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People with severe mental illness such as schizophrenia or bipolar disorder have a higher risk for substance use, especially cigarette smoking, and protective factors usually associated with lower rates of substance use do not exist in severe mental illness, according to a new study funded by the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health.

Estimates based on past studies suggest that people diagnosed with mood or anxiety disorders are about twice as likely as the general population to also suffer from a substance use disorder. Statistics from the 2012 National Survey on Drug Use and Health indicate close to 8.4 million1 adults in the United States have both a mental and substance use disorder. However, only 7.9 percent of people receive treatment for both conditions, and 53.7 percent receive no treatment at all, the statistics2 indicate.

Studies exploring the link between substance use disorders and other mental illnesses have typically not included people with severe psychotic illnesses.

“Drug use impacts many of the same brain circuits that are disrupted in severe mental disorders such as schizophrenia,” said NIDA Director Dr. Nora D. Volkow. “While we cannot always prove a connection or causality, we do know that certain mental disorders are risk factors for subsequent substance use disorders, and vice versa.”

In the current study, 9,142 people diagnosed with schizophrenia, schizoaffective disorder, or bipolar disorder with psychotic features, and 10,195 controls matched to participants according to geographic region, were selected using the Genomic Psychiatry Cohort3 program. Mental disorder diagnoses were confirmed using the Diagnostic Interview for Psychosis and Affective Disorder (DI-PAD), and controls were screened to verify the absence of schizophrenia or bipolar disorder in themselves or close family members. The DI-PAD was also used for all participants to determine substance use rates.

Compared to controls, people with severe mental illness were about 4 times more likely to be heavy alcohol users (four or more drinks per day); 3.5 times more likely to use marijuana regularly (21 times per year); and 4.6 times more likely to use other drugs at least 10 times in their lives. The greatest increases were seen with tobacco, with patients with severe mental illness 5.1 times more likely to be daily smokers. This is of concern because smoking is the leading cause of preventable death in the United States.

In addition, certain protective factors often associated with belonging to certain racial or ethnic groups – or being female – did not exist in participants with severe mental illness. “In the general population, women have lower substance use rates than men, and Asian-Americans have lower substance use rates than white Americans, but we do not see these differences among people with severe mental illness,” said Dr. Sarah Hartz, from the Washington University School of Medicine in St. Louis and first author on the study. “We also saw that among young people with severe mental illness, the smoking rates were as high as smoking rates in middle-aged adults, despite success in lowering smoking rates for young people in the general population.”

Previous research has shown that people with schizophrenia have a shorter life expectancy than the general population, and chronic cigarette smoking has been suggested as a major contributing factor to higher morbidity and mortality from malignancy as well as cardiovascular and respiratory diseases. These new findings indicate that the rates of substance use in people with severe psychosis may be underestimated, highlighting the need to improve the understanding of the association between substance use and psychotic disorders so that both conditions can be treated effectively.

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A study of 230 patients with bipolar I disorder whose symptoms were severe enough to warrant admission to a Rhode Island psychiatric hospital in 2010 reveals that more than a third were there despite taking four or more psychiatric medications. Including medicines for other conditions, such as cardiometabolic diseases, the average patient came to the hospital taking six different drugs.

The study quantifies a difficult outcome for many patients with this difficult-to-treat disorder, said study lead author Lauren Weinstock of the Alpert Medical School of Brown University and of Butler Hospital, where the patients were admitted: They accrue a high burden of prescriptions each with their own side effects, with often unknown interactions, and with a complexity that can result in not taking the medications as prescribed. This medication burden also includes high overall cost to patients and the healthcare system.

Yet for those patients who’ve needed to come to the hospital, these complex combinations of drugs haven’t proven sufficiently effective, Weinstock said.

The study, published online in the journal Psychiatry Research, also reports the likelihood of a high medication burden was significantly greater for women than men.

