and complex illness, with multiple symptom and behavioral manifestations. Antipsychotic medications are the mainstay of treatment; however, many patients only partially respond to treatment. Development of new treatment has not progressed rapidly, in part, because the underlying etiopathophysiology of the illness is not well understood. To date, all pharmacological treatments approved for use in schizophrenia involve primary modulation of the dopamine system. Many agents without dopamine action have failed to demonstrate efficacy. There is growing evidence that schizophrenia may be, in part, due to an inflammatory process and pharmacological treatment approaches that decrease inflammation have shown promise. Thus, treatments that may have anti-inflammatory properties (e.g., TNF-alpha inhibition), but also possess dopamine modulation may prove to be beneficial. This novel medication, l-tetrahydropalmatine (l-THP), has robust anti-inflammatory properties, particularly TNF-alpha and ICAM inhibition; has antiprotozoal activity; and possesses an antipsychotic-like pharmacological profile of D1, D2 and D3 receptor antagonism. The high affinity of l-THP for D1 versus D2 receptors distinguishes it from first generation antipsychotics and its D1 to D2 ratio resembles that of the superior antipsychotic, clozapine. Also, an almost identical compound, l-stepholindine (l-SPD), demonstrates robust antipsychotic activity in humans (both positive and negative symptoms) and is currently used clinically in China. l-THP has been used for over 40 years clinically in China, has a good safety profile to date, and represents a novel and exciting mechanism for schizophrenia treatment. Initial safety data from our phase I study of l-THP (20 healthy controls) shows excellent tolerability and lack of any substantial side effects. L-THP has been tested in outpatient drug abuse trials for 4 weeks with good safety data, (Hu et al 2006, Yang et al 2003). Yang et al (2003) randomized this medication in over 120 participants for 4 weeks with 4 week observation without any notable side effects.

We will test this compound (30 mg BID) as an adjunct treatment in a randomized, double-blind, 4-week trial, in which we will assess treatment efficacy, changes in peripheral cytokine concentrations, and, secondarily, antiprotozoal effects, (antibody titers to Toxoplasma gondii), an infection that is known to occur at higher rates in schizophrenia than healthy controls and may be related in part to the illness.

Detailed description:

Arms: arm 1: l-tetrahydropalmatine (30 mg BID) arm 2: None
Interventions: intervention 1: L-tetrahydropalmatine (30mg) intervention 2: Sugar pill
Intervention descriptions: intervention 1: Active comparator intervention 2: Placebo

Protocol documents:
Prot_SAP_000.pdf: 
1 
 
 
 
 
 
 
 
 
 
 
 
 
5/17/2018 
 
 
 
 
 
 
NCT02118610 
 
 
 
Treatment of Schizophrenia with l-tetrahydropalmatine (l-THP): a Novel Dopamine Antagonist 
with Anti-inflammatory and Antiprotozoal Activity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2 
 
Abstract 
 
Schizophrenia is a devastating and complex illness, with multiple symptom and behavioral 
manifestations. Antipsychotic medications are the mainstay of treatment; however, many 
patients only partially respond to treatment. Development of new treatment has not progressed 
rapidly, in part, because the underlying etiopathophysiology of the illness is not well 
understood. To date, all pharmacological treatments approved for use in schizophrenia involve 
primary modulation of the dopamine system.  Many agents without dopamine action have failed 
to demonstrate efficacy. There is growing evidence that schizophrenia may be, in part, due to 
an inflammatory process and pharmacological treatment approaches that decrease 
inflammation have shown promise. Thus, treatments that may have anti-inflammatory 
properties (e.g., TNF-alpha inhibition), but also possess dopamine modulation may prove to be 
beneficial. This novel medication, l-tetrahydropalmatine (l-THP), has robust anti-inflammatory 
properties, particularly TNF-alpha and ICAM inhibition; has antiprotozoal activity; and 
possesses an antipsychotic-like pharmacological profile of D1, D2 and D3 receptor 
antagonism. The high affinity of l-THP for D1 versus D2 receptors distinguishes it from first 
generation antipsychotics and its D1 to D2 ratio resembles that of the superior antipsychotic, 
clozapine. Also, an almost identical compound, l-stepholindine (l-SPD), demonstrates robust 
antipsychotic activity in humans (both positive and negative symptoms) and is currently used 
clinically in China. l-THP has been used for over 40 years clinically in China, has a good safety 
profile to date, and represents a novel and exciting mechanism for schizophrenia treatment. 
Initial safety data from our phase I study of l-THP (20 healthy controls) shows excellent 
tolerability and lack of any substantial side effects. L-THP has been tested in outpatient drug 
abuse trials for  4 weeks with good safety data, (Hu et al 2006, Yang et al 2003). Yang et al 
(2003) randomized this medication in over 120 participants for 4 weeks with 4 week 
observation without any notable side effects. 
 
We will test this compound (30 mg BID) as an adjunct treatment in a randomized, double-blind, 
4-week trial, in which we will assess treatment efficacy, changes in peripheral cytokine 
concentrations, and, secondarily, antiprotozoal effects, (antibody titers to Toxoplasma gondii), 
an infection that is known to occur at higher rates in schizophrenia than healthy controls and 
may be related in part to the illness..  We hypothesize that adjunctive l-THP added to 
antipsychotics in people with schizophrenia will significantly improve positive and negative 
symptoms, cognition, and inflammation, particularly through TNF-alpha inhibition, and may 
have antiprotozoal effects. We hypothesize it will be effective and safely tolerated.   In addition 
subjects can optionally participate with the addition of magnetic resonance imaging (MRI). 
 
Research Strategy:  
 
We have recently been funded by the Stanley Medical Research Institute to investigate l-THP, 
a novel drug having anti-inflammatory and antiprotozoal activity, as well dopamine antagonism 
and modulatory activity at GABA(A) and 5-HT 1A and 2A receptors. This drug could represent 
a breakthrough treatment in people with schizophrenia.  
 
Study Aims:  
 
1. To determine if adjunctive l-THP is superior to placebo for the treatment of positive and 
negative symptoms of schizophrenia.  (PRIMARY OUTCOME) 
 


3 
 
2. To determine if adjunctive l-THP is superior to placebo for reducing inflammatory 
response, assessed through peripheral cytokine concentrations (serum TNF-alpha, IL-
6 and ICAM-1 (primary); IL-1beta IL2, IL8, IL10, IL12, IL17, and IFNgamma) 
(secondary)), in people with schizophrenia  
 
3. To determine if adjunctive l-THP is superior to placebo for the treatment of cognitive 
impairments and depressive symptoms in people with schizophrenia 
 
4. To examine the tolerability and safety profile in l-THP relative to placebo in people with 
schizophrenia 
 
5. To evaluate the effects of l-THP in a subgroup of people who are positive for antibodies 
to Toxoplasma gondii at baseline (Exploratory Aim) 
 
Optional MRI Aims: 
1) To determine the effect of adjunct l-THP on brain glutamate and GABA concentrations and 
blood flow as measured with proton magnetic resonance spectroscopy (1H-MRS) and 
arterial spin labeling (ASL) respectively.  
We hypothesize that the addition of l-THP will significantly change glutamate, GABA and blood 
flow concentrations from pre- to post-l-THP treatment.  
2) To determine if the change in glutamate, GABA and blood flow relates to the improvement 
in positive, negative, and cognitive symptoms. 
We hypothesize that the amount of glutamate, GABA and blood flow change will correlate with 
the magnitude of improvement in positive, negative, and cognitive symptoms.   
3) To determine if the change in glutamate, GABA and blood flow relates to the change in 
peripheral inflammatory markers. 
We hypothesize that the amount of glutamate, GABA and blood flow change will correlate with 
the reduction in serum proinflammatory cytokines. 
 
