Treatment of Schizophrenia With L-tetrahydropalmatine (l-THP): a Novel Dopamine Antagonist With Anti-inflammatory and Antiprotozoal Activity
| Status: | Recruiting |
|---|---|
| Conditions: | Schizophrenia |
| Therapuetic Areas: | Psychiatry / Psychology |
| Healthy: | No |
| Age Range: | 18 - 64 |
| Updated: | 2/3/2019 |
| Start Date: | September 2014 |
| End Date: | December 2019 |
| Contact: | Ann Kearns, BS |
| Email: | akearns@mprc.umaryland.edu |
| Phone: | 410-402-6854 |
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.
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.
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
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