When working with other providers, I've noticed I end up sharing my version a great deal and so thought to make it available to any one who might find it useful.
Taking my cue from pain management clinics, I developed a controlled substances contract (of sorts) for benzodiazepine prescribing. Although, informed consent does not completely eliminate the risk of legal issues (still need to prove I'm prescribing judiciously...), I feel it goes a long way to facilitating and formalizing a much needed conversation with my patients.
When working with other providers, I've noticed I end up sharing my version a great deal and so thought to make it available to any one who might find it useful.
January 1 2017 | Rhiannon Doherty APRN
Do you feel tired, achy and depressed every winter? It could be that you’re not getting enough vitamin D. Researchers estimate that as many as half of all adults are at risk for this deficiency. Many Americans feel they aren't at risk because they consume vitamin D fortified foods, like milk, but very few foods have natural vitamin D in therapeutic levels and even fortified foods don’t contain enough of the vitamin to support all your health needs.
Despite its name, vitamin D is not a regular vitamin, but a steroid with hormone-like activity. Vitamin D is essential to growth and development and performs a host of actions, including helping to regulate the function of over 200 genes, promoting calcium absorption, maintaining normal calcium and phosphate levels, promoting bone and cell growth, and reducing inflammation.
As much as 90% of vitamin D is produced by sun exposure, so adults who have limited time outdoors (as many do in the winter) or who consistently wear sun protection may not be getting enough. Also at risk are individuals who have darkly pigmented skin, those who are obese, breastfeeding, or elderly, and those with certain medical conditions, like Crohn’s or IBS, that make it difficult to process and/or utilize vitamin D.
Vitamin D deficiency doesn’t always cause symptoms; sometimes issues won’t appear until levels get very low or have been low for some time. However, there are some symptoms you might notice. If any of these apply to you, see your doctor to have your levels checked with a simple blood test:
Boosting Your Vitamin D Levels
You can help to ensure adequate vitamin D levels by increasing your sun exposure in a sensible way, going outdoors for 10-30 minutes daily, especially between late morning and early afternoon. This produces vitamin D that may last twice as long in the body as vitamin D from supplements. If you can’t get outside, consider investing in a good quality light box that supplies 10,000 lux of full-spectrum light for 30 minutes every morning.
For many people, supplementation is the easiest, safest, and most effective way to get one’s vitamin D level within a normal range (50-100ng/mL). Adults can take vitamin D3 (cholecalciferol) in regular capsule form at levels between 1000 IU and 5000 IU daily but should speak to their provider before doing so.
Rhiannon Doherty, MS APRN is a psychiatric Nurse Practitioner practicing at Day Kimball Hospital - Behavioral Health. She is also the author of the Beyond the Brain blog at www.beyondthebrain.net and a clinical editor for online nursing education modules.
SOURCE: Healio - Psychiatric Annals
September 20, 2016
Erythropoietin, commonly used as a performance-enhancing drug in sports, improved cognitive functioning among individuals with unipolar or bipolar depression, according to findings presented at the European College of Neuropsychopharmacology Congress.
“Erythropoietin (EPO) treated patients showed a five times greater cognitive improvement from their individual baseline levels compared with placebo treated patients. EPO-treated patients showed 11% improvement while placebo treated patients improved only by 2%. This effect of EPO on cognition was maintained 6 weeks after patients had completed their treatment,” study researcher Kamilla Miskowiak, PhD, of Copenhagen University Hospital, Denmark, said in a press release.
To assess effects of EPO on speed of complex cognitive processing in individuals with unipolar or bipolar depression, researchers randomly assigned individuals to 8 weekly EPO (n = 40) or saline (n = 39) infusions. Speed of complex cognitive processing and mood symptoms were assessed at baseline, week 9 and week 14.
Participants who received EPO had improved speed of complex cognitive processing at weeks 9 and 14 (P .05).
Objective cognitive baseline deficits increased likelihood of achieving clinically relevant improvement in cognition by 9.7 (95% CI, 1.2-81.1) at week 9 and 9.9 (95% CI, 1.1-88.4) at week 14 among participants who received EPO.
Cognitive improvement associated with EPO was correlated with reduced subjective cognitive complaints at week 9 (P = .01), which was mediated by lower depressive symptom severity.
However, the significant correlation persisted independently of change in depressive symptoms at week 14 (P < .01).
Improved objective cognition was not associated with change in quality of life or socio-occupational function.
“The results of this study, albeit preliminary, give hope to people suffering from mood disorders and associated neurocognitive symptoms. Those symptoms are now recognized as a core part of affective disorders and are not appropriately tackled by the currently available pharmacological armamentarium, despite their close association with relevant clinical outcomes such as the ability to return to work,” Eduard Vieta, PhD, treasurer of the European College of Neuropsychopharmacology, said in the release. – by Amanda Oldt
Ott CV, et al. The effect of erythropoietin on cognition in affective disorders — associations with baseline deficits and change in subjective cognitive complaints. Presented at: European College of Neuropsychopharmacology Congress; September 17-20, 2016; Vienna.