We plan to conduct a double-blind, randomized, parallel group clinical trial of adjunct l-THP vs. 
placebo in 85 people with schizophrenia who are maintained on a stable antipsychotic 
regimen. This study will consist of 4 weeks of randomized treatment. 
 
Schizophrenia and Inflammation: Schizophrenia is a devastating and complex illness, with 
multiple symptom and behavioral manifestations. Antipsychotic medications are the mainstay 
of treatment; however, many people with schizophrenia only partially respond to treatment. 
Treatment development has not progressed rapidly, in part, because the underlying 
etiopathophysiology of the illness is not well understood. To date, all pharmacologic 
treatments approved for use in schizophrenia involve modulation of the dopamine system. 
Many agents without dopamine involvement have failed. There is growing evidence that 
schizophrenia may be, in part, due to an inflammatory process (Meyer et al 2011, Debnath 
and Venkatasubramanian 2013) and pharmacologic treatment approaches that decrease 
inflammation show promise (Sommer et al 2012, Keller et al 2013). Thus, treatments that 
encompass both effects on inflammation and also antagonism at dopamine receptors may 
prove of benefit in people with schizophrenia.  TNF-alpha is an inflammatory mediator that has 
been implicated extensively in schizophrenia. A recent meta analysis found TNF-alpha to be a 
significant trait marker that is elevated consistently in schizophrenia (Miller et al., 2010). Levels 
of TNF receptor 1 (TNFR1) mRNA are increased post-mortem in several brain regions of 
people with schizophrenia, demonstrating not only peripheral inflammation but also brain 
involvement of  TNF-alpha, which has not been shown  in other psychiatric disorders (Dean et 


4 
 
al 2013). TNF-alpha might contribute to the pathogenesis of schizophrenia by activation of the 
hypothalamo-pituitary-adrenocortical (HPA) axis, activation of neuronal serotonin transporters, 
stimulation of indoleamine 2,3-dioxygenase, which increases kynurenic acid, by 
immunologically mediated destruction of neurons, or release of glutamate (Himmerich et al 
2009). Interleukin-6 (IL-6) and intracellular adhesion molecule (ICAM)-1 are both mediated by 
TNF-alpha. (Yu et al 2008). IL-6 is consistently shown to be elevated in schizophrenia 
(Zakharyan et al 2012), while ICAM-1 levels are significantly lower in schizophrenia compared 
to healthy controls. Some genetic polymorphisms in ICAM have been related to schizophrenia 
(Kronig et al 2005).  
 
 
Effects of l-tetrahydropalmatine (l-THP) on inflammation: Tetrahydroprotoberberines 
(THPBs) are a class of alkaloids isolated from the Chinese species Stephania intermedia of 
the Cordydalis ambigua herbs. THPBs have effects on inflammation; the unpurified herb has 
been widely used in China since the 1970s for inflammatory disorders such as endometriosis, 
arthritis, menstrual inflammation, and pain (Zhao et al 2011). L-tetrahydropalmatine (l-THP) is 
one of the most interesting THPBs, used in China under the trade name Rotundine. l-THP has 
robust anti-inflammatory properties in immune pathways (Zhang et al 2005) implicated in 
schizophrenia.  For example, l-THP decreases TNF-alpha synthesis and neutrophil infiltration, 
thereby lessening the extent of apoptosis through a decrease in nitric oxide (NO) synthesis 
(Han et al 2012). It has neuroprotective effects, possibly modulated through 
neuroinflammation, and decreases glutamate concentrations and reduces cerebral ischemia in 
mice (Zhang et al 2004). These same effects protect against myocardial ischaemia-reperfusion 
injury in rats (Han et al 2012) by suppression of adhesion molecules and cytokine release. l-
THP markedly attenuated adhesion molecule expression induced by LPS in human umbilical 
vein endothelium cells (HUVEC). ICAM-1 and E-selectin expression were both markedly 
attenuated, suggesting that l-THP represents a promising candidate for the treatment of 
inflammation (Zhang et al 2005).  
 
 
Effects of l-THP on dopamine: In addition to its anti-inflammatory properties, l-THP has a 
pharmacologic profile similar to many medications that are effective for schizophrenia. Among 
the class of THPBs, l-THP and l-stepholidine (l-SPD) are two of the most potent binders to 
dopamine receptors (Xu et al 1989). l-THP has antagonist properties at D1 and D2 receptors. 
The higher affinity of l-THP for D1 (Ki=124 nM) versus D2 (Ki=388 nM) receptors resembles 
that of clozapine (Wang and Mantsch 2012), distinguishes it from conventional antipsychotics. 
l-THP also has antagonistic properties at D3 receptors and may exert antagonism at 
presynaptic autoreceptors, leading to increased dopamine release in the striatum. In rats, l-
THP acts on nigro-striatal neurons as a dopaminergic antagonist that can block both pre- and 
postsynaptic receptors. l-THP functions as an alpha-1 adrenergic receptor antagonist, a 
positive allosteric modulator of GABA(A), and modulates alpha -2 adrenergic receptors and 5-
HT 1A receptors (Lu et al 1996, Halbsguth et al 2003). L-THP also has serotonin (5HT 1A and 
2A) agonist activity (Qian et al 2012).  
 
l l-SPD  has a very similar pharmacologic profile to that of l-THP. In animal models, it 
increases the hind-limb retraction tie on the paw test and reverses apomorphine-induced 
disruption in prepulse inhibition. Overall, L-SPD has effects similar to clozapine but different 
than haloperidol (Ellenbroek et al 2006). For example, it preferentially increases Fos 
expression in corticolimbic areas, like clozapine and unlike haloperidol, possibly through non-
DA mechanisms (Mo et al 2005). Three clinical trials examined the effects of l-SPD in 


5 
 
schizophrenia. In the first placebo-controlled study, l-SPD (150 mg daily) for 8 weeks, together 
with a first generation antipsychotic, significantly improved BPRS scores and reduced tardive 
dyskinesia relative to placebo (Cai et al 1988). In the second study, l-SPD monotherapy (400-
600 mg daily) (N=13) significantly improved global symptomatology--baseline and endpoint 
Global Assessment Scale (GAS) scores were 39.4 ± 7.5 and 60.6 ± 12.4, respectively 
(p<0.05) (Wang et al 2000). The most recent study (Wu et al 2003) compared the effects of l-
SPD 225-625 mg daily (N=31) to perphenazine 16-44 mg daily (N=30) in an 8-week double 
blind randomized trial. l-SPD had earlier onset of effect and was significantly more effective for 
positive and negative symptoms than perphenazine and had no extrapyramidal side effects. 
The dopamine and 5HT1A effects of the THBPs suggest that they are promising novel lead 
drugs for the treatment of schizophrenia (Sun et al 2013). 
 
 
Effects of l-THP on Protozoal Infections:  Accumulating evidence shows that antibodies to 
Toxoplasma gondii (T. gondii), a protozoa that infects humans, along with its tissue cysts, are 
present in people with schizophrenia at increased rates and may be associated with 
neurologic and psychiatric manifestations of schizophrenia. At least 38 studies found T.gondii 
to be present in people with schizophrenia more frequently than in controls, with an odds ratio 
(2.71-2.73 95% CI) (Torrey et al 2012) suggesting T gondii is a moderate risk factor for 
schizophrenia. l-THP has strong to moderate anti-protozoal activity (IC50 0.08 ± 0.001 – 2.4 ± 
0.001 ug/ml, SI 1.5-1,154) (Malebo et al 2013, Baghdikian et al 2013).  While this may not be 
its primary mechanism of efficacy in schizophrenia, this anti-protozoal effect could contribute to 
improvements in symptoms in those positive for T.gondii, so we will perform exploratory 
analyses in this subgroup. 
 