“The high rate of complex polypharmacy reflects the enormous challenge of symptom management that we currently face for bipolar disorder,” said Weinstock, an assistant professor of psychiatry and human behavior at Brown. “Without many treatment alternatives, this is where we are as a field. It is important for us to advance science and treatment of bipolar disorder so that this medication burden can be minimized for our patients.”

Weinstock, who studies psychotherapy as a complement to medical treatment at Butler, said she and her colleagues became motivated to quantify the pharmacological burden for those with biploar disorder after witnessing it anecdotally among patients.

‘Complex polypharmacy’

Graph of results
While 19 percent of bipolar disorder patients in the study were not taking any psychotropic medications, 36 percent were taking three or more meeting the definition of “complex polypharmacy.”
Image credit: Brown University

Weinstock and her co-authors therefore compiled data from patients’ hospital admission records in the calendar year 2010. The only inclusion criteria were being 18 or older, and having a diagnosis of bipolar I disorder at hospital admission and discharge.

“The data aren’t confounded by someone’s active participation in a research study,” Weinstock said. “We wanted to measure what was happening in routine community practice.”

What they found is that when they came to the hospital, patients were taking an average of 3.3 psychotropic drugs and an average of 5.9 drugs overall. Nearly one in five patients weren’t on any psychotropic drugs, but more than half were taking 3 or more and more than a third were taking four or more, meeting the definition of “complex polypharmacy.”

The complex polypharmacy rate of 36 percent is higher than in a few previous studies that looked at bipolar patients, Weinstock said, because those studies did not always include all psychotropic medications, such as the commonly prescribed antianxiety medications.

Weinstock noted that because no clinical trial of bipolar medications has ever tested more than two drugs in combination, prescribing three or four exceeds practices supported by the field.

“By definition that’s not evidence-based treatment,” she said.

No prior studies had looked at the total medication burden, rather than just that of pyschotropics. It’s important to do so, Weinstock said, because cardiometabolic diseases, in particular, are often concurrent with bipolar disorder. Among the 230 patients in the study, for example, about half had such medical problems.

More so for women

Women, the data showed, were 58 percent of the total patients, but 68 percent of those with complex polypharmacy. Women were more likely to be on an antidepressant, antianxiety medication, and on stimulants, all of which which remain somewhat controversial in bipolar disorder treatment, Weinstock said.

The proportion of women taking an antidepressant (43 percent) was nearly twice that of men (23 percent). The significance of the gender disparities in the study endured even after statistically controlling for depressive symptoms in their diagnosis.

“Women weren’t prescribed more medications just because they were more likely to be depressed,” Weinstock said. “This finding raises the question of what other factors may influence higher rates of polypharmacy among female patients, such as patient or provider characteristics.”

But the study does not provide information that could reveal why that is.

Still, combined with other studies and epidemiological data, the study points to a trend that needs improving, Weinstock and her co-authors wrote: “This increased reliance on polypharmacy does not appear to be contributing to decreased rates of illness chronicity or functional impairment in BD.”

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Researchers from Trinity College in Dublin, Ireland, have identified a risk gene mutation for schizophrenia and bipolar disorder that increases chances of developing the conditions by more than 10-fold. The team says they found this mutation is inherited from a distant but common European ancestor.

The international team, led by Prof. Aiden Corvin at Trinity’s School of Medicine, says identifying this genetic mutation provides the medical community with insight into potential risk mechanisms for these disorders, the cause of which is poorly understood.

Results of their study are published in the journal Human Molecular Genetics.

Although treatments are available for schizophrenia and bipolar disorder, and evidence is increasingly suggesting these disorders share common genetic risk factors, the team says response to treatments varies and knowledge of the underlying biology has mostly eluded scientists.

Bipolar disorder affects around 4% of the world’s population, and schizophrenia impacts around 51 million people around the world (about 1% of the world’s population), the team says.

For their research, the investigators analyzed blood samples from over 1,564 Irish people with schizophrenia and 1,748 controls who did not have the disorder. They looked for small structural differences in the genome where material is either duplicated or deleted.

