Schizophrenia

Delta waves, relational encoding, paliperidone injections and early life events.

Delta Waves.

Schizophrenia affects millions of people worldwide but the cause of its wide-ranging symptoms remains largely unknown.

At Brandeis University, researchers believe they have discovered an abnormality in the schizophrenic brain that could be responsible for many of the disease’s symptoms and could provide a drug target for therapeutic treatments.

Led by John Lisman, the Zalman Abraham Kekst Chair in Neuroscience and professor of biology, the research team published their findings in a recent issue of the Journal of Biological Psychiatry. The paper was co-authored by Aranda Duan, Carmen Varela, Yuchun Zhang, Yinghua Shen, Lealia Xiong, and Matthew Wilson.

Unusual neural oscillations, brain waves, have long been associated with schizophrenia. The oscillations, called delta waves, are similar to slow oscillations seen in normal brains during sleep, but in schizophrenic brains, they occur during wakefulness. The connection between these oscillations and schizophrenic symptoms, particularly cognitive deficits such as memory impairment, has long been unclear.

Lisman and his team set out to understand that connection by artificially producing delta waves in mammalian brains using a new technique called optogenetics, which activates brain signals using light.

When the delta frequency light was turned on, Lisman observed disruption in the working memory of rats. When it was turned off, the rodents were once again able to perform working memory tasks. More important, Lisman and his team were able to activate the abnormal oscillations only in a tiny subpart of the thalamus, a region of the brain that has long been a focus of schizophrenia research.

An information hub and relay centre, the thalamus is central to working memory, sleep, consciousness and sensory-information processing.

“The oscillations produce an artificial signal that jams normal communication,” Lisman says. “The part of the thalamus that is supposed to carry information about working memory couldn’t do the task at all with these sleep-like delta waves. We suspect the abnormal delta oscillations seen in patients with schizophrenia are producing a similar jamming of normal signals.”

Delta waves require a specific type of ion channel called a T-type Ca channel. These channels are of particular interest because they are one of the few types of ion channel implicated in schizophrenia by genetic studies. The next step, Lisman says, is to figure out what kind of agents could be used to block these channels.

“If you could block these channels, you could block these bad oscillations,” he says. “That may have therapeutic value in patients.”


Relational Encoding.

As disabling as its delusions and hallucinations, psychosis’ devastating toll on memory arises from dysfunction of frontal and temporal lobe regions in the brain that rob sufferers of the ability to make associative connections, a UC Davis study has found, pinpointing potential target areas for treatments to help the more than 3.2 million Americans for whom medication quells the voices and visions, but not the struggle to remember.

The study found that memory is most impaired when people with schizophrenia try to form relationships between items -remembering to also buy eggs, milk and butter when buying flour to make pancakes, and that this relational encoding problem is accompanied by regionally specific dysfunction in the dorsolateral prefrontal cortex.

People with schizophrenia also have greater difficulty retrieving this relational information even when they can remember the individual items, and this relational retrieval deficit is accompanied by functionally specific dysfunction in a brain area called the hippocampus. The research is published online in JAMA Psychiatry.

Schizophrenia is well-known for its more florid manifestations, said J. Daniel Ragland, professor of psychiatry in the UC Davis School of Medicine and lead author of the study.

“Everyone has had the experience of hearing their name called or phone ring, or that someone is standing beside them. When these events take place initially we experience them as real,” Ragland said. “What happens in psychosis is that you continue to have the experience, and the feeling becomes more developed, more real and more intrusive.”

Decades-old medications treat these symptoms effectively. But what remains is often more intractable: memory loss and other cognitive difficulties that make it difficult to perform the activities of daily living.

“People with schizophrenia have difficulty retrieving associations within a context, and this creates a pervasive loss of memory that makes everyday life a challenge,” Ragland said. “You can’t work if you can’t remember the next step in what your boss told you to do.”

