Stressful Environment May Counteract Antidepressant Efficacy (duh)
VIENNA — A stressful environment may counteract the effect antidepressant medications, new research suggests.
An animal study conducted by investigators at the Istituto Superiore di Sanità in Rome, Italy, supports previous research in humans that showed that depressed individuals with a high-status occupation are less likely to respond to antidepressant therapy.
Silvia Poggini, a PhD student in the Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, showed that the effect of fluoxetine (multiple brands) on inflammatory markers in the hippocampus was completely reversed in mice that were placed in a stressful environment. This was not the case with those that were not subjected to stress.
While emphasizing that the results are preliminary, Poggini said the research "indicates that simply taking an SSRI [selective serotonin reuptake inhibitor] is probably not enough. To use an analogy, the SSRIs put you in the boat, but a rough sea can determine whether you will enjoy the trip. For an SSRI to work well, you may need to be in a favorable environment."
The findings were presented here at the 29th European College of Neuropsychopharmacology (ECNP) Congress.
In another study that lends credence to this theory, Austrian researchers found that a high occupational level (OL), in which there are high levels of responsibility and stress, influences antidepressant efficacy.
Investigators at the Medical University of Vienna found that individuals with a high OL were significantly more likely to be resistant to antidepressant therapy and significantly less likely to be currently in remission from depression than their counterparts with a middle or low OL.
Siegfried Kasper, MD, who led the study, believes that "a number of factors" may explain these results.
"For example, there may be specific working environment demands and stressors; people may find it difficult to accept or cope with illness, or to continue with medication; or there may be other factors, related, for example, to cognitive, personality, and behavioral differences," he said.
Poggini told Medscape Medical News that it is difficult for patients to change their environment, "but maybe with cognitive-behavioral therapy they can change their approach to their environment."
In cases of patients who do not respond to antidepressant therapy, "our suggestion is to [combine] antidepressant treatment with psychotherapy, and only in this way may the antidepressant help improve the depressive symptoms."
In the first study, which was published in the July issue of Brain, Behavior, and Immunity, Poggini and colleagues exposed C57BL/6 adult male mice to a 14-day period of chronic stress to induce a depressionlike phenotype. The mice were then randomly allocated to receive fluoxetine or vehicle for 21 days, during which they were exposed to either a stressful or an enriched condition.
The animals' behavior was assessed throughout the treatment period. In addition, expression of the proinflammatory cytokines interleukin (IL)–6, IL-1b, tumor necrosis factor (TNF)–alpha, and interferon (IFN)–gamma, as well as the anti-inflammatory cytokines IL-4 and transforming growth factor (TGF)-beta, in the hippocampus was measured at the end of the 21 days.
Fluoxetine significantly decreased TNF-alpha and IFN-gamma mRNA expression in the stress condition compared with the vehicle but had no effect in the enrichment condition, whereas the drug had the opposite effect on IL-1b mRNA expression, significantly increasing it in the enrichment condition but having no effect in the stress condition.
Reverse transcription polymerase chain reaction analysis in microglia revealed that fluoxetine increased proinflammatory gene expression, including expression of iNOS, CD86, IL- 15, IL-1b and IL-23 genes, and decreased anti-inflammatory gene expression, including expression of arg-1, ym-1, IL-10, and IL-1ra in the enriched condition compared with the vehicle. When fluoxetine was administered during the stress condition, it had the opposite effect.
"It seems that the SSRIs open the brain to being moved from a fixed state of unhappiness to a condition where other circumstances can determine whether or not you recover," said Poginini.
Laurence Lanfumey, PhD, Centre de Psychiatrie et Neuroscience Inserm, Paris, and Member of the ECNP Executive Committee, who was not involved in the study, described it as a "nice model for combined behavioral and pharmacological treatments in depressionlike disorders.
"The idea that environment could impact the output of a pharmacological treatment has been suggested for years, but this work brings direct biological evidences of such an interaction," he added.
"Although the present work also raised several questions, this kind of experiment is important to do to bridge the gap between behavior and SSRI efficacy."
The second study, which was published in the August issue of European Neuropsychopharmacology, involved 654 individuals with major depression who had undergone at least one adequate antidepressant trial and who were stratified into high, middle, and low OLs.
Dr Kasper and colleagues excluded individuals who were unemployed, students, lived off stock market investments, and were invalid or infirm, as well as those with a diagnosis of bipolar disorder or schizophrenia spectrum disorder.
