Depression Strongly Linked to Stroke Risk

Pauline Anderson May 16, 2013 Middle-aged women with depression are more than twice as likely to have a stroke as those without depression, a new study shows, suggesting the stroke risk in these women is stronger than previously thought. Because traditional risk factors, such as diabetes and hypertension, accounted for only some of the association, the study authors surmise that a biological mechanism may play a role. The study results underline the importance of identifying depression as a possible preventable risk factor for stroke, said study author Caroline A. Jackson, PhD, Centre for Longitudinal and Life Course Research, University of Queensland, Brisbane, Australia. "We're adding to the growing body of evidence which shows there's a strong relationship between mental health and physical health," said Dr. Jackson. "It's important to raise awareness not just among individual patients — men and women — but also among doctors, to make sure that people can access proper treatment and care." The research is published online May 16 in Stroke. Other studies have looked at the association of depression and stroke, although most didn't stratify results by age. The Nurses' Health Study found a 30% higher risk for stroke among depressed women, but it included women who were 14 years older than those in the current study. "Our study wasn't novel in terms of saying that it's possible that there's a relationship between depression and stroke risk; we're saying it's possibly stronger in these younger-aged women." Dr. Jackson hopes to next use a bigger data set that includes both older and younger participants to clarify whether there's an age interaction for the effect of depression on stroke risk. Depression Prevalence The study included 10,547 participants (mean age, 52.5 years), who were enrolled in the population-based Australian Longitudinal Study on Women's Health (ALSWH). The women completed questionnaires in 1998 and every 3 years during the 12-year follow-up. Researchers determined the prevalence of depression to be 25.1%. Depression was present if women reported taking antidepressant medication or if they scored 10 or more on the Center for Epidemiological Studies Depression scale shortened version (CESD-10).

During follow-up, the women were asked whether they had been diagnosed or treated for stroke in the previous 3 years. Researchers identified deaths and cause of death through linkage with the National Death Index. Researchers identified 177 first-ever strokes, 5 of which were fatal, giving a stroke prevalence of 1.5%. Of these, 143 were included in the primary analysis, which found that depression was associated with more than a 2-fold greater odds of stroke (odds ratio [OR], 2.41; 95% confidence interval, 1.78 - 3.27; P < .001). The association lessened but remained statistically significant after adjustment for age, socioeconomic status (SES), lifestyle, and physiologic stroke risk factors (OR, 1.94; 95% CI, 1.37 - 2.74; P < .001). "When we adjusted for known established stroke risk factors, the odds ratio, or the effect, did attenuate slightly," said Dr. Jackson. "We know it's partly operating through things like hypertension and diabetes but this didn't account for all of the association; there was still almost a doubling of the risk of stroke." A sensitivity analysis that used alternative definitions of depression came up with similar results, as did an analysis that included missing covariate data. Although it has been suggested that antidepressants themselves increase stroke risk, possibly via the inhibition of platelet aggregation that increases bleeding risk, the association between depressive symptoms and stroke remained when researchers excluded women taking antidepressants. Although experts can't pinpoint the exact mechanism through which depression raises stroke risk in middle-aged women, research has linked inflammatory pathways with depression in heart disease, and a similar mechanism may be at play here, said Dr. Jackson. "One mechanism that has been proposed in terms of cardiovascular disease is that depression has an effect on the vasculature of the body, and could be adversely affecting the blood vessels or the endothelium of the blood vessels." Depression Overlooked Unfortunately, depression is underrecognized as a risk factor for stroke, said Dr. Jackson. "When I looked at guidelines and reviews of primary prevention of stroke, I couldn't find any mention of depression in some pretty key documents, so I think it has been overlooked." A limitation of the study was that stroke was self-reported Also, the study didn't collect information on stroke type, and although a sensitivity analysis using alternative definitions of depression showed robust results, depressive symptoms identified using the CESD-10 in a selfadministered questionnaire could have introduced errors in ascertaining depression, the researchers note.
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Invited to comment, Ralph Sacco, MD, professor and chair, neurology, University of Miami, Florida, and spokesperson for the American Heart Association, said the study was important because of its large size, its focus on middle-aged women, and its finding of a very robust effect of depression on stroke risk. Dr. Sacco agreed that a vascular mechanism may be involved somehow in the link between depression and stroke, and that risk factors may overlap. "The same risk factors that lead to stroke — high blood pressure, diabetes, heart disease — may also affect the brain and affect the risk of depression." Although the authors did factor in these risk factors in their analysis, Dr. Sacco added, "if there is, let's say, a common causal connection between what we can call vascular depression and vascular stroke, the adjustment may not handle that." The authors have disclosed no relevant financial relationships. Stroke. Published online May 16, 2013.