“If you’re going to develop a drug or other therapy to improve memory, we found that this frontal and temporal lobe relational memory network may be a target or ‘biomarker’ for treatment development,” he said.

The multi-site functional magnetic resonance (fMRI) study was conducted in approximately 60 male and female patients with schizophrenia who were age matched with unaffected control subjects. Participants with psychosis were clinically stable, had remained on medication for one month, and were experiencing mild symptoms. Participants were located at UC Davis, Washington University in St. Louis, University of Maryland and Rutgers University.

For the study, participants viewed a series of pictures of everyday objects, and made either an item-specific encoding decision about whether the object was living or non-living, or made a relational encoding decision about whether one of the objects could fit inside of the other during fMRI scanning.

This was followed by an item-recognition task consisting of previously studied objects presented together with never-studied objects. Participants had to assess whether or not the object was previously studied.

Participants also were tested on their associative recognition of which objects were paired together during the relational encoding task. The more severe pattern of relational memory deficits and dorsolateral prefrontal and hippocampal dysfunction was revealed by contrasting the item-specific and relational memory conditions during encoding and retrieval.

In the participants diagnosed with psychosis, the dorsolateral prefrontal cortex appeared substantially less activated than in healthy control participants – 28 percent to 30 percent less activated.

Although participants with schizophrenia activated the ventrolateral prefrontal cortex during relational versus item encoding, they failed to activate the dorsolateral prefrontal cortex – a finding that is consistent with earlier fMRI studies of attention and problem-solving in individuals with schizophrenia.

In addition, the study revealed that healthy controls exhibited increased activation in the hippocampus, while activation was significantly reduced in the participants with psychosis for retrieval following relational-memory encoding, but not for retrieval following item memory encoding.

Thus, the hippocampus, which plays a unique role in creating relational memories, joins the dorsolateral prefrontal cortex in helping to explain the disproportionate relational memory deficits experienced by people with schizophrenia.

Cameron Carter, senior author and professor of psychiatry, said that the finding is exciting because it points the way to potential pathways to improve the lives of people with psychosis.

“This shows that the memory problems in people with schizophrenia are not the same as those of people with Alzheimer’s disease,” where the brain region is damaged and deteriorating. “It’s more like those of people with other cognitive deficits, such as ADHD,” said Carter, who is director of the Imaging Research, Behavioral Health and Neuroscience centers at UC Davis.

“We now know that, if we’re going to improve memory in people with psychosis we have to improve the functioning of the dorsolateral prefrontal cortex. And there are many different ways that we can do that, such as through cognitive brain training,” he said.

Carter said that another experimental treatment, called transcranial direct current stimulation, is designed to activate and enhance the function of the brain region.

“This research is directly informing the next steps in our research. And the area that we’ll stimulate will be this one.

“Twenty or 30 years ago we couldn’t do any of this,” Carter said. “So this is real progress.”


Paliperidone Injections.

An injectable drug given every two weeks works better than a daily pill for those who have been recently diagnosed with schizophrenia, a study shows.

Now, a UCLA study has found that people who took a long-acting injectable form of risperidone, one given every two weeks, had a substantially lower risk for the symptoms returning than people who took the daily medication as a pill.

The study, which is published in the journal JAMA Psychiatry, concluded that doctors should consider prescribing the long-lasting injectable medication much earlier in the course of treatment than they typically do today.

“We know that not taking antipsychotic medication is the single greatest modifiable risk factor for psychotic symptoms returning,” said Kenneth Subotnik, an adjunct professor of psychiatry at the UCLA Semel Institute for Neuroscience and Human Behavior and the study’s first author, adding that patients who have only recently developed the disease are especially susceptible to not taking their medication daily.

Although long-acting medications have been around since the 1970s, most previous studies have focused on patients who had experienced schizophrenia for many years. In those patients, the long-acting medications were not always a better alternative. The UCLA study focused specifically on patients who had recently developed the disorder.