The mean age of the participants was 49 years, and 65.6% were women. Of the participants, 336 had a high OL, 161 had a middle OL, and 157 had a low OL. Those with a high OL were significantly younger and had a significantly higher educational level than those with a middle or low OL (P < .001 for both).
Logistic regression analysis revealed that individuals with a high OL were more likely to be treatment resistant to antidepressant therapy, at 55.9% vs 40.2% of those with a middle OL and 44.3% of those with a low OL (P = .009). Moreover, participants with a high OL were less likely than those with a middle or low OL to be currently in remission, at 13.7% vs 25.5% and 23.6%, respectively (P = .02).
A high OL was also associated with an increase in the mean number of failed antidepressant treatments per patient, at 1.5 vs 1.4 and 1.1 for middle- and low-OL individuals, respectively (P = .003).
Commenting on these findings, Eduard Vieta, MD, PhD, chair of the Department of Psychiatry and Psychology at the University of Barcelona Hospital Clinic, Spain, and treasurer of the ECNP, said that the results of the study "might sound counterintuitive.
"But people with highly demanding jobs are subject to a lot of stress, and when they breakdown with depression, it may be particularly difficult to cope."
Nevertheless, Dr Vieta noted that an "alternative explanation, which cannot be ruled out, given the naturalistic design of the study, is that high-status-job patients may be more prone to request psychosocial treatments without the support of pharmacotherapy.
"The ideal treatment of depression is, in general, the combination of both pharmacotherapy and psychotherapy."
The first study was supported by the Italian Ministry of Health. The second study was funded by the Expert Platform on Mental Health Focus on Depression. The authors have disclosed no relevant financial relationships.
29th European College of Neuropsychopharmacology (ECNP) Congress. Abstracts P.2.e.012 and P.2.f.024. Presented September 20, 2016.
And for you old farts, eat your yogurt!
Healthy postmenopausal women who eat at least one serving of yogurt a day have a lower body mass index (BMI), less fat, and better bone density — at least at some skeletal sites — than women who never consume yogurt, new research shows.
Over time, women who ate yogurt also had less cortical bone loss than women who never ate it, and this was independent of any other factor that could account for differences in bone density, such as physical activity and total calcium intake.
"Yogurt is a source of nutrients, in particular calcium and protein, but it also contains fermented daily products and probiotics, all of which are potentially beneficial for bone health," Emmanuel Biver, MD, PhD, chief resident at the Geneva University Hospitals, Switzerland told attendees here at the American Society of Bone and Mineral Research 2016 Annual Meeting.
"So we hypothesized that yogurt consumption might attenuate bone loss in postmenopausal women, and this benefit would be independent of total dietary calcium and protein intake," he added.
"And our data suggest that there is a possible protective effect of fermented dairy products on postmenopausal cortical bone loss," he stressed.
Asked by Medscape Medical News to comment, session cochair Marian Hannan, DSc, MPH, professor of medicine, Harvard Medical School, Boston, Massachusetts, said she was "very taken" with the study and that the investigators had addressed all of her concerns.
She suggested the effects observed could have been because the women were more physically active and/or because of the protein in the yogurt, "but they controlled for physical activity" and "they did the best they could for adjusting for total protein."
"So I would take away from this study that there appears to be something to yogurt," she noted.
Dr Biver used members of the Geneva Retirees Cohort (GERICO), made up of healthy men and women who were recruited at the age of 65 to investigate the effects of aging on bone and muscle health.
A food frequency questionnaire was taken at baseline and physical activity assessed.
This study included 733 healthy postmenopausal women who underwent bone-mineral-density (BMD) assessment at baseline and again 3 years later.
Yogurt consumption was categorized as never, less than one serving per day, and one or more servings per day, and total calcium and protein intake, as well as total energy intake, were all evaluated.
At baseline, women who consumed yogurt (over 91% of the cohort) had a 4.4% higher BMD value at the lumbar spine than women who never consumed yogurt.
BMD at the distal radius was also 3.4% greater, as was as the tibia cortical area at 5.3% greater, among yogurt consumers compared with nonconsumers, even after adjustment for BMI, physical activity, and total calcium and protein intake, Dr Biver added.
Women who consumed yogurt were also 6.4% leaner than those who never ate it, again independent of total energy intake and physical activity. And the prevalence of low trauma fractures trended toward a lower rate, at 19% among yogurt consumers vs 29% for nonconsumers, as Dr Biver also pointed out.
