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Sunday, February 8, 2015

February 2015

Ketamine, a Quick Guide to Receptors

DR. RAISON: Hi, I’m Dr. Charles Raison. I’m with the Steering Committee for the U.S. Psychiatric Congress. I’m here with Dr. David Nichols. You’ve got so much expertise on how receptors work, and of course so much of our field is based on modulating receptors.
For years we’ve mostly focused on dopamine, norepinephrine, serotonin, but clearly in the last couple of years there’s been an explosion of interest in the NMDA receptor. Can you talk to us a little about what we know about why something like ketamine seems to have this rather powerful and rapid antidepressant effect? 
DR. NICHOLS: Well, you’ve asked the unanswerable question. I think in 2000 the first study was done, with seven subjects, showing that it had a dramatic antidepressant effect. The problem with treating depression is that there’s been this paradigm that you have to increase synaptic levels of monoamines, so every antidepressant that they’ve developed has been one that’s increased serotonin, increased norepinephrine, or both. 
And so now, within the last five to ten years, there’s really been an explosion of interest in the fact that ketamine, which is an antagonist of the NMDA type of glutamate receptor, has a robust antidepressant effect that manifests literally within minutes. And no one really understands how that works. We know that it blocks NMDA type glutamate receptors. Those seem to be on an inhibitory type of GABA interneuron. So the GABA interneurons, if they’re active, they’re releasing GABA, which is inhibitory. So they shut down other glutamate systems, so when you block the glutamate activation, you shut off the GABA tone, and then those glutamate neurons start spilling out glutamate. 
DR. RAISON: So it’s paradoxical. Really, you say, ‘it’s an NMDA antagonist’ so we’re blocking glutamate signaling, but because of its location, you’re actually potentiating—
DR. NICHOLS: What you actually see is an increase in glutamate. If you did a microdialysis experiment and you put in ketamine, what you see is an increase in glutamate. So you block NMDA type glutamate receptors, but you increase— 
DR. RAISON: In the synaptic space. 
DR. NICHOLS: Right, in the general area. And so that glutamate presumably activates GABA and AMPA receptors. 
DR. RAISON: Which are different glutamate receptors. 
DR. NICHOLS: Right. They’re in that same family. They’re ionotropic. Now, the cascade that follows that is what everyone is focusing on now—what’s actually happening there. We know now there’s probably an increase in BDNF, which is decreased in depression, so that may be one thing that’s happening. And that would increase synaptogenesis in the hippocampus. 
Right now though, they’re just trying to put together the pieces. The other thing that’s really puzzling is why [the effects of ketamine] only last for 72 hours or so for most people. 
DR. NICHOLS: You get this immediate effect, and then it wears off. What’s happening? And if they can solve that problem, that will really be a breakthrough.
The other issue is that ketamine is psychoactive and produces these psychotomimetic effects. And so they’d like to find some kind of NMDA antagonist that doesn’t do that. I’ve seen a couple of studies where they’ve used memantine. I don’t know how well that works. 
DR. RAISON: I don’t think it does. The interesting thing is that other NMDA antagonists are not the same kettle of fish. They don’t seem to have that same potency. 
DR. NICHOLS: And there’s another interesting thing with this rapid onset. In patients who are acutely suicidal and come in—what do you do? Well, boom, you might be able to give them a day or two of alleviation of that. 
And then there’s at least one study where they use ketamine as anesthesia for ECT. That produced better response, and usually it takes five or six sessions of ECT. This was one session, so there’s a lot of interest in that too for refractory patients. 
DR. RAISON: Thank you. Fascinating, cutting-edge stuff.

Insulin nasal spray shows promise as treatment for adults with dementia and Alzheimer's

A man-made form of insulin delivered by nasal spray may improve working memory and other mental capabilities in adults with mild cognitive impairment and Alzheimer's disease dementia, according to a pilot study led by researchers at Wake Forest Baptist Medical Center.

The study's subjects were 60 adults diagnosed with amnesic mild cognitive impairment (MCI) or mild to moderate Alzheimer's dementia (AD). Those who received nasally-administered 40 international unit (IU) doses of insulin detemir, a manufactured form of the hormone, for 21 days showed significant improvement in their short-term ability to retain and process verbal and visual information compared with those who received 20 IU does or a placebo.

Additionally, the recipients of 40 IU doses carrying the APOE-e4 gene - which is known to increase the risk for Alzheimer's - recorded significantly higher memory scores than those who received the loser dosage or placebo, while non-carriers across all three groups posted significantly lower scores.

