Public Release: 

New evidence suggests reconsidering causes and treatments for schizophrenia

University of Michigan Health System

Schizophrenia is an extremely debilitating and costly disease that is difficult to understand and treat. Now, researchers in the University of Michigan Health System are offering new evidence that may alter the way the disease is viewed and may ultimately impact the way schizophrenia is treated.

They have just completed a multi-facetted study that re-examines the role of the cholinergic system in schizophrenia. The cholinergic system comprises the nerve cells or fibers that employ acetylcholine as their neurotransmitter. Cholinergic nerve connections, or synapses, are of two major types, utilizing muscarinic receptors and nicotinic receptors. More than 90 percent of the cholinergic receptors are muscarinic.

Investigators reviewed a series of 15 studies they conducted over the previous decade and then performed two clinical trials. Through these, the authors find that the cholinergic system may be a far more important player in schizophrenia than previously believed. Their findings are published in a recent issue of the journal Neuropsychopharmacology.

Schizophrenia comprises a group of psychotic illnesses, characterized by disturbances in perception, thinking, emotional reaction and behavior, along with extensive withdrawal of interest in other people and the outside world. Its symptoms are categorized into three groups:

  • Positive symptoms: Extreme symptoms such as delusions and hallucinations.
  • Negative symptoms: More depressive in nature and also more debilitating. They include lack of motivation, inability to communicate, inability to relate, and inability to experience pleasure.
  • Cognitive symptoms: Inability to accurately receive and process information.

The negative and cognitive symptoms are the hardest to treat and the most debilitating.

For several decades, the dopaminergic system -- the system that uses dopamine as it's neurotransmitter -- has been thought to be the main regulator of schizophrenic activity. The authors say their findings show there is a direct relationship between the cholinergic and dopaminergic systems as it pertains to the pathology of schizophrenia.

"The main importance of this study is that it very strongly indicates the role of the cholinergic system in schizophrenia in that it presents strong evidence that there is an alteration of cholinergic function in patients with schizophrenia," says Rajiv Tandon, professor of psychiatry and director of the U-M Health System Schizophrenia Program. "It also shows that there are important interactions between the cholinergic and dopaminergic systems in schizophrenia. Finally, it shows that modulation of cholinergic function in schizophrenic patients has significant impact on both positive and negative symptoms."

In the first part of the paper, Tandon and his colleagues reviewed several studies that examined the effects of altering the cholinergic system on schizophrenic symptoms. They write that disruptions in the balance of acetylcholine and dopamine are of critical importance in the pathology of schizophrenia. The cholinergic system tends to suppress positive side effects that are exacerbated by an increase in dopaminergic activity, and that the corresponding increase in cholinergic activity then leads to an intensification of negative schizophrenic symptoms in the acute phase of the illness.

Tandon and colleagues then set out to examine what happens when cholinergic activity is modulated in schizophrenic patients. To do this, they chose polysomnograhy or sleep studies.

The muscarinic cholinergic system exerts a strong influence over REM -- or dream -- sleep, especially the first dream phase after onset of sleep. Therefore, Tandon says, they set out to examine what happens when drug-free schizophrenic patients have their muscarinic cholinergic system challenged. One way to measure this is to examine the sleep recordings of these patients.

In the first trial, they challenged the muscarinic system with a medication called biperiden, which is primarily used to treat symptoms of Parkinson's Disease and has proven anti-muscarinic properties. They also chose to compare biperiden to an active placebo, in this case glycopyrrolate, a drug typically used to dry up secretions, but one that does not cross the blood-brain barrier.

Study patients were divided into two groups. Each group received a sugar pill for four days. One group then was given biperiden for four days, followed by glycopyrrolate for four days, while the other group first received glycopyrrolate and then biperiden.

They found that biperiden significantly increased the positive symptoms and lowered negative symptoms. Interestingly, the group that received biperiden first experienced an eventual reduction in positive symptoms, while the other group did not. Tandon says this relates to coming off biperiden and may be very relevant because it suggests that, if you give a patient an agent that increases cholinergic activity, you might actually find a treatment for positive symptoms.

In the second study, Tandon and his colleagues looked to establish a dose pattern for an anti-muscarinic agent. They tested 24 normal control subjects and 24 drug-free schizophrenic subjects. Twelve from each group were given 6 milligrams of biperiden, while the remaining 12 subjects in each group were given 10 milligrams of biperiden.

Both groups experienced a significant disruption in sleep patterns, but the schizophrenic subjects experienced a shorter time between onset of sleep and onset of REM activity at all doses. Both groups had an equal intensity of REM sleep at baseline, but only schizophrenic patients experienced a drop in amount of REM as the dose increased.

Tandon says these results appear to be contradictory -- the first part relating to amount of time from sleep onset to REM sleep suggest an increase in cholinergic activity, while the results of the measure of amount of time spent in REM sleep suggest diminished cholinergic activity. Tandon says this reinforces their supposition that sleep abnormalities in schizophrenia - like positive symptoms - are reliant on the balance of cholinergic and other transmitters, primarily those of the dopaminergic system. As cholinergic activity is suppressed, there is an increase in dopaminergic activity and vice versa.

"The results of these studies show that the cholinergic system plays an important role in all three types of schizophrenic symptoms, especially in treating the negative and cognitive symptoms," Tandon says. "I think a significant consequence of this study is going to be the fact that this will increase interest in pursuing medications that will manipulate the cholinergic system to treat schizophrenia."

Trials of donepezil, an agent that increases cholinergic activity and is currently used to treat Alzheimer's disease in patients suffering from refractory schizophrenia, are currently underway.

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The trial was funded by the National Institutes of Health, the National Alliance for Research on Schizophrenia and Depression (NARSAD), and by Scottish Rite.

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