Schizophrenia and substance use disorder: The split molecular genetics of Dopamine and Endorphins

Kenneth Blum, Ph.D.

Schizophrenia Ranks among the top 10 causes of disability in developed countries worldwide. The prevalence rate for schizophrenia at any given time is the number of individuals affected per 1,000 total population in the United States, that figure is 7.2 per 1,000, approximately 1.1% of the population over the age of 18. At any one time, as many as 51 million people worldwide have schizophrenia. This means that a city of 3 million people will have over 21,000 individuals who have schizophrenia.

The Relative Prevalence of Schizophrenia

Modified from J.A. Lieberman, Source: BCSS
Therefore, the approximate number of people in the United States
suffering from:
• Schizophrenia: Over 2.2 million people
˙ Multiple Sclerosis: 400,000 people
˙ Insulin-dependent Diabetes: 350,000 people
˙ Muscular Dystrophy: 35,000 people

Approximately 200,000 individuals with schizophrenia or manicdepressive illness are homeless, constituting one-third of the approximately 600,000 homeless population (total homeless population statistic based on data from Department of Health and Human Services). These 200,000 individuals comprise more than all the people of many U.S. cities, such as Hartford, Connecticut; Charleston, South Carolina; Reno, Nevada; Boise, Idaho; Scottsdale, Arizona; Orlando, Florida; Winston-Salem, North Carolina; Ann Arbor, Michigan; Abilene, Texas or Topeka, Kansas.

At any given time, there are more people with untreated severe psychiatric illnesses living on America’s streets than are receiving care in hospitals. Approximately 90,000 individuals with schizophrenia or manicdepressive illness are in hospitals receiving treatment for their disease. Approximately 10% of Americans who have schizophrenia commit suicide, a sobering reality for families with loved ones who have been diagnosed. There is currently no medical test to diagnose schizophrenia, demonstrating that we have much more to learn about the brain. Without such a test, doctors must rely on observations to come to a diagnosis. The annual cost of schizophrenia is estimated at $236 million.

Schizophrenia has a similar prevalence between males and females, and it strikes males in their late teens and early 20s, interfering with this stage of early adulthood and professional development. Schizophrenia tends to occur later in women, showing up in their mid to late 20s, disrupting their adult lives. One interesting fact is that people who are treated for Schizophrenia are not more likely to commit violent crimes than anyone in the general population. Schizophrenia affects people differently, and there are some subsets of the disease.

The major symptoms include hallucinations, delusions, thought disorders, poor executive functioning, and the inability to sustain everyday activity. The major form of treatment is the known antipsychotics which favor blocking of dopaminergic activity, particularly in the dopamine D2 receptor sites.

This article explores one very perplexing observation; the ever increasing rise of Substance Use Disorder (SUD) especially alcoholism in many patients diagnosed with Schizophrenia. The molecular basis of this puzzle is related to variations (polymorphisms) of at least one foundational gene- the Dopamine D2 Receptor Gene (DRD2). Understanding of this idea (hypothesis) may give rise to better diagnosis and targeted treatment in the future. It is by no means a universal remedy; it should spark scientific responses and further investigation.

Split Molecular Dopamine and Endorphin Mechanisms
The dopamine system has been implicated in both SUD and schizophrenia. A recent meta- analysis suggests that A1 allele of the DRD2 gene imposes a genetic risk for SUD, especially alcoholism and has been implicated in Reward Deficiency Syndrome (RDS) an umbrella term I coined in 1995, to help explain dopaminergic genetics and all common addictive behaviors. This article simply highlights two very essential but linked concepts. The first is a molecular mechanism which might explain why a subtype of people suffering from a schizophrenic diagnosis also have SUD. The second is a molecular mechanism that might explain why many people with schizophrenia, especially during a hallucinogenic phase, prefer to abuse alcohol as their drug of choice.

In simple terms, the first idea (hypothesis) about why a subtype of people with schizophrenia also suffers from Substance Use Disorder (SUD) may be the involvement of dopaminergic genetics. The second idea is about why people, especially during the psychotic (hallucinogenic) phase of schizophrenia, choose alcohol as their drug of choice.

Detailing the two hypotheses
Since some psychotic symptoms caused by substances of abuse, mimic schizophrenia, it is hard to separate symptoms of schizophrenia, from SUD. It was suggested that psychiatric patients use substances to cope with anxiety and cognitive decline. It is believed that acute self-medication is pursued to ameliorate the symptoms associated with impaired processing of the reward system defined as Reward Deficiency Syndrome (RDS)

Hypothesis 1
People with schizophrenia may be protected against SUD if they carry the usual complement of D2 receptors with the DRD2 A2 variant. With this said other gene variants could also be abnormal and cause too much dopamine activity including higher dopamine receptor activity. The possibility that D2 receptor (DRD2) gene A2 allele may act as a protective agent against the development of addiction to alcohol or other drugs of abuse; a subtype of non-SUD Schizophrenics was published in the journal Medical Hypotheses in 2014.

