A Metabolic Link to Schizophrenia?

Welcome back to Team Squints! This week we will be exploring the apparent metabolic link between the mental disorder schizophrenia and metabolic disturbances including Irritable Bowel Syndrome (IBS), obesity, and Type II diabetes.

Schizophrenia is a mental disorder is characterized by positive and negative symptoms. Positive symptoms are mental disturbances that are not usually present such as hallucinations, delusions, and disordered speech. Negative symptoms are mental disturbances that are usually there such as depression, apathy, anxiety, and social withdrawal. Paranoia, false beliefs, confused thinking, lack of motivation, and IBS are also symptoms of schizophrenia.

There is a lot of conflicting evidence of the the cause of schizophrenia, but it is believed that the it is rooted in a combination of environmental and genetic factors. The leading theories for the cause of schizophrenia is hyperdopaminergic activity, or an excess of the dopamine in the Central Nervous System (CNS). Another theory stems from the belief that there are serotonin abnormalities in the CNS, although it is unknown if there is too little or too much serotonin in the CNS with schizophrenic patients. The last leading theory behind the cause of schizophrenia is Glutamate idea, which stems from the belief that the NMDA glutamate receptor, specifically the mGlu2/3 receptor, has a reduced function in recognizing and uptaking the amino acid.

A number of antipsychotic drugs have been developed over the years to help alleviate the symptoms of schizophrenia. I say alleviate the symptoms and not actually cure schizophrenia because we are still very confused about what causes of schizophrenia.

The first class of drugs that were used to help schizophrenic patients are known as “First Generation Antipsychotics” or FGAs and includes drugs such as haloperidol and chlorpromazine. These drugs were both introduced into the market in 1958 and 1954 respectively and are both still known as “benchmark” antipsychotic drugs. These drugs mostly blocked the dopamine D2 receptors in the CNS, response to the dopamine theory of schizophrenia. The drugs alleviated some of symptoms of schizophrenia, but they came with some nasty side effects. Including EPS, or Extrapyramidal Symptoms. EPS is similar to the jerky movements seen in Parkinson’s Disease, which are caused by a lack of dopamine in the body. This makes sense because if the FGA drugs completely block D2 receptors then the whole body doesn’t have as much access to dopamine.

The new type of antipsychotic drugs are known as “Second Generation Antipsychotics” or SGAs. This class of antiseptics includes drugs like clozapine, olanzapine, and risperidone which were approved for use in the United States in 1975, 1969 ,and 1993 respectively. These drugs function by having a “hit and run” relationship with the dopamine D2 receptors as well as an antagonistic effect on certain serotonin receptors including 5-HT1A. However, these SGA has major metabolic side effects that we will go into greater detail in a moment.

Interestingly enough people who are diagnosed with schizophrenia, even before treatment with SGAs, have a two to four times higher rate of metabolic disturbances such as Type II diabetes, insulin resistance, and obesity than people without schizophrenia. Antipsychotic drugs that are often prescribed to individuals with psychiatric disorders such as Schizophrenia, tend to cause metabolic disturbances (hyperglycemia, impaired glucose tolerance, and Type II diabetes) in and of themselves. Although, by prescribing these antipsychotic drugs as the primary form of treatment has aided the psychotic symptoms, it has caused these metabolic issues. It has been shown with the SGAs that they tend have an effect on weight gain. In some cases, individuals prescribed these drugs can gain more than 20lbs. SGAs have been seen to also increase levels blood glucose, can cause insulin resistance, and increase chances of acquiring Type II diabetes. Also, the SGAs have been seen to have unfavorable effects on a person’s blood lipid profiles (increased cholesterol levels, low-density lipoprotein, etc.). Clozapine and Olanzapine have had the most adverse effects on individuals.

Researchers have come up with a few mechanisms that may be causing the metabolic disturbances within these individuals. One mechanism noticed is glucose transporter inhibition and this has been associated with disturbances in insulin regulation and production. In addition, alterations in the PI3K/Akt insulin signaling pathway has been noted as another potential mechanism. Secondary effects of weight gain and adiposity may be due to interactions between the antipsychotics and different types of receptors and leptin. All of these factors are being closely studied by researchers, with the hopes that one day we will be able to manage and hopefully prevent this disorder.

The most important point that researchers are trying to uncover are the mechanisms of hyperglycemia and insulin resistance in regards to glucose utilization and the insulin signaling pathway all within individuals with Schizophrenia. Researchers are working tirelessly to understand the mechanisms of glucose metabolism disorders and its association with SGAs. Let me paint you a picture…it is as if there is a wall with a hole in it and water is spewing out of that hole and is flooding the other side (psychotic symptoms seen in Schizophrenia). Researchers have found a way to manage the water flow by patching up the hole (with antipsychotic medication). But, there is still pressure from the water on the other side of the wall and all of a sudden, a new hole is formed (metabolic disturbances as a result of antipsychotic medications) and now researchers are looking for ways to better patch the new hole up while still managing to keep the other hole secure. The pressure of the water may be caused by a multitude of factors, and researchers are working on uncovering the reasons.

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