Antidepressants versus running for depression: Is there a winner?

by European College of Neuropsychopharmacology

Credit: Pixabay/CC0 Public Domain

The first study to compare effects of antidepressants with running exercises for anxiety, depression and overall health shows that they have about the same benefits for mental health—but a 16-week course of running over the same period scores higher in terms of physical health improvement, whereas antidepressants lead to a slightly worse physical condition, as has been suggested by previous studies. However, the drop-out rate was much higher in the group which initially chose exercise.

14 oct 2023--Professor Brenda Penninx (Vrije University, Amsterdam) is set to present the work at the 36th ECNP Congress, Barcelona, 7–10 October 2023, after recent publication in the Journal of Affective Disorders, saying, "We wanted to compare how exercise or antidepressants affect your general health, not just your mental health."

The researchers studied 141 patients with depression and/or anxiety. They were offered a choice of treatment; SSRI antidepressants for 16 weeks, or group-based running therapy for 16 weeks. 45 chose antidepressants, with 96 participating in running. The members of the group which chose antidepressants were slightly more depressed than the members of the group which chose to take running.

Professor Penninx said, "This study gave anxious and depressed people a real-life choice, medication or exercise. Interestingly, the majority opted for exercise, which led to the numbers in the running group being larger than in the medication group."

Treatment with antidepressants required patients to adhere to their prescribed medication intake but this generally does not directly impact on daily behaviors. In contrast, exercise directly addresses the sedentary lifestyle often found in patients with depressive and anxiety disorders by encouraging persons to go outside, set personal goals, improve their fitness and participate in a group activity.

The antidepressant group took the SSRI Escitalopram for 16 weeks. The running group aimed for two to three closely supervised 45-minute group sessions per week (over 16 weeks). The adherence to the protocol was lower in the running group (52%) than in the antidepressant group (82%), despite the initial preference for running over antidepressants.

At the end of the trial, around 44% % in both groups showed an improvement in depression and anxiety, however the running group also showed improvements in weight, waist circumference, blood pressure, and heart function, whereas the antidepressant group showed a tendency towards a slight deterioration in these metabolic markers.

Brenda Penninx said, "Both interventions helped with the depression to around the same extent. Antidepressants generally had worse impact on body weight, heart rate variability and blood pressure, whereas running therapy led to improved effect on general fitness and heart rate for instance. We are currently looking in more detail for effects on biological aging and processes of inflammation."

"It is important to say that there is room for both therapies in care for depression. The study shows that lots of people like the idea of exercising, but it can be difficult to carry this through, even though the benefits are significant.

"We found that most people are compliant in taking antidepressants, whereas around half of the running group adhered to the two-times-a-week exercise therapy. Telling patients to go run is not enough. Changing physical activity behavior will require adequate supervision and encouragement as we did by implementing exercise therapy in a mental health care institution."

She added, "Antidepressants are generally safe and effective. They work for most people. We know that not treating depression at all leads to worse outcomes; so antidepressants are generally a good choice. Nevertheless, we need to extend our treatment arsenal as not all patients respond to antidepressants or are willing to take them. Our results suggest that implementing exercise therapy is something we should take much more seriously, as it could be a good—and maybe even better—choice for some of our patients."

"In addition, let's also face potential side effects our treatments can have. Doctors should be aware of the dysregulation in nervous system activity that certain antidepressants can cause, especially in patients who already have heart problems. This also provides an argument to seriously consider tapering and discontinuing antidepressants when depressed or anxious episodes have remitted. In the end, patients are only truly helped when we are improving their mental health without unnecessarily worsening their physical health."

This is adapted from a commentary recently published in the journal European Neuropsychopharmacology.

Commenting, Dr. Eric Ruhe (Amsterdam University Medical Centers) said, "These are very interesting results that again show that physical health can influence mental health and that treatment of depression and anxiety can be achieved by exercising, obviously without the adverse effects of antidepressant drugs. "

"However, several remarks are important. First the patients followed their preference, which is common practice, but ideally we should advise patients what will work best. Following this choice is understandable from a pragmatic point of view when patients have strong preferences, which you have to take into account when doing a study like this.

"The downside is that the comparisons between groups might be biased compared to doing this in a truly randomized study. For example, patients in the antidepressant group were more depressed which might be associated with less chance of persisting engagement in the exercises. So, we have to be careful not to overinterpret the comparisons between groups, which the authors acknowledge properly.

