Substance Abuse Main Driver of Violence in Schizophrenia, Psychoses

Caroline Cassels

August 31, 2009 — An excess risk for violence and violent crime, including homicide, in individuals with schizophrenia
and other psychoses is not primarily attributable to the mental illness itself, but rather to comorbid substance abuse, a
new meta-analysis suggests.

The systematic review, which is the first of its kind, looked at 20 studies comparing the risk for violence or violent crime in individuals with schizophrenia and other psychoses and in that in the general population. In all, there were 18,423 patients with schizophrenia and other psychoses and 1,714,904 individuals from the general population.

“The main reason we undertook this meta-analysis, which includes all of the studies that look at this issue to date, is
because there has been a great deal of uncertainty about whether the relationship between violence and schizophrenia
is causal or related to other factors,” study investigator Martin Grann, PhD, from the Centre for Violence Prevention,
Karolinska Institutet, in Stockholm, Sweden, told Medscape Psychiatry.

“When you look at these 20 studies combined, the pattern is clear that in people with schizophrenia with no alcohol or
drug misuse, the risk of violence is insignificant compared with the general population. But when alcohol and drug
abuse are added to the equation, then you have a problem,” added Dr. Grann.

The study was published online August 11 in PloS Medicine.

People With Schizophrenia Not Dangerous

Among individuals with schizophrenia and other psychoses, 1832 (9.9%) were violent; among the general population,
27,185 (1.6%) were violent. When pooled data from the 2 groups were compared, researchers found that men with
schizophrenia had a pooled odds ratio for violence ranging from 1 to 7, compared with those without mental illness.

In women, the odds ratio for violence ranged from 4 to 29 in those with schizophrenia and other psychoses, compared
with their counterparts without mental illness.

The effects of comorbid substance abuse was marked with the random-effects odds ratios of 2.1 without comorbidity
and an odds ratio of 8.9 with comorbidity, the authors report. Importantly, said Dr. Grann, risk estimates of violence in individuals with substance abuse but without psychosis were similar to those in individuals with psychosis and
comorbid substance abuse. The risk for homicide was increased in individuals with psychosis — with or without
comorbid substance abuse.

Dr. Grann described the increased risk for violence and homicide among individuals with severe mental illness without
substance abuse as “very modest,” compared with the general population.

“People with schizophrenia are not dangerous. Individuals without schizophrenia with drug and alcohol abuse are morelikely to be violent than individuals with schizophrenia who also have abuse problems. In other words, if a person is an alcoholic or a drug addict, he is less likely to be violent if he also has schizophrenia. So, in this context, you could say schizophrenia is actually protective,” said Dr. Grann.

This review, he added, highlights the “critical need” for clinicians to address issues of substance and alcohol abuse in
this patient population, an issue he said is often neglected.

Lack of Integrated Care

Asked by Medscape Psychiatry to comment on the findings, Jeffrey A. Lieberman, MD, Lawrence E. Kolb professor
and chair of psychiatry at the Columbia University College of Physicians and Surgeons and director of the New York
State Psychiatric Institute in New York City, agreed that the study underlines the importance of addressing substance
abuse in these patients.

He agreed with Dr. Grann that current management of substance abuse in patients with severe mental illness is not
optimal. One of the barriers to effective treatment in the United States, said Dr. Lieberman, is a lack of integrated care.

“Diagnosis is not really a problem. However, as far as treatment is concerned, there is a systemic problem because
frequently substance-abuse treatment isn’t available in mental healthcare clinical settings, and vice versa. This makes
it difficult to provide a broad array of treatments in a single clinical setting, and it is similarly difficult to get patients to go to 2 separate centers for treatment, “he said.

One of the study’s limitations, said Dr. Lieberman, is the fact that it did not examine the issue of treatment adherence,
which can be a risk factor for violence.

“The features that tend to characterize violence in patients with mental illness are psychotic disorders, treatment
nonadherence, and substance abuse. Another influencing factor is homelessness, but the triad of psychotic illness,
treatment nonadherence, and comorbid substance abuse point to the highest risk for violent behavior in mentally ill
people,” he said.

Both Drs. Grann and Lieberman said that more research is needed to determine whether treatments used to address a
primary diagnosis of substance abuse are effective in individuals with psychosis who have comorbid substance abuse,
and whether such treatments lower the risk for violence.

