When we feel emotions or think about various things, “neurotransmitters” come and go in the brain. Neurotransmitters are secreted from the synapses that connect neurons and transmit information to other neurons. There are various types of neurotransmitters, and those with amino groups are called brain monoamines. Typical monoamines are gamma-aminobutyric acid (GABA) with an anti-stress effect, serotonin that brings mental stability, and dopamine that increases motivation and euphoria. These are known to be involved in the development of psychiatric disorders such as autism spectrum disorder and premenstrual syndrome / premenstrual dysphoric mood disorder.
We have been developing pyridoxamine, which is one type of natural vitamin B6. It is a water-soluble vitamin and an extremely safe medicine, but it is unapproved in developed countries including Japan. It is inferred from the chemistry and the animal studies that pyridoxamine improves the production and metabolism of GABA and serotonin and increases these neurotransmitters in the brain.
In collaboration with the Tokyo Metropolitan Institute of Medical Science, our laboratory has begun to investigate in the field of psychiatric disorders, starting with the finding that glyoxalase 1 (GLO1) gene mutation were responsible for familial severe schizophrenia with self-injurious and other harmful behaviors such as suicide and homicide. Glyoxalase detoxifies methylglyoxal, a reactive carbonyl compounds (RCOs) produced by the glycolytic system, suggesting that the trapping of brain monoamines by RCOs that accumulate as the lower glyoxalase activity due to the mutation is a possible pathogenic mechanism for some forms of schizophrenia. Pyridoxamine is an essential cofactor for the biosynthesis of brain monoamines and is thought to regulate the amount of brain monoamines by not only promoting their production but also inhibiting their degradation by carbonyl compounds.
The clinical studies of pyridoxamine are as follows: an early phase II investigator-initiated clinical trial for schizophrenia was completed; a clinical study and a phase II investigator-initiated clinical trials for autism spectrum disorder were completed; and a clinical study for premenstrual syndrome (PMS) and premenstrual dysphoric mood disorder (PMDD) was completed and a phase II investigator-initiated clinical trials for PMS/PMDD is currently ongoing. A clinical study for menopausal disorder is in preparation.
Important points of a phase II study to evaluate the efficacy of a drug in the psychiatric field are 1) appropriate patient selection and 2) a clinical trial design that reduces the placebo effect. Schizophrenia, autism spectrum disorders, and premenstrual syndrome (PMS) all involve heterogeneous patient populations with a wide variety of psychiatric symptoms. However, pyridoxamine may not be effective for all symptoms. The key issue is to select the appropriate patient population to adequately evaluate the efficacy of the drug, and we consider the following patient populations should be the treatment targets: patients with sensory (auditory) sensitivity for autism spectrum disorder, patients with severe psychiatric symptoms for premenstrual syndrome (PMS), and patients with negative symptoms for schizophrenia.
Due to the heterogeneous nature of the diseases and symptoms, a large number of patients is essential to obtain statistically significant differences. In addition, the strong influence of the placebo effect in psychiatric trials is a major cause of difficulty in evaluating clinical efficacies.
In the phase II trials for schizophrenia and autism spectrum disorder, the placebo effect had a strong impact. Therefore, in the ongoing phase II trial for PMS/PMDD, all enrolled patients will first take placebo medication only, and the patients who showed efficacy (a group of patients with high placebo effect) will be excluded. A double-blind study of the active drug and placebo will be performed for the remaining patients (placebo lead-in method). We consider this is the appropriate method of drug evaluation by elimination of the placebo effect.