"Finally, a very important finding is the difference in adherence between the interventions: 52% in the exercise group and 82% in the antidepressant group. This shows that it is more difficult to change a lifestyle habit than taking a pill. This is not exclusively found in psychiatry, indicating that we also have to focus on how to improve compliance to healthy behavior. This could have tremendous impact on health care more generally, but also on psychiatric diseases."

More information: Josine E. Verhoeven et al, Antidepressants or running therapy: Comparing effects on mental and physical health in patients with depression and anxiety disorders, Journal of Affective Disorders (2023). DOI: 10.1016/j.jad.2023.02.064

Conference abstract: "Medication and lifestyle interventions in regulating immune function and mental health."

 

Researchers identify biomarker for depression, antidepressant response

by University of Illinois at Chicago

Credit: Pixabay/CC0 Public Domain

Researchers are one step closer to developing a blood test that provides a simple biochemical hallmark for depression and reveals the efficacy of drug therapy in individual patients.

29 jan 2022--Published in a new proof of concept study, researchers led by Mark Rasenick, University of Illinois Chicago distinguished professor of physiology and biophysics and psychiatry, have identified a biomarker in human platelets that tracks the extent of depression.

The research builds off of previous studies by several investigators that have shown in humans and animal models that depression is consistent with decreased adenylyl cyclase—a small molecule inside the cell that is made in response to neurotransmitters such as serotonin and epinephrine.

"When you are depressed, adenylyl cyclase is low. The reason adenylyl cyclase is attenuated is that the intermediary protein that allows the neurotransmitter to make the adenylyl cyclase, Gs alpha, is stuck in a cholesterol-rich matrix of the membrane—a lipid raft—where they don't work very well," Rasenick said.

The new study, "A Novel Peripheral Biomarker for Depression and Antidepressant Response," published in Molecular Psychiatry, has identified the cellular biomarker for translocation of Gs alpha from lipid rafts. The biomarker can be identified through a blood test.

"What we have developed is a test that can not only indicate the presence of depression but it can also indicate therapeutic response with a single biomarker, and that is something that has not existed to date," said Rasenick, who is also a research career scientist at Jesse Brown VA Medical Center. 

The researchers hypothesize they will be able to use this blood test to determine if antidepressant therapies are working, perhaps as soon as one week after beginning treatment. Previous research has shown that when patients showed improvement in their depression symptoms, the Gs alpha was out of the lipid raft. However, in patients who took antidepressants but showed no improvement in their symptoms, the Gs alpha was still stuck in the raft—meaning simply having antidepressants in the bloodstream was not good enough to improve symptoms.

A blood test may be able to show whether or not the Gs alpha was out of the lipid raft after one week. 

"Because platelets turn over in one week, you would see a change in people who were going to get better. You'd be able to see the biomarker that should presage successful treatment," Rasenick said.

Currently, patients and their physicians have to wait several weeks, sometimes months, to determine if antidepressants are working, and when it is determined they aren't working, different therapies are tried. 

"About 30% of people don't get better—their depression doesn't resolve. Perhaps, failure begets failure and both doctors and patients make the assumption that nothing is going to work," Rasenick said. "Most depression is diagnosed in primary care doctor's offices where they don't have sophisticated screening. With this test, a doctor could say, 'Gee, they look like they are depressed, but their blood doesn't tell us they are. So, maybe we need to re-examine this.'"

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More information: Steven D. Targum et al, A novel peripheral biomarker for depression and antidepressant response, Molecular Psychiatry (2021). DOI: 10.1038/s41380-021-01399-1

 

Prescribe fewer antidepressants, and for shorter periods, doctors advised

by British Medical Journal

Credit: Unsplash/CC0 Public Domain

Doctors should prescribe fewer antidepressants and for shorter periods of time, because of the ongoing uncertainties about their effectiveness and the potential severity and durability of the withdrawal symptoms associated with them, suggests a review of the evidence on antidepressant use, published online in the Drug and Therapeutics Bulletin.

26 dec 2021--The use of antidepressants is also associated with a range of side effects, while the clinical trial data mostly don't assess the outcomes that matter most to patients, say the authors. And there is no clinically relevant difference between these drugs and placebo on depression.

While there might be a role for antidepressants among patients with severe depression, the cons may outweigh the pros in those with mild to moderate depression or in those whose symptoms don't yet qualify as depression, they add.