More Calcium and Vitamin D in Some Yogurts Than in Milk; Gut Microbiota Also Implicated
At the follow-up assessment 3 years later, Dr Biver and colleagues also found that loss of BMD at the total hip and at the distal radius was attenuated among yogurt consumers, and this effect was again independent of BMI, physical activity, and total calcium and protein intake.
For example, the median annual change in total hip BMD was +0.1% among women who consumed at least one serving of yogurt a day; minus 0.4% for those who consumed less than one serving per day, and minus 0.6% for women who never consumed yogurt.
Significant differences were also seen in losses in the radius cortical area as well as thickness between daily consumers of yogurt and never-consumers, Dr Biver noted (P = .007). In contrast, no significant difference was seen in BMD at the lumbar spine between yogurt consumers and nonconsumers. "As expected…total dietary calcium and protein increased in parallel with yogurt consumption," Dr Biver noted. However, total energy intake was similar between the three categories of yogurt consumers, he noted.
Senior author Rene Ruzzoli, MD, Geneva University Hospitals, Switzerland, told Medscape Medical News , "Yogurt is composed of plain milk, but in many countries, it contains additional milk powder, so for the same volume of milk, there is more calcium, more phosphorous, and more vitamin D in yogurt." Bacteria contained in high-quality yogurt are also present to ferment the milk, and these bacteria populate the large intestine, where they improve calcium absorption and decrease inflammation, Dr Ruzzoli added.
Dr Biver also suggested that yogurt consumption may simply be a marker of a healthy lifestyle, where women who consume a nutritious diet overall would be better protected against bone loss. On the other hand, fermented dairy products may have a favorable influence on the gut microbiota, which is now implemented in a wide range of disorders, including skeletal health. The researchers plan to explore the latter hypothesis in greater detail.
Dr Hannan concluded: "I think they are probably correct in suggesting that [yogurt's] protective effect on bone has to do not only with protein and…with calcium but also the fermentation that happens in yogurt, all three of which we believe to be good things for bone health."
American Society of Bone and Mineral Research 2016 Annual Meeting; September 18, 2016; Atlanta, Georgia. Abstract 1112.
VIENNA — A stressful environment may counteract the effect antidepressant medications, new research suggests.
An animal study conducted by investigators at the Istituto Superiore di Sanità in Rome, Italy, supports previous research in humans that showed that depressed individuals with a high-status occupation are less likely to respond to antidepressant therapy.
Silvia Poggini, a PhD student in the Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, showed that the effect of fluoxetine (multiple brands) on inflammatory markers in the hippocampus was completely reversed in mice that were placed in a stressful environment. This was not the case with those that were not subjected to stress.
While emphasizing that the results are preliminary, Poggini said the research "indicates that simply taking an SSRI [selective serotonin reuptake inhibitor] is probably not enough. To use an analogy, the SSRIs put you in the boat, but a rough sea can determine whether you will enjoy the trip. For an SSRI to work well, you may need to be in a favorable environment."
The findings were presented here at the 29th European College of Neuropsychopharmacology (ECNP) Congress.
In another study that lends credence to this theory, Austrian researchers found that a high occupational level (OL), in which there are high levels of responsibility and stress, influences antidepressant efficacy.
Investigators at the Medical University of Vienna found that individuals with a high OL were significantly more likely to be resistant to antidepressant therapy and significantly less likely to be currently in remission from depression than their counterparts with a middle or low OL.
Siegfried Kasper, MD, who led the study, believes that "a number of factors" may explain these results.
"For example, there may be specific working environment demands and stressors; people may find it difficult to accept or cope with illness, or to continue with medication; or there may be other factors, related, for example, to cognitive, personality, and behavioral differences," he said.
Poggini told Medscape Medical News that it is difficult for patients to change their environment, "but maybe with cognitive-behavioral therapy they can change their approach to their environment."
In cases of patients who do not respond to antidepressant therapy, "our suggestion is to [combine] antidepressant treatment with psychotherapy, and only in this way may the antidepressant help improve the depressive symptoms."
In the first study, which was published in the July issue of Brain, Behavior, and Immunity, Poggini and colleagues exposed C57BL/6 adult male mice to a 14-day period of chronic stress to induce a depressionlike phenotype. The mice were then randomly allocated to receive fluoxetine or vehicle for 21 days, during which they were exposed to either a stressful or an enriched condition.
