Antipsychotic drugs linked to slight decrease in brain volume

A study published today has confirmed a link between antipsychotic medication and a slight, but measureable, decrease in brain volume in patients with schizophrenia. For the first time, researchers have been able to examine whether this decrease is harmful for patients’ cognitive function and symptoms, and noted that over a nine year follow-up, this decrease did not appear to have any effect.

As we age, our brains naturally lose some of their volume – in other words, brain cells and connections. This process, known as atrophy, typically begins in our thirties and continues into old age. Researchers have known for some time that patients with schizophrenia lose brain volume at a faster rate than healthy individuals, though the reason why is unclear.

Now, in a study published in the open access journal PLOS ONE, a team of researchers from the University of Oulu, Finland, and the University of Cambridge has identified the rate of decrease in both healthy individuals and patients with schizophrenia. They also documented where in the brain schizophrenia patients have more atrophy, and have examined links between atrophy and antipsychotic medication.

By comparing brain scans of 33 patients with schizophrenia with 71 control subjects over a period of 9 years – from age 34 to 43 – the researchers were able to show that schizophrenia patients lost brain volume at a rate of 0.7% each year. The control participants lost brain volume at a rate of 0.5% per year.

Scientists have previously speculated that antipsychotic medication used to treat schizophrenia may be linked to this decrease in brain volume. Today’s research confirms this association, showing that the rate of decrease in volume was greater when the dose of medication was higher. However, the mechanisms behind this – and whether it was in fact the medication that was causing this greater loss of tissue – are not clear. Some researchers have previously argued that whilst older antipsychotic medications might cause brain volume decreases, newer antipsychotic medications may protect against these decreases. However, today’s research suggests that both classes of antipsychotic medication are associated with similar declines in brain volume.

The researchers also looked at whether there was any link between the volume of brain lost and the severity of symptoms or loss of cognitive function, but found no effect.

Professor Juha Veijola from the Department of Psychiatry at the University of Oulu, Finland says: “We all lose some brain tissue as we get older, but people with schizophrenia lose it at a faster rate. We’ve shown that this loss seems to be linked to the antipsychotic medication people are taking. Research like this where patients are studied for many years can help to develop guidelines about when clinicians can reduce the dosage of antipsychotic medication in the long term treatment of people with schizophrenia.”

“It’s important to stress that the loss of brain volume doesn’t appear to have any effect on people over the nine year follow-up we conducted, and patients should not stop their medication on the basis of this research,” adds Dr Graham Murray from the Behavioural and Clinical Neuroscience Institute and the Department of Psychiatry at University of Cambridge. “A key question in future will be to examine whether there is any effect of this loss of brain volume later in life. We need more research in larger studies with longer follow-ups to evaluate the significance of these brain changes.”

Do drugs for bipolar disorder “normalize” brain gene function?

Every day, millions of people with bipolar disorder take medicines that help keep them from swinging into manic or depressed moods. But just how these drugs produce their effects is still a mystery.

Now, a new University of Michigan Medical School study of brain tissue helps reveal what might actually be happening. And further research using stem cells programmed to act like brain cells is already underway.

Using genetic analysis, the new study suggests that certain medications may help “normalize” the activity of a number of genes involved in communication between brain cells. It is published in the current issue of Bipolar Disorders.

The study involved brain tissue from deceased people with and without bipolar disorder, which the U-M team analyzed to see how often certain genes were activated, or expressed. Funding support came from the National Institutes of Health and the Heinz C. Prechter Bipolar Research Fund.

“We found there are hundreds of genes whose activity is adjusted in individuals taking medication – consistent with the fact that there are a number of genes that are potentially amiss in people with bipolar,” says senior author Melvin McInnis, M.D., the U-M psychiatrist, U-M Depression Center member and principal investigator of the Prechter Fund Projects who helped lead the study. “Taking the medications, specifically ones in a class called antipsychotics, seemed to normalize the gene expression pattern in these individuals so that it approached that of a person without bipolar.”

Digging deeper into bipolar genetics

Scientists already know that bipolar disorder’s roots lie in genetic differences in the brain — though they are still searching for the specific gene combinations involved.  

McInnis and his colleagues have now embarked on research developing several a lines of induced pluripotent stem cells derived (iPSC) from volunteers with and without bipolar disorder, which will allow even more in-depth study of the development and genetics of bipolar disorder.

The newly published study looked at the expression, or activity levels, of 2,191 different genes in the brains of 14 people with bipolar disorder, and 12 with no mental health conditions. The brains were all part of a privately funded nonprofit brain bank that collected and stored donated brains, and recorded what medications the individuals were taking at the time of death.

Seven of the brains were from people with bipolar disorder who had been taking one or more antipsychotics when they died. These drugs include clozapine, risperidone, and haloperidol, and are often used to treat bipolar disorder. Most of the 14 brain donors with bipolar disorder were also taking other medications, such as antidepressants, at the time of death.

When the researchers compared the gene activity patterns among the brains of bipolar disorder patients who had been exposed to antipsychotics with patterns among those who weren’t, they saw striking differences.

Then, when they compared the activity patterns of patients who had been taking antipsychotics with those of people without bipolar disorder, they found similar patterns.

The similarities were strongest in the expression of genes involved in the transmission of signals across synapses – the gaps between brain cells that allow cells to ‘talk’ to one another. There were also similarities in the organization of nodes of Ranvier – locations along nerve cells where signals can travel faster.

McInnis, who is the Thomas B. and Nancy Upjohn Woodworth Professor of Bipolar Disorder and Depression in the U-M Department of Psychiatry, worked with U-M scientists Haiming Chen, M.D. and K. Sue O’Shea, Ph.D., of the U-M Department of Cell and Developmental Biology. They also teamed with Johns Hopkins University researcher Christopher Ross, M.D., Ph.D. on the new research; U-M and Johns Hopkins have a long history of collaboration on bipolar disorder research.

The research used brain tissue samples from the Stanley Brain Collection of the Stanley Medical Research Institute in Maryland.

Using “gene chip” analysis to measure the presence of messenger RNA molecules that indicate gene activity, and sophisticated data analysis, they were able to map the expression patterns from the brains and break the results down by bipolar status and medication use. The bipolar and control (non-bipolar) brains were matched by age, gender and other factors.

“In bipolar disorder, it’s not just one gene that’s involved – it’s a whole symphony of them,” says McInnis, who has helped lead U-M’s bipolar genetics research for nearly a decade. “Medications appear to nudge them in a direction that aligns more with the normal expression pattern.”

Among those that were “nudged” were genes that have already been shown to be linked to bipolar disorder, including glycogen synthase kinase 3 beta (GSK3β), FK506 binding protein 5 (FKBP5), and Ankyrin 3 (ANK3).

Going forward, says McInnis, cell culture studies will be critical to studying how medications for bipolar disorder work, and to screen new molecules as potential new medications.

More Kids Taking Antipsychotics for ADHD: Study

Use of powerful antipsychotic medications such as Abilify and Risperdal to control youngsters with attention-deficit/hyperactivity disorder (ADHD) and other behavior problems has skyrocketed in recent years, a new study finds.

Antipsychotics are approved to treat bipolar disorder, schizophrenia, other serious mental problems and irritability related to autism. But they don’t have U.S. Food and Drug Administration approval for ADHD or other childhood behavior problems, and their use for this purpose is considered “off label.”

"Only a small proportion of antipsychotic treatment of children (6 percent) and adolescents (13 percent) is for FDA-approved clinical indications," said lead researcher Dr. Mark Olfson, a professor of clinical psychiatry at Columbia University Medical Center in New York City.