The prescribing of antidepressants, primarily the newer generation classes—selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs)—has risen steadily in England, with an estimated 7.8 million people issued at least one prescription in 2019-20.

This is equivalent to an antidepressant prescribed to one in every six adults, with prescription rates 50% higher among women.

Much of the evidence for the effectiveness of antidepressants in adults comes from placebo-controlled trials lasting just 6–12 weeks. And the results don't meet the threshold for a clinically important difference, say the authors.

The findings in teenagers and children are even less convincing. Yet the number of 12 to 17 year-olds prescribed antidepressants more than doubled between 2005 and 2017, they add.

What's more, most of the studies don't include outcomes that matter most to patients, such as social functioning or quality of life, focusing instead only on symptom measures.

Side effects are also common. Around 1 in 5 patients on SSRIs report daytime sleepiness, dry mouth, profuse sweating, or weight gain; at least 1 in 4 report sexual difficulties; and about 1 in 10 report restlessness, muscle spasms or twitching, nausea, constipation, diarrhoea or dizziness.

The prevalence of side effects may be even higher among those taking antidepressants for more than 3 years, and can include emotional numbness and mental 'fogginess'.

Patients trying to come off their treatment often experience withdrawal symptoms: these can include anxiety, insomnia, depression, agitation and appetite changes, and can interfere with social functioning and professional life, particularly if treatment is stopped abruptly.

"The recognition that withdrawal effects from antidepressants are more common, more long-lasting and more severe than previously recognised prompted the Royal College of Psychiatrists to issue a position paper, alerting prescribers to this issue, including the recommendation that patients be informed of this risk," note the authors.

Gradual dose tapering may best help patients to stop, say the authors, although "there is no guarantee that patients will avoid consequences such as long-lasting sexual side effects or persistent withdrawal symptoms even with a cautious taper," they write.

But they point out: "The gradual reductions in dose and the very small final doses required for pharmacologically informed tapering will necessitate the use of formulations of medication other than the commonly available tablet forms."

Patients attempting to stop antidepressant use, particularly long term users, may very well need additional help, say the authors. But "there are currently no dedicated NHS services to support antidepressant de-prescribing," they add.

They conclude: "There continues to be considerable uncertainty about the benefits of antidepressant use in the short- and long-term, particularly in regard to the lack of a clinically significant difference between antidepressant and placebo treatment.

"In light of this uncertain balance of benefits and harms, we should re-visit the widespread—and growing—prescription of antidepressants."

They go on to say: "Increasing knowledge about the difficulty that some patients have in stopping antidepressants should lead to more cautious prescribing practice—with antidepressants given to fewer patients, for shorter periods of time."

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More information: Newer generation antidepressants and withdrawal effects: reconsidering the role of antidepressants and helping patients to stop, Drug and Therapeutics Bulletin (2021). DOI: 10.1136/dtb.2020.000080

Provided by British Medical Journal 

Antidepressant may enhance drug delivery to the brain

Normally, P-glycoprotein prevents most medicines from entering the brain by pumping them back into the blood stream (left). The addition of amitriptyline temporarily turns off P-glycoprotein pumps, allowing drug molecules to cross the blood-brain barrier (right). 