Previous trials had shown promising effects of nasally-administered insulin for adults with AD and MCI, but this study was the first to use insulin detemir, whose effects are longer-lasting than those of "regular" insulin.

"The study provides preliminary evidence that insulin detemir can provide effective treatment for people diagnosed with mild cognitive impairment and Alzheimer's-related dementia similar to our previous work with regular insulin," said Suzanne Craft, Ph.D., professor of gerontology and geriatric medicine at Wake Forest Baptist and lead author of the study, which is published online in advance of the February issue of the Journal of Alzheimer's Disease. "We are also especially encouraged that we were able to improve memory for adults with MCI who have the APOE-e4 gene, as these patients are notoriously resistant to other therapies and interventions."

The researchers also sought to determine if the insulin detemir doses would cause any negative side effects, and found only minor adverse reactions among the subjects.

The study's overall results support further investigation of the therapeutic value of insulin detemir as a treatment for Alzheimer's and other neurodegenerative diseases, Craft said.

"Alzheimer's is a devastating illness, for which even small therapeutic gains have the potential to improve quality of life and significantly reduce the overall burden for patients, families and society," she said. "Future studies are warranted to examine the safety and efficacy of this promising treatment."

PTSD: A Trigger for Type 2 Diabetes

JAMA Psychiatry


Posttraumatic stress disorder (PTSD) is a common, debilitating mental disorder that has been associated with type 2 diabetes mellitus (T2D) and its risk factors, including obesity, in cross-sectional studies. If PTSD increases risk of incident T2D, enhanced surveillance in high-risk populations may be warranted.
To conduct one of the first longitudinal studies of PTSD and incidence of T2D in a civilian sample of women.
Design, Setting, and Participants
The Nurses’ Health Study II, a US longitudinal cohort of women (N = 49 739). We examined the association between PTSD symptoms and T2D incidence over a 22-year follow-up period.
Main Outcomes and Measures
Type 2 diabetes, self-reported and confirmed with self-report of diagnostic test results, symptoms, and medications, a method previously validated by physician medical record review. Posttraumatic stress disorder was assessed by the Short Screening Scale for DSM-IV PTSD. We examined longitudinal assessments of body mass index, smoking, alcohol intake, diet quality, physical activity, and antidepressant use as mediators of possible increased risk of T2D for women with PTSD. The study hypothesis was formulated prior to PTSD ascertainment.
Symptoms of PTSD were associated in a dose-response fashion with T2D incidence (1-3 symptoms: hazard ratio, 1.4 [95% CI, 1.2-1.6]; 4 or 5 symptoms; hazard ratio, 1.5 [95% CI, 1.3-1.7]; 6 or 7 symptoms: hazard ratio, 1.8 [95% CI, 1.5-2.1]). Antidepressant use and a higher body mass index associated with PTSD accounted for nearly half of the increased risk of T2D for women with PTSD. Smoking, diet quality, alcohol intake, and physical activity did not further account for increased risk of T2D for women with PTSD.
Conclusions and Relevance
Women with the highest number of PTSD symptoms had a nearly 2-fold increased risk of T2D over follow-up than women with no trauma exposure. Health professionals treating women with PTSD should be aware that these patients are at risk of increased body mass index and T2D. Comprehensive PTSD treatment should be expanded to address the health behaviors that contribute to obesity and chronic disease in affected populations.

Fronto-temporal transcranial Direct Current Stimulation (tDCS) reduces source-monitoring deficits and auditory hallucinations in patients with schizophrenia

Shizophrenia Research


Auditory verbal hallucinations (AVH) in patients with schizophrenia have been associated with abnormal activity within the frontal and temporo-parietal areas (Jardri et al., 2011) and with a failure in source-monitoring processes (Frith, 1995; Waters et al., 2012). For instance, patients with AVH are more likely to confuse imagined and performed self-generated speech as revealed by the number of misattributions between words they were required to imagine saying (covert speech) and words they were required to say aloud (overt speech) during a source-monitoring task (Brunelin et al., 2006a).

Treatment-Resistant Bipolar Disorder Responds Better to ECT Than Medication

The American Journal of Psychiatry


Electroconvulsive therapy (ECT) is regarded by many clinicians as the most effective treatment for treatment-resistant bipolar depression, but no randomized controlled trials have been conducted, to the authors’ knowledge. They compared efficacy measures of ECT and algorithm-based pharmacological treatment in treatment-resistant bipolar depression.