September 26, 2016 | Debra Hughes, MS
During the initial 2 weeks of treatment with first-line fluoxetine, patients with major depressive disorder (MDD) who spent 8 hours in bed had significantly lower depression severity and an earlier onset of remission when compared with those who spent only 6 hours in bed, one of the first studies to examine adequate sleep and antidepressant treatment response has found.
Among those who slept only 6 hours, no difference was observed between those who went to bed 2 hours later versus arising 2 hours earlier, reported J. Todd Arnedt, PhD, associate professor of psychiatry and neurology at the Sleep and Circadian Research Laboratory, University of Michigan Medical School, Ann Arbor, MI, and colleagues in the Journal of Clinical Psychiatry.
“Effective and practical clinical strategies are critically needed to improve response and remission rates to first-line antidepressant medications,” the study authors wrote. MDD affects approximately 16.5% of US adults in their lifetime.
Although one night of total sleep deprivation is shown to improve mood in 60% of patients with MDD, in those who are unmedicated, relapse in up to 80% is observed after recovery sleep. Recent studies have investigated combining sleep deprivation with medication, light therapy, and sleep schedule adjustments. Also explored as an alternative to total sleep deprivation in a laboratory setting is single-night partial sleep deprivation (4–5 hours of sleep), with repetition “during the initial 1-4 weeks of antidepressant therapy” accelerating treatment response, Dr Arnedt noted.
However, “to date, no study has assessed the effects of a modest repeated restriction of time in bed on treatment response in outpatients with depression initiating an antidepressant treatment trial.”
From September 2009 to December 2012, the investigators recruited 68 adults with DSM-IV–diagnosed MDD. Mean age was 25.4 years and 34 were women. Mean age at onset of MDD was 16.6 years and the current MDD episode, a mean of 11.6 months.
Participants were excluded if they had lifetime psychotic disorder, substance or alcohol dependence, eating disorder, posttraumatic stress disorders, and obsessive-compulsive disorder, and those post 6-month substance or alcohol abuse. The 8-hour time in bed group had more years of education than the other 2 groups (P<.005). The majority of the patients were white, unmarried, employed part-time or unemployed, and had a positive family history of MDD. About one-third of the patients had no history of prior MDD treatment; the others had received medication, psychotherapy, or both.
Each subject received 8 weeks of open-label fluoxetine 20 to 40mg and, for the first 2 weeks, was randomly assigned to 1 of 3 nightly “time in bed” conditions as adjunctive therapy: 19 adults were restricted to 8 hours in bed; 24 to 6 hours in bed, with a 2-hour bedtime delay (“late bedtime”); and 25 to 6 hours in bed with a 2-hour rise time advance (“early rise time).”
The initial dose of fluoxetine 20mg was taken after the first time in bed condition night, followed by fluoxetine 20mg/day for 8 weeks. Based on clinician-rated response, dose could be increased to 40mg after week 4.
Symptom severity was rated at baseline and then weekly by clinicians blinded to the time in bed condition. Primary outcome measures, as rated by the 17-item Hamilton Depression Rating Scale, were symptom severity, remission rates, and remission onset. Compliance was evaluated by pill count at each in-laboratory visit.
Study subjects also completed depression scales at baseline and at weeks 1, 2, 4, and 8; quality-of-life ratings were completed at baseline and weeks 4 and 8.
A total of 58 subjects (85.2%) completed the 2-week time in bed condition and 54 (79.4%) completed the 8-week study. Among those randomly assigned, 11 (16.2%) discontinued participation, 3 in the 8-hour, 5 in the late bedtime, and 3 in the early rise time groups; in addition, 4 subjects were discontinued for protocol violations.
When the 8-hour time in bed group was compared with both 6-hour time in bed groups, lower depression severity was observed in the 8-hour group (P<.05). Among those in the 8-hour group, 63.2% remitted by week 8, compared to 32.6% of subjects in the 6-hour groups, and this remission occurred earlier (hazard ratio = 0.43; 95% CI, 0.20-0.91; P<.03). No difference in remission onset was seen between the 6-hour time in bed conditions.
The Self-Rated 12-Item Short-Form Health Survey indicated a significant difference between the 8-hour time in bed and 6-hour time in bed groups in the mental composite score at Week 8 compared to baseline (–7.9; P = .04).
These findings “raise the possibility that adequate time in bed duration may positively impact treatment response,” they reported, adding that “these effects were not due to better medication compliance or to a higher medication dose in the 8-hour time in bed group. Importantly, objective compliance monitoring indicated that subjects were compliant with the 8-hour time in bed schedule, but subjects assigned to the 6-hour time in bed schedule were not. To our knowledge, this study is the first to evaluate experimentally a modest repeated time in bed restriction in antidepressant treatment response.”
