Trace Amines: A promising treatment pathway in psychiatry

Cells in the brain, called neurons, communicate with one another using chemicals referred to as  neurotransmitters. Many neurotransmitters are derived from amino acids, the building blocks of protein. Amino acids are molecules having an acid group plus one or more amine groups attached. Specific enzymes remove the acid group and, with one or two other minor alterations often occurring, the result may be an active amine-type of neurotransmitter.  Dopamine, norepinephrine, and serotonin are three such neurotransmitters in a major class called the monoamines. Many psychiatric drugs target these three neurotransmitters, and many psychiatric disorders are thought to be due to abnormalities in their activities.

Although psychiatry has largely focused on dopamine, norepinephrine and serotonin, it has long been known that small amounts of other amino acid-derived amines are also produced in the brain. These chemicals are often referred to as trace amines, with the name suggesting little significance in brain function. However, over recent years there has been growing evidence that trace amines play more important roles than had previously been suspected. Among the dozens of trace amines that have been identified in the human brain  are phenethylamine, tyramine, tryptamine, dimethyltryptamine, epinephrine, agmatine, spermine, synephrine, cadaverine, putrescine, and octopamine. As one might suspect from the name, octopamine was first discovered as a major neurotransmitter in the octopus brain. It is also important in the nervous systems of insects.  Another interesting trace amine is 3-iodothyronamine. It is derived from thyroid hormone, which itself is a highly modified amino acid.

A defining characteristic of neurotransmitters is that they are released from neurons and bind to receptors on adjacent neurons that transduce that binding into signals. The significance of trace amines became better appreciated when Trace Amine Related Receptors, or TAARs, were identified in human brain tissue. The various trace amines can activate these receptors. There are at least 6 different subtypes of TAARs in the human  brain, and many are located in areas of the brain  involved in the processing of emotions, reward and cognition. Thus, trace amines and TAARs appear likely to play roles in the higher functions of the mind, with abnormalities in their levels and function possibly contributing to psychiatric illness.

There is evidence of aberrations in TAAR activity in the brains of patients with certain mental illnesses. For example, the number of the TAAR-1 subtype of the receptor is increased in the prefrontal cortex of some individuals suffering schizophrenia. This may be the brain trying to adapt to insufficient stimulation by trace amines. Moreover, individuals carrying certain TAAR gene mutations appear to be predisposed to schizophrenia and bipolar affective disorder. Abnormal levels of certain trace amines in the brain may also contribute to psychiatric illness. Phenethylamine is deficient in the brains of some who suffer ADHD. Levels of agmatine are low in brains of suicide victims. Octopamine activity may be low in depressed patients, while increases of octopamine in certain liver diseases may contribute to delirium. Some trace amines, including  bufotenine and dimethyltryptamine, have hallucinogenic properties and are thought to activate certain TAARs. Though their overabundance was once suspected of contributing to psychosis, proper levels may calm the mind.

The possibility that trace amines play important roles in psychiatric conditions is further bolstered by the fact that many psychiatric medications, as well as some substances of abuse, may act through TAARs. The uniquely effective antipsychotic drug, clozapine, acts in part by stimulating the TAAR-1 subtype.  Amphetamine, which is used to treat ADHD, stimulates release of dopamine, norepinephrine and serotonin. However, it also stimulates TAAR-1s. The medication clonidine, which is most often used as a blood pressure lowering medication, can also be used to treat ADHD. In most respects, clonidine acts in ways entirely opposite to amphetamine. It does not cause release of monoamine neurotransmitters as amphetamine does. In fact, it blocks release of norepinephrine. However, like amphetamine, clonidine stimulates TAAR-1s. Supplementation with the thyroid hormone, triiodothyronine, can sometimes help relieve treatment-resistant Major Depression. The brain can convert triiodothyronine to 3-iodothyronamine in one enzymatic step. 3-Iodothyronamine appears to act at TAAR-1s and TAAR-5s.

Of particular interest is the new medication, ulotaront, which is in clinical trials as a treatment for schizophrenia. Ulotaront selectively stimulates TAAR-1s, as well as a type of serotonin receptor called the 5-HT1A receptor. Unlike almost all existing medications used to treat schizophrenia, it does not block dopamine receptors.  It is the blocking of dopamine receptors that causes many of the unpleasant and, at times, dangerous side effects of most antipsychotic drugs. Ulotaront also helps relieve the so-called negative symptoms of schizophrenia, e.g., apathy, withdrawal, and depression, that are not much improved by standard treatments. Thus, this new and unique medication may greatly improve symptoms and quality of life of those with that illness.  The study of trace amines is a promising direction in psychiatry. However, their therapeutic value remains largely unexplored.