28 april 2017--NIH rat study suggests amitriptyline temporarily inhibits the blood-brain barrier, allowing drugs to enter the brain.
New research from the National Institutes of Health found that pairing the antidepressant amitriptyline with drugs designed to treat central nervous system diseases, enhances drug delivery to the brain by inhibiting the blood-brain barrier in rats. The blood-brain barrier serves as a natural, protective boundary, preventing most drugs from entering the brain. The research, performed in rats, appeared online April 27 in the Journal of Cerebral Blood Flow and Metabolism.
Although researchers caution that more studies are needed to determine whether people will benefit from the discovery, the new finding has the potential to revolutionize treatment for a whole host of brain-centered conditions, including epilepsy, stroke, human amyotrophic lateral sclerosis (ALS), depression, and others. The results are so promising that a provisional patent application has been filed for methods of co-administration of amitriptyline with central nervous system drugs.
According to Ronald Cannon, Ph.D., staff scientist at NIH's National Institute of Environmental Health Sciences (NIEHS), the biggest obstacle to efficiently delivering drugs to the brain is a protein pump called P-glycoprotein. Located along the inner lining of brain blood vessels, P-glycoprotein directs toxins and pharmaceuticals back into the body's circulation before they pass into the brain.
To get an idea of how P-glycoprotein works, Cannon said to think of the protein as a hotel doorman, standing in front of a revolving door at a lobby entrance. A person who is not authorized to enter would get turned away, being ushered back around the revolving door and out into the street.
"For example, as good as vegetables are for us to eat, they have molecules that could be toxic if they slipped into the brain," Cannon said. "They don't get in, because of P-glycoprotein, but this same protector also keeps out helpful therapeutics."
Cannon and his NIEHS colleagues initially found that amitriptyline significantly reduced P-glycoprotein's pump activity in brain capillaries from wild-type rats. Later, they saw amitriptyline had the same effect in brain capillaries from genetically modified rats designed to mimic human ALS. In both rat models, amitriptyline turned off P-glycoprotein within 10-15 minutes. When amitriptyline was removed, P-glycoprotein pump activity returned to full-strength.
NIEHS postbaccalaureate fellow David Banks is lead author on the paper and described amitriptyline's action on P-glycoprotein as rapid and reversible. It's these advantages that make the therapy so appealing.
"Most inventions developed at the bench don't make it to the clinic, but I'm hopeful that our findings will translate into better treatment options for doctors and their patients," Banks said.
Cannon anticipates that administering amitriptyline along with a lower dose of an opioid could relieve pain and reduce the negative side effects, such as constipation and addiction, usually seen with higher doses of prescribed opioids.
"As our nation faces increases in Alzheimer's disease, autism, and opioid abuse, we're hopeful that this discovery will help address these serious health challenges," said NIEHS Director Linda Birnbaum, Ph.D.

More information: David B Banks et al, Lysophosphatidic acid and amitriptyline signal through LPA1R to reduce P-glycoprotein transport at the blood–brain barrier, Journal of Cerebral Blood Flow & Metabolism (2017). DOI: 10.1177/0271678X17705786


Provided by National Institutes of Health

Research shows why ketamine is an effective antidepressant but memantine is not

One 10 ml vial of 1000 mg ketamine. Credit: Psychonaught/Wikipedia

27 may 2014—Ketamine is a fast-acting antidepressant. However, it can create symptoms that mimic psychosis. Therefore, doctors don't give it to depressed patients. Memantine, a similar drug, does not have psychotomimetic effects, but it also does not appear to alleviate depression. Lisa M. Monteggia of the University of Texas Southwestern Medical Center and her colleagues have determined that these drugs have different effects on neurotransmitter pathways. In particular, ketamine promotes the expression of neurotrophic factors but memantine doesn't. The research appears in the Proceedings of the National Academy of Sciences.

Traditional antidepressants target the monoamine system. Patients who take them require several weeks of treatment before they begin to feel an effect. In some cases, for example, if the patient is suicidal, waiting this long can be dangerous. A fast-acting antidepressant would be a preferable treatment.

Ketamine is such a fast-acting drug. Patients have reported experiencing its antidepressant effects within 30 minutes to a few hours after a single intravenous dose. Unlike traditional antidepressants, ketamine does not affect the monoamine system. It is an NMDA receptor antagonist. Unfortunately, it can cause psychotic symptoms; therefore, doctors do not prescribe it for treatment of depression.

As an alternative to ketamine, pharmacologists have considered using the drug memantine, another NMDA receptor antagonist. Memantine, used to treat patients with Alzheimer's disease, does not cause psychotic symptoms and therefore would be safer to use. Clinical studies, however, have shown that it does not behave as an antidepressant. Until now, researchers haven't understood why.

To understand the differences between these two drugs, Monteggia's team first tested their antidepressant properties on mice. Tests confirmed previous observations that ketamine acts as an antidepressant but memantine does not.

The team then used electrophysiology to examine the effect of ketamine and memantine on cultured mouse hippocampal neurons. They found key functional differences in how the drugs suppress NMDA receptor function at rest and how they inhibit the eukaryotic elongation factor 2 kinase (eEF2K) signaling pathway.

When the extracellular recording solution did not contain magnesium, both ketamine and memantine antagonized NMDA receptors. However, with the addition of magnesium, ketamine blocked NMDA receptors, but memantine did not. In addition, ketamine inhibited the phosphorylation of eeF2 and augmented expression of brain derived neurotrophic factor (BDNF). Memantine did not produce these effects. Augmentation of BNDF makes ketamine an effective antidepressant.