Opioid Detox Improves Depression, Anxiety
Alice Goodman May 13, 2013 New Orleans, Louisiana — Depressive symptoms are improved during acute opioid detoxification and improvement can be sustained several months later, new results from a small study suggest. The Stanford Comprehensive Interdisciplinary Pain Program is a week-long, interdisciplinary inpatient program designed to taper opioid use while managing pain, withdrawal, and psychological comorbid conditions. The program depends on the expertise of pain medicine physicians, pain psychologists, psychiatrists, physical therapists, and addiction medicine specialists. "We've known for decades that comprehensive, intensive, interdisciplinary inpatient programs can provide the best results for complex pain care. We are committed to maintaining this model and would like to see more programs like this," explained Sean C. Mackey, MD, Stanford University School of Medicine, California. He noted that the only other multidisciplinary inpatient pain clinic in the United States he was aware of is at Johns Hopkins Medical Center in Baltimore, Maryland. The results were presented here at the American Pain Society (APS) 32nd Annual Scientific Meeting. Complex Pain Syndromes

The study included 15 participants, aged 28 to 64 years, with a range of complex pain conditions, including low back pain, abdominal pain, joint pain, migraine, fibromyalgia, and complex regional pain syndrome. The average duration of pain was 14 years. Patients were severely functionally impaired, most of them unable to work. Before admission to the 5-day program, their opioid medications included morphine, hydrocodone, oxycodone, and fentanyl patches. During the 5-day stay, methadone was given and the dosage reduced to 0 by day 5. Other medications to manage pain were optimized, and patients underwent psychological, physical, and occupational therapies. Symptoms of depression, as measured by the Hospital Anxiety and Depression Scale, were significantly reduced from admission at discharge (P = .047) and at the 3-month follow-up (P = .044). Anxiety symptoms were also reduced at follow-up. "The symptoms of anxiety and depression were both within the normal range at follow-up," Dr. Mackey noted. Interestingly, the reduction in depressed mood was proportional to the magnitude of opioid reduction. The magnitude of opioid reduction during the program was significantly correlated with reduction in depression score (r = 0.75; P = .001). At discharge and at follow-up, a significant and sustained reduction was observed for pain interference with daily functioning (P = .008). In an interview with Medscape Medical News, Dr. Mackey explained that the inpatient program only accepts patients who are covered by insurance. "We are a fiscally sound program that has been in place for 24 years. Our inpatient resources help other areas of the hospital in their pain management efforts," he said. Although multidisciplinary approaches to drug abuse have repeatedly been shown to be effective, reimbursement issues are a disincentive for this approach, according to APS President Roger Fillingim, PhD, professor of psychology, University of Florida in Gainesville. "Even though this is the most cost-effective model for treating drug misuse and chronic pain, multidisciplinary clinics are resource-intensive. The Stanford Clinic is an efficient care model at a magnet institution, and it may be easier for them to obtain reimbursement than for other centers not as well positioned," Dr. Fillingim stated. "We hope to get back to that model with healthcare reform," he added. The study was supported by the National Institute on Drug Abuse. Dr. Mackey has disclosed no relevant financial relationships. Dr. Fillingim disclosed financial relationships with Algynomics, Cytogel Pharma, Curatio Medical Education, and Medscape. American Pain Society (APS) 32nd Annual Scientific Meeting. Abstract 410. Presented May 10, 2013.