The researchers have disclosed no relevant financial relationships.
PLoS Medicine. Published online before print August 11, 2009. Abstract

Caroline Cassels
Caroline Cassels is the news editor for Medscape Psychiatry. A medical and health journalist for 20 years, Caroline has written extensively for both physician and consumer audiences. She helped launch and was the editor of Health Digest, an award-winning Canadian consumer health publication. She was also national editor of the Heart & Stroke
Foundation of Canada’s Web site before joining Medscape Neurology & Neurosurgery in 2005. She is the recipient of
the 2008 American Academy of Neurology Journalism Fellowship Award. She can be contacted at

The Neurobiology of Schizophrenia: An Expert Interview With Joshua L. Roffman, MD

Pippa Wysong
Published: 08/11/2009

Medscape: Can you start with defining neurobiology?
Dr. Roffman: Neurobiologists study the structure and function of the nervous system, including the brain. In psychiatry, we use MRI [magnetic resonance imaging] and other neuroimaging techniques to look at the ways the brain is put together anatomically and the way it works when performing certain tasks. Clinical neurobiology researchers may also look at electrical activity of neurons using technologies such as electroencephalography and magnetoencephalography [MEG]. Some neurobiologists use probes to look at how neurons and other supporting cells work on the level of proteins and even down to the level of DNA. Researchers also use animal models and study donated postmortem brain tissue. In sum, neurobiology is the study of how all these things work in concert to influence the way the brain works in both healthy people and in [patients with] neurological and psychiatric disorders.

Medscape: What are key challenges in schizophrenia?
Dr. Roffman: Schizophrenia is complex. Even though the clinical manifestations of schizophrenia are quite dramatic,
changes in the brain itself are actually fairly subtle. A challenge is to understand what those subtle changes are and
how they translate into symptoms.

Medscape: A majority of neurobiology research is focused on genetics. Could you tell Medscape readers
about that?

Dr. Roffman: About 80% of someone’s risk for developing schizophrenia has to do with their genetic makeup. Still, it’s
a challenge to find specific genes that are implicated in the disorder because it’s not like there’s one or two genes that
in most cases will cause the illness. If that were the case, we would have already found them.

Medscape: There could be different combinations of genes in different people leading to the disease, right?
Dr. Roffman: Right. Each gene by itself has a very small effect. Recently, rare mutations were found that are less
subtle and which, in some cases, may be more directly responsible for the illness. So far, those kinds of mutations
(called copy-number variance) appear to cause the disorder in a relatively small number of patients.
For most schizophrenia genes, the reason why the effects are so small is because what you’re measuring are clinical
problems — but from a biological standpoint those problems occur far downstream [from] the level of the gene. Many
researchers are working on ways to amplify these genetic signals.

Medscape: How do you see what genes are doing?
Dr. Roffman:
Genes code for proteins, and proteins organize themselves into cells, and cells into neural networks.
There are many processes that happen between the level of the gene and what we see clinically. To really understand
what’s happening, we bring in brain imaging, which allows us to measure the effects of the gene directly on the level of
brain structure and function. This sort of research shows that many genes involved in what has long been suspected to
be important biochemical processes in schizophrenia, do affect brain activity.

Medscape: Are there many candidate genes in the field?
Dr. Roffman:
Several dozen genes are being studied. New genes are also being discovered using genome-wide
association [GWA] studies, which use a high-throughput method that captures most of the genetic variation within an
individual. GWA studies help identify specific genes which occur more frequently in schizophrenia patients than in
healthy individuals.

Medscape: If 80% of an individual’s risk has to do with the genes, does that mean 20% of cases are sporadic?
Dr. Roffman:
It probably isn’t the case that 20% of schizophrenia patients have sporadic or nongenetic developmental causes of the disorder. It’s more like within an individual, 80% of that individual’s chance has to do with genetic factors and 20% has to do with nongenetic factors.

Medscape: What about the recent finding that the offspring of older men fathering children have a higher risk for schizophrenia? Is that inherited or environmental?
Dr. Roffman:
Good question, and it’s a fairly robust finding. We don’t know. There could be something related to
environmental factors, or maybe how stable the DNA is in sperm cells in older men versus younger men. Studies like
that open up new avenues to explore.

Medscape: You mentioned studying electrical activity of neurons. What’s new there?
Dr. Roffman:
There are several different ways to look at brain electrical activity. One new method is MEG, which
provides a precise way of looking at electrical activity across the cortex. It can measure how that activity changes from millisecond to millisecond. Measures such as functional MRI and positron emission tomography, which have good spatial resolution, lack the degree of temporal resolution MEG has.

Medscape: In schizophrenia neurobiology research, what has trickled down into practice?
Dr. Roffman:
Some research has trickled down through pharmacology. For instance, the new antipsychotics that came out in the nineties emerged from basic and animal research looking at brain chemistry systems in schizophrenia. This research led to newer drugs with different mechanisms of action.