First author of the study Dr. Derek Morris, from the National University of Ireland (NUI), Galway, explains that when replication of a genome takes place, there can be small “editing” problems known as mutations:

“This is how diversity happens in biology and is like a typo in a book; it happens rarely and the context will determine how the ‘word,’ or in our case a protein, is affected.”

Carriers of genetic mutation share common European ancestor

Through their study, the researchers found five patients in which a gene – called Protein-Activated Kinase 7 (PAK7) – was duplicated. This duplication was not found in anyone in the control group, they note.

Diagram of a DNA strand under a magnifying glass
After looking for structural differences in the genomes of European subjects, the researchers found that a rare duplication in the PAK7 gene increased risks of developing schizophrenia or bipolar disorder 10-fold.

After identifying this genetic mutation in Irish people, the team extended their sample to include more than 25,000 people from Europe.

They confirmed that although this duplication is rare, it increases the risks of developing schizophrenia or bipolar disorder more than 10-fold.

Additionally, the team observed that in all cases, the duplications were very similar, suggesting the carriers share a single mutation that was inherited from a common European ancestor long ago.

Prof. Corvin says their findings show how gene discovery can provide new information on devastating disorders that are not well understood.

“Treatment in this area has advanced little in the last 40 years,” he adds. “Making progress in understanding the molecular mechanisms of disease gives me hope that new, effective treatments will emerge as has been the case in other branches of medicine, such as cancer treatment.”

According to the authors, the PAK7 gene family promotes growth and maintenance of brain connections in a pathway that is regulated by a previously known risk gene, called DISC1.

Both DISC1 and PAK7 interact with each other at the synapse level, the researchers say, which suggests that PAK signaling helps maintain synaptic networks – a mechanism that may play a role in development of schizophrenia and bipolar disorder.

Next step: how to reverse duplication interference with brain cell function

Prof. Corvin explains that their study shows the Irish population may be perfect for their gene discovery program, adding that the gene mutation likely came from a Northern European individual over 500 years ago.

“We believe that more is to be found in the Irish population and this will help us to reach a more general understanding about the nature of these disorders,” he says.

Regarding future research, Dr. Morris says:

“In our PAK7 example, about a third of the gene was replicated. For us the next steps will be to understand how this duplication interferes with brain cell function and to test how this might be reversed.”

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To answer the seemingly simple question “Have I been here before?” we must use our memories of previous experiences to determine if our current location is familiar or novel. In a new study published in the Journal of Neuroscience researchers from the RIKEN Brain Science Institute have identified a region of the hippocampus, called CA2, which is sensitive to even small changes in a familiar context. The results provide the first clue to the contributions of CA2 to memory and may help shed light on why this area is often found to be abnormal in the schizophrenic brain.

Change comes in many flavors; if we move to a new country, city or house it is easy to recognize the novelty of the environment, but if we come home to find the furniture rearranged or a new piece of art on the wall, this recognition may be much slower. Scientists believe this is because memory formation requires comparing current information with previous experience and the larger the overlap, the more difficult the distinction. It has long been known that the hippocampus is a region of the brain crucial for this type of memory, however the identification of neurons responsible for this comparison has remained elusive.

In this study Marie Wintzer, Roman Boehringer, Denis Polygalov and Thomas McHugh used genetically modified mice and advanced cell imaging techniques to demonstrate that while the entire hippocampus is capable of detecting large changes in context, the small and often overlooked CA2 region is exquisitely sensitive to small changes.

Mice were familiarized with one context and then placed either in a much different context or back in the original with small alterations, such as several new small objects. By detecting the expression of activity induced genes Wintzer and colleagues were able to demonstrate that just a few new objects in the otherwise unchanged context completely altered the pattern of active cells specifically in CA2. Mice that had been genetically engineered to lack this CA2 response explored the new context much less than their normal siblings.

“CA2 has often been overlooked or simply grouped together with its more prominent neighbors, but these data suggest it’s unique and important for recognizing and reacting to changes in our environments” explains Dr. McHugh, the leader of the study.