Research Design and Outcome Measurements:  
We propose to conduct a double-blind, randomized clinical trial of four weeks of treatment with 
adjunct l-THP vs. placebo in 85 people with schizophrenia who are maintained on a stable 
antipsychotic regimen (inpatients and outpatients).  Participants will be seen weekly and given 
their medication on a weekly basis.  The Schedule of Events is listed below.  In addition to the 
PI, primary research staff will include a medically accountable physician, a regulatory 
compliance specialist, a study coordinator, a research nurse, a study pharmacist, a data 
analysist, a statistician, a research study supervisor and several co-investigators and staff. 
Participants will receive state-of-the-art care at the Maryland Psychiatric Research Center and 
24-hour availability of research personnel. 
 
Medical Workup: At baseline, all participants will undergo a medical work-up, including a 
comprehensive medical history and physical examination. We will obtain baseline, 
midpoint and end-of-study EKG, CBC, Chemistry Panel, liver enzymes, thyroid panel and 
urinalysis assessments. Weight, height and vital signs (heart rate, pulse, blood pressure) 
will be assessed weekly throughout the trial. The diagnosis of schizophrenia from the 
medical record will be confirmed by a structured psychiatric examination, the Structured 
Clinical Interview for DSM-IV (SCID). Following assessments of recent symptom history 
and current symptom levels, participants will be reassessed one week later, prior to 
randomization, to verify their continued symptom stability. Lab values that are considered 
to be abnormal may be repeated to verify accuracy. 
 
 
 
Inclusion Criteria:  


6 
 
1) DSM-IV diagnosis of schizophrenia or schizoaffective disorder; 
2) minimum score of 45 on the total Brief Psychiatric Rating scale; or a CGI socre of 4 
3) Age 18-64 years;  
4) currently taking antipsychotic regimen with no dose changes in last 30 days; and  
5) ability to consent determined by a score of 10 or greater on the Evaluation to Sign Consent. 
 
Exclusion criteria: 
1) women who are pregnant, nursing, or not using effective contraception (if capable of getting 
pregnant);  
2) current organic brain disorder or mental retardation;  
3) medical condition whose pathology or treatment could alter the presentation or treatment of 
schizophrenia or significantly increase the risk associated with study medication. This 
includes HIV, kidney disease, congestive heart failure, pheochromocytoma, untreated 
hyperthyroidism, dehydration, fever, uncorrected congenital heart defect, seizures, 
electrolyte imbalance, uncontrolled diabetes mellitus, porphyria variegate, superventricular 
tachycardia, atrial fibrillation, cardiomyopathy, or cancer. This also may include other 
medical conditions where the medically accountable investigator in the study does not think 
it would be in the best interest of the participant to participate in the study. 
4) current (past month) substance abuse or dependence (DSM-IV criteria) other than nicotine 
or caffeine; substance use, per se, will not be exclusionary;  
5) inability to provide valid informed consent. 
6) inability to understand English 
7) inability to cooperate with study procedures 
8) taking herbal or homeopathic medications where the metabolism of the drug is not known 
9) FOR MRI ONLY Contraindication for MRI scanning (e.g. metal in body, pacemaker). 
 
Symptom Outcomes: The primary symptom outcomes for this trial will be psychosis and 
negative symptoms.  
 
The Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham 1962) will be administered at 
baseline and at the end of each week. The BPRS is a widely used symptom rating scale in 
psychiatric research, is highly sensitive to change, and has excellent inter-rater reliability with 
appropriate training of raters. At MPRC, raters are required to show agreement >0.8 with gold 
standard ratings of training tapes.. Psychosis (sum of BPRS items for conceptual 
disorganization, hallucinations, delusions and suspiciousness) is one of two primary symptom 
outcomes. BPRS total score is a secondary symptom outcome.  
 
The Schedule for Assessment of Negative Symptoms (SANS) will be used to assess negative 
symptoms (Andreasen 1983). In this trial, we will use an adaptation of the SANS developed by 
the CONSIST investigators which allows for improved assessment of avolition in inpatient 
studies. In recent clinical trials at the MPRC, the SANS has shown high (>0.8) within-patient 
intra-class correlations (ICC). Inter-rater training and achieved reliability at the MPRC on the 
SANS is comparable to that for the BPRS. The SANS total score will be the other primary 
symptom outcome.  
 
Calgary Depression Rating Scale (CDS) (9 items) is designed specifically to assess 
depressive symptoms in people with schizophrenia and has been shown to be a reliable 
measure with good construct validity (Addington 1993). The CDS total score and suicide item 
will be secondary symptom outcomes.  
 


7 
 
The Columbia-Suicide Severity Rating Scale (C-SSRS) (Posner et al 2011) assesses suicidal 
ideation/behavior. 
Clinical Global Impression Scale (CGI): the CGI severity of illness and change scores items will 
assess severity of illness and global changes.  
Brief Negative Symptom Scale (BNSS) (Strauss et al 2012) will also be used as a measure of 
negative symptoms. It is a brief 13 item scale with good psychometric properties that provide 
good domains of negative symptomatology measurement. 
 
Peripheral Cytokines and Laboratory Measures (Baseline and endpoint during the trial): 
Plasma TNF-alpha, IL-6, and ICAM-1 (primary) and other inflammatory cytokines (IL-1beta 
IL2, IL8, IL10, IL12, IL17, highly sensitive c reactive protein, and IFNgamma) (secondary) will 
be measured in peripheral venous blood at baseline, 2 weeks, and at the end of the study. 
Serum cytokines will be measured by the Cytokine Core Laboratory at the University of 
Maryland using Luminex® 100 Multianalyte System or ELISA. Plasma levels of l-THP and its 
metabolites will be measured at midpoint and endpoint at the University of Maryland School of 
Pharmacy Pharmacokinetics Laboratory. CBC, Chemistry panel, EKG, liver enzymes, and 
thyroid function will be done at baseline, midpoint, and endpoint of the study.  
 
Antibodies to T. gondii will be measured at baseline and endpoint by solid phase 
immunoassay by Dr. Robert Yolken at Johns Hopkins University. The results are expressed in 
terms of ratios to arbitrary standards and are thus useful for comparison within groups.  In 
addition to T. gondii, the Hopkins laboratory will measure a panel of viruses, including Herpes 
Simplex Virus Type 2 (HSV-2), Cytomegalovirus (CMV), Epstein Barr Virus (EBV-EBNA), 
Varicella Zoster Virus (VZV), Human, Herpes Virus Type 6 (HHV-6), Influenza A Virus (H3N2), 
Influenza B Virus and Gliadin IgG.  Values greater than 1 are considered positive for all titers 
except for HHV6, which is considered positive if greater than 6. T. gondii serotyping for type 1, 
type 2, and type 3 will also be performed. 
 