Needed to confirm these finding are studies that “optimize or extend sleep duration while initiating antidepressant therapy,” including in “larger, more ethnically diverse, and older samples.” In addition, diurnal mood variation and circadian preference or insomnia, potentially important clinical and sleep-related moderators, respectively, should be systematically included in studies to measure treatment response and evaluate mechanisms of adjunctive treatments for depression.
The authors concluded: “Patients initiating a new trial of antidepressant medication should be cautioned against restricting their time in bed.”
1. Arnedt JT, Swanson LM, Dopp RR, et al. Effects of restricted time in bed on antidepressant treatment response: A randomized controlled trial. J Clin Psychiatry. Dx.doi.org/10.4088/JCP.15m09879.
September 27, 2016 | Da Hee Han, PharmD
Insomnia-specific treatment proved effective at improving daytime and psychological functioning in the short-term, and maintenance therapy added further value to optimizing long-term outcomes, according to a study published in Behaviour Research and Therapy.
Few studies have examined the clinical impact of insomnia therapies on daytime outcomes though daytime functioning impairment is typically the main reason for seeking treatment. Researchers from Canada and Spain evaluated the impact of cognitive-behavior therapy (CBT) alone and in combination with medication, on various outcomes of daytime and psychological functioning.
A total of 160 individuals with chronic insomnia received CBT alone or CBT + zolpidem for an initial 6 weeks followed by an extended 6-month therapy. Patients in the CBT group received maintenance CBT or no additional treatment; those in the combination treatment group continued with CBT + intermittent medication or CBT without medication (taper).
Researchers measured patients' anxiety and depressive symptoms, fatigue, quality of life, and perceived impact of sleep difficulties on various indices of daytime functioning at baseline, after each treatment stage, and at 6-month follow-up.
They found that after acute treatment, significant improvements of fatigue, quality of life (mental component), anxiety, and depression were obtained in the CBT alone group but not in the CBT + medication group. After extended treatment, more improvements were seen for the subcohort receiving extended CBT with no additional treatment and for the subcohort receiving CBT with intermittent medication vs. CBT alone. These improvements were sustained through the 6-month follow-up.
August 24, 2016 | JAMA Cardiology
Among more than 26,000 patients with HIV, those who also had major depressive disorder (MDD) were more likely to experience a myocardial infarction (MI) than those without MDD, according to a study published online by JAMA Cardiology.
People with HIV are living longer and are now at an increased risk for cardiovascular disease (CVD). There is an urgent need to identify novel risk factors and primary prevention approaches for CVD in HIV.
Although depression is prevalent in HIV-positive patients and is associated with future CVD in the general population, its association with CVD events has not been examined in the HIV-infected population.
Matthew S. Freiberg, MD, Vanderbilt University School of Medicine, Nashville, Tennessee, and colleagues conducted a study that included 26,144 HIV-positive veterans without CVD at baseline (1998-2003) participating in the US Department of Veterans Affairs Veterans Aging Cohort Study from April 2003 through December 2009. At study entry, 4,853 veterans (19%) with MDD were identified.
During 5.8 years of follow-up, 490 acute MI events occurred. After adjustment for demographics, CVD risk factors, and HIV-specific factors, the researchers found that HIV-positive patients with MDD had a 30% greater risk for having an acute MI than did HIV-positive patients without MDD.
This elevation in acute MI risk was slightly lessened to 25% after further adjustment for other variables, such as hepatitis C infection, kidney disease, alcohol/cocaine abuse or dependence, and haemoglobin levels.
“Our findings raise the possibility that, similar to the general population, MDD may be independently associated with incident atherosclerotic CVD in the HIV-infected population,” the authors wrote. “Considering the dearth of research in this area, future epidemiologic and mechanistic studies that include women and non-VA populations with HIV are needed.”
July 5 2016 | Da Hee Han, PharmD
Antipsychotic-induced somnolence should be managed with sleep hygiene education, selecting an antipsychotic with a lower risk of somnolence, and initiating at a lower dose with a slower titration based on psychiatric diagnoses, a review published in CNS Drugs reports.
Study authors evaluated the incidence of somnolence through a MEDLINE search for randomized, double-blind, placebo- or active-controlled studies of adults treated with antipsychotics for schizophrenia, mania, bipolar depression, or bipolar disorder. They estimated the absolute risk increase (ARI) and the number needed to harm (NNH) of an antipsychotic agent vs. placebo or an active comparator for the same psychiatric disorder.
Based on the ARI for acute schizophrenia, bipolar mania, and bipolar depression, antipsychotics were categorized as high somnolence (eg, clozapine), moderate somnolence (eg, olanzapine, perphenazine, quetiapine, risperidone, ziprasidone), and low somnolence (eg, aripiprazole, asenapine, haloperidol, lurasidone, paliperidone, cariprazine). The rates of somnolence and dose and duration were positively correlated for some antipsychotics but not for others.