Internet-Based Cognitive Behavioral Therapy Helps Kids With Chronic Fatigue
May 14, 2013 By Will Boggs, MD NEW YORK (Reuters Health) May 14 - The benefits of internet-based cognitive behavioral therapy for adolescents with chronic fatigue syndrome were maintained during long-term followup, in a study from The Netherlands. "Chronic fatigue syndrome (CFS) in adolescents often has an extensive disease course that may lead to considerable school absence and long-term consequences for their educational and social development," Dr. Sanne L. Nijhof from Wilhelmina Children's Hospital and University Medical Center Utrecht told Reuters Health in an email. With the online FITNET program (Fatigue in Teenagers on the Internet), "effective treatment is within reach for any adolescent with CFS," Dr. Nijhof said. In a previous study reported last year in The Lancet, the FITNET program was linked with an eight-fold higher chance of recovery after six months, compared with usual care. At long-term follow up, the usual care and FITNET groups had similar recovery rates, although recovery had followed a slower pace in the control group. "This shortened recovery period is crucial during adolescence, when school attendance and social contacts are crucial for social and academic development," Dr. Nijhof said. The new findings were published Monday online in Pediatrics. Dr. Nijhof and colleagues report on 112 participants in the original FITNET trial who completed follow-up assessments 2.7 years later, on average. Nearly two-thirds of the 59 youngsters (64%) originally assigned to FITNET had stable recovery at long-term follow-up, compared with 52% of the 25 patients who crossed over from usual care to FITNET and 53.6% of 28 patients who remained in the usual care group. Relapse rates during long-term follow-up were 8.5% (five patients) in the original FITNET group, 10.7% (three patients) in the usual care group, and 16% (four patients) in the group that crossed over from usual care to FITNET. The researchers also investigated factors related to recovery. Every additional month of pretreatment disease duration lowered the odds of recovery by 4%. Worse, every additional point scored on maternal focus on bodily symptoms lowered the odds of recovery by 11%.

"The finding that longer disease duration was related to long-term non-recovery in our study underlines the necessity for prompt diagnosis and treatment of CFS," Dr. Nijhof said.

DSM-5 Criteria for Bipolar Disorder May Further Cloud Diagnosis
Fran Lowry May 14, 2013 The soon-to-be released fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) will likely further confuse the diagnosis and treatment of bipolar disorder (BD), according to one expert. A comment written by Gin Malhi, MD, of the University of Sydney in Australia and published online May 10 in the Lancet as part of a special series on BD expresses concern that the inclusion in the DSM-5 of a "mixed states specifier," which is broadly defined as the coexistence of depressive and manic features, may lead to diagnostic confusion and complicate treatment. Dr. Malhi notes that mixed states have long contributed to the concept of manic-depressive illness and that the criteria for mixed states have narrowed in successive editions of the DSM, from DSM-I to DSM-IV, from manic-depressive reaction mixed type to mixed episodes. However, in the DSM-5, this trend is reversed, and the mixed episode diagnosis has been replaced in the DSM-5 by a mixed features specifier (MxFS). The MxFS, Dr. Malhi explains, "denotes the concurrence of at least three symptoms from the opposite pole of the illness within either a manic or hypomanic, or depressive, episode." He adds that this definition is more flexible than the DSM-IV criteria for a BD mixed episode, in which the complete criteria for both a depressive and a manic episode had to be met for 1 week. "In practice, such a high threshold for diagnosis was often unattainable and consequently mixed episodes had low clinical use. Furthermore, the absence of any subtypes — for example indicating the predominance of depressive or manic symptoms — stifled research," Dr. Malhi notes. Although a change in the diagnostic criteria was necessary, Dr. Malhi notes that it is unclear whether the MxFS will fix the problem and improve diagnosis. He expresses concern that the MxFS will increase the diagnosis of bipolarity and may identify missed diagnoses but that because of its low specificity, it will simultaneously increase the likelihood of misdiagnosis.

"The risk is that [the diagnostic criterion of mixed states] will be used loosely and its application will expand far beyond bipolar disorder type I and across the whole bipolar spectrum, without any prognostic significance of therapeutic benefit," he writes. Genetic Basis for BD In the first Lancet series article, researchers note that compelling evidence suggests that BD has genetic underpinnings, and they review current knowledge in this area. Nick Craddock, MD, from the School of Medicine, Cardiff University, in the United Kingdom, and Pamela Sklar, MD, from the Icahn School of Medicine at Mount Sinai, in New York City, note that studies of families and twins highlight the importance of genetic factors affecting susceptibility to BP and suggest "substantial genetic and phenotypic complexity." Significant associations with BP and several common polymorphisms, including variants with the genes CACNA1C, ODZ4, and NCAN, have been discovered, they note. They add that a "notable finding" is the overlap of susceptibility between BP and schizophrenia for several of these polymorphisms. Further investigation of these genetic findings "might eventually pave the way for major improvements in clinical management" of BP, they write. "The association between genotype and phenotype for psychiatric disorders is clearly complex. Reductionist thinking has no place, and to think of any case as being either genetic or environmental, or to talk about a gene for bipolar disorder, makes no sense. The key point is that most cases of bipolar disorder involve the interplay of several genes or more complex genetic mechanisms, together with the effects of the environment, and chance," Dr. Craddock said in a statement. BD researchers now need to follow up genetic studies with imaging and psychological studies to try to unravel the complex biological mechanisms involved in BP and bring biological understanding closer to the experience of the patient. "While several genes which increase a patient's risk of acquiring bipolar disorder have been discovered to date, no clear biological mechanism to explain why these genes affect a person's risk of developing bipolar has been elucidated," the authors note. Neuroimaging for BD Diagnosis In the second series article, David J. Kupfer, MD, DSM-5 Task Force Chair, and Mary L. Phillips, MD, both from the University of Pittsburgh, in Pennsylvania, write that neuroimaging studies could eventually discover biomarkers that could help determine where a patient might lie on the behavioral scale of BD and also help identify biological targets for treatment, not only for BD but for all affective disorders.