These findings could help scientists develop new, fast-acting antidepressants with fewer side effects.

More information: Mechanisms underlying differential effectiveness of memantine and ketamine in rapid antidepressant responses, PNAS, 2014. www.pnas.org/cgi/doi/10.1073/pnas.1323920111

Link between antidepressants and diabetes risk is real

Clinicians should be extra vigilant when prescribing antidepressants as they could pose a risk of type 2 diabetes, researchers at the University of Southampton have warned.

29 sept 2013--A systematic review, carried out by the University, showed that people taking antidepressants are at a higher risk of type 2 diabetes; however it is not certain whether the medication is responsible.

The use of antidepressant medication has risen sharply over recent years reaching 46.7 million prescriptions issued in the UK in 2011.

A number of studies have been carried out to establish whether antidepressants are linked with diabetes but results have varied depending on the methods used, type of medication and the number of participants.

University of Southampton researchers assessed 22 studies and three previous systematic reviews that looked into the effects of antidepressants on diabetes risk. Overall, people taking antidepressants were more likely to have diabetes. However, the researchers warned that different types of antidepressants may carry different risks and long-term prospective randomized control trials are needed to look at the effects of individual tablets.

Published in Diabetes Care, the team said that there are "several plausible" reasons why antidepressants are associated with an increased risk of diabetes. For example, several antidepressants are associated with significant weight gain which increases the risk of type 2 diabetes. However, they also say that several studies which explored this association still observed an increased risk of diabetes after adjustment for changes in body weight, implying other factors could be involved.

Dr Katharine Barnard, Health Psychologist from the University of Southampton comments: "Antidepressants are used widely in the UK, with a significant increase in their use recently. Our research shows that when you take away all the classic risk factors of type 2 diabetes; weight gain, lifestyle etc, there is something about antidepressants that appears to be an independent risk factor. With 46 million prescriptions a year, this potential increased risk is worrying. Heightened alertness to the possibility of diabetes in people taking antidepressants is necessary until further research is conducted."

Richard Holt, Professor in Diabetes and Endocrinology at the University of Southampton, adds: "While depression is an important clinical problem and antidepressants are effective treatments for this debilitating condition, clinicians need to be aware of the potential risk of diabetes, particularly when using antidepressants in higher doses or for longer duration. When prescribing antidepressants, doctors should be aware of this risk and take steps to monitor for diabetes and reduce that risk of diabetes through lifestyle modification."

More information: Antidepressant Medication as a Risk Factor for Type 2 Diabetes and Impaired Glucose Regulation: Systematic Review, Diabetes Care, 2013.

Provided by University of Southampton

Antidepressants linked to thicker arteries

Antidepressant use has been linked to thicker arteries, possibly contributing to the risk of heart disease and stroke, in a study of twin veterans. The data is being presented Tuesday, April 5 at the American College of Cardiology meeting in New Orleans.

03 april 2011--Depression can heighten the risk for heart disease, but the effect of antidepressant use revealed by the study is separate and independent from depression itself, says first author Amit Shah, MD, a cardiology fellow at Emory University School of Medicine. The data suggest that antidepressants may combine with depression for a negative effect on blood vessels, he says. Shah is a researcher working with Viola Vaccarino, MD, PhD, chair of the Department of Epidemiology at Emory's Rollins School of Public Health.

The study included 513 middle-aged male twins who both served in the U.S. military during the Vietnam War. Twins are genetically the same but may be different when it comes to other risk factors such as diet, smoking and exercise, so studying them is a good way to distill out the effects of genetics, Shah says.

Researchers measured carotid intima-media thickness – the thickness of the lining of the main arteries in the neck -- by ultrasound. Among the 59 pairs of twins where only one brother took antidepressants, the one taking the drugs tended to have higher carotid intima-media thickness (IMT), even when standard heart disease risk factors were taken into account. The effect was seen both in twins with or without a previous heart attack or stroke. A higher level of depressive symptoms was associated with higher IMT only in those taking antidepressants.

"One of the strongest and best-studied factors that thickens someone's arteries is age, and that happens at around 10 microns per year," Shah says. "In our study, users of antidepressants see an average 40 micron increase in IMT, so their carotid arteries are in effect four years older."

Antidepressants' effects on blood vessels may come from changes in serotonin, a chemical that helps some brain cells communicate but also functions outside the brain, Shah says. The most commonly prescribed antidepressants are selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Prozac), which increase the level of serotonin in the brain. Other types of antidepressants also affect serotonin levels, and antidepressants can act on other multi-functional brain chemicals such as norepinephrine.