Antipsychotic-induced somnolence may be affected to various factors such as the method used to measure somnolence, patient population, study design, and dosing schedule. The mechanism of somnolence may be primarily due to the blocking of histamine 1 receptors and alpha-1 receptors.
Further ways to manage antipsychotic-induced somnolence include adjusting doses when needed and minimizing concomitant agents that may cause somnolence. As most cases evaluated were mild to moderate, allowing tolerance to develop over ≥4 weeks is sensible before discontinuing the agent.
For more information visit link.springer.com
SOURCE: Lopez-Castroman et al. Clustering suicide attempters: impulsive-ambivalent, well-planned, or frequent. J Clin Psychiatry.2016 Mar 29.
Suicidality is one of the most important problems that mental health professionals deal with. Suicide attempts are common and we are trained to assess the clinical significance of the events.
However, a better understanding of the different types of suicide attempts may help us as clinicians and may facilitate research into their management.
The most important thing for clinicians to remember is that nearly half of suicide attempts are preceded by a previous suicide attempt. Therefore, suicide prevention efforts focused on persons who have attempted suicide are of crucial importance.
However, it has been very hard to predict suicidal behavior, even in persons who have attempted suicide.
One of the reasons for this is probably that, as every clinician knows, not all suicide attempts are the same. Previous research has focused on the severity of the suicide attempts and on the personality of the person attempting suicide. However, there has been little research using statistical methods to classify suicide attempts based on characteristics of the attempts.
1,009 hospitalized suicide attempters were included in the study. Data on 11 clinically relevant items about the suicidal behavior were assessed. These 11 items were statistically analyzed to identify subgroups (“clusters”) of suicidal behavior.
Three clusters were identified:
1. “Impulse-ambivalent” subgroup: This was the most common cluster. The means used were less lethal and there was less planning.
2. The “Frequent” subgroup: This cluster had the fewest number of persons. It included persons who reported a greater number of previous suicide attempts, who more often had serious or violent attempts, and who had an earlier age at the first suicide attempt. These persons were also less likely to have used alcohol or drugs prior to the suicide attempt. Many persons in the this cluster had experienced high levels of childhood abuse. The authors noted that, clinically, frequent attempters would be easily differentiated from the other clusters by the early onset, higher number of attempts, accompanying psychiatric morbidity, family history of suicidal behavior, and high levels of harm avoidance and childhood maltreatment. Thus, frequent attempters had many of the clinical characteristics of borderline personality disorder.
3. The “Well-planned” subgroup: Persons in this cluster had more carefully planned and prepared attempts, with more alcohol or drug use before the attempt, and more precautions to avoid interruptions or be rescued. High scores on severe emotional abuse in childhood were much more likely to be associated with the “Well-planned” group than with the “Impulsive-ambivalent” group.
The term harm avoidance refers to the tendency to inhibit behavior to avoid negative consequences. It has been associated with aggression against oneself and with the severity of suicide attempts. The “Well-planned” suicide attempts were associated with one of the following two combinations:
a) High harm avoidance plus childhood emotional neglect
b) Low harm avoidance plus high hopelessness.
Cluster analysis showed three distinct clusters of persons who had attempted suicide. The specific clinical features of these persons and their suicidal behaviors may help us to plan suicide prevention strategies aimed at each subgroup.
Every suicide attempt must be taken seriously. Categorizing suicide attempts into these three categories can help during clinical evaluation.
In addition to the characteristics of the suicide attempt itself, childhood emotional abuse or neglect, hopelessness, and harm avoidance should be evaluated.
In a stunning discovery that overturns decades of textbook teaching, researchers at the University of Virginia School of Medicine have determined that the brain is directly connected to the immune system by vessels previously thought not to exist. That such vessels could have escaped detection when the lymphatic system has been so thoroughly mapped throughout the body is surprising on its own, but the true significance of the discovery lies in the effects it could have on the study and treatment of neurological diseases ranging from autism to Alzheimer's disease to multiple sclerosis.
"Instead of asking, 'How do we study the immune response of the brain?' 'Why do multiple sclerosis patients have the immune attacks?' now we can approach this mechanistically. Because the brain is like every other tissue connected to the peripheral immune system through meningeal lymphatic vessels," said Jonathan Kipnis, PhD, professor in the UVA Department of Neuroscience and director of UVA's Center for Brain Immunology and Glia (BIG). "It changes entirely the way we perceive the neuro-immune interaction. We always perceived it before as something esoteric that can't be studied. But now we can ask mechanistic questions."
"We believe that for every neurological disease that has an immune component to it, these vessels may play a major role," Kipnis said. "Hard to imagine that these vessels would not be involved in a [neurological] disease with an immune component."
New Discovery in Human Body
Kevin Lee, PhD, chairman of the UVA Department of Neuroscience, described his reaction to the discovery by Kipnis' lab: "The first time these guys showed me the basic result, I just said one sentence: 'They'll have to change the textbooks.' There has never been a lymphatic system for the central nervous system, and it was very clear from that first singular observation -- and they've done many studies since then to bolster the finding -- that it will fundamentally change the way people look at the central nervous system's relationship with the immune system."