“Individuals with a single episode of schizophrenia who have responded well to antipsychotic medication, even if they do understand they have a mental disorder, very often doubt whether medication continues to be necessary,” said Keith Nuechterlein, a UCLA professor of psychiatry and senior author of the study.

The researchers followed 83 people recently diagnosed with schizophrenia for a one-year period. Half were given the daily oral form of risperidone and the others were given the long-acting injectable form. All interventions were given as part of the UCLA Aftercare Research Program.

The researchers found that patients taking the injectable medicine were much more likely to stick with their treatment than patients taking the oral form, and that the injectable did a better job of controlling psychotic symptoms. During the 12-month period, just 5 percent of those taking the injectable medication had their psychotic symptoms return, versus 33 percent of those taking the pill.

In addition, Subotnik said, the benefits appear to be greater than when given after individuals have had the disorder for many years, which indicates that the long-acting injectable should be offered to patients earlier in the course of schizophrenia.

Subotnik said another benefit of the injectable is that because it’s administered at a doctor’s office rather than taken at home, doctors can more easily track whether patients are regularly taking the medication.

“Because of that, we had nearly perfect adherence to the long-acting form of risperidone,” he said.

Analyzing the same group of people, the researchers also found that consistent adherence to antipsychotic medication led to improvements in the patients’ cognitive functioning, Nuechterlein said. (Those results have been presented at a conference but not yet published.) And in a 2012 study led by the late George Bartzokis, a UCLA professor of psychiatry, MRI scans of some of these participants found that the long-acting medication also increased the amount of brain myelin, the coating on nerve fibers which, like insulation around a wire, improves communication between nerve cells. Myelination often decreases in people with schizophrenia, which leads to impairments in brain function and cognition.

Nuechterlein said the next stage of the research will be examining whether there are additional benefits of a long-acting injectable antipsychotic medication, and if it is just as effective if given only once a month instead of every two weeks.

Schizophrenia, which affects 2 million to 3 million people in the U.S., causes hallucinations, delusions and disorganization. Left untreated, the disease can cause a significant loss in quality of life, including unemployment and estrangement from loved ones. But many people with schizophrenia can control the disorder and live without symptoms for several years if they consistently take prescribed antipsychotic medication, typically a daily pill.

The problem is that many people don’t continue taking their medication once their symptoms improve.

“Individuals with a single episode of schizophrenia who have responded well to antipsychotic medication, even if they do understand they have a mental disorder, very often doubt whether medication continues to be necessary,” said Keith Nuechterlein, a UCLA professor of psychiatry and senior author of the study.

The researchers followed 83 people recently diagnosed with schizophrenia for a one-year period. Half were given the daily oral form of risperidone and the others were given the long-acting injectable form. All interventions were given as part of the UCLA Aftercare Research Program.

The researchers found that patients taking the injectable medicine were much more likely to stick with their treatment than patients taking the oral form, and that the injectable did a better job of controlling psychotic symptoms. During the 12-month period, just 5 percent of those taking the injectable medication had their psychotic symptoms return, versus 33 percent of those taking the pill.

In addition, Subotnik said, the benefits appear to be greater than when given after individuals have had the disorder for many years, which indicates that the long-acting injectable should be offered to patients earlier in the course of schizophrenia.

Subotnik said another benefit of the injectable is that because it’s administered at a doctor’s office rather than taken at home, doctors can more easily track whether patients are regularly taking the medication.

“Because of that, we had nearly perfect adherence to the long-acting form of risperidone,” he said.

Analyzing the same group of people, the researchers also found that consistent adherence to antipsychotic medication led to improvements in the patients’ cognitive functioning, Nuechterlein said. (Those results have been presented at a conference but not yet published.) And in a 2012 study led by the late George Bartzokis, a UCLA professor of psychiatry, MRI scans of some of these participants found that the long-acting medication also increased the amount of brain myelin, the coating on nerve fibers which, like insulation around a wire, improves communication between nerve cells. Myelination often decreases in people with schizophrenia, which leads to impairments in brain function and cognition.