Compared to rodents, human CA2 is proportionally larger, but still as mysterious. One intriguing finding has been that early in the onset of schizophrenia and bipolar disorder there is a loss of inhibitory neurons specifically in CA2. In addition to the memory problems that accompany these diseases, patients often exhibit a hyper-sensitivity to changes in environment and routine. This study suggests there may be a functional relationship between this sensitivity and CA2 dysfunction, hinting at a new circuit to target in our attempts to understand the function of both the normal and diseased brain.

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Treatment regimens often evolve without strong scientific evidence of their benefits and drawbacks, particularly in comparison to other drugs or approaches.

Now Duke Medicine is participating in a large national initiative aiming to fill in that missing information.

In separate articles published in the Annals of Internal Medicine, teams led by the Duke Clinical Research Institute detailed the research priorities necessary to address gaps in knowledge about two conditions – bipolar disorder among adolescents and early breast tumors in women.

The two diverse conditions provide similar challenges for patients, doctors and health system administrators: The diagnosis is often not clear-cut, while typical treatments come with a trade-off of benefits and serious side effects.

Collaborating with clinical experts, patients, patient advocates, and other stakeholders, the two Duke-led teams worked to identify and rank the important gaps in knowledge that should be the focus of new research.

Aiming patient-focused research efforts and dollars at such clinical uncertainties is the mission of a national initiative called the Patient-Centered Outcomes Research Institute (PCORI), which was established three years ago under the Affordable Care Act. Using funds from the insurance mandate, PCORI is working to improve the quality of research, speed it into clinical practice, and assure that it answers the most pressing questions and concerns of patients.

In the case of bipolar disorder among adolescents and young adults, the Duke researchers noted that establishing this diagnosis is particularly complex, and the condition can be difficult to distinguish from other behavioral disorders, including attention deficit hyperactivity disorder. Yet the use of antipsychotic drugs for this condition has increased dramatically over the past two decades, and carries with it a high risk of weight gain, diabetes and other problems.

“This is clearly an important area of clinical uncertainty that will benefit from more research,” said Matthew J. Crowley, M.D., assistant professor of medicine in the Division of Endocrinology, Diabetes and Metabolism at Duke and lead author of the study addressing research priorities for adolescents with bipolar disorder.

Likewise with ductal carcinoma in situ – tiny breast lesions detected via mammography – considerable uncertainty has evolved over whether to treat the condition as cancer. Many of the lesions may never progress to life-threatening invasive cancer, while treatment plans call for mastectomy, lumpectomy and radiation.

“We don’t have a good handle on how to distinguish between the cases that will develop into invasive cancers, and those that are harmless,” said Jennifer Gierisch, Ph.D., assistant professor of medicine in the Division of General Internal Medicine at Duke and lead author of the breast cancer paper. “There is a lot of uncertainty about what a diagnosis means and how to proceed around a diagnosis. Our goal is to identify research priorities to address these questions and reduce the uncertainty for both patients and doctors.”

Members of the Duke Clinical Research Institute have been key players in the PCORI initiative, led by Robert Califf, M.D., who is a co-principal investigator of PCORI’s national clinical research network. The group will amass, coordinate and manage the database of medical information that researchers can use to learn how well treatments work.

PCORI has also funded research at Duke, including the work of the two teams that identified research priorities in bipolar disorder and breast cancer. PCORI has provided additional funding for other Duke Clinical Research Institute members to:
◾ Track the effectiveness of stroke treatments, particularly among older people, women and minority patients;
◾ Determine the benefits and risks of different stroke rehabilitation services after hospitalizations;
◾ Develop and expand a network of patients, advocates and doctors around pediatric arthritis and other rheumatic diseases;
◾ Study the effectiveness of treatments for aortic heart valve disease, comparing “real-world” outcomes for two different methods of valve replacement;
◾ Compare the results of randomized trials, which are considered the gold standard, against observational studies.

“We are pleased to be able to contribute to such an important national enterprise,” Califf said. “Patients deserve to know the comparative risks and benefits of treatment alternatives, and PCORI is providing the focus to provide this critical knowledge.”

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