Even Kipnis was skeptical initially. "I really did not believe there are structures in the body that we are not aware of. I thought the body was mapped," he said. "I thought that these discoveries ended somewhere around the middle of the last century. But apparently they have not."
'Very Well Hidden'
The discovery was made possible by the work of Antoine Louveau, PhD, a postdoctoral fellow in Kipnis' lab. The vessels were detected after Louveau developed a method to mount a mouse's meninges -- the membranes covering the brain -- on a single slide so that they could be examined as a whole. "It was fairly easy, actually," he said. "There was one trick: We fixed the meninges within the skullcap, so that the tissue is secured in its physiological condition, and then we dissected it. If we had done it the other way around, it wouldn't have worked."
After noticing vessel-like patterns in the distribution of immune cells on his slides, he tested for lymphatic vessels and there they were. The impossible existed. The soft-spoken Louveau recalled the moment: "I called Jony [Kipnis] to the microscope and I said, 'I think we have something.'"
As to how the brain's lymphatic vessels managed to escape notice all this time, Kipnis described them as "very well hidden" and noted that they follow a major blood vessel down into the sinuses, an area difficult to image. "It's so close to the blood vessel, you just miss it," he said. "If you don't know what you're after, you just miss it."
"Live imaging of these vessels was crucial to demonstrate their function, and it would not be possible without collaboration with Tajie Harris," Kipnis noted. Harris, a PhD, is an assistant professor of neuroscience and a member of the BIG center. Kipnis also saluted the "phenomenal" surgical skills of Igor Smirnov, a research associate in the Kipnis lab whose work was critical to the imaging success of the study.
Alzheimer's, Autism, MS and Beyond
The unexpected presence of the lymphatic vessels raises a tremendous number of questions that now need answers, both about the workings of the brain and the diseases that plague it. For example, take Alzheimer's disease. "In Alzheimer's, there are accumulations of big protein chunks in the brain," Kipnis said. "We think they may be accumulating in the brain because they're not being efficiently removed by these vessels." He noted that the vessels look different with age, so the role they play in aging is another avenue to explore. And there's an enormous array of other neurological diseases, from autism to multiple sclerosis, that must be reconsidered in light of the presence of something science insisted did not exist.
Antoine Louveau, Igor Smirnov, Timothy J. Keyes, Jacob D. Eccles, Sherin J. Rouhani, J. David Peske, Noel C. Derecki, David Castle, James W. Mandell, Kevin S. Lee, Tajie H. Harris, Jonathan Kipnis. Structural and functional features of central nervous system lymphatic vessels. Nature, 2015; DOI: 10.1038/nature14432
They’ll Have to Rewrite the Textbooks by Josh Barney
SOURCE: Psychiatric Annals
February 2, 2016
Versions of a gene associated with schizophrenia may prompt synaptic pruning during adolescence, according to recent findings from an NIH-funded study.
“Normally, pruning gets rid of excess connections we no longer need, streamlining our brain for optimal performance, but too much pruning can impair mental function,” Thomas Lehner, PhD, director of the Office of Genomics Research Coordination at the NIMH, said in a press release. “It could help explain schizophrenia's delayed age-of-onset of symptoms in late adolescence/early adulthood and shrinkage of the brain's working tissue. Interventions that put the brakes on this pruning process-gone-awry could prove transformative.”
To investigate the most well-known genetic risk for schizophrenia, researchers analyzed genomes from 65,000 individuals and 700 postmortem brain samples with mouse genetic engineering.
Genome-wide analyses indicated that chromosome 6, which includes several genes known to be associated with immune function, was most significantly associated with schizophrenia risk.
To determine how the immune-related region confers risk for schizophrenia, researchers looked for subtle genetic influences that may produce unconventional signs.
They considered complement component 4 (C4), which has a known role in immunity and is unusually variable across individuals.
Analysis indicated structurally distinct versions that affected expression of the two main gene forms in the brain.
One of the expressions, C4A, was associated with increasing schizophrenia risk.
Further, risk for schizophrenia increased as the number of suspect versions of C4 and the expression of C4 increased.
Using mouse molecular genetic techniques to study synaptic pruning and C4, researchers found that C4 indicates a synapse for pruning by depositing a sister protein in it (C3) during critical periods of postnatal brain development.
“This study marks a crucial turning point in the fight against mental illness. It changes the game," Bruce Cuthbert, PhD, acting director of the NIMH, said in the release. “Thanks to this genetic breakthrough, we can finally see the potential for clinical tests, early detection, new treatments and even prevention.
December 22, 2015 | Megan Brooks
High cumulative exposure to benzodiazepines is common in patients with schizophrenia and is associated with a significantly increased risk for premature death, according to new data from Sweden.