The article notes the substantial difficulties in diagnosing BD, including misdiagnosis of BD as unipolar depression, a substantial delay of 5 to 10 years between the onset of BD and diagnosis, and the fact that depressive symptoms are more prevalent than manic symptoms, and so people are more likely to seek treatment for depression. This can be a major problem because medication used to treat unipolar depression is not the same as that used to treat BD and could even exacerbate the manic symptoms seen in BD, the authors write. "Identifying objective biomarkers that differ between bipolar and unipolar depression would not only lead to more accurate diagnosis but potentially to new, personalized treatments, yet very little research has been undertaken in this area. For instance, very few neuroimaging studies have been done in which the brains of people with bipolar disorder have been compared to those of people with unipolar disorder, and further research into this area is urgently needed," Dr. Phillips said in a statement. Obstacles to New Treatments In the third series article, authors John R. Geddes, MD, from the University of Oxford, in the United Kingdom, and David J. Miklowitz, PhD, from the University of California, Los Angeles (UCLA), write that overall, advances in drug treatment remain "quite modest." There have been no fundamental advances in the search for more effective treatment for BD in the last 20 years, despite a substantial expansion of research into the subject, and development of effective treatments is being hampered by scarce knowledge of basic disease mechanisms or clear targets for medicines, they note. Although antidepressants are commonly used to treat the depressive phase of the disorder, there is scarce evidence for their efficacy, Dr. Geddes and Dr. Miklowitz point out. Lithium, first introduced in 1949, remains the best-established long-term treatment for BD, but its benefits are restricted by adverse effects, and alternatives are often needed for long-term treatment, they note. "Combining psychosocial treatments, which can include not just psychotherapy for the patient, but family therapy involving education for their family or caregiver, with mood stabilising drugs, might well be one of the most promising lines of treatment for bipolar disorder," Dr. Geddes writes. "However, drug and psychological treatment studies have largely proceeded independently of one another, and research including both would help to move the field forward." Dr. Malhi, Dr. Craddock, Dr. Sklar, Dr. Phillips, and Dr. Kupfer report no relevant financial relationships. Dr. Geddes reports financial relationships with the UK Medical Research Council, the European Union, the National Institute of Health Research, and the Stanley Medical Research Institute. He also reports that he was expert witness for Dr. Reddys Laboratories

(India) and is chief investigator on the CEQUEL trial, to which GlaxoSmithKline has contributed and supplied investigational drugs and placebo. Dr. Miklowitz reports financial relationships with the National Institute of Mental Health, the National Alliance for Research on Schizophrenia and Depression, the Danny Alberts Foundation, the Daniel and Diana Attias Family Foundation, the Carl and Roberta Deutsch Foundation, and the Kayne Foundation. Lancet. Published online May 10, 2013.

Intranasal Oxytocin Normalizes Core ASD Deficit
Pam Harrison May 10, 2013 DONOSTIA / SAN SEBASTIÁN, Spain — Intranasal oxytocin appears to normalize fixated or restricted interest, a core deficit in autistic spectrum disorder (ASD), new research shows. This expands the spectrum of normalizing effects now being reported for intranasal oxytocin, essentially "completing the picture" of how the neuropeptide ameliorates the 3 key distinguishing features of ASD. "In autism, there are 3 basic deficits — social communication, repetitive behavior, and fixated or restricted interest, where children get fixated on a particular pattern or sensory stimulation and have difficulty paying attention to other, more socially relevant cues," Lane Strathearn, MD, PhD, assistant professor of pediatrics, psychiatry and behavioral sciences, Baylor College of Medicine, Houston, Texas, told Medscape Medical News. "So this is the first time that this particular aspect of autistic behavior has been examined in relation to oxytocin, and we've shown that oxytocin has some effect on all 3 aspects of autism behavior, including now fixated interest." The study was presented here at the 12th Annual International Meeting for Autism Research (IMFAR). Impact on the Amygdala? As part of a randomized, double-blind, placebo-controlled crossover study, a total of 32 individuals, 16 with ASD and 16 matched control participants, were given either intranasal oxytocin or placebo on their first study visit. They were given the alternate solution on a subsequent visit 2 weeks later. The mean age of the study group was 13 years, and all participants were male.