Medscape: What are possible scenarios about how all this can affect practice?
Dr. Roffman:
As genetic research into schizophrenia has really taken off, the cost of genotyping has plummeted. It’s
easy to imagine that some day patients would come in, and as part of an evaluation for schizophrenia, a simple blood
test or saliva test would be performed. We would canvas their entire genome looking for the presence of schizophrenia related genes. Then we’d use that information to confirm the diagnosis, help subtype the illness, and, more importantly, know ahead of time whether someone is likely to respond to a specific treatment. For example, a few years ago several studies showed that patients with a certain version of the COMT gene were likely to respond to olanzapine. However, genetic tests are not yet routinely used in schizophrenia.

Medscape: While neurobiology sounds so mechanistic, traditional approaches to treatment won’t disappear,right?
Dr. Roffman:
No. Other forms of treatment such as psychotherapy can be complementary to neurobiologically focused treatments, and can help patients handle the symptoms of schizophrenia. However, unlike with depression or anxiety, psychotherapy cannot take away the symptoms of schizophrenia.

Medscape: Do you have any general messages for physicians about the neurobiology of schizophrenia?
Dr. Roffman:
It’s an exciting time in schizophrenia research. I think the genetics of schizophrenia, in particular, is an
alluring and rapidly moving target. As with other areas of medicine, we expect that over the next several years we’ll
have a much better idea of how particular genetic variants contribute to the disease. The pace of genetics research has
accelerated to the point where it’s now possible to look at all the genetic variants in an individual quickly and
inexpensively. We all hope this will translate into clinical progress in schizophrenia.

Pippa Wysong
Pippa Wysong is a freelance writer for Medscape.
Disclosure: Pippa Wysong has disclosed no relevant financial relationships.

Science and Service News Updates

NIMH: Schizophrenia Linked to Over-expression of Gene in Fetal Brain: Excess of Shortened Forms Could Lead to Abnormal Brain Development

A gene called DISC1, (for “disrupted in schizophrenia”) has been a leading contender among possible genetic causes since it was implicated in schizophrenia in a large Scottish clan two decades ago. The DISC1 gene codes for a protein important for brain development, as well as for mood and memory – functions that are disturbed in schizophrenia. However, until now there have been few clues as to how DISC1 might increase risk. A new study suggests how impaired expression of DISC1 might wreak havoc during early critical periods as the developing brain gets wired up. NIMH researchers have discovered that previously unknown shortened forms of the gene were expressed 2.5 times more in the fetal brain than after birth. By contrast, other forms were expressed more evenly across development. The shortened forms were also over-expressed in brains of adults who had schizophrenia. Researchers report on their discoveries in postmortem brain tissue online, during the week of August 24, 2009 in the Proceedings of the National Academy of Science (PNAS).

Science Update:

HHS Announces $25.7 Million in Grants to Expand, Improve Health Center Services

The US Department of Health and Human Services (HHS) announced more than $25.7 million in grants to increase and improve health and support services at the nation’s health centers. A total of 180 grants worth more than $21.9 million will give existing health centers the funds to add or increase mental health/substance abuse treatment, enabling (i.e., outreach, transportation, case management services), and oral health or pharmacy services. Additionally, 48 planning grants totaling more than $3.8 million will be distributed to organizations in hard hit areas that do not have health centers to help them develop new service delivery sites. New health center sites must meet federal requirements for governance, community involvement, quality of care and financial feasibility.

Press release:

NIMH is on YouTube

NIMH has posted several videos on its YouTube channel. These include a four-minute video on depression and Brain’s Inner Workings I and II narrated by Leonard Nemoy and Tom Bosley.  The two Brain’s Inner Workings videos explore the biological function of neurons and neurotransmitters, and higher brain function. Other videos include short clips of MRI and FMRI that show changes in brain structure and function in the developing brain.

Follow NIMH on Twitter

Receive updates about the latest science news and publications.

Trastorno Bipolar

NIMH’s easy-to-read booklet on bipolar disorder is now available in Spanish online.

The suicide prevention information on the NIMH website is highlighted during Suicide Prevention Week.

Leveling the Playing Field: Practical Strategies for Increasing Veterans Involvement in Diversion and Reentry Programs

This guide from SAMHSA’s GAINS Center was designed to ensure that veterans with histories of incarceration are positioned to inform, support, and lead efforts to reform the criminal justice and mental health systems by identifying and addressing the obstacles that prevent meaningful veteran involvement.