Treatment of Schizophrenia With L-tetrahydropalmatine (l-THP): a Novel Dopamine Antagonist With Anti-inflammatory and Antiprotozoal Activity

Study Overview
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Brief Summary
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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.

Official Title
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Treatment of Schizophrenia With L-tetrahydropalmatine (l-THP): a Novel Dopamine Antagonist With Anti-inflammatory and Antiprotozoal Activity

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: L-tetrahydropalmatine (30mg)
* Drug: Sugar pill


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: DSM-IV diagnosis of schizophrenia or schizoaffective disorder Minimum score of 45 on the total Brief Psychiatric Rating scale or a CGI of 4 Age 18-64 years Currently taking antipsychotic regimen with no dose changes in last 30 days Ability to consent determined by a score of 10 or greater on the Evaluation to Sign Consent Exclusion Criteria: Women who are pregnant, nursing, or not using effective contraception (if capable of getting pregnant) Current organic brain disorder or mental retardation 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. Current (past month) substance abuse or dependence (DSM-IV criteria) other than nicotine or caffeine; substance use, per se, will not be exclusionary Inability to provide valid informed consent Inability to understand English Inability to cooperate with study procedures Taking herbal or homeopathic medications where the metabolism of the drug is not known

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: l-tetrahydropalmatine<br>l-tetrahydropalmatine (30 mg BID) | Drug: L-tetrahydropalmatine (30mg)<br>* Active comparator<br>|
| Placebo Comparator: Sugar Pill<br> | Drug: Sugar pill<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Positive and Negative Symptom Improvement | Measured by the Brief Psychiatric Rating Scale, positive symptom subfactor, Scale for the Assessment of Negative Symptoms (SANS) and Brief Negative Symptom Scale (BNSS). The total BPRS score is calculated by adding the scores for scales #1-#18. Each scale ranges from 1=Not Present to 7=Very Severe. Total scores range from a minimum score of 18 to a maximum score of 126. A higher total score indicates a more severe psychiatric symptom rating. | Baseline and 4 weeks (endpoint) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement in Cognitive Function | Neuropsychological testing will be done at baseline and endpoint using the MATRICS battery. A composite score as well as individual scores will be will be the outcome. This assessment total minimum score of -10 and maximum score of 80. The higher the score the better the outcome. | Baseline and 4 weeks (endpoint) |