In the study, researchers saw higher carotid IMT in both participants who used SSRIs (60 percent of those who took antidepressants) and those who used other types of antidepressants.

Most of the serotonin in the body is found outside the brain, especially in the intestines, Shah notes. In addition, serotonin is stored by platelets, the cells that promote blood clotting, and is released when they bind to a clot. However, serotonin's effects on blood vessels are complex and act in multiple ways. It can either constrict or relax blood vessels, depending on whether the vessels are damaged or not.

"I think we have to keep an open mind about the effects of antidepressants on neurochemicals like serotonin in places outside the brain, such as the vasculature. The body often compensates over time for drugs' immediate effects," Shah says. "Antidepressants have a clinical benefit that has been established, so nobody taking these medications should stop based only on these results. This isn't the kind of study where we can know cause and effect, let alone mechanism, and we need to see whether this holds up in other population groups."

Provided by Emory University

Participants in antidepressant drug trials are atypical patients, UT Southwestern researchers report

DALLAS, 14 may 2009 – May 13, 2009 – One reason antidepressant medication treatments do not work as well in real life as they do in clinical studies could be the limited type of study participants selected, researchers at UT Southwestern Medical Center have found.

"We are basing our judgment of clinical care in the United States on samples of patients that are totally different from the patient population actually treated in primary care and mental health facilities," said Dr. Madhukar Trivedi, professor of psychiatry at UT Southwestern and senior author of a study published in the May issue of the American Journal of Psychiatry. "Antidepressants should not be seen as a panacea. The general belief is that they work well, but they are less effective in real-world practice, and more work is needed."

As part of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study scientists found that only 22 percent of the 2,855 participants treated with a commonly prescribed antidepressant would have met the criteria for inclusion in a typical antidepressant efficacy trial. Those who did meet criteria had shorter bouts of depression, quicker response to medication, less severe side effects and fewer adverse events compared with those people with depression who would have been excluded from such a trial, used to gain Food and Drug Administration approval of the drugs used.

The STAR*D trial was the first large-scale study to define the effectiveness of several treatment steps in primary care and mental health settings for people with depression, Dr. Trivedi said.

The six-year, $35 million STAR*D study is the largest investigation on the treatment of major depressive disorder and is considered a benchmark in the field of depression research. It initially included more than 4,000 people from outpatient treatment sites across the country. About 65 percent of STAR*D participants, however, had a medical co-morbidity such as diabetes that typically would have excluded them from participating in other clinical trials to test the efficacy of antidepressants, said Dr. Trivedi, co-principal investigator of STAR*D.

"Evidence is growing that depression is like other chronic medical illnesses where it's not just one small, short bout, but a longer battle. People with depression may be at higher risk for other illnesses including obesity or diabetes, yet people with these conditions are excluded from drug trials for depression," Dr. Trivedi said.

STAR*D provided evidence for step-by-step guidelines to address treatment-resistant depression. Many treatment-resistant depression patients would be excluded from drug efficacy trials because those trials typically eliminate study candidates who have previously tried treatment, have suicidal thoughts or have other psychiatric illnesses.

"These are the patients impacted by depression the most – highest suicide potential, highest unemployment rates, highest social impairment – and they are likely to produce poorer outcomes," Dr. Trivedi said. "That population doesn't get studied systematically in traditional pharmaceutical industry studies."

More research involving patients routinely seen in clinical practice coupled with pharmacogenetics is sorely needed to better understand how to best match patients with specific antidepressant treatments, Dr. Trivedi said.

He recommended that clinicians continue to prescribe antidepressants but with more realistic expectations about the disease's long-term nature. Dr. Trivedi said researchers should design future trials in real clinical practice settings where patients have co-morbidities, as he is doing in his current research.

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Other UT Southwestern researchers involved in the study were Dr. Mustafa Husain, professor of psychiatry and internal medicine; and Drs. Diane Warden and David Morris, both assistant professors of psychiatry. Researchers from seven other medical institutions were also involved.

STAR*D is funded by the National Institute of Mental Health. Antidepressant medications were provided by Bristol-Myers Squibb, Forest, GlaxoSmithKline, King Pharmaceuticals, Organon, Pfizer and Wyeth.