Measures of Neurocognition (Baseline and endpoint). We will use the MATRICS 
(Measurement and Treatment Research to Improve Cognition in Schizophrenia) Consensus 
Cognitive Battery (MCCB), which is the standard for clinical trials in schizophrenia. The tests 
include Trail Making Test, Part A; BACS symbol coding subtest; Hopkins Verbal Learning Test, 
revised; immediate recall with three learning trials only; Wechsler Memory Scale, spatial span 
subtest; Letter-Number Span test; Neuropsychological Assessment Battery, mazes subtest; 
Brief Visuospatial Memory Test, Revised; Category fluency test, animal naming; Mayer-
Salovey-Caruso Emotional intelligence Test, managing emotions branch; and Continuous 
Performance Test, Identical Pairs version. These tests have good reliability and validity and 
require about 90 minutes. In recent multicenter clinical trials in which the MPRC has 
participated, individual tests of the MCCB have had ICCs between 0.6 and 0.8, and the overall 
MCCB composite score had an ICC of 0.9.  
 
Measures for Safety and Tolerability: We will do the following tests weekly throughout the 
study:  
 
Simpson Angus Extrapyramidal Symptom Rating Scale (SAS) (Simpson and Angus 1970) (a 
modified 11-item version of the SAS will be used to assess extrapyramidal symptoms (EPS)), 
 


8 
 
Barnes Akathisia Scale (BAS) (Barnes 1989) (a 4-item scale designed to assess objective and 
subjective components of akathisia)  
 
Side Effect Checklist (SEC) is designed to assess commonly occurring side effects and those 
relevant to l-THP 
 
Epworth Sleepiness Scale (ESS) is an 8-item scale rated 0-3 that evaluates daytime 
sleepiness 
 
Optional Magnetic Resonance Imaging (MRI).  
 
Magnetic resonance techniques allow us to non-invasively examine the human body in vivo 
and gather information about different structures, functions, connectivity, and chemistry.   
Brain anatomy, chemistry, and blood flow will be investigated with noninvasive magnetic 
resonance (MR) techniques. MRI scanning will take place at the UM Center for Brain Imaging 
Research. MRI scans will be conducted on a Siemens 3 Tesla magnet).   
 
Subjects will be screened twice for eligibility to enter the MR scanner, once by the research 
assistant and again by the MR technologist immediately prior to entering the MR suite. Prior to 
entering the MR suite, subjects will be asked to remove all metal from their clothing and/or 
change into MRI-compatible clothing before undergoing a study protocol. To protect the 
subject's hearing, earplugs or earphones will be provided, but the subject will still be able to 
hear instructions. Subjects will lay down on the examination table, be made as comfortable as 
possible, and moved inside the MR scanner for the duration of the study. Two anatomical 
scans will be conducted, T1-weighted imaging and diffusion tensor imaging (white matter 
anatomical imaging).  Glutamate concentrations will be collected with proton magnetic 
resonance spectroscopy (1H-MRS) and blood flow will be collected with arterial spin labeling 
(ASL).  Functional connectivity will be examined with resting-state functional MRI (fMRI). The 
total MR scan time will be about 1.5 hours. No intravenous contrast will be injected. 
 
Subjects will be communicated with by the MR technician and study team members in the MR 
control room throughout the scan and reminded that individual(s) in the control room can see 
and hear them at all times. Each subject will be reminded that if they become uncomfortable 
and wish to leave the magnet, they can tell the study staff or MR technologist and they will be 
promptly removed from the scanner. Once the study protocol is completed, the subject will be 
removed from the MR scanner. 
 
 
Schedule of 
Events 
 
 
 
 
 
 
Encounter # → 
1 
(Screening) 
2 
(Baseline)
3
4
5
6 
(Endpoint) 
Week of Study →  
W -1-4  
W0
W1
W2
W3
W4 
Procedure ↓ 
 
Informed consent 
and ESC 
X 
 
 
 
 
 
Demographic 
Forms 
X 
 
 
 
 
 


9 
 
Past Psychiatric 
and Medication 
History Form 
X 
 
 
 
 
 
 SCID-Interview 
X 
Medical History 
X 
Physical Exam and 
height 
X 
 
 
 
 
 
SMAC, BUN, 
glucose,  
X 
X
 
X
 
X 
CBC, UA, lipids, c-
reactive protein 
 
X 
 
X 
 
X 
LFT 
 
X
X
X
X
X 
Urine Pregnancy 
Test (female 
participants) 
X 
X
X
X
X
X 
EKG 
X 
X
X
X 
Fagerstrom Test 
for Nicotine 
Dependence 
 
X
 
 
 
X 
 QSU-B 
(Questionnaire for 
Smoking Urges - 
Brief) and the 
Nicotine 
Dependence 15 
item 
 
X
 
 
 
X 
MATRICS 
Consensus 
Cognitive Battery  
 
X
 
 
 
X 
Clinical Global 
Impression Scale 
(CGI) 
X 
X
 
 
 
X 
Brief Negative 
Symptom Scale 
(BNSS) 
 
X
 
 
 
X 
Brief Psychiatric 
Rating Scale  
X 
X
X
X
X
X 
Positive and 
Negative 
Syndrome Scale 
(PANSS) 
 
X 
 
 
 
X 
Scale for the 
Assessment of 
Negative 
Symptoms  
 
X
X
X
X
X 
Calgary 
Depression Scale  
 
X
X
X
X
X 
C-SSRS 
 
X
X
X
X
X 


10 
 
Simpson Angus 
Scale  
 
X
 
 
 
X 
Barnes Akathisia 
Scale  
 
X
 
 
 
X 
Cytokines 
 
X
X 
T. gondii, HSV 
 
X
X 
l-THP and 
metabolite levels 
 
 
X 
X
X 
X 
Prolactin Level 
 
X
X 
Side Effect 
Checklist and ESS 
 
X
X
X
X
X 
Vital Signs, 
including weight, 
BP and pulse 
X 
X
X
X
X
X 
Pill Count 
 
X
X
X
X 
Optional MRI  
 
X
X 
 
 
Treatment and Acquisition: Treatments will be assigned at random, using separate 
permuted block randomization sequences. The l-THP (or matching placebo) will be dosed as 
one capsule (30 mg) twice daily (total 60 mg daily). The l-THP has already been prepared at 
the University of Maryland School of Pharmacy to Chemistry, Manufacturing and Controls 
CMC standards after obtaining the purified l-THP from China and receiving the IND from the 
FDA. Identical placebo and active capsules will be manufactured and sent to the Maryland 
Psychiatric Research Center Pharmacy, where they will be stored and dispensed.  
 
Preliminary Data on Safety: In conjunction with Dr. Jia Bei Wang from the University of 
Maryland School of Pharmacy, l-THP has been formulated in a GMP laboratory as 30 mg 
tablets, which we plan to give twice daily, the dose found effective in prior studies. Since 
February, 2013, our group has enrolled 20 healthy participants into a 3-day inpatient study to 
test tolerability and safety of l-THP. These controls (without drug use histories) experienced no 
significant or unexpected side effects (a 25-item list of potential side effects was read to 
participants daily) and no clinically significant laboratory changes were seen.   
 