Treatment guidelines recommend that benzodiazepines not be used for longer than 1 month. "Therefore, it is alarming that one-third of the population of patients with psychosis in Sweden had used on average more than 0.5 defined daily dose per day of benzodiazepines, which is equal to more than 5 mg of diazepam or 25 mg of oxazepam every day during the 5-year follow-up," Jari Tiihonen, MD, PhD, of the Karolinska Institutet, Stockholm, and colleagues note.
"As common as long-term benzodiazepine use was in our study population, the literature indicates that it is probably more common among patients with schizophrenia in other developed countries, such as the United States," they add.
"When starting benzodiazepine treatment, it would be wise to try to limit the duration up to 1 month and to use antidepressants for long-term treatment of anxiety symptoms," Dr Tiihonen told Medscape Medical News.
The study was published online December 7 in the American Journal of Psychiatry.
Iatrogenic Cause of Early Death
The researchers investigated the association between mortality and cumulative exposure to antipsychotics, antidepressants, and benzodiazepines using two Swedish nationwide healthcare registers. Among roughly 7 million people aged 17 to 64 years, they identified 21,492 patients with schizophrenia, a prevalence of 0.34%.
Altogether, 1591 (7.4%) schizophrenia patients died during the 5-year follow-up period. Compared with 214,670 age- and sex-matched individuals from the general Swedish population, the mortality of the schizophrenia cohort was 4.8-fold higher. The most common specific cause of death was cardiovascular disease (32.7%), followed by neoplasms (16.5%), respiratory diseases (11.0%), and suicide (9.5%).
According to the researchers, any amount of antipsychotic and antidepressant use was associated with overall mortality rates 15% to 40% lower compared with no use of these medications. In contrast, benzodiazepine exposure was associated with a clear dose-response curve for mortality, with high exposure associated with a 70% higher risk for death compared with no exposure.
To date, two studies have assessed the relationship between benzodiazepine use and mortality in schizophrenia. In both studies, current benzodiazepine use was associated with an increase of 80% to 90% in mortality, Dr Tiihonen and colleagues note in their article.
"While it is probable that patients who need additional benzodiazepine treatment have more anxiety, insomnia, and depressive symptoms than other patients, it is also likely that high-dose chronic use of benzodiazepines, in violation of treatment guidelines, may have become an iatrogenic cause for excess mortality in this patient population," they point out. "On the other hand, patients who need add-on antidepressant treatment may also suffer from anxiety and depressive symptoms, which increase cardiovascular morbidity, suicidal behavior, and mortality."
"Physicians treating patients with schizophrenia should acknowledge the high mortality associated with chronic high-dose benzodiazepine use," the researchers conclude.
"It is important to realize that although monitoring of patients with moderate or high-dose antipsychotic treatment is relevant, it is essential to focus the preventive interventions on those patients who have an even higher risk of death, that is, patients not using antipsychotics and patients using high doses of benzodiazepines," said Dr Tiihonen.
Reached for comment, John Kane, MD, senior vice president, Behavioral Health Services, North Shore-LIJ Health System, Glen Oaks, New York, said that the study was important and provides "further evidence of an overall favorable benefit-to-risk ratio of antipsychotic medications in the treatment of individuals with a diagnosis of schizophrenia.
"In addition, antidepressant use was also associated with a reduction in overall mortality rates, whereas benzodiazepine use was associated with higher mortality. It is difficult to draw conclusions about the potential mechanism(s) of the benzodiazepine effect, but it should remind clinicians to be cautious in the long-term use of such agents in patients with schizophrenia," Dr Kane said.
The study was supported by the Karolinska Institutet (Stockholm); Niuvanniemi Hospital (Kuopio, Finland); and a grant from the Sigrid Juselius Foundation (Finland). Dr Tiihonen has served as a consultant, adviser, or speaker for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Hoffman-La Roche, Janssen-Cilag, Lundbeck, Novartis, Organon, Otsuka, and Pfizer and has received a grant from the Stanley Foundation. The other authors report no relevant financial relationships.
Aberrant NMDA receptor DNA methylation detected by epigenome-wide analysis of hippocampus and prefrontal cortex in major depression
Current perspectives on the molecular underpinnings of major depressive disorder (MDD) posit a mechanistic role of epigenetic DNA modifications in mediating the interaction between environmental risk factors and a genetic predisposition. However, conclusive evidence for differential methylation signatures in the brain's epigenome of MDD patients as compared to controls is still lacking.
To address this issue, we conducted a pilot study including an epigenome-wide methylation analysis in six individuals diagnosed with recurrent MDD and six control subjects matched for age and gender, with a priori focus on the hippocampus and prefrontal cortex as pathophysiologically relevant candidate regions.
