Combined drugs and therapy most effective for severe nonchronic depression

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"The odds that a person who suffers from severe, nonchronic depression will recover are improved by as much as 30 percent if they are treated with a combination of cognitive therapy and antidepressant medicine rather than by antidepressants alone. However, a person with chronic or less severe depression does not receive the same additional benefit from combining the two. That is the result of a major new clinical trial published online by the journal JAMA Psychiatry on Aug. 20. In North America, about one in five women and one in 10 men suffer from major depression in her or his lifetime. "Our results indicate that combining cognitive therapy with antidepressant medicine can make a much bigger difference than we had thought to about one-third of patients suffering from major depressive disorder," said Steven Hollon, the Gertrude Conaway Professor of Psychology at Vanderbilt University, who directed the study. "On the other hand, it does not appear to provide any additional benefit for the other two-thirds." Previous studies have found that about two-thirds of all patients with major depressive disorder will improve on antidepressant medications and about one-third of patients will achieve full remission, but half then relapse before fully recovering. Cognitive therapy has proven to be about as effective as medication alone but its effects tend to be longer lasting. Combining the two has been estimated to improve recovery rates by 6 to 33 percent. "Now, we have to reconsider our general rule of thumb that combining the two treatments keeps the benefits of both," said Hollon. The new study was a randomized clinical trial involving 452 adult outpatients with chronic or recurrent major depressive disorder. Unlike previous studies that followed subjects for a set period of time, this study treated them for as long as it took first to remission (full normalization of symptoms) and then to recovery (six months without relapse), which in some cases took as long as three years. "This provided us with enough data so that we could drill down and see how the combined treatment was working for patients with different types and severity of depression: chronic, recurrent, severe and moderate," Hollon said. According to the psychologist, the results could have a major impact on how major depressive disorder is treated. The most immediate effect is likely to be in the United Kingdom, which, he said, is 10 years ahead of the United States in treatment of depression. The use of combined cognitive therapy and antidepressive medicine is standard for severe cases in the UK, and the English National Health Service is actively training its therapists in cognitive therapy and other empirically supported psychotherapies." ### Collaborators in the study were Robert DeRubeis and Jay Amsterdam from the University of Pennsylvania; Jan Fawcett from the University of New Mexico, Albuquerque; Richard Shelton from the University of Alabama, Birmingham; John Zajecka and Paula Young from Rush University; and Robert Gallop from West Chester University. The study was supported by grants MH60713, MH01697, MH60998 and MH060768 from the National Institute of Mental Health. For more information on mental health and counseling related topics, please visit Counselor CEUs