On each occasion, participants viewed 14 slides, each containing 4 related pictures of real-life scenes. Within that set of related pictures, participants were shown some that were highly organized, such as football players lined up straight across the field, and some that were disorganized, such as crowd shots at a football game. Researchers then tracked participants' gaze using an automated eye tracker as they examined each set of pictures and documented which pictures those with ASD preferred compared with which pictures the normal control participants preferred. "Our hypothesis was that individuals with ASD would like the highly structured, organized pictures more than pictures that were less organized, and under normal conditions, that's exactly what we found," Dr. Strathearn said. In contrast, participants without ASD showed no preference for any type of picture, giving each picture equal attention. However, when researchers assessed picture preference following administration of intranasal oxytocin, "the difference between ASD subjects and normal controls was eliminated — there was no difference between the 2 groups in their gaze preference when looking at the same pictures," said Dr. Strathearn. Dr. Strathearn noted that oxytocin has been shown to enhance social bonding and attachment. It has subsequently been explored in a range of studies involving mother-infant attachment, social development and exchange, and recognition of facial emotion. "It's not completely clear where or how oxytocin is acting in these particular situations, but functional MRI [magnetic resonance imaging] studies suggest that oxytocin does affect the amygdala, which is the emotional center in the brain," Dr. Strathearn said. Studies have shown that blood levels of oxytocin are lower in children with ASD as well. Research also indicates that ASD children process facial emotions differently from typically developing children, and if they are missing out on information about facial emotion, "that is a lot of information they're not able to take in, so this may have a cascading effect on developing appropriate emotional responses," Dr. Strathearn suggested. Growing Evidence of Therapeutic Effect Asked by Medscape Medical News to comment on this study, Daniel Smith, PhD, senior director, Autism Speaks, New York City, noted that findings from this study build on the growing body of literature that oxytocin appears to elicit a therapeutic response in individuals with ASD. "We need larger studies to confirm if this is a reliable finding," Dr. Smith told Medscape Medical News. "But it is interesting that they are showing a difference in attention and in response to organized pictures vs unorganized ones, and in a larger study, it would be useful to

incorporate a more objective functional endpoint to complement the typical clinical scales we typically use in ASD studies." Dr. Strathearn and Dr. Smith report no relevant financial relationships. 12th Annual International Meeting for Autism Research (IMFAR). Abstract 122.007. Presented May 3, 2013.

'Clock Genes' Disrupted in Depression
Fran Lowry May 16, 2013 The circadian clock gene mechanisms in the brain that control virtually all 24-hour rhythms in the human body are significantly disrupted in patients with depression, compared with normal, healthy individuals, new research shows. "Clock genes, a central part of the circadian machinery, function as pacemakers in the brain to synchronize rhythms to daily changes in daylight length," senior author William Bunney, MD, Distinguished Professor and Della Martin Chair of Psychiatry, University of California, Irvine, told Medscape Medical News. "This process is one of the most pervasive influences throughout evolution from single organisms to man. In this research, we found evidence for faulty clock gene machinery in depressed patients," Dr. Bunney said. The study was published online May 13 in the Proceedings of the National Academy of Sciences. First Evidence of Altered "Clock" Genes The study identifies hundreds of genes in the human brain that are likely involved in important daily rhythmic events, including the sleep/wake cycle and metabolism, said first author Jun Z. Li, PhD, of the University of Michigan, in Ann Arbor.