This multicenter, randomized controlled trial was carried out at seven acute-care psychiatric inpatient clinics throughout Norway and included 73 bipolar disorder patients with treatment-resistant depression. The patients were randomly assigned to receive either ECT or algorithm-based pharmacological treatment. ECT included three sessions per week for up to 6 weeks, right unilateral placement of stimulus electrodes, and brief pulse stimulation.

Linear mixed-effects modeling analysis revealed that ECT was significantly more effective than algorithm-based pharmacological treatment. The mean scores at the end of the 6-week treatment period were lower for the ECT group than for the pharmacological treatment group: by 6.6 points on the Montgomery-Åsberg Depression Rating Scale (SE=2.05, 95% CI=2.5–10.6), by 9.4 points on the 30-item version of the Inventory of Depressive Symptomatology–Clinician-Rated (SE=2.49, 95% CI=4.6–14.3), and by 0.7 points on the Clinical Global Impression for Bipolar Disorder (SE=0.31, 95% CI=0.13–1.36). The response rate was significantly higher in the ECT group than in the group that received algorithm-based pharmacological treatment (73.9% versus 35.0%), but the remission rate did not differ between the groups (34.8% versus 30.0%).

Remission rates remained modest regardless of treatment choice for this challenging clinical condition.

Breaking the Law May Be a Sign of Dementia

Jama Neurology


Neurodegenerative diseases can cause dysfunction of neural structures involved in judgment, executive function, emotional processing, sexual behavior, violence, and self-awareness. Such dysfunctions can lead to antisocial and criminal behavior that appears for the first time in the adult or middle-aged individual or even later in life.

To investigate the frequency and type of criminal behavior among patients with a diagnosed dementing disorder.

Design, Setting, and Participants  
We conducted a retrospective medical record review of 2397 patients who were seen at the University of California, San Francisco, Memory and Aging Center between 1999 and 2012, including 545 patients with Alzheimer disease (AD), 171 patients with behavioral variant of frontotemporal dementia (bvFTD), 89 patients with semantic variant of primary progressive aphasia, and 30 patients with Huntington disease. Patient notes containing specific keywords denoting criminal behavior were reviewed. Data were stratified by criminal behavior type and diagnostic groups.

Main Outcomes and Measures
Frequencies of criminal behavior and χ2 statistics were calculated.

Of the 2397 patients studied, 204 (8.5%) had a history of criminal behavior that emerged during their illness. Of the major diagnostic groups, 42 of 545 patients (7.7%) with AD, 64 of 171 patients (37.4%) with bvFTD, 24 of 89 patients (27.0%) with semantic variant of primary progressive aphasia, and 6 of 30 patients (20%) with Huntington disease exhibited criminal behavior. A total of 14% of patients with bvFTD were statistically significantly more likely to present with criminal behavior compared with 2% of patients with AD (P < .001) and 6.4% were statistically significantly more likely to exhibit violence compared with 2% of patients with AD (P = .003). Common manifestations of criminal behavior in the bvFTD group included theft, traffic violations, sexual advances, trespassing, and public urination in contrast with those in the AD group, who commonly committed traffic violations, often related to cognitive impairment.

Conclusions and Relevance  
Criminal behavior is more common in patients with bvFTD and semantic variant of primary progressive aphasia than in those with AD and is more likely to be an early manifestation of the disorder. Judicial evaluations of criminality in the demented individual might require different criteria than the classic “insanity defense” used in the American legal system; these individuals should be treated differently by the law. The appearance of new-onset criminal behavior in an adult should elicit a search for frontal and anterior temporal brain disease and for dementing disorders.

Therapists are using neurofeedback to treat ADHD, PTSD and other conditions

By Arlene Karidis 

In September 2013, Chris Gardner went from kicking and spinning as a black belt in taekwondo to being locked in a world where he could not follow conversations — or even walk his dog. The 58-year-old Vienna, Va., resident had just had brain surgery to remove a large tumor, and the operation affected his mobility and cognition.

After nine months of physical and occupational therapy, he’d made little progress. So he tried neurofeedback, hoping this controversial treatment would improve his balance and mental processes.

Neurofeedback — a type of biofeedback — uses movies, video games, computers and other tools to help individuals regulate their brain waves. A patient might watch a movie, for example, while hooked to sensors that send data to a computer. A therapist, following the brain activity on a monitor, programs the computer to stop the movie if an abnormal number of fast or slow brain waves is detected or if the brain waves are erratic, moving rapidly from fast to slow waves.

The stop-and-start feedback, repeated over and over in numerous sessions, seems to yield more-normal brain waves. Researchers who endorse the technique say they don’t know exactly how it works but they say the changes in brain waves result in improved ability to focus and relax.