Alcohol, tobacco, drug use far higher in severely mentally ill

In the largest ever assessment of substance use among people with severe psychiatric illness, researchers at Washington University School of Medicine in St. Louis and the University of Southern California have found that rates of smoking, drinking and drug use are significantly higher among those who have psychotic disorders than among those in the general population. The study is published online in the journal JAMA Psychiatry. The finding is of particular concern because individuals with severe mental illness are more likely to die younger than people without severe psychiatric disorders. "These patients tend to pass away much younger, with estimates ranging from 12 to 25 years earlier than individuals in the general population," said first author Sarah M. Hartz, MD, PhD, assistant professor of psychiatry at Washington University. "They don't die from drug overdoses or commit suicide — the kinds of things you might suspect in severe psychiatric illness. They die from heart disease and cancer, problems caused by chronic alcohol and tobacco use." The study analyzed smoking, drinking and drug use in nearly 20,000 people. That included 9,142 psychiatric patients diagnosed with schizophrenia, bipolar disorder or schizoaffective disorder — an illness characterized by psychotic symptoms such as hallucinations and delusions, and mood disorders such as depression. The investigators also assessed nicotine use, heavy drinking, heavy marijuana use and recreational drug use in more than 10,000 healthy people without mental illness. The researchers found that 30 percent of those with severe psychiatric illness engaged in binge drinking, defined as drinking four servings of alcohol at one time. In comparison, the rate of binge drinking in the general population is 8 percent. Among those with mental illness, more than 75 percent were regular smokers. This compares with 33 percent of those in the control group who smoked regularly. There were similar findings with heavy marijuana use: 50 percent of people with psychotic disorders used marijuana regularly, versus 18 percent in the general population. Half of those with mental illness also used other illicit drugs, while the rate of recreational drug use in the general population is 12 percent. "I take care of a lot of patients with severe mental illness, many of whom are sick enough that they are on disability," said Hartz. "And it's always surprising when I encounter a patient who doesn't smoke or hasn't used drugs or had alcohol problems." Hartz said another striking finding from the study is that once a person develops a psychotic illness, protective factors such as race and gender don't have their typical influence. Previous research indicates that Hispanics and Asians tend to have lower rates of substance abuse than European Americans. The same is true for women, who tend to smoke, drink and use illicit drugs less often than men. "We see protective effects in these subpopulations," Hartz explained. "But once a person has a severe mental illness, that seems to trump everything." That's particularly true, she said, with smoking. During the last few decades, smoking rates have declined in the general population. People over age 50 are much more likely than younger people to have been regular smokers at some point in their lives. For example, about 40 percent of those over 50 used to smoke regularly. Among those under 30, fewer than 20 percent have been regular smokers. But among the mentally ill, the smoking rate is more than 75 percent, regardless of the patient's age. "With public health efforts, we've effectively cut smoking rates in half in healthy people, but in the severely mentally ill, we haven't made a dent at all," she said. Until recently, smoking was permitted in most psychiatric hospitals and mental wards. Hartz believes that many psychiatrists decided that their sickest patients had enough problems without having to worry about quitting smoking, too. There also were concerns about potential dangers from using nicotine-replacement therapy, while continuing to smoke since smoking is so prevalent among the mentally ill. Recent studies, however, have found those concerns were overblown. The question, she said, is whether being more aggressive in trying to curb nicotine, alcohol and substance use in patients with severe psychiatric illness can lengthen their lives. Hartz believes health professionals who treat the mentally ill need to do a better job of trying to get them to stop smoking, drinking and using drugs. "Some studies have shown that although we psychiatrists know that smoking, drinking and substance use are major problems among the mentally ill, we often don't ask our patients about those things," she said. "We can do better, but we also need to develop new strategies because many interventions to reduce smoking, drinking and drug use that have worked in other patient populations don't seem to be very effective in these psychiatric patients." CADC I & II Continuing Education ### Funding for this research comes from the National Institute on Drug Abuse (NIDA), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the National Institute of Mental Health (NIMH) and the National Cancer Institute (NCI) of the National Institutes of Health (NIH), and the American Cancer Society. NIH grant numbers R01 DA032843, R01 DA025888, U10 AA008401, UL1 RR024992, P01 CA089392, R01 MH085548, R01 MH085542, K08 DA032680-1, Kl2 RR024994, K01 DA025733. Hartz SM, Pato CN, Medeiros H, Cavazos-Rehg P, Sobell JL, Knowles JA, Bierut LJ, Pato MT and the Genomic Psychiatry Cohort Consortium. JAMA Psychiatry Published online Jan. 1, 2014. doi:10.1001/jamapsychiatry.2013.3276 Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.