Dr. William Bunney "The link between depression and abnormal sleep has been known before. The novelty of our study is to bring this understanding to the cell and molecular level. We show that brain cells keep a molecular 'clock,' and that this clock is ticking in multiple brain regions, and we identify the genes that are involved in the time-keeping process. We also show the disruption of this process in major depression," Dr. Li told Medscape Medical News. The investigators hypothesized over a decade ago that depressed patients may have abnormal clock gene machinery. "Our hypothesis was based on evidence that depressed patients have altered sleep, hormonal secretion, body temperature, and mood rhythms. These rhythms are controlled by genes called clock genes. This study provided us with the first direct evidence in brain that these clock genes are altered in major depressive disorder, a serious psychiatric disease that affects 1 in 10 Americans and is associated with a significant risk of suicide," Dr. Bunney said. The investigators made their finding by sifting through massive amounts of data gleaned from donated brains of depressed and nondepressed people shortly after their deaths. Numerous regions of the brain were dissected by hand or lasers to capture more specialized cell types and were then analyzed to measure gene activity. Potential Treatment Target The authors screened nearly 12,000 genes for daily rhythms of expression in 6 brain regions from 55 individuals with no history of psychiatric or neurologic illness. They found that more than 100 genes showed 24-hour cyclic patterns in all 6 brain regions, including genes thought to be essential for the body's daily timekeeping machinery. By contrast, analysis of the brains of 34 individuals with major depression revealed that these molecular rhythms were disrupted, mirroring the disturbed sleep/wake cycles and physiologic rhythms often associated with depression. "We hope that the findings will provide clues for potential new classes of compounds that may reset abnormal clock genes, normalize circadian rhythms, and rapidly treat depression," Dr. Bunney said.

Dr. Jun Li "If we can understand how depression and abnormal sleep reinforce each other, we may be able to find better treatment, perhaps by targeting the genes implicated in the circadian cycle," added Dr. Li. Although the study is very technical, it does have some practical implications for psychiatrists currently treating depressed patients, Dr. Bunney noted. "Two of the most rapidly acting antidepressant therapies may alter circadian rhythms. We have hypothesized that sleep deprivation therapy, which is a circadian intervention in depression, and low-dose ketamine, which has been shown to be rapidly effective in treatment-resistant depression, may in part work by resetting abnormal circadian clock genes and thus normalize altered circadian rhythms. "But this approach does not come directly from the current study. In the future, new classes of compounds may be developed based on data from this research," he said. A Step Forward "It is a fascinating piece," commented Alan J. Gelenberg, MD, Shively/Tan Professor and chair, Department of Psychiatry, Pennsylvania State University College of Medicine, in Hershey, to Medscape Medical News. "If replicated, it could be a small step forward toward understanding the pathophysiology of the symptoms in depression, and ultimately, identifying targets for treatment. But it will not have application in the clinic for a decade or longer, I fear." Dr. Li and Dr. Bunney report that they are members of the Pritzker Neuropsychiatric Disorders Research Consortium, which is supported by Pritzker Neuropsychiatric Disorders Research Fund LLC. Dr. Gelenberg reports no relevant financial relationships. Proc Natl Acad Sci. Published online May 13, 2013.

Vagus Nerve Stimulation Effective in Resistant Depression
Fran Lowry May 16, 2013 Vagus nerve stimulation (VNS) appears to be effective for treatment-resistant depression and may induce changes in brain metabolism weeks or even months before patients begin to feel better, new imaging research suggests. "These neuroimaging findings suggest that antidepressant response to VNS has very large and profound effects early on in the cortex of the brain, altering the metabolic activity in cortical regions, in individuals with treatment-resistant depression," lead author Charles R. Conway, MD, of the Washington University School of Medicine, St. Louis, Missouri, told Medscape Medical News. "The regions affected are regions known to be associated with depression, the dorsolateral prefrontal cortex, the orbitofrontal cortex, and the anterior insular cortex. "These changes in metabolic activity occur prior to any noticeable clinical effects or improvements. The patient does not appear to be getting less depressed, which suggests that the early part of VNS, the first 1 to 5 months, may actually be bringing about changes, or setting the stage, for later clinical effects which will follow 6 months or more," said Dr. Conway He added that at 12 months, he and his team of investigators also were seeing increases in regional metabolic activity in brainstem regions associated with depression, most especially a region of the brain associated with dopaminergic brain function, the ventral tegmental area. The study is published online ahead of print in Brain Stimulation. Profound and Sustained Improvement Dr. Conway and his team have implanted VNS devices in some 70 treatment-resistant depression patients. "Although not everyone responds to VNS, we have seen numerous patients experience very profound and sustained improvements in treatment-resistant depression, and many have been doing well for years," he said.