The animals' behavior was assessed throughout the treatment period. In addition, expression of the proinflammatory cytokines interleukin (IL)–6, IL-1b, tumor necrosis factor (TNF)–alpha, and interferon (IFN)–gamma, as well as the anti-inflammatory cytokines IL-4 and transforming growth factor (TGF)-beta, in the hippocampus was measured at the end of the 21 days.
Fluoxetine significantly decreased TNF-alpha and IFN-gamma mRNA expression in the stress condition compared with the vehicle but had no effect in the enrichment condition, whereas the drug had the opposite effect on IL-1b mRNA expression, significantly increasing it in the enrichment condition but having no effect in the stress condition.
Reverse transcription polymerase chain reaction analysis in microglia revealed that fluoxetine increased proinflammatory gene expression, including expression of iNOS, CD86, IL- 15, IL-1b and IL-23 genes, and decreased anti-inflammatory gene expression, including expression of arg-1, ym-1, IL-10, and IL-1ra in the enriched condition compared with the vehicle. When fluoxetine was administered during the stress condition, it had the opposite effect.
"It seems that the SSRIs open the brain to being moved from a fixed state of unhappiness to a condition where other circumstances can determine whether or not you recover," said Poginini.
Laurence Lanfumey, PhD, Centre de Psychiatrie et Neuroscience Inserm, Paris, and Member of the ECNP Executive Committee, who was not involved in the study, described it as a "nice model for combined behavioral and pharmacological treatments in depressionlike disorders.
"The idea that environment could impact the output of a pharmacological treatment has been suggested for years, but this work brings direct biological evidences of such an interaction," he added.
"Although the present work also raised several questions, this kind of experiment is important to do to bridge the gap between behavior and SSRI efficacy."
The second study, which was published in the August issue of European Neuropsychopharmacology, involved 654 individuals with major depression who had undergone at least one adequate antidepressant trial and who were stratified into high, middle, and low OLs.
Dr Kasper and colleagues excluded individuals who were unemployed, students, lived off stock market investments, and were invalid or infirm, as well as those with a diagnosis of bipolar disorder or schizophrenia spectrum disorder.
The mean age of the participants was 49 years, and 65.6% were women. Of the participants, 336 had a high OL, 161 had a middle OL, and 157 had a low OL. Those with a high OL were significantly younger and had a significantly higher educational level than those with a middle or low OL (P < .001 for both).
Logistic regression analysis revealed that individuals with a high OL were more likely to be treatment resistant to antidepressant therapy, at 55.9% vs 40.2% of those with a middle OL and 44.3% of those with a low OL (P = .009). Moreover, participants with a high OL were less likely than those with a middle or low OL to be currently in remission, at 13.7% vs 25.5% and 23.6%, respectively (P = .02).
A high OL was also associated with an increase in the mean number of failed antidepressant treatments per patient, at 1.5 vs 1.4 and 1.1 for middle- and low-OL individuals, respectively (P = .003).
Commenting on these findings, Eduard Vieta, MD, PhD, chair of the Department of Psychiatry and Psychology at the University of Barcelona Hospital Clinic, Spain, and treasurer of the ECNP, said that the results of the study "might sound counterintuitive.
"But people with highly demanding jobs are subject to a lot of stress, and when they breakdown with depression, it may be particularly difficult to cope."
Nevertheless, Dr Vieta noted that an "alternative explanation, which cannot be ruled out, given the naturalistic design of the study, is that high-status-job patients may be more prone to request psychosocial treatments without the support of pharmacotherapy.
"The ideal treatment of depression is, in general, the combination of both pharmacotherapy and psychotherapy."
The first study was supported by the Italian Ministry of Health. The second study was funded by the Expert Platform on Mental Health Focus on Depression. The authors have disclosed no relevant financial relationships.
29th European College of Neuropsychopharmacology (ECNP) Congress. Abstracts P.2.e.012 and P.2.f.024. Presented September 20, 2016.
And for you old farts, eat your yogurt!
Healthy postmenopausal women who eat at least one serving of yogurt a day have a lower body mass index (BMI), less fat, and better bone density — at least at some skeletal sites — than women who never consume yogurt, new research shows.
Over time, women who ate yogurt also had less cortical bone loss than women who never ate it, and this was independent of any other factor that could account for differences in bone density, such as physical activity and total calcium intake.