We have been approvd by the FDA with a new IND. l-THP is widely used in China for over 40 
years and approved by the Chinese SFDA (FDA equivalent) (Chu and others 2008; Jin 1987). 
The drug, according to the Chinese pharmacopeia and drug labels, is safe at the 
recommended therapeutic dosage range (60-120mg). Adverse effects include drowsiness 
(77% at dose above 90mg), dizziness, and nausea (rare). Although l-THP is a main active 
ingredient from a Chinese herb, it is regulated by the Chinese SFDA, and successfully 
completed a medication development process in the early 1960s. Therefore, it should not be 
considered an unregulated herbal product. Overdose has caused respiratory inhibition and 
extrapyramidal symptoms. Literature search (in English and Chinese) found a few reported 
cases of allergic reaction and CNS reactions after use of l-THP, but no reports of liver, kidney, 
or cardiovascular toxicity associated with the use of l-THP in humans. Our phase I study also 
found no untoward side effects. In addition, l-THP has been safely used in outpatient studies 
for heroin use (Hu et al 2006, Yang et al 2003). The 60 mg per day dose, based on previous 
studies, should minimize sedation.There are no known and reported drug interactions in 
humans however to be very cautious based on a paper with l-THP was reported to have some 


11 
 
inhibition in vitro of the CYP450 2D6 pathway (Sun et al 2013) we have created an appendix 
of mediations that are primarily metabolized by the 2D6. We initially started participants in 
the inpatient setting and saw patients more frequently than once weekly. The study is 
enrolling outpatients that are seen once weekly.  We do not believe the risk of CYP 
2D6 inhibition is high and were cautious when beginning the study in the first few 
participants. We will not include this as exclusionary but if participants are on these 
medications they will be evaluated weekly for possible drug interactions.  
  
Recruitment: Recruitment for this study will occur through 3 primary sources. 1) We will be 
specifically recruiting in the inpatient and outpatient clinics at the Maryland Psychiatric 
Research Center, the primary clinics used for study recruitment at MPRC. 2) Our program in 
the TRP, through funding from the National Institute of Drug Abuse (NIDA), has built a large 
screening database over the past 3 years with over 200 people recruited by local 
advertisements. 3) We will also utilize a developed recruitment network with community mental 
health centers, the Practice Research Network (PRN). This PRN was developed in 2008-2009 
(funded by IP-RISP, PI Dr Buchanan) to provide a network for schizophrenia research in the 
State of Maryland. We are confident we will have no trouble recruiting participants. The PI has 
successfully completed all previously funded studies. As an example, Dr. Kelly just recently 
completed an NIMH R21 study of minocycline adjunct to clozapine in schizophrenia. 
Recruitment began in June of 2011 and all 50 participants were enrolled in two years, the 
participant last finishing within 2.25 years of the start of recruitment. 
 
Participant Payment:  Participants will receive $40 for screening visits and $40 for all 4 
weeks in the study, and $25 for each completed MRI.  This totals to a payment of $200 for 
study completion, without the MRI scans and $250 with the MRI scans. Transportation will be 
provided by prepaid taxi rides. Meals may be provided if the study visit falls near meal times.  If 
an additional screening visit is required participants will be paid $40 more for the extra visit. 
 
Management of Data: Data collected for this study will be entered into the MPRC research 
data base using the usual procedures developed for MPRC clinical trials. This study will be 
reviewed UMB IRB and by a Data Safety Monitoring Board (DSMB).  
 
Data Analysis: As specified above, our primary symptom outcomes will be the BPRS 
psychosis score and SANS total score, assessed at baseline, midpoint, and end of study. We 
will analyze these two primary outcomes (as well as secondary outcomes collected on the 
same schedule) in intent-to-treat analyses using mixed models for unbalanced repeated 
measures (MMRM) analysis of covariance (ANCOVA), including all available observations 
from participants who complete at least one follow-up rating , where each primary outcome 
measure is adjusted for its baseline score.  Use of mixed models has the advantages that data 
from participants who drop out early can be included in the analysis and that estimates of 
treatment effects will be unbiased by dropout, if reasons for dropout ignorable with respect to 
the outcome, given the observed data. These models will have the basic form: follow-up score 
= baseline score + week + treatment + treatment x week, where week is a set of categorical 
indicators defining which week the follow-up score comes from.  
 
The primary test for treatment effect will be a post hoc contrast from the MMRM outlined 
above, comparing the mean outcomes scores at week 4, adjusted for baseline, in patients 
assigned to l-THP or placebo. We have chosen to focus on week 4 differences because of 
uncertainty about when treatment differences will emerge in the two strata. To take account of 


12 
 
having two primary outcomes, in testing for differences we will use the Benjamini-Hochberg 
False Discovery Rate (FDR) method. If the p-values for both primary outcomes are <0.05, both 
null hypothesis will be rejected. Otherwise, if one p-value is <0.025, the corresponding null 
hypothesis will be rejected. Secondary outcome measures collected at baseline and end of 
study will be analyzed as follows, testing at unadjusted α=0.05 for secondary analyses. 
Change scores for cytokines, which often have highly skewed distributions, will be analyzed 
using the Wilcoxon rank sum test. The FDR method will be used to adjust for multiple 
comparisons for the three primary cytokines (serum TNF-alpha, IL-6 and ICAM-1). Four weeks 
is sufficient time to detect an antipsychotic effect. Recently shorter clinical trials of 2 to 4 weeks 
duration have been recommended as a viable option for early identification of drug efficacy. 
Several large studies using a wide range of antipsychotics have found the power analyses 
show that placebo-drug differences are robust by 2 weeks (Kinon et al 2010a, Kinon et al 
2010b, Giegline et al 2012). Thus, most studies show most benefit within the first 4 weeks of 
treatment and response at 2 weeks predicts response at 6 weeks as does nonresponse at 2 
weeks predicting nonresponse at 6 weeks (Kinon et al 2010a) 
 
The MATRICS battery composite score, a normed average of the T scores representing 
different cognitive domains, will be our primary neurocognitive outcome measure and will be 
analyzed using analysis of covariance, adjusting for baseline MCCB composite score. Daytime 
drowsiness scores (from ESS) at baseline will be compared between treatment groups using 
analysis of covariance, adjusting for ESS scores measured at baseline.  
 
T.gondii antibodies we conservatively estimate to occur in 50% of people with schizophrenia 
(Hamidinejat et al 2010). In an exploratory analyses in participants initially seropositive, we will 
compare the two treatment groups on the proportion of participants who become seronegative 
at the end of the trial, and will compare symptom changes from baseline to week 4 in those 
remaining seropositive versus converting to seronegative.  Dr. Robert Yolken will advise and 
oversee the research plan, data collection and analysis of this through the Stanley Division of 
Developmental Neurovirology at Johns Hopkins University. We are unsure if we will see 
significant changes in antibody titers, but this preliminary aim will allow us to see if 
antiprotozoal effects leads to improved titers. We will also be able to test if those with 
antibodies show more improvement in symptoms than those without.  
 
MRI: Glutamate and GABA concentrations and blood flow will be the primary outcome 
variables.  Comparisons between the pre and post l-THP treatment will be conducted with t-
tests (MRS) and MANOVA (multiple brain regions for blood volume).  Specific brain regions 
that will be investigated include the anterior cingulate, hippocampus, and dorsolateral 
prefrontal cortex.  
To test specific aims 2 and 3, linear regression model will be used to estimate if glutamate and 
GABA concentrations and blood flow is correlated with positive, negative, cognitive, and 
peripheral measures of inflammation. 
 
 
Power: With n=85 participants, and 15-20% attrition by end of study, consistent with recent 
adjunctive treatment studies at MPRC, we anticipate having end-of-study ratings on at least 52 
participants, approximately evenly divided between placebo and l-THP. We estimate 
approximate power for the primary outcome using the main effect of treatment in a simple 
ANCOVA, adjusting for baseline. The effect size E, detectable by a repeated measures 
ANCOVA for a given sample size, n, per group is given by: E2 = 2(z1-α/2 + z1-β)2 (1-ρ2)/n, where 
z1-α/2 and z1-β are the quantiles of the normal distribution corresponding to the specified Type I 


13 
 
error rate and power, respectively. In this formula, the term (1-ρ2) reflects the reduction in the 
variance in follow-up scores from adjusting for the baseline score. To estimate power 
conservatively, we set α=0.025, two-sided, to reflect use of the FDR method. We anticipate 
being able to detect an effect size of d=0.57 if ρ=0.7 or d= 0.48 for ρ =0.8, consistent with 
ICCs we have seen in trials of similar length in clinically stable participants for the BPRS 
psychosis score and SANS. For the MCCB composite score, we and others have found ρ>0.9. 
Testing at α=0.05, two-sided, we should have power=0.80 to detect an effect size d=0.349 on 
the MCCB composite.  
 