Better focus and relaxation can seemingly help improve or eliminate such conditions as migraines (imbalanced brain waves are associated with certain symptoms like pain) and anxiety.

 Clinical social worker Mary Lee Esty demonstrates the hookup of neurofeedback sensors on Cliff Drake, who says the procedure has helped him deal with post-traumatic stress disorder, depression and other ailments. (Linda Davidson/The Washington Post)
Neurofeedback, which is also used for post-traumatic stress disorder and attention-deficit hyperactivity disorder, has been around since the 1960s. Some research has found it promising. Other studies have been inconclusive, and some have shown no positive outcomes.

The most solid data concern ADHD, especially a recent trial involving 104 children published in March in the Journal of Pediatrics. Those who received neurofeedback had improvements in attention and impulse control, while those who did not receive the therapy did not. These improvements persisted after six months. The authors concluded that neurofeedback may be a “promising attention training treatment for children with ADHD.”

Gardner had read that the technique could aid in recovery from brain injuries.

“I was skeptical. But I was desperate. I felt like I was wrapped in miles of cotton and could not reach through it to touch or feel anything,” said Gardner, an electronic technology consultant. His doctor was projecting a two-to-three-year recovery period, based on Gardner’s slow progress nine months after surgery.

By his ninth neurofeedback session, he was driving, taking power walks and working from home.

Neurofeedback treatments vary. In Gardner’s case, he sat in a chair while tiny, pulsed signals were sent to his brain. Research suggests that these signals enable the brain to revive its communication channels, which can become impaired after a brain injury.

“I couldn’t feel anything” while the treatments were underway, Gardner said. “I just sat there with my eyes closed. My therapist explained that the pulses basically reboot the brain.”

He has just completed the last of 10 treatments. “I am not 100 percent. I probably won’t stand on my head or get on a roller coaster. But I can do almost everything I couldn’t do before,” said Gardner, who’s back to his martial arts.

“Do most people become totally normal? No. But they improve,” said Michael Sitar, a Bethesda psychologist certified in neurofeedback. He uses it to treat depression, ADHD, chronic pain and some other conditions.

“I find [that] people with focus problems can switch tasks easier. Kids who repeat themselves and who are emotionally labile become calmer and don’t repeat as much,” Sitar said. “With some complicated cases, like bipolar disorder, people may get by on less medication. Though less common, there are documented cases of nonverbal people who become verbal.”

Like riding a bike
Deborah Stokes, an Alexandria psychologist, compares neurofeedback to riding a bike: It’s non-conscious learning, based on the feedback, that, with repetition, can be long-lasting, she said.

“We don’t know exactly how neurofeedback works,” she said. “It’s a process where if clients get out of their own way, they relax. Over time, they get the desired brain pattern, feel calm and function better. This encourages them to stay with it.” Her team sees 30 patients a week.

Thomas Nicklin, whose family was living in Alexandria, saw Stokes for debilitating migraines. A year and a half after beginning a drug regimen prescribed by a neurologist, he was not getting better.

Nicklin, a teenager who was in boarding school, did 45 neurofeedback sessions over three months last year.

“Over time, Thomas went from three or four blinding migraines a week, vomiting and daily pain, to no symptoms,” said his mother, Pat Nicklin.

Silver Spring psychologist Robb Mapou is among the skeptics.

“I have not seen enough well-controlled, rigorous studies in most conditions for which it is recommended to show, definitively, that neurofeedback is effective. I also think there are other therapeutic factors that can contribute to an individual’s outcome, such as discussing their problems with a therapist.”

Michelle Harris-Love, a neuroscience researcher at the MedStar National Rehabilitation Network in Washington, agrees.

“I believe it is applied in some situations where we do not have enough information on the cause of a disorder or how recovery happens,” she said.

But Rex Cannon, past president of the International Society for Neurofeedback and Research, based in McLean, Va., cited nearly 200 peer-reviewed published articles that indicate neurofeedback’s effectiveness. This includes a meta-analysis of 10 studies on epilepsy patients: Although they had not responded to medications, they had a significant reduction in seizures after neurofeedback treatment. And a study on migraine patients reported, “Neurofeedback appears to be dramatically effective in abolishing or significantly reducing migraine frequency in the great majority of patients.”

Patients usually have sessions two or three times a week, for a total of 10 to 40. Most sessions are 30 to 60 minutes long. They can be expensive — from $50 to $130 each. Some insurance policies cover neurofeedback, depending on the diagnosis.

Practitioners who use neurofeedback for medical and psychological disorders must have health-care degrees and are regulated by state agencies.