Carriers of the dopamine D2 receptor gene (DRD2) A1 variant, on the other hand, have 30-40 percent lower D2 receptors in the reward system of the brain; they are set up at birth to have a high risk of SUD by not having enough of the reward neurotransmitters in their brain.

People with schizophrenia and SUD may be carriers of the DRD2 Taq1 A1 allele, and other RDS reward polymorphisms and have low (hypodopaminergic) reward function. Clinical and epidemiologic studies have found a high frequency of co-occurrence of SUD and psychiatric disorders. Psychiatric comorbidity in drug abusers is associated with greater severity, higher incidence of risky behaviors; higher psychosocial impairment and an increased number of violent and criminal behaviors (see Figure 2).

This first hypothesis was developed in-part because of the extensive co-occurrence of substance use disorder (SUD) with schizophrenia. The involvement of dopaminergic neurotransmission in the genetics (antecedents) of schizophrenia, as well as genetic vulnerability to reward deficiency is well established. Multiple genes interact with multiple environmental factors that influence many psychiatric conditions (behavioral phenotypes). Evidence suggests that schizophrenia is a complex genetic disorder involving many (polygenic) inherited genes. For example, genetic studies have sought to identify subtypes (endophenotypes) of schizophrenia to improve the reliability of diagnosis. Some chromosomal regions where these genes are located have been shown more than once to have an association with being susceptible to schizophrenia. Many of the genes that are associated in genetic
studies with psychiatric conditions code for the proteins involved in neurotransmission in the synapses. Genetic studies are complicated by fuzzy diagnostic boundaries and the presence of similar behaviors (phenocopies). For example, the symptoms produced by schizophrenia are similar to some symptoms produced by drugs of abuse. The association of the DRD2 A1 variant with both high SUD risk and schizophrenia suggests this common thread.

Hypothesis 2
One plausible mechanism for alcohol seeking in people with schizophrenia and SUD, based on previous research, may be a deficiency of gamma type endorphins that has been linked to schizophrenic type psychosis. In 2014, my laboratory also proposed that alcohol-seeking behavior in people with schizophrenia may serve as a physiological self-healing process linked to the increased function of the gamma endorphins, thereby reducing abnormal dopaminergic activity at the brain reward center, the nucleus accumbens (NAc). Moreover, earlier work by van Ree and de Wied in the 80’s from the Netherlands provide an interesting idea concerning a role for gamma-endorphin in schizophrenia and alternative pathways being involved in both schizophrenia and SUD. They showed that plasma levels of gamma-endorphin (a peptide called (des-tyr) gamma-endorphin [DTGE]) were significantly lower in Schizophrenic patients compared to normal healthy volunteers.

Gamma Endorphin can reduce hallucinogenic experiences, and these studies found that people with schizophrenia have reduced amounts of this chemical that occurs naturally (endogenously) in the brain. What is even more significant, it was reported that alcohol increases these peptides in the brain and may be a physiological reason that schizophrenic patients abuse alcohol to reduce psychosis. In animal studies, Jackson and associates reported a reduction of behavioral effects of ethanol by DTGE. This is one way that this finding may explain alcohol abuse in a subtype of people with schizophrenia.

DTGE = gamma-endorphin (a peptide called (des-tyr)-gammaendorphin

Dopamine and opioid peptide interaction in Schizophrenia and alcoholism
Left side: Carrying the DRD2 A1 increases the “wanting” of alcohol and in carriers with a low gamma-endorphin (DTGE) would augment the risk for psychosis leading them to increased selfmedication by using alcohol.
Right side: Carrying the DRD2 A2 may be protective against alcohol drinking in Schizophrenics. Lack of Gamma Endorphin (DTGE) in utero leads to an over-expression of DRD2 A2.
Center: However, some Schizophrenics with the DRD2 A2 allele along with unknown reward gene polymorphisms may use substances due to lack of reward.

Conclusion
Based on these two ideas, research involving neuroimaging, genome-wide association studies (GWAS), and investigation of the environmental (epigenetic) effects, and the relationship between neurogenetics and systems biology will help to unravel the role of dopamine in psychiatric illness and SUD. Understanding the split molecular mechanisms related to both dopamine and endorphins may potentially result in better treatment and prevention of the devastating fatal effects of alcohol and drug abuse.

Kenneth Blum, B.Sc. (Pharmacy), M.Sc., Ph.D. & DHL; received
his Ph.D. in Neuropharmacology from New York Medical College
and graduated from Columbia University and New Jersey College
of Medicine. He also received a doctor of humane letters from Saint
Martin’s University Lacey, WA. He has published more than 550
abstracts; peer-reviewed articles and 14-books.