Our analysis revealed differential methylation profiles of 11 genes in hippocampus and 20 genes in prefrontal cortex, five of which were selected for replication of the methylation status using pyrosequencing. Among these replicated targets, GRIN2A was found to be hypermethylated in both prefrontal cortex and hippocampus. This finding may be of particular functional relevance as GRIN2A encodes the glutamatergic N-methyl-D-aspartate receptor subunit epsilon-1 (NR2A) and is known to be involved in a plethora of synaptic plasticity-related regulatory processes probably disturbed in MDD.
Medications for Depression Associated With Increased Intubation and Longer Hospitalisation Following Heart Surgery
October 7, 2015 | Brian Hoyle
Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) that are common relievers of depression symptoms may cause patients to need more intubation and more prolonged hospitalisation following coronary artery bypass grafting (CABG), according to results of a retrospective analysis presented at the 2015 Annual Meeting of the American College of Surgeons (ACS).
“In this study, the use of SSRIs and SNRIs was associated with prolonged intubation and hospitalisation, but not with an increased intubation rate,” clarified lead author Kortney Robinson, MD, Beth Israel Deaconess Medical Center, Boston, Massachusetts, speaking here on October 5. “The mechanism is unclear, but it could include discontinuation syndrome, confounding comorbidities, or possible CPY450 inhibition.”
Discontinued use of SSRIs and SNRIs can cause a host of non-life-threatening symptoms. Dr. Robinson and colleagues examined whether these symptoms influence the rate of intubation following CABG. The researchers searched the Society of Thoracic Surgeons database, which contains nationwide information on adult cardiac, general thoracic, and congenital heart surgery including anesthesiology data. A database search from 2002 to 2013 identified 2,092 patients who underwent CABG. Other elective and emergent cases were excluded.
The team analysed the data using 29 variables that included demographics, comorbidities, length of time in the operating room, and postoperative complications. The primary outcomes were prolonged intubation (considered to be intubation exceeding 24 hours), reintubation, and length of stay in the intensive-care unit.
Preoperatively, 231 patients (11%) were on SSRIs / SNRIs, which was consistent with the national rate of antidepressant use. Of the 2,092 patients, 282 patients (13%) required prolonged intubation, and 100 (4.8%) required reintubation.
Patients medicated with SSRI or SNRI were similar in age to the other patients in the database (65.76 years vs 66.96 years; P = .621), but otherwise had a higher prevalence of comorbid conditions, including preoperative creatinine, hypercholesterolaemia, use of dialysis, hypertension, prior cardiovascular intervention, diabetes, and chronic lung disease.
Univariate analysis revealed an association of SSRI or SNRI use with prolonged intubation compared with non-use (17.9% vs 12.8%; odds ratio [OR] = 1.48, 95% confidence interval [CI], 1.02 to 2.13; P = .037), along with associations of nearly 2 dozen other parameters, but no association between SSRI or SNRI and reintubation (OR = 0.93; 95% CI, 0.48 to 1.82).
Multivariable analysis revealed SSRI or SNRI use as an independent predictor of prolonged intubation (OR = 2.85, 95% CI, 1.1 to 7.41), along with preoperative intra-aortic balloon-pump use (OR = 15.5; 95% CI, 5.8 to 42.3), 2 or more incidences of venous anastomosis (OR = 3.2; 95% CI, 1.3 to 7.9), albumin <3 g/L (OR = 4.7; 95% CI, 1.2 to 18.8), and any postoperative use of fresh frozen plasma (OR = 9.3; 95% CI, 2.6 to 26.1).
In multivariable analysis, SSRI or SNRI use was not associated with reintubation.
SSRI or SNRI use at baseline was associated with intensive-care-unit hospitalisation exceeding 3 days in 31% of patients, as compared with 22% of patients not taking the antidepressant medications (P = .046).
It is unclear why preoperative SSRI / SNRI use is associated with prolonged intubation but not reintubation in patients undergoing urgent CABG. The researchers did not discover any compelling link with prolonged intubation or reintubation after scrutinising the data in patients who developed discontinuation syndrome less than 2 days and more than 2 days after weaning from SSRIs. Cytochrome-450 inhibition and confounding diagnoses are possibilities.
Dr. Robinson speculated that patient-specific conditions, such as length of time of SSRI / SNRI medication and possible consequences of weaning could help determine the decision to discontinue the antidepressant medication preoperatively.
[Presentation title: Preoperative Antidepressant Use: Prolonged Intubationand Reintubation after Cardiac Surgery. Abstract SF18#7]
SOURCE: The New York Times
October 20, 2015 | Benedict Carey
More than two million people in the United States have a diagnosis of schizophrenia, and the treatment for most of them mainly involves strong doses of antipsychotic drugs that blunt hallucinations and delusions but can come with unbearable side effects, like severe weight gain or debilitating tremors.
Now, results of a landmark government-funded study call that approach into question. The findings, from by far the most rigorous trial to date conducted in the United States, concluded that schizophrenia patients who received smaller doses of antipsychotic medication and a bigger emphasis on one-on-one talk therapy and family support made greater strides in recovery over the first two years of treatment than patients who got the usual drug-focused care
The report, to be published on Tuesday in The American Journal of Psychiatry and funded by the National Institute of Mental Health, comes as Congress debates mental health reform and as interest in the effectiveness of treatments grows amid a debate over the possible role of mental illness in mass shootings.