Sex differences seen in response to common antidepressant

30 aug 2008--Women are 33 percent more likely than men to experience full remission with citalopram (Celexa), suggesting a biological basis for difference in response
ANN ARBOR, Mich. — Women with depression may be much more likely than men to get relief from a commonly used, inexpensive antidepressant drug, a new national study finds. But many members of both sexes may find that it helps ease their depression symptoms.
The persistence of a gender difference in response to the drug — even after the researchers accounted for many complicating factors — suggests that there's a real biological difference in the way the medication affects women compared with men. The reasons for that difference are still unclear, but further studies are now examining hormonal variations that may play a role.
The study involved citalopram, a commonly used antidepressant that is available both as a generic drug and under the brand name Celexa.
Researchers from the University of Michigan Depression Center and their colleagues from around the country tested the drug's ability to help depression patients achieve remission, or total relief from their symptoms, in a multi-year study called STAR*D.
The gender differences emerged from a detailed analysis of data from 2,876 men and women who had a clear diagnosis of major depression, and took citalopram over a number of weeks, with the doses increasing over time.
In the end, women were 33 percent more likely to achieve a full remission of their depression, despite the fact that women in the study were more severely depressed than the men when the study began.
The study showed no differences between men and women in side effects, the amount of time that patients stuck to taking the drug, or the amount of time it took for them to achieve remission of their symptoms.
The new findings, which represent the largest and most rigorous analysis ever of gender differences in response to an antidepressant, are published online in the Journal of Psychiatric Research.
Elizabeth Young, M.D., a professor and associate chair of psychiatry at the U-M Medical School and member of the Depression Center, is the study's lead author. "Other studies have suggested that there are differences between men and women in response to different antidepressants, but the evidence has been conflicting," she says. "This study is large enough, and we were able to control for enough complicating factors, that we feel confident there is a true difference. These results have clear implications for the clinical treatment of depression."
Young and her colleagues, including Susan Kornstein, M.D., of Virginia Commonwealth University, and John Rush, M.D., formerly of the University of Texas Southwestern Medical Center at Dallas, conducted the analysis of data from men and women between the ages of 18 and 75, many of whom were being treated by primary care physicians and not psychiatrists. All of the patients had been experiencing depression for years, with the average length of experience around 12 years.
The study was funded by the National Institute of Mental Health. Unlike many previous industry-sponsored studies of antidepressants, it included a "real world" sample of people with major depression, and did not exclude people who had a history of suicidal thinking. The study did not include people with bipolar disorder. Participants in the study could continue with psychotherapy that they had been undergoing before the start of the study, but could take no other antidepressants.
Citalopram is one of a class of medicines known as SSRIs, or selective serotonin reuptake inhibitors. In earlier decades, gender differences had been seen in studies of patients taking an older generation of drugs called tricyclics, with men tending to respond better to such medications. But for more than 15 years, SSRIs have been the first choice for treating depression.
Although the current study didn't look at hormonal variations between men and women that might account for the difference in response to citalopram, Young and her colleagues note that animal studies have shown that estrogen modifies the brain systems involved in the activity of serotonin, a key brain chemical.
Kornstein is leading further analysis of the STAR*D results to look for possible differences among women according to their menopausal status and their use of hormone replacement therapy. Meanwhile, Young's research as a member of the U-M Molecular & Behavioral Neuroscience Institute focuses on the interactions of sex hormones and stress response in depression and other mood disorders.
Overall, women are more affected by depression than men, with about 12 percent of women suffering from some form of depression in a given year compared with 6 percent of men. Depression and other mood disorders are the leading cause of disability among women under the age of 45.
But the study's authors are quick to caution that their findings don't mean that citalopram should only be used in women. Raw data from the study show that 24 percent of men achieved remission with the drug, compared with 29 percent of women. The difference in remission rates grew larger once the researchers adjusted for other factors, but the fact remains that many men were helped.
Rather, they note that STAR*D and other studies have shown that many people with depression need to try several treatments to find the one that's right for them and will produce lasting results.
That's why a new study called CO-MED has begun. Young and colleagues from U-M and around the country are now enrolling people with depression for this study that will assess the impact of combinations of medications. One of the medications in that study is escitalopram, a cousin of citalopram, but it also includes other common SSRI antidepressants.
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More information on the CO-MED study is available at www.depressioncenter.org/research/co-med.asp. Information on STAR*D is available at www.nimh.nih.gov/health/trials/practical/stard.
In addition to Young, Kornstein and Rush, the study's authors include Sheila Marcus of the U-M Depression Center, Madhukar Trivedi and Diane Warden of UT-Southwestern, Anne Harvey of Via Christi Research, Stephen Wisniewski and G.K. Balasubramani of the University of Pittsburgh and Maurizio Fava of Harvard Medical School.
Reference: Journal of Psychiatric Research, doi:10.1016/j.jpsychires.2008.07.002