Dr. Charles Conway "Many of these patients have gone from being essentially incapacitated by depression to fully functional again." The researchers hypothesized that any treatment that brings about such a profound improvement must have observable brain changes associated with it, and this prompted their neuroimaging study. In the current study, Dr. Conway and his group followed 13 patients with treatment-resistant depression whose symptoms had not improved despite many months of treatment with as many as 5 different antidepressant medications. Most of the patients had been depressed for at least 2 years, but some patients had been clinically depressed for more than 20 years. All patients underwent surgery to have the VNS device inserted. The left vagus nerve runs down the side of the body from the brainstem to the abdomen; once activated, the VNS device delivers a 30-second electronic stimulus to the vagus nerve every 5 minutes. To establish the nature of the treatment's effects on brain activity, the investigators performed positron emission tomography (PET) brain imaging prior to the initiation of stimulation, and again 3 and 12 months after stimulation had begun. They then compared these brain scans with each other at different time points. "We used a form of PET which uses radioactively labeled glucose, fluorodeoxyglucose, or FDG," Dr. Conway explained. "The brain is constantly taking up glucose from the blood stream. If there is a regional decrease in metabolism, typically associated with decreased regional brain activity, this can be detected using FDG-PET, because you see less FDG uptake in a given region." FDA Approved, But Not Widely Available Eventually, 9 of the 13 patients experienced improvement in depression with the VNS treatment. However, in most cases, it took several months for improvement to occur.

Among those who responded, the FDG-PET scans showed significant changes in brain metabolism following 3 months of stimulation, and this occurred several months before any improvements in their symptoms of depression were noted. "We saw very large changes in brain metabolism occurring far in advance of any improvement in mood. It's almost as if there's an adaptive process that occurs. First the brain begins to function differently. Then the patient's mood begins to improve," Dr. Conway said. Although this study is preliminary and a larger version of this study should be done, these findings suggest that antidepressant responders to VNS undergo changes in brain activity associated with regional metabolic activity changes in regions associated with depression, Dr. Conway said. "The data also suggest that the eventual VNS-responding state involves activation of brainstem regions associated with dopamine activity," he said. Despite being FDA-approved for treatment-resistant depression, VNS is not easily available for the general public because insurance carriers will not reimburse for the treatment, Dr. Conway said. "We believe that this study, like many other recent studies as well as our extensive clinical experience, support our clinical observations that this treatment is effective. Also, this population of treatment-resistant depression patients has very few viable successful treatments, and we believe VNS is both effective and has sustained benefit in a significant subset of patients with TRD, and it should be available to those who need it." Need for Replication Commenting on the study for Medscape Medical News, William Bunney, MD, Distinguished Professor and Della Martin Chair of Psychiatry, University of California, Irvine, said that the high response rate in this patient population is "therapeutically interesting and may be due in part to the selection criteria used in this research."

Dr. William Bunney Dr. Bunney added that the observation that the patients did not relapse during a 12-month period "has important treatment implications in a disorder characterized by recurrent depressive

episodes. Although this is a somewhat invasive therapy, it may be justified by the high success rate, particularly if it is replicated in other studies using similar research designs." Dr. Conway reports financial relationships with Cyberonics, Merck, and Bristol-Myers Squibb. Dr. Bunney reports that he is a member of the Pritzker Neuropsychiatric Disorders Research Consortium, which is supported by Pritzker Neuropsychiatric Disorders Research Fund LLC. The study was supported by funding from the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Alliance for Research in Schizophrenia and Affective Disorders, and the Sidney R. Baer Jr Foundation. Cyberonics (Houston, Texas) donated 3 cost-free devices to participants in this trial. Brain Stimul. Published online ahead of print February 15, 2013. Abstract Medscape Medical News > Psychiatry

Schizophrenia 'Guideline of Guidelines' Released
Deborah Brauser May 16, 2013

A team of schizophrenia experts have joined together to release worldwide "meta-guidelines" for physicians, nurses, and other healthcare professionals in managing and treating patients with the disorder. The new guidelines, which, among other clinical issues, cover brain imaging and electroconvulsive therapy (ECT), are designed to provide "the most evidence-based and up-todate strategies for addressing treatment selection, medication-induced side effects, [and] treatment nonadherence." "We're trying to provide a service to people who are trying to reconcile different and possibly competing guidelines," guideline author Stephen M. Stahl, MD, PhD, adjunct professor of psychiatry at the University of California, San Diego, told Medscape Medical News. "So rather than saying we're creating all new guidelines that will take over, this is more of a communications exercise that's making it easier and giving 'one-stop-shopping' of what's out there," said Dr. Stahl, who is also from the Neuroscience Education Institute (NEI) in Carlsbad, California, and is editor-in-chief of CNS Spectrums, the journal of the NEI. He added that previously, there has been no definitive set of guidelines to help clinicians judge what a patient with schizophrenia needs at each stage of their illness. Their meta-guidelines, or

"guideline of guidelines," brings together existing standards and updates them with current best practices. "We are confident they will benefit anyone working in the field anywhere across the world," said Dr. Stahl in a release.