About 1,850 professionals have been certified through the Biofeedback Certification International Alliance. To earn that credential, they must undergo 36 hours of study in neurophysiology and related topics, complete a mentoring program to learn clinical skills and pass a standardized exam.

Mary Lee Esty, a Bethesda clinical social worker, has a small study underway treating veterans with PTSD. In an earlier study of seven veterans who used neurofeedback, she reported, the results were promising.

“These people [in the early study] initially had minimal function. They could not work, and many attempted suicide,” she said. “One is getting a PhD now. One has a full scholarship when he could not read after his head injury. All of them are doing well.”

Other studies describe results of the therapy in a similar way, as promising but requiring further examination.

Esty, who received a National Institutes of Health grant for an earlier study of brain-injured patients, has used neurofeedback to treat more than 2,500 people, mainly with brain injuries or PTSD. In her most recent and still ongoing study, she collaborates with the Uniformed Services University of the Health Sciences, which gives participants in her program post-treatment evaluations.

“I am in this collaboration because I want to get the hard data out there,” Esty said.

Antidepressant Use in Pregnancy and the Risk of Cardiac Defects

The New England Journal of Medicine


Whether the use of selective serotonin-reuptake inhibitors (SSRIs) and other antidepressants during pregnancy is associated with an increased risk of congenital cardiac defects is uncertain. In particular, there are concerns about a possible association between paroxetine use and right ventricular outflow tract obstruction and between sertraline use and ventricular septal defects.

We performed a cohort study nested in the nationwide Medicaid Analytic eXtract for the period 2000 through 2007. The study included 949,504 pregnant women who were enrolled in Medicaid during the period from 3 months before the last menstrual period through 1 month after delivery and their liveborn infants. We compared the risk of major cardiac defects among infants born to women who took antidepressants during the first trimester with the risk among infants born to women who did not use antidepressants, with an unadjusted analysis and analyses that restricted the cohort to women with depression and that used propensity-score adjustment to control for depression severity and other potential confounders.

A total of 64,389 women (6.8%) used antidepressants during the first trimester. Overall, 6403 infants who were not exposed to antidepressants were born with a cardiac defect (72.3 infants with a cardiac defect per 10,000 infants), as compared with 580 infants with exposure (90.1 per 10,000 infants). Associations between antidepressant use and cardiac defects were attenuated with increasing levels of adjustment for confounding. The relative risks of any cardiac defect with the use of SSRIs were 1.25 (95% confidence interval [CI], 1.13 to 1.38) in the unadjusted analysis, 1.12 (95% CI, 1.00 to 1.26) in the analysis restricted to women with depression, and 1.06 (95% CI, 0.93 to 1.22) in the fully adjusted analysis restricted to women with depression. We found no significant association between the use of paroxetine and right ventricular outflow tract obstruction (relative risk, 1.07; 95% CI, 0.59 to 1.93) or between the use of sertraline and ventricular septal defects (relative risk, 1.04; 95% CI, 0.76 to 1.41).

The results of this large, population-based cohort study suggested no substantial increase in the risk of cardiac malformations attributable to antidepressant use during the first trimester. (Funded by the Agency for Healthcare Research and Quality and the National Institutes of Health.)

Biological Pathways for Common Psych Disorders Identified 

Nature Neuroscience

Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders

FDA Approves Mobile App for Evaluating Traumatic Brain Injury

A new app will soon be available to help clinicians diagnose traumatic brain injury in as little as five minutes in almost any setting, including environments of combat.

The app, called the Defense Automated Neurobehavioral Assessment (DANA), runs on multiple mobile platforms and was recently granted U.S. Food and Drug Administration (FDA) approval. “It's like a brain thermometer,” stated Lt. Col. Chessley Atchison, a program manager for the Combat Casualty Care Research Program of the U.S. Army Medical Research and Materiel Command (USAMRMC). “And once we get it right, we’re going to put it fairly far forward in the field.”

According to the USAMRMC, DANA operates much like a video game. Service members will undergo a baseline series of on-screen exercises during which both their speed and accuracy are recorded. Those who may have had a serious head injury will then participate in a series of both cognitive efficiency tests and self-administered questionnaires. Afterward, a clinician will review the results, comparing them with the results of the baseline exercises. The combination of the app's cognitive and psychological components allows for insight into the prevalence of symptoms related to both traumatic brain injury and posttraumatic stress disorder, USAMRMC said in a press statement.

USAMRMC stated that once DANA is fully validated for battlefield use, it may be used to help assess fitness for duty. The app is currently being tested on tablet devices.

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