 
 
HUMAN SUBJECTS  
 
1. Protection of Human Subjects 
 
 
a) Human Participant Involvement, Characteristics and Design 
 
The proposed study meets the definition of a “Clinical Trial” and it will be registered in 
ClinicalTrials.gov. Participants involved in this study will be diagnosed with schizophrenia or 
schizoaffective disorder and will be stabilized on current antipsychotic medications. Included 
participants must also be judged competent to consent by the Evaluation to Sign Consent (ESC) 
questionnaire, and provide voluntary informed consent.  Women with reproductive potential 
must agree to the use of medically approved birth control, which includes oral contraceptives, 
condoms, diaphragms, and intrauterine device.  Pregnant and nursing women will be excluded.   
 
Project Timeline:  
 
Year 
Start-Up Activities 
Recruitment and Study 
Activities
End of Study
Activities
Year 1 
- Finalize protocols, IND 
amendment, data base 
design, inter-rater reliability  
- IRB, and clinical trials.gov 
registration 
- Enroll approximately 18 
participants  
-Ongoing rater reliability 
 
 
Years 
2-4 
 
- Enroll approximately 25 
participants  
-Ongoing rater reliability 
-Annual Reports
 
Year 5 
 
- Enroll approximately 17 
participants  
-Between site monthly meetings 
- Conduct data cleaning and 
analyses and manuscript 
preparation. 
-Presentation of results at 
annual meetings   
-End of Study Reports
 
 
b) 
Sources of Materials 
 
Material sources for this study include computerized and hard copy research records and blood 
and urine specimens. All research records will be kept in locked files with participants’ 


14 
 
evaluation study materials identified by code only. A separate file will hold the code key. 
Participants will not be personally identified in any publications or reports of the study. Any data 
used will be re-copied to research files with the participant identified by code only. The highest 
standards of participant confidentiality will be kept, and no participants will have identifiable 
information available to anyone other than authorized study staff. Computerized records of data 
are kept in a password-only accessible computer in a locked room. Appropriate firewalls and 
protections of computerized data are maintained to ensure that entry by those other than 
research personnel is not possible.  
Data will be entered into a Microsoft Access database. All forms are identified within this 
database by a unique participant ID number, participant initials, and the protocol ID number and 
acronym, together with the protocol phase and visit. The protocol data collection schedule is 
kept in a data base table and is used to monitor the progress of participants through the 
protocol, missing assessments, and other protocol deviations during the study. Data entry 
screens incorporate range checks or lists of valid responses for each item.  Forms with missing 
or invalid data in key identifying fields are referred back to raters for correction before entry.  
Participant confidentiality is maintained by restricting study data access to specified study 
personnel.  Most authorized personnel will have read-only access, and write/edit access will be 
restricted to data entry and data management staff assigned to the study. An electronic audit 
trail records all changes to the data base once data have been entered. The database resides 
on a central server, and all server data are backed up several times weekly. Access to the 
server from outside the MPRC is restricted by a firewall. Norton Anti-Virus software, updated 
automatically whenever new virus data files are provided, is installed on the server, and all 
computers are linked to the server. Development of the data management system for this study 
will be facilitated by the existence of this data base structure, which already contains tables and 
data entry screens for many of the assessments used in this study. 
 
All of the above data will be gathered specifically for research purposes only. Information 
collected in this study will be stored and managed by the Biostatistics and Study Management 
Core at MPRC. Access to research data stored in the database will be limited to investigators 
who have been granted user names and passwords by the PI.  
 
All blood and urine specimens are for research purposes only and will be identified at the 
laboratory by code only.  Conventional laboratory tests will be performed and evaluated by Lab 
Corp® using GLP procedures and policies. Blood for the immune measures will be kept in a 
secure -80ºC freezer until ready for analysis.  
 
c. Potential Risks to the Participants 
 
 
The major risks of the study are the risk for side effects from l-THP.  L-THP has more than 40 
years of safe clinical use in China, and its toxicity profile in a variety of patient groups is well 
established (Chu and others 2008; Jin 1987).According to the Chinese pharmacopeia and drug 
labels, l-THP is safe at the recommended therapeutic dosage range (60-120mg). Adverse 
effects include drowsiness (77% at dose above 90mg), dizziness, nausea (rare), and 
neutropenia. Although l-THP is a main active ingredient from a Chinese herb, it is regulated by 
the Chinese SFDA  and successfully completed a medication development process in the early 
1960s. Therefore, it should not be considered an unregulated herbal product. Overdose has 
caused respiratory inhibition and extrapyramidal symptoms. Literature search (in English and 
Chinese) found a few reported cases of allergic reaction and CNS reactions after use of l-THP, 
but no reports of liver, kidney, or cardiovascular toxicity associated with the use of l-THP in 
humans. Our preclinical and phase I data submitted to the FDA did not show any unexpected or 


15 
 
serious side effects. Existing data does not suggest weight gain or metabolic effects; however, 
given that these are side-effects from many standard antipsychotics, we will carefully monitor for 
them. 
Other risks include bruising from peripheral venous blood collection, skin irritation from 
EKG electrodes, and boredom from cognitive testing. The risk from research interviews is 
minimal and relatively uncommon. During assessments, participants may be uncomfortable 
discussing their smoking habits or mental health history and treatments. Participants may 
become frustrated and tense when they encounter difficulty completing tests or interviews. 
Careful planning and observation of the participant's response to these sessions will allow the 
testing to be completed with a minimum of discomfort.  Participants may take breaks at any time 
to alleviate discomfort. All interviewers are trained to recognize signs of distress or anxiety. The 
participant will be reminded that they can refuse to answer any question that makes them 
uncomfortable and may take breaks whenever they are needed. There is a slight risk of breach 
of confidentiality. All data will be coded with an ID number that is unique. All data, including 
information from chart reviews, therapist reports, and laboratory results, will be identified by ID 
number only. Only the study team will have access to the link between the ID number and 
participant’s name. Data containing names and personal information will never be included in 
published materials.  
 
MRI: The effects of magnetic fields in an MR scanner have been extensively studied, and the 
risks with an MR exam are low, particularly if the patient qualifies for the testing based upon the 
screening questions.  Both the magnetic field strength and the superconductor represent 
potential hazards: ferromagnetic objects introduced into the field can become high velocity 
projectiles capable of causing serious injury to persons in/or around the magnet, the force 
exerted by the magnetic field can cause metallic implants to move, thereby causing injury, 
current induced in an implant can cause local heating of tissue, magnetic fields and 
radiofrequency fields can interrupt the activity of electromagnetic implants, and radiofrequency 
power deposition may cause local heating of tissue. To protect against or treat these adverse 
effects, all subjects will be carefully screened for MRI contraindications using the standard MRI 
screening form, which includes questions about implants.These risks will be further minimized 
by strict adherence to standard MR operating procedures that require all ferromagnetic objects 
be kept from the magnet room and all subjects be screened for metallic objects and implants, 
and electromagnetic implants. Subjects will be required to remove metal objects from their 
person. Those with metallic or electromagnetic implants will be excluded from the study. The 
possibility of local tissue heating due to radiofrequency power deposition is mainly restricted to 
fast imaging protocols. The system automatically calculates and monitors power prior to and 
during the MR exam for each subject. Safety features of the software prevent starting an 
imaging protocol that exceeds FDA guidelines for power deposition. This safety feature is not 
subject to modification by researchers.The participant will be asked to wear earplugs or 
earphones while in the magnet.   
 