Potential new class of drugs blocks nerve cell death

Potential new class of drugs protects nerve cells in models of Parkinson's disease and amyotrophic lateral sclerosis Diseases that progressively destroy nerve cells in the brain or spinal cord, such as Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), are devastating conditions with no cures. Now, a team that includes a University of Iowa researcher has identified a new class of small molecules, called the P7C3 series, which block cell death in animal models of these forms of neurodegenerative disease. The P7C3 series could be a starting point for developing drugs that might help treat patients with these diseases. These findings are reported in two new studies published the week of Oct. 1 in PNAS Early Edition. "We believe that our strategy for identifying and testing these molecules in animal models of disease gives us a rational way to develop a new class of neuroprotective drugs, for which there is a great, unmet need," says Andrew Pieper, M.D., Ph.D., associate professor of psychiatry at the UI Carver College of Medicine, and senior author of the two studies. About six years ago, Pieper, then at the University of Texas Southwestern Medical Center, and his colleagues screened thousands of compounds in living mice in search of small, drug-like molecules that could boost production of neurons in a region of the brain called the hippocampus. They found one compound that appeared to be particularly successful and called it P7C3. "We were interested in the hippocampus because new neurons are born there every day. But, this neurogenesis is dampened by certain diseases and also by normal aging," Pieper explains. "We were looking for small drug-like molecules that might enhance production of new neurons and help maintain proper functioning in the hippocampus." However, when the researchers looked more closely at P7C3, they found that it worked by protecting the newborn neurons from cell death. That finding prompted them to ask whether P7C3 might also protect existing, mature neurons in other regions of the nervous system from dying as well, as occurs in neurodegenerative disease. Using mouse and worm models of PD and a mouse model of ALS, the research team has now shown that P7C3 and a related, more active compound, P7C3A20, do in fact potently protect the neurons that normally are destroyed by these diseases. Their studies also showed that protection of the neurons correlates with improvement of some disease symptoms, including maintaining normal movement in PD worms, and coordination and strength in ALS mice. Of mice and worms In the ALS mouse model, a highly active variant of the original P7C3 molecule, known as P7C3A20, which the investigators synthesized, largely prevented death of the nerve cells within the spinal cord that are normally destroyed by this disease. The P7C3 molecule also worked, but was not as effective at protecting neurons in this model. As cell survival increased in the ALS model, coordination and strength of the mice improved as well. Mice that were given P7C3A20 were able to stay on a rotating rod much longer than untreated animals or animals that received the less active compounds. Animals receiving P7C3A20 also performed better in analysis of their walking gait, which typically worsens in these animals as the disease progresses. In PD, dopamine-producing neurons necessary for normal movement are gradually destroyed. In patients, loss of these brain cells leads to tremors, stiffness, and difficulty walking. The study again showed that P7C3 protects these neurons from cell death and the more active analogue, P7C3A20, provided even greater protection. The two compounds also potently blocked cell death of dopaminergic neurons in a C. elegans worm model of PD. Moreover, reduced cell death in this model was associated with improved movement in the worms. Healthy C. elegans worms have a very characteristic swimming motion. This movement is disrupted in the PD worm. Hector De Jesus-Cortes, a graduate student of neuroscience at UT Southwestern Medical Center and lead author of the Parkinson's study, videotaped and analyzed the PD worms' mobility with and without treatment. Normal swimming was almost completely preserved with P7C3A20, and was also fairly well preserved with P7C3. Tweaking the molecule The research team compared the activity of several new P7C3-related compounds that they synthesized, in both the hippocampal neurogenesis screen and the mouse model of PD. "Every variation of our P7C3 molecule that works in the neurogenesis assay also works in the PD model," Pieper says. "As we continue to refine the molecule, our hope is that the results from the neurogenesis assay will accurately predict the neuroprotective potency of the compound, and thus aid in more rapidly optimizing a new neuroprotective agent." Nursing CEUs The team plans to continue tweaking the structure of the P7C3 molecule to improve its neuroprotective ability while eliminating potential side effects. "Our hope is that this work will form the basis for designing a neuroprotective drug that could eventually help patients," Pieper says. ### Pieper and De Jesus-Cortes conducted the study with colleagues at UT Southwestern Medical Center, including Steven McKnight, Ph.D., chairman of biochemistry, and Joseph Ready, Ph.D., professor of biochemistry. The work was funded in part by grants from the National Institute for Mental Health.

Antidepressant-suicide link in youths absent in new analysis

Drugs also found effective in reducing suicidal behavior in adults, elderly

In 2004, concerns about antidepressant drugs increasing suicidal thoughts and behaviors in young patients prompted the FDA to issue a rare "black box warning." Now, a new analysis of clinical trial data finds that treatment with the antidepressant fluoxetine did not increase — or decrease — suicidality in children compared to placebo treatment.