ASCO: No Antidepressant Benefit for Cancer Patients Lacking Major Depression

CHICAGO, June 3 -- Unless cancer patients have major depression, antidepressants don't seem to do anything for them, Australian researchers have found.Sertraline (Zoloft) did not lead to less depression, anxiety, or fatigue, or to a better overall quality of life than did placebo for those with advanced cancer, reported Martin R. Stockler, M.B.B.S., M.Sc., of the University of Sydney in Australia, and colleagues.
These findings of the randomized clinical trial were unexpected and disappointing, Dr. Stockler said at the American Society of Clinical Oncology meeting here.
"Treatment with a selective serotonin reuptake inhibitor should be reserved for those with a proven indication," he and colleagues concluded in the study, which was also published simultaneously online in The Lancet Oncology.
Previous studies have shown antidepressants to be effective for patients with cancer in treating major depression associated with cancer, preventing major depression during treatment with high-dose interferon, and treating hot flushes, they noted
"Our results should not affect the use of antidepressants for these indications," they said.
The researchers started the Zoloft's Effects on Symptoms and Survival Time (ZEST) Trial in July 2001 and by February 2006 had recruited 189 patients with metastatic disease, They were being given palliation and scored at least 4 of 10 for depression, anxiety, fatigue or low energy.
Patients were randomized to once-daily sertraline at a dose of 50 mg or to placebo, to be continued indefinitely.
The study excluded patients with major depression at baseline. Those who developed major depression during the study discontinued treatment and were started on antidepressant treatment under a psychiatrist's care.
However, in February 2006 study recruitment was stopped early when the safety and data-monitoring committee found shorter survival with sertraline than placebo at the first interim analysis (adjusted hazard ratio 1.62 P=0.02).
In the final analysis of 189 patients with a median follow-up of 19 months, the researchers found a trend for lower unadjusted overall survival with sertraline (HR 1.35, P=0.09) but the difference disappeared after adjusting for baseline prognostic factors (HR 1.27, P=0.20).
"Apparent effects on survival were exaggerated in our trial," Dr. Stockler said.
While the initial survival difference was unexpected, a further surprise was that "a clinically important benefit was excluded for all major outcomes," he said.
Among the findings comparing sertraline and placebo, the investigators reported:
No difference for the primary endpoint, depression as defined by theCenter for Epidemiologic Studies Depression scale (23.3 versus 23.7, P=0.8).
No difference in the anxiety portion of the Hospital Anxiety and Depression Scales (23.9 versus 25.8, P=0.3).
No difference in fatigue on the Functional Assessment of Cancer Therapy fatigue scale (56.8 versus 57.1, P=0.9).
No difference in overall physical or emotional wellbeing scores on the Functional Assessment of Cancer Therapy general scale (71.9 versus 70.2, P=0.2).
No difference in clinician-rated quality of life on the Spizter's Quality of Life Index (76.5 versus 74.5, P=0.5).
Two previous trials had shown a benefit to for depression symptoms in cancer patients for fluoxetine (Prozac) and paroxetine (Paxil), but those studies included patients with major depression and those without it.
Dr. Stockler said he would be "very surprised if the results were any different" for cancer patients without major depression with these other antidepressants.
Adverse event frequency and severity were similar between groups. No suicides were documented or reported, he added.
The main limitation of the study was the subjective definition of the study population, he said.
"Diagnosis of major depression was our main exclusion criterion, but this judgment was arbitrary and left to the responsible oncologist," the investigators wrote. "Individuals will differ in their thresholds for recognition, diagnosis, and treatment of depression."
But they noted, "this situation highlights the reality of clinical practice, and it strengthens our conclusion that sertraline should not be used indiscriminately in patients with advanced cancer who do not have major depression."
Overall, "it was a very disappointing result," Dr. Stockler said. "The aim of the trial was to help people feel better…but I think the upside is that it means that we can focus on things that are beneficial such as psychological therapies and exercise."