Its findings have already trickled out to government agencies: On Friday, the Centers for Medicare & Medicaid Services published in its influential guidelines a strong endorsement of the combined-therapy approach. Mental health reform bills now being circulated in Congress “mention the study by name,” said Dr. Robert K. Heinssen, the director of services and intervention research at the centers, who oversaw the research.
In 2014, Congress awarded $25 million in block grants to the states to be set aside for early-intervention mental health programs. So far, 32 states have begun using those grants to fund combined-treatment services, Dr. Heinssen said.
Experts said the findings could help set a new standard of care in an area of medicine that many consider woefully inadequate: the management of so-called first episode psychosis, that first break with reality in which patients (usually people in their late teens or early 20s) become afraid and deeply suspicious. The sooner people started the combined treatment after that first episode, the better they did, the study found. The average time between the first episode and receiving medical care — for those who do get it — is currently about a year and half.
The more holistic approach that the study tested is based in part on programs in Australia, Scandinavia and elsewhere that have improved patients’ lives in those countries for decades. This study is the first test of the approach in this country — in the “real world” as researchers described it, meaning delivered through the existing infrastructure, by community mental health centers.
The drugs used to treat schizophrenia, called antipsychotics, work extremely well for some people, eliminating psychosis with few side effects; but most who take them find that their bad effects, whether weight gain, extreme drowsiness, or emotional numbing, are hard to live with. Nearly three quarters of people prescribed medications for the disorder stop taking them within a year and a half, studies find.
“As for medications, I have had every side effect out there, from chills and shakes to lockjaw and lactation,” said a participant in the trial, Maggie, 20, who asked that her last name be omitted. She did well in the trial and is now attending nursing school.
Doctors praised the study results.
“I’m very favorably impressed they were able to pull this study off so successfully, and it clearly shows the importance of early intervention,” said Dr. William T. Carpenter, a professor of psychiatry at the University of Maryland School of Medicine, who was not involved in the study.
Dr. Mary E. Olson, an assistant professor of psychiatry at the University of Massachusetts Medical School, who has worked to promote approaches to psychosis that are less reliant on drugs, said the combined treatment had a lot in common with Open Dialogue, a Finnish program developed in the 1980s. “These are zeitgeist ideas, and I think it’s thrilling that this trial got such good results,” Dr. Olson said.
In the new study, doctors used the medications as part of a package of treatments and worked to keep the doses as low as possible — in some cases 50 percent lower — minimizing their bad effects. The sprawling research team, led by Dr. John M. Kane, chairman of the psychiatry department at Hofstra North Shore-LIJ School of Medicine, randomly assigned 34 community care clinics in 21 states to provide either treatment as usual, or the combined package.
The team trained staff members at the selected clinics to deliver that package, and it included three elements in addition to the medication. First, help with work or school such as assistance in deciding which classes or opportunities are most appropriate, given a person’s symptoms. Second, education for family members to increase their understanding of the disorder. And finally, one-on-one talk therapy in which the person with the diagnosis learns tools to build social relationships, reduce substance use and help manage the symptoms, which include mood problems as well as hallucinations and delusions.
For example, some patients can learn to defuse the voices in their head — depending on the severity of the episode — by ignoring them or talking back. The team recruited 404 people with first-episode psychosis, mostly diagnosed in their late teens or 20s. About half got the combined approach and half received treatment as usual. Clinicians monitored both groups using standardized checklists that rate symptom severity and quality of life, like whether a person is working, and how well he or she is getting along with family members.
The group that started on the combined treatment scored, on average, more poorly on both measures at the beginning of the trial. Over two years, both groups showed steady improvement. But by the end, those who had been in the combined program had more symptom relief, and were functioning better as well. They had also been on drug doses that were 20 percent to 50 percent lower, Dr. Kane said.
“One way to think about it is, if you look at the people who did the best — those we caught earliest after their first episode — their improvement by the end was easily noticeable by friends and family,” Dr. Kane said. The gains for those in typical treatment were apparent to doctors, but much less obvious.
Dr. Kenneth Duckworth, medical director for the National Alliance on Mental Illness, an advocacy group, called the findings “a game-changer for the field” in the way it combines multiple, individualized therapies, suited to the stage of the psychosis.
The study, begun in 2009, almost collapsed under the weight of its ambition. The original proposal called for two parallel trials, each including hundreds of first-episode patients. But recruiting was so slow for one of the trials that it was abandoned, said Dr. Heinssen.
“It’s been a long haul,” Dr. Heinssen added, “but it’s worth noting that it usually takes about 17 years for a new discovery to make it into clinical practice; or that’s the number people throw around. But this process only took seven years.