Nuechterlein said the next stage of the research will be examining whether there are additional benefits of a long-acting injectable antipsychotic medication, and if it is just as effective if given only once a month instead of every two weeks.

(P.S. Some-one known to me who has found it difficult to manage long term daily oral medication, and to deal with the side effects (of drugs like Olanzapine and Quetiapine) of grogginess, fogginess and excessive weight gain, has had a remarkable positive experience after changing to a monthly injection of paliperidone. The improvement in symptoms and the minimizing of side effects, has been pronounced.)


Early Life Events.

Scientists have identified a critical function of what they believe to be schizophrenia’s “Rosetta Stone” gene that could hold the key to decoding the function of all genes involved in the disease.

The breakthrough has revealed a vulnerable period in the early stages of the brain’s development that researchers hope can be targeted for future efforts in reversing schizophrenia.

In a paper published in the journal Science, neuroscientists from Cardiff University describe having uncovered the previously unknown influence of a gene in ensuring healthy brain development.

The gene is known as ‘disrupted in schizophrenia-1’ (DISC-1). Past studies have shown that when mutated, the gene is a high risk factor for mental illness including schizophrenia, major clinical depression and bipolar disorder.

The aim of this latest study was to determine whether DISC-1’s interactions with other proteins, early on in the brain’s development, had a bearing on the brain’s ability to adapt its structure and function (also known as ‘plasticity’) later on in adulthood.

Many genes responsible for the creation of synaptic proteins have previously shown to be strongly linked to schizophrenia and other brain disorders, but until now the reasons have not been understood.

The team, led by Professor Kevin Fox from Cardiff University’s School of Biosciences, found that in order for healthy development of the brain’s synapses to take place, the DISC-1 gene first needs to bind with two other molecules known as ‘Lis’ and ‘Nudel’.

Their experiments in mice revealed that by preventing DISC-1 from binding with these molecules, using a protein-releasing drug called Tamoxifen at an early stage of the brain’s development, it would lack plasticity once it grows to its adult state, preventing cells (cortical neurons) in the brain’s largest region from being able to form synapses.

The ability to form coherent thoughts and to properly perceive the world is damaged as a consequence of this.

Preventing DISC-1 from binding with ‘Lis’ and ‘Nudel’ molecules, when the brain was fully formed, showed no effect on its plasticity. However, the researchers were able to pinpoint a seven-day window early on in the brain’s development, one week after birth, where failure to bind had an irreversible effect on the brain’s plasticity later on in life.

“We believe that DISC-1 is schizophrenia’s Rosetta Stone gene and could hold the master key to help us unlock our understanding of the role played by all risk genes involved in the disease,” said Professor Fox.

“The potential of what we now know about this gene is immense. We have identified a critical period during brain development that directs us to test whether other schizophrenia risk genes affecting different regions of the brain create their malfunction during their own critical period.

“The challenge ahead lies in finding a way of treating people during this critical period or in finding ways of reversing the problem during adulthood by returning plasticity to the brain. This, we hope, could one day help to prevent the manifestation or recurrence of schizophrenia symptoms altogether.”

Professor Jeremy Hall, an academic mental health clinician and director of Cardiff University‘s Neuroscience and Mental Health Research Institute, said:

“This paper provides strong experimental evidence that subtle changes early on in life can lead to much bigger effects in adulthood. This helps explain how early life events can increase the risk of adult mental health disorders like schizophrenia.”

Schizophrenia affects around 1% of the global population and an estimated 635,000 people in the UK will at some stage in their lives be affected by the condition. The projected cost of schizophrenia to society is around £11.8 billion a year.

The symptoms of schizophrenia can be extremely disruptive, and have a large impact on a person’s ability to carry out everyday tasks, such as going to work, maintaining relationships and caring for themselves or others.


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