Subjects may experience a feeling of being isolated or confined by the scanner (i.e., 
claustrophobia). We minimize these discomforts by explaining the procedure in great detail and 
by maintaining voice contact with the subject at all times. The most likely difficulty will be that a 
subject is unable to hold still for the MR scan. This would degrade the quality of the image 
obtained, but it would not be dangerous for the subject.  
 
 
d) Adequacy of Protection against Risks 
 


16 
 
We will make every attempt to minimize all study-related risks. Women with reproductive 
potential must agree to the use of medically approved birth control, which includes condoms, 
oral contraceptives, diaphragms, and intrauterine device, during the study. Pregnant and 
nursing women will be excluded. We will test for pregnancy at each visit. We will carefully 
monitor for side effects and psychiatric symptoms at weekly visits throughout the study.  In 
addition, complete blood count (CBC) is drawn at baseline, midpoint, and endpoint of study to 
monitor for any changes in blood count. 
 
A partial HIPPA waiver will be obtained to permit the identification of potential participants 
through chart review. In addition, participants may be referred by their treatment team for 
consideration of study participation. No potential participant will be approached for recruitment 
without approval of a primary clinician, who will determine suitability of the person for the 
protocol.  A chart review will be completed for all potential participants to reduce the likelihood 
that they will be found ineligible after participating in more extensive assessment. The study 
recruiter will verify with the primary clinician that a potential participant is sufficiently stabilized to 
consider participation and has capacity to provide consent.  This is done prior to the study 
recruiter approaching a potential participant. The study recruiter will be introduced to the person 
and provide a brief overview of the project. Research staff members are trained to recognize 
symptoms of severe mental illness and cognitive impairment that could undermine an 
individual's ability to provide informed consent.  Interested people will be provided study 
information and an informed consent form that contains all pertinent details of participation and 
includes the following: a brief explanation of the purpose of the research and a brief explanation 
of the requirements of the participant, including: a) willingness to be randomly assigned to either 
intervention, b) completing a series of interviews about one’s symptoms, c) completing 
assessment tasks, and d) being available for follow-up assessments.  
 
Participants will remain on adjunctive anticholinergics, antidepressants, mood stabilizers, and/or 
antianxiety agents. Participants on such medications are included to increase the 
generalizability (external validity) of study results and to relate the study more closely to 
treatment issues addressed in usual clinical practice. In order to decrease the likelihood that any 
observed change in outcomes during the study is related to adjunctive treatment, a participant 
must have been on the adjunctive medication(s) for at least two months and on his/her current 
dose(s) of adjunctive medication(s) for at least one month prior to study participation. The dose 
of adjunctive medication will remain fixed throughout the study, except for required side effect-
related adjustments in anticholinergic medications. If at any time throughout the study a 
participant’s condition worsens after permissible dose adjustments are made, he/she will be 
withdrawn. 
 
All participants will be closely monitored and seen weekly during the study. Either the medically 
accountable physician or the PI may determine that the participant is experiencing clinical 
worsening, defined as: the participant is judged to be experiencing an exacerbation of his/her 
illness; an increase of 3 or more points from baseline on a BPRS positive symptom item or 
hostility; an increase of 2 or more points from baseline on the CGI global severity rating or 2 or 
more increase on CDS suicidal rating or new onset suicidal thoughts as judged by one of the 5 
questions with an answer of “yes” on the C-SSRS. We will work with treatment teams at all sites 
and we will have a 24-hour telephone number with research staff available to take the call; 
participants can call at any time with their concerns, and they will be instructed to call when they 
are experiencing suicidal thoughts or symptom worsening, in depression, mania or psychotic 
symptoms. Research staff may direct them immediately to an emergency department. In 
addition, study withdrawal will occur in case of a side effect which is,clinically significant, 
possibly life threatening or may interfere with the study procedures  . Participants may opt to 


17 
 
withdraw at any time during the study. Once a participant is planned for study withdrawal, all 
end-of-study measures will be performed, if possible, including blood collection and ratings, and 
we will refer the participant to other treatment. If serious suicidality is observed, the study 
suicide prevention plan will be implemented immediately and the participant will be withdrawn 
from study. The suicide prevention plan consists of immediate psychiatric evaluation by a 
psychiatrist, implementation of a suicide prevention contract, provision of 24-hour access to a 
physician, referral to emergency services as necessary, and continued evaluation using the 
CDS and C-SSRS. 
 
Protection from research interview and data-gathering risks. In previous studies with this target 
population, we developed procedures for conducting interviews in a manner that is sensitive to 
the needs of the participants and the emotional nature of the interviews, while maintaining high 
scientific standards.  Several of the strategies that we used successfully to minimize potential 
distress for participants include: informing participants before the interviews about the topics 
that will be covered; reminding participants that they may choose not to answer certain 
questions or to terminate the interview at any time; taking breaks during the interview when the 
participant feels anxious or distressed. Interviewers will be trained in the recognition of, and 
appropriate response to (including the involvement of other professionals), specific kinds of 
participant negative responses.  
 
Confidentiality. Careful procedures will be used to protect the privacy of participants and the 
confidentiality of the data.  Names will only appear on consent forms and on a master list that 
links them with study ID numbers (different from medical record numbers). This list will be 
stored in locked files in a separate location from the data.  At the conclusion of the project, the 
list will be destroyed, unless continuation is planned and approved by the Institutional Review 
Board. All data (whether on forms or electronic data files) will be collected, analyzed, and 
reported according to the study ID number and will contain no names or other personal 
identifiers. Paper-based data will be stored in locked files. Electronic data files reside on 
desktop computers and are password protected. All videotapes that are created for fidelity and 
reliability purposes will be coded with an ID number and kept in a locked storage area. At the 
end of the research study, all videotapes will be destroyed.  Because this study is conducted 
under an IND, there is a potential that identifiable data may be shared with the US FDA, grant 
management staff, University of Maryland IRB or quality assurance staff as part of its auditing 
process. 
 
Protection from project intervention risks. A medically accountable physician is available to see 
all study participants. All clinical and research staff will be watchful regarding the participant’s 
status, and any concerns are discussed with study PIs and will be reported to the participant’s 
treatment team at the recruitment site. Research staff members have strict procedures for 
responding to suicidal or homicidal thoughts or behaviors, including ensuring immediate follow-
up with the participant’s treatment team or the study PIs. It is made clear to participants that 
they are free to terminate participation in the project at any time and return to usual clinical 
services without any penalty.  If it is clear that involvement in any of the project’s interventions is 
contributing to the worsening of a participant’s status, the clinical staff will discuss the meaning 
and implications of this exacerbation with the participant and the research staff.    
 
Steps taken to minimize the risks for MRI. 
 Prior to MR imaging subjects are interviewed twice to screen for contraindications. Those with 
metallic or electromagnetic implants will be excluded from the study.  These risks will be further 
minimized by strict adherence to standard MR operating procedures that require all 


18 
 
ferromagnetic objects be kept from the magnet room.  Subjects will be required to remove metal 
objects from their person.   
 