An analysis built on data from 41 trials and more than 9,000 patients also found that two different popular antidepressant drugs were effective at reducing suicidal behavior and depressive symptoms in adult and geriatric patients. The findings are published online Feb. 6 in the journal Archives of General Psychiatry Alcoholism and Drug Abuse Counselors Continuing Education


The failure to replicate the link between antidepressants and suicide should reassure doctors about prescribing these drugs to depressed patients, said first author Robert Gibbons, PhD, professor of medicine, health studies, and psychiatry at the University of Chicago Medicine.

"The key finding here, when we re-analyze all the patient-level longitudinal records in these studies, is that antidepressants neither increase nor decrease suicidal thoughts or behavior in children," Gibbons said.

The FDA decision on the black box warning was based on retrospective data from 25 clinical trials of newer antidepressant medications, including the serotonin reuptake inhibitor drug fluoxetine, marketed as Prozac or Sarafem. A meta-analysis combining adverse event data (primarily based on self reports of suicidal thoughts) from the trials revealed a small, but significant, increase in suicidal thoughts and behavior in children and young adults up to the age of 25.

For the new analysis, Gibbons and colleagues from the University of Illinois at Chicago, the University of Miami and Columbia University obtained individual-level, longitudinal clinical trial data — some of it unpublished — from pharmaceutical producers and a large National Institute of Mental Health collaborative study of fluoxetine and venlafaxine. The data included weekly screening of each trial subject for depression and suicidal thoughts, allowing researchers to compare the effect of drug or placebo over time on these measures.

In the analysis of the adult and geriatric trials testing fluoxetine or venlafaxine, both antidepressants were found effective in reducing suicide risk and depression symptoms. These two effects were also found to be statistically associated, suggesting that the drugs reduced suicidality by alleviating depression. Therefore, Gibbons said, effective treatment of major depressive disorder is important for a patient's safety.

"Basically, the results say that the mechanism by which the antidepressants affect suicide rates is by decreasing depression," Gibbons said. "It follows that if a treatment is not working for an individual, the risk for suicidal behavior and perhaps worse remains high."

To analyze the effects of antidepressants in children, the researchers used four trials of fluoxetine, which until recently was the only antidepressant approved for pediatric use. Once again, a reduction in depressive symptoms was observed in the drug-treated population compared to placebo. However, no significant change in suicide risk was detected between the two patient groups.

"I think that this paper supports the general idea that the effects of antidepressants in kids and adults are not really the same, since we don't see anything but beneficial effects of antidepressants in adults and geriatrics," Gibbons said. "In kids, we don't see a harmful effect, but we do see a disassociation between the beneficial effects on depression and the potential beneficial effect on suicide."

"This raises continued questions about what's going on in children," he continued. "Maybe children think about suicide in part because of depression, but also maybe due to other reasons not related to depression that are not affected by antidepressants."

Gibbons, who sat on the Food and Drug Administration panel that considered placing the black box warning on antidepressants, said he hoped the new results would reassure clinicians about the safety of the drugs. Previous research by his group found that the addition of the warning significantly reduced antidepressant prescriptions to both children and adults and correlated with a spike in suicide rates.

"I hope that the warnings will not prevent depressed children and adults from getting treatment for depression," Gibbons said. "The greatest cause of suicide is untreated or undiagnosed depression. It's very important that this condition be recognized and appropriately treated and not discarded because doctors are afraid to be sued."


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The paper, "Suicidal Thoughts and Behavior with Antidepressant Treatment," will be published online February 6th by Archives of General Psychiatry. In addition to Gibbons, authors include C. Hendricks Brown of the University of Miami, Kwan Hur of the University of Chicago, John M. Davis of the University of Illinois at Chicago, and J. John Mann of Columbia University. Funding for the research was provided by the National Institute of Mental Health and the Agency for Healthcare Research and Quality.

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