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

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.

Study Overview

• Status: Completed
• Conditions: Schizophrenia
• Intervention / Treatment: Drug: L-tetrahydropalmatine (30mg); Drug: Sugar pill

• Study Type: Interventional
• Enrollment (Actual): 63
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Catonsville, Maryland, United States, 21228
      • Maryland Psyciatric Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 62 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. DSM-IV diagnosis of schizophrenia or schizoaffective disorder
2. Minimum score of 45 on the total Brief Psychiatric Rating scale or a CGI of 4
3. Age 18-64 years
4. Currently taking antipsychotic regimen with no dose changes in last 30 days
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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: University of Maryland, Baltimore
• Collaborators: Stanley Medical Research Institute
• Investigators: Principal Investigator: Deanna L Kelly, Parm.D., BCPP, University of Maryalnd, Baltimore

Publications and helpful links

Helpful Links

• Maryland Psychiatric Research Center

Study record dates

Study Major Dates

• Study Start: September 1, 2014
• Primary Completion (Actual): December 1, 2018
• Study Completion (Actual): June 1, 2019

Study Registration Dates

• First Submitted: April 14, 2014
• First Submitted That Met QC Criteria: April 16, 2014
• First Posted (Estimate): April 21, 2014

Study Record Updates

• Last Update Posted (Actual): January 6, 2022
• Last Update Submitted That Met QC Criteria: January 4, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Membrane Transport Modulators; Dopamine Agents; Dopamine Antagonists; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Tetrahydropalmatine
• Other Study ID Numbers: HP-00058491