The MR system automatically calculates and monitors power prior to and during the MR exam 
for each subject. Safety features of the software prevent starting an imaging protocol that 
exceeds FDA guidelines for power deposition. This safety feature is not subject to modification 
by researchers. Last, the participant will be asked to wear earplugs or earphones while in the 
magnet.   
 
Careful planning and observation of the volunteer's response to the MR scanning session will 
allow research team members to ensure volunteers do not endure discomfort. The volunteer will 
be reminded during the MR scan that they can be seen and heard at all times and can 
discontinue participation at any time without consequence prior to or during scanning. 
 
 
Consenting:  
The consent form will include an explanation of the risks and benefits of participation; 
assurances of confidentiality; and an explanation that participation is entirely voluntary, the 
decision to participate will in no way influence or restrict services at participating sites, and the 
participant is free to withdraw at any time without negative consequences. Potential participants 
will be informed that the drug used in this study is not known to be effective for the indication 
under investigation. As some potential participants will have poor reading skills, the consent 
form will be read aloud to all participants in tandem with their own silent reading of the 
document.  The individual securing consent will review any points about which the participant is 
unclear, and the participant will be invited to ask questions as needed. Our research staff is 
carefully trained in strategies for interacting with people with severe mental illness, including 
speaking slowly and clearly, stopping to summarize frequently, and providing time for questions. 
They are all supervised by senior staff members. All participants who express willingness to 
provide consent will be queried about the consent form in order to ensure that they have 
adequate understanding of the study requirements.  This questioning is performed 
systematically, and research staff members document that this review has been completed.  
After reading the consent, and before obtaining a signature, a brief questionnaire is 
administered to verify that the participant is competent to provide consent and has 
demonstrated comprehension of the consent document. This questionnaire is attached to the 
informed consent form and is completed immediately after explaining the informed consent form 
and before obtaining the participant's signature on the form. If the participant does not 
understand the consent form, the recruiter will try to explain points of confusion, and administer 
the questionnaire again. Those failing to answer the questions adequately will not be recruited 
into the study. The recruiter will also make a clinical judgment and not recruit participants who 
appear unable to grasp key aspects of the procedure. This approach, which requires a proactive 
demonstration on the part of the participant that they understand what is being requested, has 
been used extensively by investigators at the MPRC. Included participants must also be judged 
competent to consent by the Evaluation to Sign Consent (ESC) questionnaire (DeRenzo et al 
1998).  Per University of Maryland School of Medicine IRB regulations, a copy of the signed 
consent form is given to the participant, a copy is placed in the person's medical record, and the 
original is kept by the PI.  
 
Research assistants obtaining informed consent will be experienced clinicians. They will receive 
detailed and standardized training as to how to obtain informed consent from people with 
serious mental illnesses. They will be observed obtaining informed consent from a study 
participant by senior staff prior to being allowed to enroll participants on their own. 


19 
 
 
 
e) Potential Benefits of the Proposed Research to Participants and Others 
 
By participating in this study and receiving a closely observed treatment trial with an 
investigational medication, the participant may have improvement in variety of symptom 
domains. In addition, we may improve understanding of the role of immune responses in  
schizophrenia treatment. Participants receive l-THP free of charge and have close observation 
during the study. 
 
There are several other potential benefits from participating in the study.  Participants receive 
standard elements of treatment, but with a heavier emphasis on continuity of clinical care and 
close clinical monitoring for signs of exacerbation than is common in community treatment.  By 
virtue of their participation in numerous assessments and evaluations necessary in a combined 
clinical/research endeavor, they will receive more attention than is ordinarily given.  Their 
progress will be frequently and closely monitored from a variety of clinically relevant 
standpoints.  In addition, participants will gain specific information concerning their neurological 
status and observations of treatment response which might guide their future pharmacologic 
treatment.  Moreover, participants and their families receive considerable education about the 
participant’s illness.  Such knowledge can provide significant benefits by increasing the capacity 
of the participant and his/her family to monitor and seek early clinical attention for future 
manifestations of illness. 
 
 
f) Importance of the Knowledge to be Gained 
 
The importance of the knowledge gained outweighs any risks that may occur in this study. L-
THP has been used in China for 40 years and has a good safety record. This medication may 
provide an efficacious treatment for symptoms of schizophrenia and could provide benefits to 
millions of people with schizophrenia if found to be effective. 
 
 
 
2. Inclusion of Women 
  
The sample will consist of approximately 20 women. This one-third proportion of women 
is typical of previous research studies at MPRC.  
 
3. Inclusion of Minorities 
Racial data will be considered prior to ethnicity for the purpose of this study. Participants are 
permitted, however, to select more than one racial category. We expect about 32 (53% of total) 
participants to be African American, based on a 54% population of African Americans enrolled 
in previous clinical trials at the MPRC. 
 
 
4. Inclusion of Children 
 
Only those 18 and older will be included in this study because of limited safety data with 
l-THP in children and the different clinical nature of childhood schizophrenia.  
 
5. Data and Safety Monitoring Plan 
 
The Data Safety and Monitoring Board (DSMB) already established at the MPRC will be 
used for this study. The DSMB is comprised of three psychiatrists (2 involved in treatment and 
research, 1 who is a clinical practitioner), a pharmacist, and a statistician. The psychiatrists are 
experts in the clinical treatment of people with schizophrenia. The DSMB will be charged with 


20 
 
the following responsibilities:1)to establish a regular meeting schedule; 2) to review the protocol; 
3) to review the consent form; 4) to monitor the occurrence of side effects/adverse events, and 
serious adverse events throughout the course of the study; and 5) to review with investigators, 
the study data management system; and 6) to establish stop rules for the study as a whole.  
The DSMB will review prior to study enrollment and every 6 months there after.  In addition the 
DSMB will review the study once 20 participants have completed the study.  The DSMB will  
receive bi-annual side effect/adverse event updates. All serious adverse events (SAEs) will be 
reported to the DSMB, PIs, and the University of Maryland School of Medicine IRB. The PIs will 
receive all SAE reports within 24 hours of their occurrence.  If, as a result of data monitoring or 
interim analysis, the DSMB determines that the study poses an unreasonable or unnecessary 
risk to study participants, the DSMB and the PI will determine what protocol modifications are 
required to minimize the future occurrence of such events. Unexpected adverse events will be 
reported in accord with federal requirements. Non-serious and expected adverse events will be 
reported annually to the IRB.  The PI is invited to the DSMB meetings and is asked to give a 
review of the past 6 months with a particular emphasis on safety, side effects and enrollment. 
The data remain blinded unless risks to participants justify unblinding as required by DSMB, 
FDA or IRB. To safeguard confidentiality, data are presented in aggregate or are identified only 
by an ID number. 
 
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Andreasen NC. The Scale for the Assessment of Negative Symptoms (SANS). University of 
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Baghdikian B, Mahiou-Leddet V, Bory S, Bun SS, Dumetre A, Mabrouki F, Hutter S, Azas N, 
Olliver E. New antiplasmodial alkaloids from Stephania rotunda. J Ethnopharmacol 
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Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry 1989;154:672-6. 
 
Benjamini Y and Hochberg Y.  Controlling the false discovery rate: A new and powerful 
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21 
 
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Appendix Drug List 
 
 DRUG  
Alprenolol 
Amitylpline 
Atomoxetine 
Captopril 
Codeine 
Dexflenfluramine 
Duloxetine 
Fenfluramine 
Fluoxetine 
Fluvoxatine 
Hydrocodone 
Metoprolol 
Metoclopromide 


24 
 
 Ondansetron 
 Oxycodone 
 Paroxetine 
 Propoxyphene 
 Quinidine 
 Ritonavir 
Venlafaxine