"Yogurt is a source of nutrients, in particular calcium and protein, but it also contains fermented daily products and probiotics, all of which are potentially beneficial for bone health," Emmanuel Biver, MD, PhD, chief resident at the Geneva University Hospitals, Switzerland told attendees here at the American Society of Bone and Mineral Research 2016 Annual Meeting.
"So we hypothesized that yogurt consumption might attenuate bone loss in postmenopausal women, and this benefit would be independent of total dietary calcium and protein intake," he added.
"And our data suggest that there is a possible protective effect of fermented dairy products on postmenopausal cortical bone loss," he stressed.
Asked by Medscape Medical News to comment, session cochair Marian Hannan, DSc, MPH, professor of medicine, Harvard Medical School, Boston, Massachusetts, said she was "very taken" with the study and that the investigators had addressed all of her concerns.
She suggested the effects observed could have been because the women were more physically active and/or because of the protein in the yogurt, "but they controlled for physical activity" and "they did the best they could for adjusting for total protein."
"So I would take away from this study that there appears to be something to yogurt," she noted.
Dr Biver used members of the Geneva Retirees Cohort (GERICO), made up of healthy men and women who were recruited at the age of 65 to investigate the effects of aging on bone and muscle health.
A food frequency questionnaire was taken at baseline and physical activity assessed.
This study included 733 healthy postmenopausal women who underwent bone-mineral-density (BMD) assessment at baseline and again 3 years later.
Yogurt consumption was categorized as never, less than one serving per day, and one or more servings per day, and total calcium and protein intake, as well as total energy intake, were all evaluated.
At baseline, women who consumed yogurt (over 91% of the cohort) had a 4.4% higher BMD value at the lumbar spine than women who never consumed yogurt.
BMD at the distal radius was also 3.4% greater, as was as the tibia cortical area at 5.3% greater, among yogurt consumers compared with nonconsumers, even after adjustment for BMI, physical activity, and total calcium and protein intake, Dr Biver added.
Women who consumed yogurt were also 6.4% leaner than those who never ate it, again independent of total energy intake and physical activity. And the prevalence of low trauma fractures trended toward a lower rate, at 19% among yogurt consumers vs 29% for nonconsumers, as Dr Biver also pointed out.
More Calcium and Vitamin D in Some Yogurts Than in Milk; Gut Microbiota Also Implicated
At the follow-up assessment 3 years later, Dr Biver and colleagues also found that loss of BMD at the total hip and at the distal radius was attenuated among yogurt consumers, and this effect was again independent of BMI, physical activity, and total calcium and protein intake.
For example, the median annual change in total hip BMD was +0.1% among women who consumed at least one serving of yogurt a day; minus 0.4% for those who consumed less than one serving per day, and minus 0.6% for women who never consumed yogurt.
Significant differences were also seen in losses in the radius cortical area as well as thickness between daily consumers of yogurt and never-consumers, Dr Biver noted (P = .007). In contrast, no significant difference was seen in BMD at the lumbar spine between yogurt consumers and nonconsumers. "As expected…total dietary calcium and protein increased in parallel with yogurt consumption," Dr Biver noted. However, total energy intake was similar between the three categories of yogurt consumers, he noted.
Senior author Rene Ruzzoli, MD, Geneva University Hospitals, Switzerland, told Medscape Medical News , "Yogurt is composed of plain milk, but in many countries, it contains additional milk powder, so for the same volume of milk, there is more calcium, more phosphorous, and more vitamin D in yogurt." Bacteria contained in high-quality yogurt are also present to ferment the milk, and these bacteria populate the large intestine, where they improve calcium absorption and decrease inflammation, Dr Ruzzoli added.
Dr Biver also suggested that yogurt consumption may simply be a marker of a healthy lifestyle, where women who consume a nutritious diet overall would be better protected against bone loss. On the other hand, fermented dairy products may have a favorable influence on the gut microbiota, which is now implemented in a wide range of disorders, including skeletal health. The researchers plan to explore the latter hypothesis in greater detail.
Dr Hannan concluded: "I think they are probably correct in suggesting that [yogurt's] protective effect on bone has to do not only with protein and…with calcium but also the fermentation that happens in yogurt, all three of which we believe to be good things for bone health."
American Society of Bone and Mineral Research 2016 Annual Meeting; September 18, 2016; Atlanta, Georgia. Abstract 1112.
I don't have an anger problem, I have an idiot problem.