Dr. Stephen Stahl The investigators note that the guidelines are aimed toward "rank-and-file patients with schizophrenia" who are neither violent nor self-harming and who do not have any comorbidities. A set of meta-guidelines for treating more complex cases is currently being developed by the same investigative team. The new guidelines were published online April 16 in CNS Spectrums. Clearing the Confusion "Guidelines for treating various conditions can be helpful in setting practice standards," write the researchers. However, "what has been available is a confusing mix of several sets of guidelines from different countries, experts, and settings. Often these recommendations contradict one another and are quickly out of date," said Dr. Stahl. He and 8 other clinicians from California, New York, Texas, and the United Kingdom came together to provide schizophrenia guidelines that would combine the best of current standards while also providing updated information about the use of newer agents — several of which came out after the publication of current practice guidelines. They collected both published and unpublished recommendations on treating acute and maintenance phases of the disorder from many sources, including the American Psychiatric Association (APA), the Texas Medication Algorithm Project, the Patient Outcomes Research Team, and state and federal hospitals — and then worked toward reconciling all the differences. "Although clinical judgement must be exercised in the care of individual patients, these metaguidelines may serve to assist clinicians [in addressing] issues commonly encountered in treating patients with schizophrenia," write the investigators.

Advice from the opening "overview" section includes the advice that other psychiatric disorders should be considered, that a therapeutic alliance should be formed, that patients should be reassessed frequently, and that comorbid conditions such as substance abuse should be monitored for and treated in collaboration with others. User-friendly In addition, the guidelines note that low doses of atypical antipsychotics should be used to initiate treatment during first-episode illness; only if unsuccessful should conventional antipsychotics then be used; and clinicians should "strongly consider clozapine after two unsuccessful antipsychotic trials." It then provides 10 pages of detailed bullet points for assessments (including physical and laboratory tests for monitoring vital signs, body weight, and possible treatment-induced side effects), treatment in the inpatient and outpatient setting, and how to formulate and implement a treatment plan at each stage of illness, including the possibility of psychosocial interventions or ECT during the stable phase. Key points on various medications are also presented in detail. "The hope was to translate, not invent, and to communicate with visually interesting and easy-tofollow things for busy clinicians," said Dr. Stahl. "I think sometimes guidelines are written more for journals or academics. We wanted something that was aimed at practitioners and that was user-friendly." The investigators note that they are now working on a new set of meta-guidelines "for more complex, yet commonly encountered patients with schizophrenia for use and guidance for what to do when the meta-guidelines provided here fail to provide adequate outcomes." "The issue is: what do you do when these guidelines end and the patient still hasn't responded? And the problem is that there isn't a lot of evidence for what's next, not a lot of randomized, controlled trials. So the next stage will be put together with more expert consensus and cases," added Dr. Stahl. Critical Synethesis "I thought these guidelines were a very thoughtful attempt to critically synthesize the best information from experts around the world into helpful suggestions for treatment," Ira D. Glick, MD, professor emeritus in the Department of Psychiatry at the Stanford University School of Medicine, in California, told Medscape Medical News.

Dr. Ira Glick "Clinicians now have a synthesis of what world leaders think based on evidence-based data. And that's a big help," he said. Dr. Glick, who is also the former director of the Schizophrenia Clinic at Stanford Medical Center, was not involved with this research. When asked whether he thinks these new meta-guidelines could take the place of stand-alone guidelines from other organizations, Dr. Glick said that that is possible. "For some people, this could take the place. But for different countries, factors affecting treatment vary. So there will always be individualized treatment based not only on the patient (and their family) but also on the village, country, region, etc, where they're being treated," he said. What about for clinicians in the United States? Should this take the place of schizophrenia guidelines from the APA? "I think both are helpful. Just as there are many textbooks in psychiatry that suggest what to do and clinicians pick the top 2 or 3, there's always a choice. Some people will want to follow the APA guidelines because it has the APA imprimatur. Others might say that these have something to add. So I think it'll vary from clinician to clinician," replied Dr. Glick. "I do feel that this is a nice contribution to the literature. What all of us try to do is not just rely on our clinical experience. We try to look at the evidence-based data, then put that together with what's in the journals and texts and what we learn in CME courses, and then try to factor all that into our individual experiences. So I think this will be very helpful, and I'm appreciative of the effort that went into it." The study authors report several relevant financial relationships, which are provided in the original article. CMS Spectr. Published online April 16, 2013. Abstract